Compositions and formulations for preventing, treating and ameliorating skin diseases, conditions and disorders using PK inhibitors

Abstract

Provided herein are compositions comprising a rubersta free base and salts thereof, and methods of use for the treatment of skin conditions.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 344,422 filed on May 20, 2022, U.S. Provisional Application No. 63 / 399,946 filed on August 22, 2022, and U.S. Provisional Application No. 63 / 489,697 filed on March 10, 2023, the contents of which are incorporated herein by reference in their entireties. Background Art

[0003] Hyperpigmentation is a commonly diagnosed condition that forms dark patches in the skin. This skin darkening occurs in response to excessive production or irregular dispersion of melanin, a brown pigment produced by melanocytes in various skin layers after skin inflammation. Hyperpigmentation includes different skin discoloration conditions, such as melasma, post-inflammatory hyperpigmentation, freckles, and lentigos. Changes in skin color are the result of internal factors and external damage to the skin, including hormonal changes, inflammation, injury, acne, eczema, drug side effects, sun damage, etc. Hyperpigmentation of the skin can affect any race or gender, but is most common among patients with colored skin and women.

[0004] Currently, the most commonly used treatment for hyperpigmentation is hydroquinone, alone or in combination with other drugs. Hydroquinone is toxic to melanocytes and therefore non-selectively inhibits melanin synthesis. Hydroquinone-containing products are only slightly effective at safe low concentrations, but are toxic at high concentrations, sometimes leading to permanent pigment loss or skin pigmentation, causing ochronosis. Topical application of bisindolylmaleimide, a selective PKC inhibitor, has been shown to inhibit UV-induced neomelanogenesis in a guinea pig model. Summary of the invention

[0005] A PKC-β inhibitor represented by the following formula, referred to herein as rubostat or rubostat mesylate (also referred to herein as "mesylate") monohydrate:

[0006]

[0007] and their acceptable salts, are particularly difficult to dissolve into compositions that are easy to apply, effective, and non-irritating to the skin.

[0008] Common solvents used to formulate other small molecule compounds cannot dissolve certain PK inhibitors described herein, including but not limited to rubostar free base or rubostar salts (e.g., rubostar mesylate monohydrate) for use in clinically or cosmetically acceptable compositions. Therefore, there is an urgent need to develop topical compositions comprising PK inhibitors described herein, including but not limited to rubostar free base or rubostar salts (e.g., rubostar mesylate monohydrate) that can be topically delivered with reduced skin irritation to treat skin conditions such as hyperpigmentation.

[0009] In a first aspect, the present disclosure provides a composition. The composition comprises a compound having the following structure:

[0010]

[0011] or an acceptable salt thereof, and an excipient comprising:

[0012] a) organic solvents and / or penetration enhancers;

[0013] b) antioxidants;

[0014] c) a gelling agent; or

[0015] d) alcohol, or a combination thereof;

[0016] Wherein organic solvent and / or penetration enhancer, antioxidant, alcohol and gelling agent are defined and described in this article. The composition can be formulated with 0.1% or 0.8% of Rubusta free base, Rubusta mesylate monohydrate or other salts thereof. In some cases, the composition is applied once or twice a day. In some cases, the composition is applied for about 12 weeks to about 6 months. In some cases, the composition is applied for about 4 weeks to about 8 weeks. In some cases, the composition is applied for about 8 weeks to about 12 weeks.

[0017] In a second aspect, the present disclosure provides a composition comprising a compound having the following structure:

[0018]

[0019] Or its acceptable salt, and propylene glycol, 2-(2-ethoxyethoxy) ethanol, hydroxypropyl cellulose, polyethylene glycol, antioxidant and alcohol. The composition can be prepared with 0.1% or 0.8% of Rubusta free base, Rubusta mesylate monohydrate or their other salts. The composition can be prepared with 0.08% to 0.8% of Rubusta mesylate monohydrate, Rubusta free base or its salt. In some cases, the composition is applied once or twice a day. In some cases, the composition is applied for about 12 weeks to about 6 months. In some cases, the composition is applied for about 4 weeks to about 8 weeks. In some cases, the composition is applied for about 8 weeks to about 12 weeks.

[0020] In a third aspect, the present disclosure provides a method for treating a skin disease, condition or illness of an object in need thereof, the method comprising applying a composition as described herein to the object. In some aspects, the present disclosure further provides a method for treating a condition or illness of hair or hair follicles. The composition can be formulated with 0.08% to 0.8% of a PK inhibitor as described herein, including but not limited to Rubusta free alkali or Rubusta salt (e.g., Rubusta mesylate monohydrate). In some cases, the composition is applied once or twice a day. In some cases, the composition is applied to 0.01% to 100% of a body surface area. In some cases, the composition is applied for about 12 weeks to about 6 months. In some cases, the composition is applied for about 4 weeks to about 8 weeks. In some cases, the composition is applied for about 8 weeks to about 12 weeks.

[0021] In a fourth aspect, the present disclosure provides a kit comprising a composition as described herein in a container, tube, flexible aluminum tube or laminated plastic tube that can block UV light and / or minimize exposure to oxygen, and instructions for use. The composition can be formulated with 0.1% or 0.8% of Rubusta free alkali, Rubusta mesylate monohydrate or their other salts. The composition can be formulated with 0.08% to 0.8% of Rubusta (Rubusta mesylate monohydrate) or its other salts. In some cases, the composition is applied once or twice a day. In some cases, the composition is applied for about 12 weeks to about 6 months. In some cases, the composition is applied for about 4 weeks to about 8 weeks. In some cases, the composition is applied for about 8 weeks to about 12 weeks. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1A-1E : Microscopic appearance (400x magnification, non-polarized) of A) NA21, B) NA16, C) NA17, D) NA25 and E) NA26 after storage at 25°C for 2 months.

[0023] Figure 2A: Percentage of subjects with -1 IDGA values ​​(slightly lighter than untreated controls) on the dorsum of the hand within 12 weeks of treatment with 0.8% w / w Rubusta mesylate monohydrate gel, 4% w / w hydroquinone, or vehicle (** is p<0.01).

[0024] Figure 2B : Percentage of subjects with -1 IDGA values ​​(slightly lighter than untreated controls) on the volar upper arm within 12 weeks of treatment with 0.8% w / w Rubusta mesylate monohydrate gel, 4% w / w hydroquinone, or vehicle (* is p<0.05).

[0025] Figure 3A : Percentage of subjects with -2 IDGA values ​​(slightly lighter than untreated controls) on the dorsum of the hand within 12 weeks of treatment with 0.8% w / w Rubusta mesylate monohydrate gel, 4% w / w hydroquinone, or vehicle (* is p<0.05).

[0026] Figure 3B : Percentage of subjects with -2 IDGA values ​​(slightly lighter than untreated controls) on the volar upper arm during 12 weeks of treatment with 0.8% w / w Rubusta mesylate monohydrate gel, 4% w / w hydroquinone, or vehicle.

[0027] Figure 4A : Percentage of subjects with solar lentigo on the dorsal hand treated with 0.8% w / w Rubustadine mesylate monohydrate gel having an IDGA value of -2, -1, 0 or 1.

[0028] Figure 4B : Percentage of subjects with IDGA values ​​of -2, -1, 0 or 1 on the volar side of the arm treated with 0.8% w / w Rubusta mesylate monohydrate gel.

[0029] Figure 4C : Percentage of all subjects with solar lentigo on the dorsal hand treated with 0.8% w / w Rubustadine mesylate monohydrate gel at all time points having IDGA values ​​of -2, -1, 0 or 1.

[0030] Figure 4D : Percentage of all subjects at all time points on the volar side of the arm treated with 0.8% w / w Rubusta mesylate monohydrate gel with an IDGA value of -2, -1, 0 or 1.

[0031] Figure 5A: Change in colorimetric values ​​(as measured by value at observation minus screening value) in subjects with lentigo treated with 0.8% w / w Rubustadine mesylate monohydrate gel on the back of the hand compared to untreated sites, with positive values ​​indicating reduced pigmentation (* is p<0.05 and *** is p<0.001).

[0032] Figure 5B : Change in colorimetric values ​​(as measured by value at observation minus screening value) in subjects having lentigo treated with 0.8% w / w Rubusta mesylate monohydrate gel on the volar side of the upper arm compared to untreated sites, with positive values ​​indicating reduced pigmentation.

[0033] Figure 5C : Change in colorimetric values ​​at all time points in all subjects with lentigo treated with 0.8% w / w Rubustadine mesylate monohydrate gel on the back of the hand compared to untreated sites (as measured by value at observation - screening value), positive values ​​indicating reduced pigmentation (* is p<0.05 and *** is p<0.001).

[0034] Figure 5D : Change in colorimetric values ​​(as measured by value at observation minus screening value) at all time points in all subjects treated with 0.8% w / w Rubusta mesylate monohydrate gel on the volar side of the upper arm compared to untreated sites, with positive values ​​indicating reduced pigmentation. DETAILED DESCRIPTION

[0035] summary

[0036] Protein kinase C (PKC or PRKC) is an intracellular signaling molecule that can regulate many vascular functions (including permeability, vasodilator release, endothelial activation and growth factor signaling). Protein kinase C is an isozyme family that includes at least 12 members, and the β isoforms of these members have been associated with the development of diabetic microvascular complications and the production of melanin. In the skin, the PKC-β expression that causes the production of melanin and pigmentation in human skin seems to be limited to melanocytes. The inhibition of PKC-β and the subsequent inhibition of melanin production are attractive and selective targets for the treatment of hyperpigmentation. Although normal redistribution and increased melanin production after exposure to ultraviolet (UV) radiation may be beneficial, excessive or uneven melanin production may produce undesirable hyperpigmentation, thereby causing conditions such as chloasma, lentigo, PIH and other color vision disorders (uneven and / or abnormal pigmentation). Tyrosinase, which converts tyrosine to DOPA and DOPA to dopaquinone, is a key enzyme in the melanin synthesis pathway and requires phosphorylation by PKC-β to be active. Inhibitors of PKC-β have been shown to reduce melanogenesis.

[0037] Provided herein are compositions comprising rubustadine free base, rubustadine mesylate or an acceptable salt thereof, and methods of using these compositions to treat skin diseases, conditions or disorders. In some embodiments, the composition is applied topically to treat skin diseases, conditions or disorders. In some embodiments, skin diseases, conditions or disorders include, but are not limited to, hyperpigmentation, hypopigmentation, skin discoloration, melasma, post-inflammatory hyperpigmentation or hypopigmentation, discoid lupus erythematosus, phytophotodermatitis, lentigo (e.g., age spots), birthmarks, café au lait spots, acanthosis nigricans, burn-related hyperpigmentation or hypopigmentation, drug-induced hyperpigmentation or hypopigmentation (e.g., hyperpigmentation induced by sulfonamides, tetracyclines, NSAIDs, barbiturates and carbamazepine), injury-induced hyperpigmentation or hypopigmentation, hyperpigmentation or hypopigmentation associated with primary biliary cirrhosis, pigmentation associated with Addison's disease, hyperpigmentation or hypopigment ... Hyperpigmentation or hypopigmentation, hyperpigmentation or hypopigmentation associated with hemochromatosis, hyperpigmentation or hypopigmentation associated with hyperthyroidism, melanocytic nevus, freckles (spots), seborrheic keratosis, hyperpigmentation or hypopigmentation associated with skin cancer, hyperpigmentation or hypopigmentation associated with infection (e.g., tinea versicolor, tinea versicolor, erythrasma), eczema, photocontact, photoallergic or phototoxic dermatitis, ichthyosis, axillary freckles or café au lait spots associated with neurofibromatosis, or hyperpigmentation or hypopigmentation associated with ultraviolet (UV) radiation exposure or photodamage (e.g., sun exposure or tanning reaction), or a combination of two or more thereof. In some embodiments, the condition, disease or disorder includes aesthetic indications, including skin whitening, skin lightening, even skin tone, photodamaged hyperpigmentation or polychromatic pigmentation. In some embodiments, this also includes evening out skin pigment irregularities caused by vitiligo or other depigmentation conditions and pigmentation abnormalities. The condition may also be a condition, disease or disorder of the hair or hair follicles and may be hirsutism / excessive hair and hair pigmentation. In particular, the composition may be used to treat hyperpigmentation disorders and skin discoloration.

[0038] definition

[0039] Abbreviations used herein have their conventional meanings in the fields of chemistry and biology.

[0040] "Alkylene glycol" refers to a compound having the formula H-[O-alkylene]-OH, wherein the alkylene group has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. In some embodiments, the alkylene glycol is C 2-6 In some embodiments, C 2-6 The alkylene glycol is propylene glycol (1,2-propanediol).

[0041] "Di-alkylene glycol" refers to a compound having the formula HO-(alkylene-O)2-H, wherein the alkylene group has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. In some embodiments, the di-alkylene glycol is a di-(C 2-6 In some embodiments, di-(C 2-6 The alkylene) glycol is dipropylene glycol. The dipropylene glycol may 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).

[0042] "Polyethylene glycol" refers to a compound having the formula HO-(CH2CH2O) n -OH (wherein the subscript "n" can vary). Suitable polyethylene glycols may have free hydroxyl groups at each end of the polymer molecule, or may have one or more hydroxyl groups etherified with lower alkyl groups such as methyl groups. Derivatives of polyethylene glycol with esterifiable carboxyl groups are also suitable. Polyethylene glycols that can be used in the present invention can be polymers of any chain length or molecular weight, and may include branching. In some embodiments, the average molecular weight of polyethylene glycol is from about 200 to about 9000. In some embodiments, the average molecular weight of polyethylene glycol is from about 200 to about 5000. In some embodiments, the average molecular weight of polyethylene glycol is from about 200 to about 900. In some embodiments, the average molecular weight of polyethylene glycol is about 400. Suitable polyethylene glycols include, but are not limited to, PEG200, PEG300, PEG400, PEG600, and PEG900. The number after "PEG" in the name refers to the average molecular weight of the polymer.

[0043] "USP / NF grade, Ph.Eur. grade, BP grade and JP grade, etc." excipients refer to excipients (e.g., propylene glycol, glycerol, polyethylene glycol such as PEG200 and PEG400, etc.) that meet or exceed the requirements of the United States Pharmacopoeia / National Formulary (USP / NF), the European Pharmacopoeia, the British Pharmacopoeia and the Japanese Pharmacopoeia, respectively.

[0044] "Ultra-refined" excipients refer to excipients from which impurities have been removed. Ultra-refining removes polar impurities (which may include reactive primary and secondary oxidation products) from the excipient without changing its chemical composition. Removing these impurities helps to reduce excipient-active pharmaceutical ingredient (API) interactions and subsequent API degradation, thereby maintaining the stability of the drug and the final composition or formulation. In addition, removing these impurities can minimize cell stimulation, which is ideal for various drug administration routes. The ultra-refined excipients of the present invention include ultra-refined propylene glycol.

[0045] "Super refined propylene glycol" or "SR propylene glycol" refers to highly purified propylene glycol that can enhance pharmaceutical activity and composition (or formulation) stability. In some embodiments, SR propylene glycol has a purity of not less than about 99.5%, 99.6%, 99.7%, 99.8% or 99.9%. In some embodiments, SR propylene glycol has a purity of not less than about 99.8% or 99.9%.

[0046] "Transcutol" is represented by the formula: CH3CH2OCH2CH2OCH2CH2OH, which has a preferred IUPAC name of 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, dioxitol, 3,6-dioxa-1-octanol, Carbitol, Carbitol Cellosolve, Polysolv DE or Dowanal DE. Transcutol includes "Transcutol P", "Transcutol CG" and "Transcutol HP".

[0047] "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 powerful solubilizer and efficacy enhancer that has been used in the cosmetic and pharmaceutical industries. "Transcutol HP" refers to a high-purity grade of 2-(2-ethoxyethoxy)ethanol that can enhance drug activity and composition (or formulation) stability. In some embodiments, Transcutol P, CG or HP has a purity of not less than about 99.5%, 99.6%, 99.7%, 99.8% or 99.9%. In some embodiments, Transcutol P or HP has a purity of not less than 99.8% or 99.9%. In some embodiments, Transcutol HP has a purity of about 99.90%.

[0048] "Fatty alcohol" refers to a primary alcohol with a long aliphatic chain, which is saturated or unsaturated. The carbons of the fatty alcohol can also range from as few as 4-6 to as many as 22-26. Fatty alcohols include, but are not limited to, decyl alcohol, undecanol, lauryl alcohol, tridecanol, myristyl alcohol, pentadecanol, cetyl alcohol, palmitoleyl alcohol (unsaturated), heptadecanol, stearyl alcohol, oleyl alcohol (unsaturated), nonadecanol, arachidyl alcohol, heneicosyl alcohol, behenyl alcohol, erucyl alcohol (unsaturated), and lignocerol.

[0049] "Fatty ester" or "fatty acid ester" refers to a type of ester produced by the combination of fatty acids and alcohols. When the alcohol is polyethylene glycol, the fatty ester refers to polyoxyethylene fatty ester or polyoxyethylene fatty acid ester.

[0050] "Fat ether" refers to a type of ether produced by the combination of a fatty alcohol and a secondary alcohol. When the secondary alcohol is polyethylene glycol, the fatty ether refers to a polyoxyethylene fatty ether.

[0051] "Polysorbate" refers to a type of fatty ester produced by ethoxylated sorbitan (a polyethylene glycol derivative of sorbitol) and 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, Tween TM 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 RC Rowe and PJ Shesky, Handbook of pharmaceutical excipients, (2006), 5th edition, which is incorporated herein by reference in its entirety.

[0052] "Glyceride" refers to a fatty ester when the alcohol component is glycerol. The glyceryl fatty esters (or glycerides) produced can be monoglycerides, diglycerides, or triglycerides. "Monoglycerides" are glycerides consisting of one fatty acid chain covalently bonded to a glycerol molecule via an ester bond. "Diglycerides" are glycerides consisting of two fatty acid chains covalently bonded to a glycerol molecule via an ester bond. "Triglycerides" are glycerides consisting of three fatty acid chains covalently bonded to a glycerol molecule via an ester bond.

[0053] "Salt" refers to an acid or base salt of a compound of the present invention. Illustrative examples of pharmaceutically acceptable salts are inorganic acid (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts, quaternary ammonium (methyl iodide, ethyl iodide, etc.) salts. It should be understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0054] "Solvate" refers to a compound provided herein or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0055] "Hydrate" refers to a compound complexed with water molecules. The compound of the present invention may be complexed with 1 / 2 water molecules or 1 to 10 water molecules.

[0056] As used herein, "composition" or "formulation" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product resulting, directly or indirectly, from combination of 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.

[0057] For any of the surface compositions described herein, the water content refers to the total amount by weight, including the portion from the pH adjustment solution (when present) (e.g., 0.1M, 0.5M or 1M aqueous citric acid solution), ethanol (if the ethanol is not anhydrous ethanol), and finally QS100 (QS stands for sufficient).

[0058] "Relative purity of a compound in a surface composition" refers to the purity of a compound (e.g., a PK inhibitor as described herein, including but not limited to, rubostat free base or rubostat salt (e.g., rubostat mesylate monohydrate)) stored under stress conditions (e.g., 40°C) or under normal storage conditions (e.g., room temperature or 25°C) at a certain time point (e.g., 8 weeks) compared to the initial purity of the compound at time zero (i.e., day 0). As always, the relative purity of the compound at time zero (i.e., day 0) is set to 100%.

[0059] "About" refers to a range of values ​​including the specified value that 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, approximately refers to a range extending to + / -10% of the specified value. In some embodiments, approximately refers to the specified value.

[0060] "Substantially free of..." refers to a composition containing no more than 1% by weight of other excipients, such as di-(C 2-6 alkylene) glycol, glycerol, fatty alcohol, fatty ester (e.g., polysorbate), fatty ether, or a combination thereof, each of which is defined and described herein. Polyethylene glycol (e.g., PEG200 and / or PEG400) and / or C 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. When polyethylene glycol (e.g., PEG200 and / or PEG400) and / or C 1-3 Alkyl-(OCH2CH2) 1-5 When -OH (e.g., 2-(2-ethoxyethoxy)ethanol or Transcutol HP) is present in the composition, the composition contains no more than 0.5% by weight of ethylene glycol and / or diethylene glycol as an impurity. In some embodiments, when polyethylene glycol (e.g., PEG200 and / or PEG400) 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 of ethylene glycol and / or diethylene glycol as an impurity.

[0061] "Inhibit" and "inhibitor" refer to a compound or a method of inhibiting a specific effect or function.

[0062] "Administering" refers to providing a composition or formulation to a subject (e.g., a patient, such as a human patient) by a desired route, such as by topical administration. Topical administration can include, for example, applying the composition in the form of a gel, ointment, lotion, foam, emollient, or as a component of a patch, tape, film, sheet, or bandage to a surface of a subject, such as the skin of a subject. The area to which the composition is applied can vary based on, for example, the condition of the subject and the characteristics of the composition (e.g., form, drug load, etc.).

[0063] "Treatment" and "treatment" refer to any indicator of successful treatment or amelioration of an injury, pathology, or condition, including any objective or subjective parameter, such as elimination; remission; alleviation of symptoms or making the injury, pathology, or condition more tolerable to the patient; slowing the rate of degeneration or decline; making the endpoint of degeneration less debilitating; improving the patient's physical or mental well-being. Treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation.

[0064] "Patient" or "subject" refers to a living organism suffering from or susceptible to a disease or condition that can be treated by administering a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, cattle, rats, mice, dogs, cats, primates, goats, sheep, cows, deer, and other non-mammals. In some embodiments, the patient or subject is a human.

[0065] "Therapeutically effective amount" refers to the amount of a compound or pharmaceutical composition that can be used to treat or improve an established disease or condition, or can be used to show a detectable therapeutic or inhibitory effect. The exact amount will depend on the purpose of the treatment and will be determined by those skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (Volumes 1-3, 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, Lippincott, Williams & Wilkins).

[0066] When used herein to refer to a group of substituents or "substituents", "a", "an" or "an / kind" means at least one. For example, when a compound is substituted with "an" alkyl or aryl, the compound is optionally substituted with at least one alkyl and / or at least one aryl, wherein each alkyl and / or aryl is optionally different. In another example, when a compound is substituted with "a" substituent, the compound is substituted with at least one substituent, wherein each substituent is optionally different.

[0067] Composition

[0068] I. Composition

[0069] In the first aspect, the present disclosure provides a composition. The composition comprises a PK inhibitor as described herein (including but not limited to, rubusta free base, rubusta salt (e.g., mesylate or another acceptable salt thereof)) and one or more excipients. As will be appreciated, some of the one or more excipients of the composition as described herein may have multiple functions. For example, a given substance may act as both a solvent and a promoter, 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 to be single, even if its properties may allow for multiple functionalities. The composition may be formulated with 0.1% or 0.8% of a PK inhibitor as described herein, such as, but not limited to, rubusta free base or rubusta salt (e.g., rubusta mesylate monohydrate). The composition may be formulated with 0.08% or 0.8% w / w of rubusta free base, rubusta mesylate monohydrate or other salts thereof. In some cases, the composition is administered once or twice a day. In some cases, the composition is administered for about 12 weeks to about 6 months. In some cases, the composition is administered for about 4 weeks to about 8 weeks. In some cases, the composition is administered for about 8 weeks to about 12 weeks.

[0070] In some embodiments, exemplary PK inhibitors as used herein include rubostat mesylate monohydrate, rubostat free base, or an acceptable salt thereof, including compounds having the following structure:

[0071]

[0072] or an acceptable salt thereof.

[0073] The non-limiting examples of excipients include: organic solvents and / or penetration enhancers, antioxidants, gelling agents and one or more other agents (such as alcohol or wetting agents). In some compositions, the excipient in one or more excipients includes an organic solvent, which includes one or more organic solvents, such as 1, 2, 3, 4 or 5 kinds of organic solvents. In some compositions, the excipient in one or more excipients includes a penetration enhancer, which includes one or more penetration enhancers, such as 1, 2, 3, 4 or 5 kinds of penetration enhancers. In some cases, the organic solvent is a penetration enhancer. In some compositions, the excipient in one or more excipients includes an antioxidant, which includes one or more antioxidants, such as 1, 2, 3, 4 or 5 kinds of antioxidants. In some compositions, the excipient in one or more excipients includes a gelling agent, which includes one or more gelling agents, such as 1, 2, 3, 4 or 5 kinds of gelling agents. In some compositions, the excipient in one or more excipients includes one or more other agents, such as alcohol. In some compositions, alcohol is a wetting agent.

[0074] In some embodiments, the composition comprises an organic solvent and / or a penetration enhancer. The organic solvent may be a penetration enhancer. In some embodiments, the composition comprises an organic solvent or a penetration enhancer. Non-limiting example compositions comprise an organic solvent and / or a penetration enhancer and one or more additional excipients. One or more additional excipients may be an antioxidant. One or more additional excipients may be an alcohol. One or more additional excipients may be a gelling agent. One or more additional excipients may comprise an antioxidant, an alcohol, a gelling agent, or two or more thereof. One or more additional excipients may comprise an antioxidant, an alcohol, and a gelling agent.

[0075] In some embodiments, the composition comprises an antioxidant. Non-limiting example compositions comprise an antioxidant and one or more additional excipients. One or more additional excipients may be an organic solvent and / or a penetration enhancer. One or more additional excipients may be an alcohol. One or more additional excipients may be a gelling agent. One or more additional excipients may comprise an organic solvent and / or a penetration enhancer, an alcohol, a gelling agent, or two or more thereof. One or more additional excipients may comprise an organic solvent and / or a penetration enhancer, an alcohol, and a gelling agent.

[0076] In some embodiments, the composition comprises a gelling agent. Non-limiting example compositions comprise a gelling agent and one or more additional excipients. One or more additional excipients may be an antioxidant. One or more additional excipients may be an alcohol. One or more additional excipients may be an organic solvent and / or a penetration enhancer. One or more additional excipients may comprise an antioxidant, an alcohol, an organic solvent and / or a penetration enhancer, or two or more thereof. One or more additional excipients may comprise an antioxidant, an alcohol and an organic solvent and / or a penetration enhancer.

[0077] In some embodiments, the composition comprises an alcohol. Non-limiting example compositions comprise a solvent and one or more additional excipients. One or more additional excipients may be a penetration enhancer. One or more additional excipients may be an antioxidant. One or more additional excipients may be a gelling agent. One or more additional excipients may comprise an antioxidant, a penetration enhancer, a gelling agent, or two or more thereof. One or more additional excipients may comprise an antioxidant, a penetration enhancer, and a gelling agent.

[0078] II. PK Inhibitors

[0079] In some embodiments, the composition comprises a PK inhibitor as described herein, which prevents, inhibits or reduces melanin production by inhibiting or regulating protein kinases. In some embodiments, the composition inhibits or regulates protein kinases, including but not limited to protein kinase C, protein kinase Cα, protein kinase Cβ, protein kinase B and / or protein kinase A. In some embodiments, the composition inhibits PKCα, PKCβ, PKCβ1, PKCβ2, PKCδ, PKCε, PKCθ, PKCζ, PKCγ, PKCλ, PKCμ, PKCι, PKCη. In some embodiments, the composition inhibits or regulates PRKCA, PKCα, PRKCB, PKCβ, PRKCG, PKCγ, PRKCD, PKCσ, PRKCQ, PKCθ, PRKCE, PKCε, PRKCH, PKCη, PRKCI, PKCζ, PRKCZ, PKCι. In some embodiments, the compounds described herein inhibit or regulate PKA. In some embodiments, the compound inhibits or modulates PRKACA, PRKACB, PRKACG, PRKAR1A, PRKAR1B, PRKAR2A, PRKAR2B. In some embodiments, the composition comprises a pan-protein kinase inhibitor. In some embodiments, the composition comprises a pan-protein kinase C inhibitor. In some embodiments, the composition inhibits or activates a modulator of a protein kinase.

[0080] In some embodiments described herein, the composition comprises a PKC inhibitor. In some embodiments, the PKC inhibitor is a PKCβ inhibitor. In some embodiments, the PKC inhibitor is a PKCβ1 and / or PKCβ2 inhibitor. In some embodiments, the PKCβ inhibitor includes Rubusta free alkali or a salt thereof. In some embodiments, Rubusta free alkali or a salt thereof is Rubusta free alkali. In some embodiments, Rubusta or a salt thereof is Rubusta methanesulfonate monohydrate, Rubusta hydrochloride, Rubusta sulfate, Rubusta tartrate, Rubusta succinate, Rubusta acetate or Rubusta phosphate.

[0081] The disclosure features a PKC-β inhibitor for use in treating a disease or condition described herein (e.g., a hyperpigmentation condition). In some embodiments, the PKC-β inhibitor comprises a bisindolemaleimide, a phthalimide, or a derivative thereof. In some embodiments, the PKC-β inhibitor is a compound of formula (I):

[0082]

[0083] or a pharmaceutically acceptable salt, stereoisomer, racemate or solvate thereof, wherein:

[0084] W is –O–, –S–, –S(O)–, –S(O)2–, –C(O)–, C2-C6 alkylene, substituted alkylene, C2-C6 alkenylene, substituted alkenylene, aryl, aryl(CH2) m O, heterocyclic group, heterocyclic group (CH2) m O, –NR 3 –, –N(O)R 3 –, –C(O)NH– or –NHC(O)–;

[0085] X and Y are each independently C1-C4 alkylene, substituted alkylene, or X, Y and W are combined to form -(CH2) n –AA–;

[0086] Each R 1 are independently hydrogen, halogen, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, C1-C4 haloalkyl, nitro, –NR 4 R 5 or –NHC(O)(C1-C4 alkyl);

[0087] R 2 is hydrogen, –CH3C(O), –NH2 or hydroxyl;

[0088] R 3 is hydrogen, (CH2) m Aryl, C1-C4 alkyl, –C(O)O(C1-C4 alkyl), –C(O)NR 4 R 5 、-(C=NH)NH2、-S(O)(C1-C4 alkyl)、-S(O)2(NR 4 R 5 ) or –S(O)2(C1-C4alkyl);

[0089] R 4 and R 5 are independently hydrogen, C1-C4 alkyl, phenyl, benzyl, or R 4 and R 5 Together with the nitrogen to which they are bound, they form a saturated or unsaturated 5- or 6-membered ring;

[0090] AA is an amino acid residue;

[0091] Each m is independently 0, 1, 2 or 3; and

[0092] n is independently 2, 3, 4 or 5.

[0093] In some embodiments, XWY contains 4 to 30 atoms, which may be further substituted or unsubstituted. In some embodiments, XWY contains 5 atoms, 6 atoms, 7 atoms, 8 atoms, 9 atoms, 10 atoms, 11 atoms, 12 atoms, 13 atoms, 14 atoms, 15 atoms, 16 atoms, 17 atoms, 18 atoms, 19 atoms, 20 atoms, 21 atoms, 22 atoms, 23 atoms, 24 atoms, 25 atoms, 26 atoms, 27 atoms, 28 atoms, 29 atoms, or 30 atoms, which may be further substituted or unsubstituted. In some embodiments, XWY contains 10 to 30 atoms, which may be further substituted or unsubstituted. In some embodiments, XWY contains 20 to 30 atoms, which may be further substituted or unsubstituted.

[0094] In some embodiments, R 1 and R 2 Each is independently hydrogen. In some embodiments, X and Y are each independently alkylene or substituted alkylene. In some embodiments, W is substituted alkylene, -O-, -S-, -C(O)NH-, -NHC(O)-, or NR 3 In some embodiments, R 1 and R 2 are each independently hydrogen, X and Y are each independently alkylene or substituted alkylene, and W is substituted alkylene, -O-, -S-, -C(O)NH-, -NHC(O)-, or NR 3 .

[0095] In some embodiments, the compound of formula (I) is a compound of formula (la):

[0096]

[0097] or a pharmaceutically acceptable salt, stereoisomer, racemate or solvate thereof, wherein

[0098] Z is – (CH2) p – or – (CH2) p –O–(CH2) p ;

[0099] R 6 Hydroxyl, –SH, C1-C4 alkyl, (CH2) m Aryl, –NH(aryl), N(CH3)(CF3), NH(CF3), or –NR 4 R 5 ;

[0100] R 4is hydrogen or C1-C4 alkyl;

[0101] R 5 is hydrogen, C1-C4 alkyl, or benzyl;

[0102] p is 0, 1, or 2; and

[0103] Each m is independently 2 or 3.

[0104] In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, Z is CH2. In some embodiments, R 6 is NH2, NH(CF3) or N(CH3)2. In some embodiments, Z is CH2, and R 6 is NH2, NH(CF3) or N(CH3)2. In some embodiments, m is 2, Z is CH2, and R 6 It is NH2, NH(CF3) or N(CH3)2.

[0105] In other embodiments, the compound of formula (I) is a compound of formula (Ib):

[0106]

[0107] or a pharmaceutically acceptable salt, stereoisomer, racemate or solvate thereof, wherein

[0108] Z is – (CH2) p –

[0109] R 6 is N(CH3)(CF3), NH(CF3) or –NR 4 R 5 ;

[0110] R 4 and R 5 Each is independently hydrogen or C1-C4 alkyl;

[0111] R 5 is hydrogen, C1-C4 alkyl, or benzyl;

[0112] p is 0, 1, or 2; and

[0113] Each m is independently 2 or 3.

[0114] In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, R 6 Yes – NR 4 R5 , and R 4 and R 5 Each is independently C1-C4 alkyl (e.g., CH3). 6 is N(CH3)2. In some embodiments, m is 2, and p is 1. In some embodiments, m is 2, p is 1, and R 6 It is N(CH3)2.

[0115] In other embodiments, the compound of formula (I) is a compound of formula (Ic):

[0116]

[0117] or a pharmaceutically acceptable salt, stereoisomer, racemate or solvate thereof, wherein: R 6 is N(CH3)(CF3), NH(CF3) or –NR 4 R 5 .

[0118] In some embodiments, R 6 Yes – NR 4 R 5 , and R 4 and R 5 Each is independently C1-C4 alkyl (e.g., CH3). 6 It is N(CH3)2.

[0119] In other embodiments, the compound of formula (I) is a compound of formula (Id):

[0120]

[0121] Or a pharmaceutically acceptable salt, stereoisomer, racemate or solvate thereof. In some embodiments, the compound of formula (Id) is 9-[(dimethylamino)methyl]-6,7,10,11-tetrahydro-9H,18H-5,21:12,17-di(methylbridge)dibenzo[e,k]pyrrolo[3,4-h][1,2,13]oxadiazahexadecane-18,20-dione, such as rubustadine, or a pharmaceutically acceptable salt, stereoisomer, racemate or solvate thereof.

[0122] In other embodiments, the compound of formula (I) is a compound of formula (Ie):

[0123]

[0124] Or a pharmaceutically acceptable salt, stereoisomer, racemate or solvate thereof, wherein A is a counterion of the N(CH3)2 moiety. In some embodiments, the compound of formula (Ie) is 9-[(dimethylamino)methyl]-6,7,10,11-tetrahydro-9H,18H-5,21:12,17-di(methylbridge)dibenzo[e,k]pyrrolo[3,4-h][1,2,13]oxadiazahexadecene-18,20-dione salt, such as the rubesta salt, or a pharmaceutically acceptable salt, stereoisomer, racemate or solvate thereof.

[0125] In some embodiments, A is acetic acid, benzoic acid, bromine, carbonic acid, chlorine, citric acid, fluorine, fumaric acid, gluconic acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, iodine, lactic acid, phosphonic acid, phosphoric acid, methanesulfonic acid, sulfonic acid, tartaric acid or a salt thereof. In some embodiments, A is acetic acid, benzoic acid, citric acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, methanesulfonic acid, tartaric acid or a salt thereof. In some embodiments, A is methanesulfonic acid or a salt thereof.

[0126] In other embodiments, the compound of formula (I) is a compound of formula (If):

[0127]

[0128] or a pharmaceutically acceptable salt, stereoisomer, racemate or solvate thereof.

[0129] In some embodiments, the PKC-β inhibitor (e.g., a compound of Formula (If)) is 9-[(dimethylamino)methyl]-6,7,10,11-tetrahydro-9H,18H-5,21:12,17-di(methoxy)dibenzo[e,k]pyrrolo[3,4-h][1,2,13]oxadiazahexadecane-18,20-dione mesylate, such as rubustadine mesylate, or a pharmaceutically acceptable salt, stereoisomer, racemate, or solvate thereof.

[0130] The compound of formula (I) (e.g., a compound of formula (Ia), (Ib), (Ic), (Id), (Ie) or (If)) can exist in the form of a solvate, such as a solvate with water (i.e., a hydrate), methanol, ethanol, dimethylformamide, ethyl acetate, etc. A mixture of solvates can also be prepared. The source of the solvate can be derived from a solvent encountered during the synthesis of the compound, such as a solvent for purification (e.g., crystallization) or preparation for purification (e.g., crystallization), or an incidental solvent of such a solvent. In one embodiment, the compound of formula (I) (e.g., a compound of formula (Ia), (Ib), (Ic), (Id), (Ie) or (If)) exists in the form of a monohydrate or trihydrate solvate.

[0131] In some embodiments, the PKC-β inhibitor of formula (I) can be a stereoisomer or racemate of the compound of formula (I). In certain embodiments, the PKC-β inhibitor of formula (If) is a compound of formula (If-1) or a compound of formula (If-2):

[0132]

[0133] or a pharmaceutically acceptable salt, stereoisomer, racemate or solvate thereof. In some embodiments, the PKC-β inhibitor (e.g., a compound of formula (I)) is (9S)-9-[(dimethylamino)methyl]-6,7,10,11-tetrahydro-9H,18H-5,21:12,17-di(methylbridge)dibenzo[e,k]pyrrolo[3,4-h][1,2,13]oxadiazahexadecene-18,20-dione mesylate (e.g., formula (If-1)) or (9R )-9-[(dimethylamino)methyl]-6,7,10,11-tetrahydro-9H,18H-5,21:12,17-di(methyl)dibenzo[e,k]pyrrolo[3,4-h][1,2,13]oxadiazahexadecane-18,20-dione mesylate (e.g., formula (If-2)), such as rubusta mesylate, or a pharmaceutically acceptable salt, stereoisomer, racemate or solvate thereof.

[0134] The preparation of compounds of formula (I) (e.g., compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (If-1) or (If-2)) can be achieved by the methods described in U.S. Pat. No. 5,552,396 and U.S. Pat. No. 6,015,807, each of which is incorporated herein by reference in its entirety. However, the preparation of compounds of formula (I) (e.g., compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (If-1) or (If-2)) can be accomplished using other protocols or methods known to those skilled in the art.

[0135] In some embodiments, the PKC-β inhibitor is a compound of formula (II):

[0136]

[0137] or a pharmaceutically acceptable salt, stereoisomer, racemate or solvate thereof, wherein:

[0138] Each R 1 are independently hydrogen, halogen, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, haloalkyl, nitro, NR 4 R 5or –NHC(O)(C1-C4 alkyl);

[0139] R 2 is hydrogen, –CH3C(O), –NH2 or hydroxyl;

[0140] R 4 and R 5 are independently hydrogen, C1-C4 alkyl, phenyl, benzyl, or R 4 and R 5 Together with the nitrogen to which they are bound, they form a saturated or unsaturated 5- or 6-membered ring;

[0141] R 7 is hydrogen or C1-C4 alkyl;

[0142] R 8 is a cycloalkyl or heterocyclic group, each of which is replaced by one or more R 9 replace;

[0143] R 9 is C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, halogen, cyano, nitro, aryl, arylalkyl, heteroaryl or heteroarylalkyl, each of which is optionally substituted by one or more R 10 replace;

[0144] Each R 10 are independently halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, cyano or nitro; and

[0145] Each m is independently 0, 1, 2 or 3.

[0146] In some embodiments, each m is 0.

[0147] In some embodiments, R 2 It's hydrogen.

[0148] In some embodiments, R 7 is C1-C4 alkyl (eg, methyl or ethyl). 7 It's methyl.

[0149] In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 is a 6-membered nitrogen-containing heterocyclic group. 8 is piperidinyl (eg, 1,4-piperidinyl).

[0150] In some embodiments, R 9 In some embodiments, R9 Yes (CH2) n -pyridinyl, wherein n is 1, 2, 3 or 4. In some embodiments, R 9 is (CH2)-pyridinyl. In some embodiments, R 9 It is 2-(CH2)-pyridinyl.

[0151] In some embodiments, the compound of formula (II) is a compound of formula (IIa):

[0152]

[0153] or a pharmaceutically acceptable salt, stereoisomer, racemate or solvate thereof, wherein:

[0154] R 2 is hydrogen, –CH3C(O), –NH2 or hydroxyl;

[0155] R 7 is hydrogen or C1-C4 alkyl;

[0156] R 9 is C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, halogen, cyano or nitro;

[0157] R 9a is aryl, arylalkyl, heteroaryl or heteroarylalkyl, each of which is optionally substituted by one or more R 10 replace; and

[0158] Each R 10 are independently halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, cyano or nitro.

[0159] In some embodiments, each m is 0.

[0160] In some embodiments, R 2 It's hydrogen.

[0161] In some embodiments, R 7 is C1-C4 alkyl (eg, methyl or ethyl). 7 It's methyl.

[0162] In some embodiments, R 9a In some embodiments, R 9a Yes (CH2) n -pyridinyl, wherein n is 1, 2, 3 or 4. In some embodiments, R 9a is (CH2)-pyridinyl. In some embodiments, R 9aIt is 2-(CH2)-pyridinyl.

[0163] In some embodiments, the compound of formula (II) is a compound of formula (IIb):

[0164]

[0165] or a pharmaceutically acceptable salt, stereoisomer, racemate or solvate thereof, wherein:

[0166] R 9a is aryl, arylalkyl, heteroaryl or heteroarylalkyl, each of which is optionally substituted by one or more R 10 replace; and

[0167] Each R 10 are independently halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, cyano or nitro; and

[0168] In some embodiments, R 9a In some embodiments, R 9a Yes (CH2) n -pyridinyl, wherein n is 1, 2, 3 or 4. In some embodiments, R 9a is (CH2)-pyridinyl. In some embodiments, R 9a It is 2-(CH2)-pyridinyl.

[0169] In some embodiments, the PKC-β inhibitor of formula (II) is a compound of formula (IIc):

[0170]

[0171] Or a pharmaceutically acceptable salt, stereoisomer, racemate or solvate thereof. In some embodiments, the PKC-β inhibitor (e.g., a compound of formula (II)) is 3-(1-methyl-1H-indol-3-yl)-4-(1-(1-(pyridin-2-ylmethyl)piperidin-4-yl)-1H-indol-3-yl)-1H-pyrrole-2,5-dione (e.g., formula (IIc)), for example, LY-317615 or enzastaurin, or a pharmaceutically acceptable salt, stereoisomer, racemate or solvate thereof. In some embodiments, the PKC-β inhibitor (e.g., a compound of formula (II)) is enzastaurin hydrochloride.

[0172] In some embodiments, the PKC-β inhibitor is a compound of formula (III):

[0173]

[0174] or a pharmaceutically acceptable salt, stereoisomer, racemate or solvate thereof, wherein:

[0175] X 1 and X 2 Each independently is –O–, –NR 4 – or –S–;

[0176] A 1 and A 2 are each independently aryl or heteroaryl, wherein each aryl or heteroaryl is optionally substituted by one or more R 9 replace;

[0177] R 2 is hydrogen, –CH3C(O), –NH2 or hydroxyl;

[0178] R 4 is hydrogen or C1-C4 alkyl; and

[0179] R 9 It is C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, halogen, cyano or nitro.

[0180] In some embodiments, X 1 and X 2 One of them is independently –NR 4 In some embodiments, X 1 and X 2 Each independently is –NR 4 In some embodiments, X 1 and X 2 Each is independently –NH–.

[0181] In some embodiments, A 1 and A 2 In some embodiments, A 1 and A 2 Each is independently aryl. In some embodiments, A 1 and A 2 Each is independently phenyl. In some embodiments, A 1 and A 2 Each is independently 9 In some embodiments, A 1 and A 2 Each is independently 9 In some embodiments, R 9 is a halogen (eg, fluorine).

[0182] In some embodiments, the PKC-β inhibitor is a compound of formula (IIIa):

[0183]

[0184] or a pharmaceutically acceptable salt, stereoisomer, racemate or solvate thereof, wherein:

[0185] X 1 and X 2 Each independently is –O–, –NR 4 – or –S–;

[0186] R 2 is hydrogen, –CH3C(O), –NH2 or hydroxyl;

[0187] R 4 is hydrogen or C1-C4 alkyl; and

[0188] R 9a and R 9b Each is C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, halogen, cyano or nitro.

[0189] In some embodiments, X 1 and X 2 One of them is independently –NR 4 In some embodiments, X 1 and X 2 Each independently is –NR 4 In some embodiments, X 1 and X 2 Each is independently –NH–.

[0190] In some embodiments, each phenyl ring is replaced by 1 R 9a and 1 R 9b In some embodiments, each phenyl ring is replaced by 1 R 9a and 1 R 9b In some embodiments, R 9a and R 9b In some embodiments, R 9a and R 9b Each is a halogen (eg, fluorine).

[0191] In some embodiments, the PKC-β inhibitor of formula (III) is a compound of formula (IIIb):

[0192]

[0193] Or a pharmaceutically acceptable salt, stereoisomer, racemate or solvate thereof. In some embodiments, the PKC-β inhibitor (e.g., a compound of formula (III)) is 5,6-bis(4-fluorophenoxy)isoindoline-1,3-dione (e.g., formula (IIIb)), such as CGP 53353, CG 53353, or a pharmaceutically acceptable salt, stereoisomer, racemate or solvate thereof.

[0194] Other PKCβ inhibitors disclosed herein include, for example, PKCβ pseudosubstrates, as described in Park et al. (1999) Protein Kinase C-β Activates Tyrosinase by Phosphorylating Serine Residues in Its Cytoplasmic Domain. JBC Vol. 274, No. 23, June 4, pp. 16470–16478; and Park et al. (2004) The receptor for activated C-kinase-I (RACK-I) anchors activated PKC-β on melanosomes. Journal of Cell Science 117 (16) p. 3659. Exemplary PKCβ pseudosubstrates include, for example, amino acids comprising the amino acid sequence Glu-Asp-Tyr-His-Ser-Leu-Tyr-Gln-Ser-His-Leu (SEQ ID NO: 1), amino acids consisting essentially of the amino acid sequence Glu-Asp-Tyr-His-Ser-Leu-Tyr-Gln-Ser-His-Leu (SEQ ID NO: 1); and amino acids consisting of the amino acid sequence Glu-Asp-Tyr-His-Ser-Leu-Tyr-Gln-Ser-His-Leu (SEQ ID NO: 1). PKCβ pseudosubstrates having at least 75%, 80%, 85%, 90%, 95%, 99% homology to SEQ ID NO: 1 are also contemplated.

[0195] III-1. Excipients

[0196] A. Organic solvents and / or penetration enhancers

[0197] In some embodiments, the composition comprises an organic solvent and / or a penetration enhancer. In some cases, the composition comprises an organic solvent. In some cases, the composition comprises a penetration enhancer. In some cases, the composition comprises an organic solvent and a penetration enhancer. The organic solvent may be a penetration enhancer. The penetration enhancer may be an organic solvent. Suitable solvents and / or penetration enhancers include, but are not limited to, C2-6 Alkylene glycol (e.g., propylene glycol), di-(C 2-6 Alkylene) glycol (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., PEG200 and / or PEG400), glycerol, fatty alcohol (e.g., octyldodecanol), fatty esters (e.g., diisopropyl adipate, isopropyl myristate, medium chain triglycerides, sorbitan monooleate, etc.), fatty ethers (e.g., Laureth-4), and combinations thereof. In some embodiments, the organic solvent and / or penetration enhancer comprises 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.

[0198] In some embodiments, the composition herein comprises two or more organic solvents and / or penetration enhancers. For example, in some embodiments, the composition comprises a first organic solvent and / or a penetration enhancer, and a second organic solvent and / or a penetration enhancer. In some cases, the first organic solvent and / or a penetration enhancer comprises an organic solvent. In some cases, the first organic solvent and / or a penetration enhancer comprises a penetration enhancer. In some cases, the first organic solvent and / or a penetration enhancer is an organic solvent and a penetration enhancer. In some cases, the second organic solvent and / or a penetration enhancer comprises an organic solvent. In some cases, the second organic solvent and / or a penetration enhancer comprises a penetration enhancer. In some cases, the second organic solvent and / or a penetration enhancer is an organic solvent and a penetration enhancer. In some embodiments, the composition herein comprises 2, 3, 4 or 5 kinds of organic solvents and / or penetration enhancers.

[0199] Non-limiting exemplary organic solvents include C 2-6 Alkylene glycol (e.g., propylene glycol), C 2-6 Alcohol, di-(C 2-6 Alkylene) glycol (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., PEG200 and / or PEG400), glycerol, fatty alcohol (e.g., octyldodecanol), fatty esters (e.g., diisopropyl adipate, isopropyl myristate, medium chain triglycerides, sorbitan monooleate, etc.), fatty ethers (e.g., Laureth-4), and combinations thereof. In some embodiments, the organic solvent comprises C2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, polyethylene glycol, C 2-6 Alcohol, glycerol, fatty alcohol, fatty ester or fatty ether, or a combination of two or more thereof. In some embodiments, the solvent comprises C 2-6 Alkylene glycol, C 2-6 Alcohol or C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, or a combination thereof. In some embodiments, the solvent comprises C 2-6 In some embodiments, the solvent includes C 2-6 In some embodiments, the solvent includes C 1-3 Alkyl-(OCH2CH2) 1-5 -OH. In some embodiments, the solvent includes C 2-6 Alcohol and C 1-3 Alkyl-(OCH2CH2) 1-5 -OH. In some embodiments, the solvent includes C 2-6 Alcohol and C 2-6 In some embodiments, the composition comprises C 2-6 Alcohol, C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 A mixture of -OH.

[0200] Non-limiting exemplary penetration enhancers include C 2-6 Alkylene glycol (e.g., propylene glycol), C 2-6 Alcohol, di-(C 2-6 Alkylene) glycol (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., PEG200 and / or PEG400), glycerol, fatty alcohol (e.g., octyldodecanol), fatty esters (e.g., diisopropyl adipate, isopropyl myristate, medium chain triglycerides, sorbitan monooleate, etc.), fatty ethers (e.g., Laureth-4), and combinations thereof. In some embodiments, the penetration enhancer comprises C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, polyethylene glycol, C 2-6 Alcohol, glycerol, fatty alcohol, fatty ester or fatty ether, or a combination of two or more thereof. In some embodiments, the penetration enhancer comprises C2-6 Alkylene glycol, C 2-6 Alcohol or C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, or a combination thereof. In some embodiments, the penetration enhancer comprises C 2-6 In some embodiments, the penetration enhancer comprises C 2-6 In some embodiments, the penetration enhancer comprises C 1-3 Alkyl-(OCH2CH2) 1-5 -OH. In some embodiments, the penetration enhancer comprises C 2-6 Alcohol and C 1-3 Alkyl-(OCH2CH2) 1-5 -OH. In some embodiments, the penetration enhancer comprises C 2-6 Alcohol and C 2-6 In some embodiments, the composition comprises C 2-6 Alcohol, C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 A mixture of -OH.

[0201] In some embodiments, the organic solvent and / or penetration enhancer comprises C 2-6 Alkylene glycol and / or C 1-3 Alkyl-(OCH2CH2) 1-5 -OH. In some embodiments, the organic solvent and / or penetration enhancer comprises C 2-6 In some embodiments, the organic solvent and / or penetration enhancer comprises C 1-3 Alkyl-(OCH2CH2) 1-5 -OH. In some embodiments, the organic solvent and / or penetration enhancer comprises C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 -OH. In some embodiments, the organic solvent and / or penetration enhancer comprises C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 In some embodiments, the composition comprises C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 -OH.

[0202] In some embodiments, C 1-3 Alkyl-(OCH2CH2) 1-5-OH is 2-(2-ethoxyethoxy)ethanol (e.g., Transcutol P). In some embodiments, C 2-6 The alkylene glycol is propylene glycol.

[0203] In some embodiments, the organic solvent and / or the penetration enhancer include propylene glycol and / or 2-(2-ethoxyethoxy)ethanol. In some embodiments, the organic solvent and / or the penetration enhancer include propylene glycol. In some embodiments, the organic solvent and / or the penetration enhancer include 2-(2-ethoxyethoxy)ethanol. In some embodiments, the organic solvent and / or the penetration enhancer include propylene glycol and 2-(2-ethoxyethoxy)ethanol. In some embodiments, the organic solvent and / or the penetration enhancer include a mixture of propylene glycol and 2-(2-ethoxyethoxy)ethanol. In some embodiments, the composition includes propylene glycol and 2-(2-ethoxyethoxy)ethanol.

[0204] In some embodiments, the organic solvent and / or penetration enhancer comprises C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH or polyethylene glycol, or a combination thereof or two or more thereof. In some embodiments, the organic solvent and / or penetration enhancer comprises C 2-6 In some embodiments, the organic solvent and / or penetration enhancer comprises C 1-3 Alkyl-(OCH2CH2) 1-5 -OH. In some embodiments, the organic solvent and / or penetration enhancer comprises polyethylene glycol. In some embodiments, the organic solvent and / or penetration enhancer comprises C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 -OH. In some embodiments, the organic solvent and / or penetration enhancer comprises C 1-3 Alkyl-(OCH2CH2) 1-5 -OH and polyethylene glycol. In some embodiments, the organic solvent and / or penetration enhancer comprises C 2-6 In some embodiments, the organic solvent and / or penetration enhancer comprises C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH and polyethylene glycol. In some embodiments, the organic solvent and / or penetration enhancer comprises C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 A mixture of two or more of -OH and polyethylene glycol.

[0205] In some embodiments, the organic solvent and / or the penetration enhancer include polyethylene glycol (PEG). In some embodiments, the polyethylene glycol includes PEG200, PEG300, PEG400, PEG500, PEG600, PEG700, PEG800 or PEG900 or a combination thereof. In some embodiments, the polyethylene glycol includes PEG-200 and / or PEG-400. In some embodiments, the polyethylene glycol includes PEG200. In some embodiments, the polyethylene glycol includes PEG400. In some embodiments, the polyethylene glycol includes a mixture of PEG200 and PEG400. In some embodiments, the polyethylene glycol includes PEG-200 and / or PEG-400. In some embodiments, the organic solvent and / or the penetration enhancer include PEG200. In some embodiments, the organic solvent and / or the penetration enhancer include PEG400. In some embodiments, the organic solvent and / or the penetration enhancer include a mixture of PEG200 and PEG400. In some embodiments, the composition includes PEG200. In some embodiments, the composition comprises PEG 400. In some embodiments, the composition comprises a mixture of PEG 200 and PEG 400. In some embodiments, the polyethylene glycol is super refined or "SR" polyethylene glycol.

[0206] In some embodiments, organic solvent and / or penetration enhancer include fatty alcohol. As used herein, term "fatty alcohol" refers to saturated or unsaturated aliphatic alcohol. In some embodiments, fatty alcohol is in the form of a mixture of different fatty alcohols. In some embodiments, fatty alcohol has an average of about 12-20, 14-20, 12-18, 14-18 or 16-18 carbon. Suitable fatty alcohol includes but is not limited to decyl alcohol, undecyl alcohol, lauryl alcohol, tridecanol, myristyl alcohol, pentadecanol, cetyl alcohol, palmitoleyl alcohol, heptadecanol, stearyl alcohol, oleyl alcohol, nonadecanol, arachidyl alcohol, heneicosyl alcohol, behenyl alcohol, erucyl alcohol, tetracosyl alcohol, octyldodecanol and mixtures thereof. In some embodiments, organic solvent and / or penetration enhancer include one or more fatty alcohols selected from decyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, palmitoleyl alcohol, stearyl alcohol, oleyl alcohol, arachidyl alcohol, heneicosyl alcohol, behenyl alcohol, erucyl alcohol and tetracosyl alcohol. In some embodiments, the organic solvent and / or penetration enhancer comprises octyldodecanol.In some embodiments, the composition comprises octyldodecanol.

[0207] In some embodiments, the organic solvent and / or penetration enhancer comprises a fatty ester. In some embodiments, the fatty ester is a glycerol fatty ester, ethylene glycol monoesters and diesters of fatty acids, propylene glycol monoesters and diesters of fatty acids, sorbitan esters, C 1-6Alkyl esters, di-(C 1-6 alkyl) esters, or a combination of two or more thereof.

[0208] In some embodiments, fatty ester is glyceride. In some embodiments, glyceride is monoglyceride, diglyceride or triglyceride. Glyceride can be optionally substituted by sulfonic acid group or its pharmaceutically acceptable salt. Suitable fatty acid for deriving fatty acid glyceride includes but is not limited to those described herein. In some embodiments, glyceride is monoglyceride of fatty acid with 12 to 18 carbon atoms. In some embodiments, glyceride is diglyceride of fatty acid with 12 to 18 carbon atoms. In some embodiments, glyceride is triglyceride (for example, also referred to as medium chain triglyceride herein) of fatty acid with 12 to 18 carbon atoms. In some embodiments, organic solvent and / or penetration enhancer include triglyceride (for example, also referred to as medium chain triglyceride herein) of fatty acid with 12 to 18 carbon atoms. In some embodiments, composition includes triglyceride (for example, also referred to as medium chain triglyceride herein) of fatty acid with 12 to 18 carbon atoms.

[0209] 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 1-4 Alkyl esters. Ethylene glycol monoesters, propylene glycol monoesters and C 1-4 Suitable fatty acids for any 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 C 2-18 fatty acid. 1-4 Alkyl esters. Non-limiting examples of esters of fatty acids include laurate, myristate, palmitate, stearate, and oleate. In some embodiments, the fatty ester is isopropyl myristate. In some embodiments, the organic solvent and / or penetration enhancer includes isopropyl myristate. In some embodiments, the composition comprises isopropyl myristate.

[0210] In some embodiments, the fatty ester is a sorbitan ester. Suitable fatty acids for deriving sorbitan esters include, but are not limited to, those described herein. Suitable sorbitan esters include, but are not limited to, the SpanTM series (available from Uniqema), including Span 20 (sorbitan monolaurate), 40 (sorbitan monopalmitate), 60 (sorbitan monostearate), 65 (sorbitan tristearate), 80 (sorbitan monooleate), and 85 (sorbitan trioleate). In some embodiments, the fatty ester is sorbitan monooleate. In some embodiments, the organic solvent and / or penetration enhancer include sorbitan monooleate. In some embodiments, the composition comprises sorbitan monooleate.

[0211] In some embodiments, the fatty ester is di-(C 1-4 alkyl) ester (i.e., adipate) or di-(C 1-4 In some embodiments, the fatty 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.

[0212] 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.

[0213] In some embodiments, the total amount of organic solvents and / or penetration enhancers is present in the composition in an amount of about 60% to about 99%, about 80% to about 99%, about 90-99%, or about 95% to about 99% by weight. In some embodiments, the total amount of organic solvents and / or penetration enhancers is present in the composition in an amount of about 85% by weight. In some embodiments, the total amount of organic solvents and / or penetration enhancers is present in the composition in an amount of about 90% by weight. In some embodiments, the total amount of organic solvents and / or penetration enhancers is present in the composition in an amount of about 96% by weight.

[0214] In some embodiments, organic solvents and / or penetration enhancers include 2-(2-ethoxyethoxy)ethanol. In some embodiments, the composition comprises 2-(2-ethoxyethoxy)ethanol. In some embodiments, 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of about 40% to about 50%, about 43% to about 49%, about 47-49% or about 47-48% by weight. In some embodiments, 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of about 40% to about 50%, about 43% to about 49%, about 47-49% or about 47-48% by weight. In some embodiments, 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of about 40% to about 50% by weight. In some embodiments, 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of about 47-48% by weight.

[0215] In some embodiments, organic solvents and / or penetration enhancers include propylene glycol. In some embodiments, the composition comprises propylene glycol. In some embodiments, propylene glycol is present in the composition in an amount of about 8-30%, 9-22%, 18-22%, 19-21% or 19-20% by weight. In some embodiments, propylene glycol is present in the composition in an amount of about 8-30%, 9-22%, 18-22%, 19-21% or 19-20% by weight. In some embodiments, propylene glycol is present in the composition in an amount of about 19-20% by weight.

[0216] In some embodiments, organic solvents and / or penetration enhancers include polyethylene glycol. In some embodiments, the composition comprises polyethylene glycol. In some embodiments, polyethylene glycol is present in the composition in an amount of about 2-45%, 3-24%, 3-14%, 13-15% or about 13-14% by weight. In some embodiments, polyethylene glycol is present in the composition in an amount of about 2-45%, 3-24%, 3-14%, 13-15% or about 13-14% by weight. In some embodiments, polyethylene glycol is present in the composition in an amount of about 10% to about 20% by weight. In some embodiments, polyethylene glycol is present in the composition in an amount of about 13-14% by weight.

[0217] In some embodiments, the organic solvent and / or penetration enhancer comprises propylene glycol and / or 2-(2-ethoxyethoxy)ethanol; wherein the total amount of propylene glycol and / or 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of about 50% to about 80%, about 50% to about 70%, or about 67% by weight. In some embodiments, the organic solvent and / or penetration enhancer is propylene glycol and / or 2-(2-ethoxyethoxy)ethanol; wherein the total amount of propylene glycol and / or 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of 50% to 80%, 50% to 70%, or about 67% by weight. In some embodiments, the organic solvent and / or penetration enhancer comprises propylene glycol and / or 2-(2-ethoxyethoxy)ethanol; wherein the total amount of propylene glycol and / or 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of about 50% to about 70% by weight. In some embodiments, the organic solvent and / or penetration enhancer comprises propylene glycol and / or 2-(2-ethoxyethoxy)ethanol; wherein the total amount of propylene glycol and / or 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of about 67% by weight.

[0218] In some embodiments, the composition comprises propylene glycol and / or 2-(2-ethoxyethoxy)ethanol; wherein the total amount of propylene glycol and / or 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of about 50% to about 80%, about 50% to about 70%, or about 67% by weight. In some embodiments, the composition comprises propylene glycol and / or 2-(2-ethoxyethoxy)ethanol; wherein the total amount of propylene glycol and / or 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of about 50% to about 70% by weight. In some embodiments, the composition comprises propylene glycol and / or 2-(2-ethoxyethoxy)ethanol; wherein the total amount of propylene glycol and / or 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of about 67% by weight.

[0219] In some embodiments, the organic solvent and / or penetration enhancer comprises a mixture of polyethylene glycol and 2-(2-ethoxyethoxy)ethanol; wherein the total amount of the mixture is present in the composition in an amount of about 50% to about 80%, about 50% to about 70%, or about 61% by weight. In some embodiments, the organic solvent and / or penetration enhancer comprises a mixture of polyethylene glycol and 2-(2-ethoxyethoxy)ethanol; wherein the total amount of the mixture is present in the composition in an amount of about 50% to about 80%, about 50% to about 70%, or about 61% by weight. In some embodiments, the organic solvent and / or penetration enhancer comprises a mixture of polyethylene glycol and 2-(2-ethoxyethoxy)ethanol; wherein the total amount of the mixture is present in the composition in an amount of about 50% to about 70% or about 61% by weight. In some embodiments, the organic solvent and / or penetration enhancer comprises a mixture of polyethylene glycol and 2-(2-ethoxyethoxy)ethanol; wherein the total amount of the mixture is present in the composition in an amount of about 50% to about 70% by weight. In some embodiments, the organic solvent and / or penetration enhancer comprises a mixture of polyethylene glycol and 2-(2-ethoxyethoxy)ethanol; wherein the total amount of the mixture is present in the composition in an amount of about 61% by weight.

[0220] In some embodiments, the composition comprises a mixture of polyethylene glycol and 2-(2-ethoxyethoxy)ethanol; wherein the total amount of the mixture is present in the composition in an amount of about 50% to about 80%, about 50% to about 70%, or about 61% by weight. In some embodiments, the composition comprises a mixture of polyethylene glycol and 2-(2-ethoxyethoxy)ethanol; wherein the total amount of the mixture is present in the composition in an amount of about 50% to about 80%, about 50% to about 70%, or about 61% by weight. In some embodiments, the composition comprises a mixture of polyethylene glycol and 2-(2-ethoxyethoxy)ethanol; wherein the total amount of the mixture is present in the composition in an amount of about 50% to about 70% or about 61% by weight. In some embodiments, the composition comprises a mixture of polyethylene glycol and 2-(2-ethoxyethoxy)ethanol; wherein the total amount of the mixture is present in the composition in an amount of about 50% to about 70% by weight. In some embodiments, the composition comprises a mixture of polyethylene glycol and 2-(2-ethoxyethoxy)ethanol; wherein the total amount of the mixture is present in the composition in an amount of about 61% by weight.

[0221] In some embodiments, the organic solvent and / or penetration enhancer comprises a mixture of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol; wherein the total amount of the mixture is present in the composition in an amount of about 50% to about 100%, about 70% to about 90%, or about 81% by weight. In some embodiments, the organic solvent and / or penetration enhancer comprises a mixture of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol; and the total amount of the mixture is present in the composition in an amount of about 50% to about 100%, about 70% to about 90%, or about 81% by weight. In some embodiments, the organic solvent and / or penetration enhancer comprises a mixture of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol; and the total amount of the mixture is present in the composition in an amount of about 60% to about 90% or about 81% by weight. In some embodiments, the organic solvent and / or penetration enhancer comprises a mixture of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol; and the total amount of the mixture is present in the composition in an amount of about 60% to about 90% by weight. In some embodiments, the organic solvent and / or penetration enhancer comprises a mixture of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol; and the total amount of the mixture is present in the composition in an amount of about 81% by weight.

[0222] In some embodiments, the composition comprises a mixture of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol; wherein the total amount of the mixture is present in the composition in an amount of about 50% to about 100%, about 70% to about 90%, or about 81% by weight. In some embodiments, the composition comprises a mixture of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol; and the total amount of the mixture is present in the composition in an amount of about 50% to about 100%, about 70% to about 90%, or about 81% by weight. In some embodiments, the composition comprises a mixture of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol; and the total amount of the mixture is present in the composition in an amount of about 60% to about 90% or about 81% by weight. In some embodiments, the composition comprises a mixture of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol; and the total amount of the mixture is present in the composition in an amount of about 60% to about 90% by weight. In some embodiments, the composition comprises a mixture of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol; and the total amount of the mixture is present in the composition in an amount of about 81% by weight.

[0223] In some embodiments, the organic solvent and / or penetration enhancer includes propylene glycol and 2-(2-ethoxyethoxy)ethanol. In some embodiments, the composition comprises propylene glycol and 2-(2-ethoxyethoxy)ethanol. In some embodiments, propylene glycol is present in an amount of about 10% to about 30% by weight of the composition; and 2-(2-ethoxyethoxy)ethanol is present in an amount of about 40% to about 50% by weight of the composition. In some embodiments, propylene glycol is present in an amount of about 20% by weight of the composition; and 2-(2-ethoxyethoxy)ethanol is present in an amount of about 47% by weight of the composition.

[0224] In some embodiments, the organic solvent and / or penetration enhancer comprises polyethylene glycol and 2-(2-ethoxyethoxy)ethanol. In some embodiments, the composition comprises polyethylene glycol and 2-(2-ethoxyethoxy)ethanol. In some embodiments, polyethylene glycol is present in an amount of about 10% to about 20% by weight of the composition; and 2-(2-ethoxyethoxy)ethanol is present in an amount of about 40% to about 50% by weight of the composition. In some embodiments, polyethylene glycol is present in an amount of about 14% by weight of the composition; and 2-(2-ethoxyethoxy)ethanol is present in an amount of about 47% by weight of the composition.

[0225] In some embodiments, the organic solvent and / or penetration enhancer includes propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol. In some embodiments, the composition comprises propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol. In some embodiments, propylene glycol is present in an amount of about 10% to about 30% by weight of the composition; polyethylene glycol is present in an amount of about 10% to about 20% by weight of the composition; and 2-(2-ethoxyethoxy)ethanol is present in an amount of about 40% to about 50% by weight of the composition. In some embodiments, propylene glycol is present in an amount of about 20% by weight of the composition; polyethylene glycol is present in an amount of about 14% by weight of the composition; and 2-(2-ethoxyethoxy)ethanol is present in an amount of about 47% by weight of the composition.

[0226] In some embodiments, the propylene glycol is super refined propylene glycol.

[0227] In some embodiments, the polyethylene glycol is super refined polyethylene glycol.

[0228] In some embodiments, 2-(2-ethoxyethoxy)ethanol has a purity of at least about 95%, 96%, 97%, 98%, or 99%. In some embodiments, 2-(2-ethoxyethoxy)ethanol is Transcutol HP. In some embodiments, 2-(2-ethoxyethoxy)ethanol is Transcutol HP having a purity of at least about 98% or 99% (e.g., about >99.90%).

[0229] In some embodiments, the organic solvent and / or penetration enhancer comprises C 2-6 In some embodiments, the composition comprises C 2-6 In some embodiments, C 2-6 The alcohol is selected from ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, tert-butanol and glycerol, and combinations of two or more thereof. 2-6 The alcohol is glycerol. In some embodiments, the composition comprises C in an amount of about 5% to about 30%, about 5% to about 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 about 5% to about 20% by weight. 2-6 The alcohol is present in the composition in an amount of about 15% by weight.

[0230] In some embodiments, the composition comprises glycerol in an amount of about 12-24%, 14-20%, 13-17%, 14-16%, or 14-15% by weight. In some embodiments, glycerol is present in an amount of about 10% to about 20% by weight. In some embodiments, glycerol is present in an amount of about 14-15% by weight.

[0231] In some embodiments, the composition comprises ethanol in an amount of about 3-12%, 4-6%, or 9-11% by weight in the composition. In some embodiments, ethanol is present in an amount of about 5% by weight. In some embodiments, ethanol is present in an amount of about 10% by weight.

[0232] In some embodiments, the composition does not contain C 2-6 In some embodiments, the composition does not include ethanol. In some embodiments, the composition does not include glycerol.

[0233] B. Antioxidants

[0234] In some embodiments, the composition comprises an antioxidant. In some embodiments, the composition does not comprise an antioxidant. In some embodiments, the composition as described herein comprises two or more antioxidants. For example, in some embodiments, the composition comprises a first antioxidant and a second antioxidant. In some embodiments, the composition as described herein comprises 2, 3, 4 or 5 antioxidants.

[0235] Non-limiting examples of antioxidants include butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, ascorbic acid, alpha-tocopheryl acetate, and ascorbyl palmitate. In some embodiments, the antioxidant includes butylated hydroxytoluene. In some embodiments, the antioxidant includes butylated hydroxyanisole. In some embodiments, the antioxidant includes propyl gallate. In some embodiments, the antioxidant includes a mixture of butylated hydroxytoluene and butylated hydroxyanisole.

[0236] In some embodiments, the total amount of antioxidant is present in the composition in an amount of about 0.01% to about 1% by weight of the composition. In some embodiments, the total amount of antioxidant is present in an amount of about 0.01% to about 1%, about 0.01% to about 0.5%, or about 0.2% by weight. In some embodiments, any antioxidant is present in the composition in an amount of about 0.01% to about 1% by weight. In some embodiments, any antioxidant is present in the composition in an amount of about 0.1% to about 1% by weight. In some embodiments, any antioxidant is present in the composition in an amount of about 0.1% by weight. In some embodiments, the antioxidant is butylated hydroxytoluene in an amount of about 0.01% to about 1% or about 0.1% by weight of the composition. In some embodiments, the antioxidant includes butylated hydroxytoluene in an amount of about 0.01% to about 1% by weight of the composition. In some embodiments, the antioxidant comprises butylated hydroxytoluene in an amount of about 0.1% by weight of the composition. In some embodiments, the antioxidant comprises butylated hydroxyanisole in an amount of about 0.01% to about 1% or about 0.1% by weight of the composition. In some embodiments, the antioxidant comprises butylated hydroxyanisole in an amount of about 0.1% by weight of the composition. In some embodiments, the antioxidant comprises propyl gallate in an amount of about 0.01% to about 0.5% or about 0.1% by weight of the composition. In some embodiments, the antioxidant comprises propyl gallate in an amount of about 0.01% to about 0.5% by weight of the composition. In some embodiments, the antioxidant comprises propyl gallate in an amount of about 0.1% by weight of the composition. In some embodiments, the antioxidant comprises a mixture of butylated hydroxytoluene and butylated hydroxyanisole, each of which is present in an amount of about 0.01% to about 1% or about 0.1% by weight of the composition. In some embodiments, the antioxidant comprises a mixture of butylated hydroxytoluene and butylated hydroxyanisole, each of which is present in an amount of about 0.01% to about 1% by weight of the composition. In some embodiments, the antioxidant comprises a mixture of butylated hydroxytoluene and butylated hydroxyanisole, each of which is present in an amount of about 0.1% by weight of the composition.

[0237] C. Alcohol and wetting agent

[0238] In some embodiments, the composition comprises an additional agent (such as an alcohol or a wetting agent). Suitable agents include, but are not limited to, C 2-6 Alcohol, C 2-6 Alkylene glycol (e.g., propylene glycol), di-(C 2-6 Alkylene) glycol (e.g., dipropylene glycol), C1-3 Alkyl-(OCH2CH2) 1-5 -OH (e.g., 2-(2-ethoxyethoxy)ethanol or Transcutol P), polyethylene glycol (e.g., PEG200 and / or PEG400), glycerol, fatty alcohol (e.g., octyldodecanol), fatty esters (e.g., diisopropyl adipate, isopropyl myristate, medium chain triglycerides, sorbitan monooleate, etc.), fatty ethers (e.g., Laureth-4), and combinations thereof. In some embodiments, the agent comprises C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, polyethylene glycol, C 2-6 Alcohols, glycerol, fatty alcohols, fatty esters, fatty ethers and combinations thereof.

[0239] In some embodiments, the reagent comprises C 2-6 Alcohol, C 2-6 Alkylene glycol or C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, or a combination thereof. In some embodiments, the reagent comprises C 2-6 In some embodiments, the reagent includes C 2-6 In some embodiments, the reagent includes C 1-3 Alkyl-(OCH2CH2) 1-5 -OH. In some embodiments, the reagent includes C 2-6 Alcohol and C 1-3 Alkyl-(OCH2CH2) 1-5 -OH. In some embodiments, the reagent includes C 2-6 Alcohol and C 2-6 In some embodiments, the composition comprises C 2-6 Alcohol, C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 A mixture of -OH.

[0240] In some embodiments, the additional agent is C 2-6 In some embodiments, C 2-6 The alcohol is selected from ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, tert-butanol, glycerol, and combinations thereof. 2-6 The alcohol is glycerol.

[0241] In some embodiments, the composition does not contain C 2-6 In some embodiments, the composition does not include ethanol. In some embodiments, the composition does not include glycerol.

[0242] In some embodiments, the composition comprises one or more agents, alcohols, or wetting agents. In some embodiments, the agent is an amount of about 5% to 20%, or about 15%, by weight of the composition. 2-6 In some embodiments, C 2-6 The alcohol is present in the composition in an amount of 5% to 20% by weight of the composition. 2-6 The alcohol is present in an amount of about 15% by weight of the composition.

[0243] In some embodiments, the composition comprises glycerol in an amount of about 12-24%, 14-20%, 13-17%, 14-16%, or 14-15% by weight. In some embodiments, glycerol is present in an amount of about 10% to about 20% by weight. In some embodiments, glycerol is present in an amount of about 14-15% by weight.

[0244] In some embodiments, the composition comprises ethanol in an amount of about 3-12%, 4-6%, or 9-11% by weight in the composition. In some embodiments, ethanol is present in an amount of about 5% by weight. In some embodiments, ethanol is present in an amount of about 10% by weight.

[0245] In some embodiments, the composition does not contain C 2-6 In some embodiments, the composition does not include ethanol. In some embodiments, the composition does not include glycerol.

[0246] D. Gelling agent

[0247] In some embodiments, the composition comprises a gelling agent. In some cases, the gelling agent is a polymer thickener). In some embodiments, the gelling agent increases the viscosity of the composition. In some embodiments, the composition herein comprises two or more gelling agents. For example, in some embodiments, the composition comprises a first gelling agent and a second gelling agent. In some embodiments, the composition herein comprises 2, 3, 4, or 5 gelling agents.

[0248] Gelling agent includes hydrophilic and water alcohol gelling agent such as commonly used in cosmetics and pharmaceutical industry.Other non-limiting examples include Carbopol (also referred to as Carbomer), carboxymethylcellulose, ethylcellulose, gelatin, hydroxyethylcellulose, hydroxypropylcellulose, magnesium aluminum silicate (Veegum), methylcellulose, poloxamer (Pluronics), polyvinyl alcohol, sodium alginate, tragacanth, xanthan gum, Sepineo P600, mean molecular weight is at least about 2500Da polyethylene glycol, and two or more combinations thereof.In some embodiments, gelling agent includes Sepineo P600.In some embodiments, gelling agent is Sepineo P600.In some embodiments, gelling agent includes mean molecular weight is about 2500 to 3500Da polyethylene glycol (for example, PEG3350).In some embodiments, gelling agent is mean molecular weight is about 2500 to 3500Da polyethylene glycol (for example, PEG3350). In some embodiments, the gelling agent comprises hydroxypropyl cellulose. In some embodiments, the gelling agent is hydroxypropyl cellulose.

[0249] In some embodiments, the gelling agent includes hydroxypropyl cellulose. In some embodiments, the composition comprises hydroxypropyl cellulose. In some cases, 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 140,000Da, about 180,000Da, about 280,000Da, about 370,000Da, about 700,000Da, about 850,000Da, about 1,000,000Da, or about 1,150,000Da. In some embodiments, the hydroxypropyl cellulose has an average molecular weight of about 700,000Da, about 850,000Da, about 1,000,000Da, or about 1,150,000Da. In some embodiments, the hydroxypropyl cellulose has an average molecular weight of about 700,000Da to about 1,150,000Da.

[0250] Hydroxypropyl cellulose (HPC) includes, 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, and Klucel HF.

[0251] 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 powders (e.g., 40 mesh), fine powders (e.g., 100 mesh), and ultrafine powders (e.g., 300 mesh). See Nisso HPC's Technical date sheet, which is incorporated herein by reference in its entirety.

[0252] 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.

[0253] 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 for Klucel HPC in the composition include regular grades and fine grades. See the Technical date sheet for Klucel HPC products, the entire contents of which are incorporated herein by reference.

[0254] 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.

[0255] When a gelling agent is present in the composition, in some embodiments, the composition has a viscosity of about 5,000 cP to about 100,000 cP. When a gelling agent is present, in some embodiments, the composition has a viscosity of about 5,000 cP to about 50,000 cP. When a gelling agent is present, in some embodiments, the composition has a viscosity of about 5,000 cP to about 40,000 cP. When a gelling agent is present, in some embodiments, the composition has a viscosity of about 5,000 cP to about 30,000 cP. When a gelling agent is present, in some embodiments, the composition has a viscosity of about 10,000 cP to about 30,000 cP. When a gelling agent is present, in some embodiments, the composition has a viscosity of about 15,000 cP to about 30,000 cP. When a gelling agent is present, in some embodiments, the composition has a viscosity of about 20,000 cP to about 30,000 cP.

[0256] When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of about 5,000cP to about 100,000cP. When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of about 5,000cP to about 50,000cP. When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of about 5,000cP to about 40,000cP. When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of about 5,000cP to about 30,000cP. When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of about 10,000cP to about 30,000cP. When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of about 15,000cP to about 30,000cP. When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of about 20,000cP to about 30,000cP.

[0257] In some embodiments, the gelling agent is present in the composition in an amount of about 0.5% to about 30% by weight, and the composition has a viscosity of about 5,000 cP to about 100,000 cP. In some embodiments, the gelling agent is present in an amount of about 0.5% to about 30% by weight, and the composition has a viscosity of about 5,000 cP to about 50,000 cP. In some embodiments, the gelling agent is present in an amount of about 0.5% to about 30% by weight, and the composition has a viscosity of about 5,000 cP to about 40,000 cP. In some embodiments, the gelling agent is present in an amount of about 0.5% to about 30% by weight, and the composition has a viscosity of about 5,000 cP to about 30,000 cP. In some embodiments, the gelling agent is present in an amount of about 0.5% to about 30% by weight, and the composition has a viscosity of about 10,000 cP to about 30,000 cP. In some embodiments, the gelling agent is present in an amount of about 0.5% to about 30% by weight, and the composition has a viscosity of about 15,000 cP to about 30,000 cP. In some embodiments, the gelling agent is present in an amount of about 0.5% to 30% by weight, and the composition has a viscosity of about 20,000 cP to about 30,000 cP.

[0258] In some embodiments, the gelling agent includes hydroxypropyl cellulose (HPC). In some embodiments, the composition includes hydroxypropyl cellulose. In some embodiments, hydroxypropyl cellulose is present in an amount of about 0.5% to about 5% to about 30% by weight, and the composition has a viscosity of about 5,000cP to about 100,000cP. When using hydroxypropyl cellulose with an average molecular weight less than about 700,000Da, in some embodiments, hydroxypropyl cellulose is present in an amount of about 5% to about 30% by weight, and the composition has a viscosity of about 5,000cP to about 100,000cP. In some embodiments, hydroxypropyl cellulose is present in an amount of about 0.5% to about 5%, and the composition has a viscosity of about 5,000cP to about 50,000cP. In some embodiments, hydroxypropyl cellulose is present in an amount of about 0.5% to about 5%, and the composition has a viscosity of about 5,000cP to about 40,000cP. In some embodiments, hydroxypropyl cellulose is present in an amount of about 0.5% to about 5%, and the composition has a viscosity of about 5,000 cP to about 30,000 cP. In some embodiments, hydroxypropyl cellulose is present in an amount of about 0.5% to about 4%, and the composition has a viscosity of about 10,000 cP to about 30,000 cP. In some embodiments, hydroxypropyl cellulose is present in an amount of about 0.5% to about 4%, and the composition has a viscosity of about 15,000 cP to about 30,000 cP. In some embodiments, hydroxypropyl cellulose is present in an amount of about 0.5% to about 4%, and the composition has a viscosity of about 20,000 cP to about 30,000 cP.

[0259] In some embodiments, hydroxypropyl cellulose having an average molecular weight of about 700,000Da to about 1,150,000Da is present in the composition in an amount of about 0.5% to about 2% by weight. In some embodiments, hydroxypropyl cellulose having an average molecular weight of about 700,000Da to about 1,150,000Da is present in the composition in an amount of about 0.5% to about 2% by weight, and the composition has a viscosity of about 5,000cP to about 50,000cP. In some embodiments, hydroxypropyl cellulose having an average molecular weight of about 700,000Da to about 1,150,000Da is present in the composition in an amount of about 0.5% to about 2% by weight, and the composition has a viscosity of about 5,000cP to about 40,000cP. In some embodiments, hydroxypropyl cellulose having an average molecular weight of about 700,000Da to about 1,150,000Da is present in the composition in an amount of about 0.5% to about 2% by weight, and the composition has a viscosity of about 5,000cP to about 30,000cP. In some embodiments, hydroxypropyl cellulose having an average molecular weight of about 700,000Da to about 1,150,000Da is present in the composition in an amount of about 0.5% to about 2% by weight, and the composition has a viscosity of about 10,000cP to about 30,000cP. In some embodiments, hydroxypropyl cellulose having an average molecular weight of about 700,000Da to about 1,150,000Da is present in the composition in an amount of about 0.5% to about 2% by weight, and the composition has a viscosity of about 15,000cP to about 30,000cP. In some embodiments, hydroxypropyl cellulose having an average molecular weight of about 700,000 Da to about 1,150,000 Da is present in the composition in an amount of about 0.5% to about 2% by weight, and the composition has a viscosity of about 20,000 cP to about 30,000 cP.

[0260] In some embodiments, hydroxypropyl cellulose having an average molecular weight of about 700,000 Da to about 1,150,000 Da is present in the composition in an amount of about 3% by weight.

[0261] III-2. Apparent pH

[0262] When the composition is a non-aqueous formulation, the pH of the composition is the apparent pH. When the composition comprises water, the composition comprises a large amount of other excipients (e.g., C 2-6alcohol, organic solvents and / or penetration enhancers, gelling agents). Therefore, the pH value of some aqueous solutions can only be regarded as the apparent pH value. <791> Chapter 1, variability in the apparent pH of nonaqueous or partially aqueous solutions is expected, up to about 1 pH unit. <791> The entire contents of this chapter are incorporated into this article.

[0263] In some embodiments, when the pH adjusting agent 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 the pH adjusting agent 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 the pH adjusting agent 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 the pH adjusting agent is not present in the composition, the composition has an apparent pH value of about 8. In some embodiments, when the pH adjusting agent is not present in the composition, the composition has an apparent pH value of about 9.

[0264] In some embodiments, when a pH adjuster is present in the composition, the composition has an apparent pH of no greater than about 7. In some embodiments, when a pH adjuster is present in the composition, the composition has an apparent pH of about 5 to about 7 or about 6 to about 7. In some embodiments, when a pH adjuster is present in the composition, the composition has an apparent pH of about 6 to about 7.

[0265] III-3. Compounds

[0266] In any of the compositions described herein, the compound is a PK inhibitor, such as, but not limited to, rubostat free base or a rubostat salt (e.g., rubostat mesylate monohydrate), in some cases represented by any of the following formulas:

[0267]

[0268] In any of the compositions described herein, the compound may be an acceptable salt of rubustard free base, rubustard mesylate monohydrate, or a mixture thereof. Illustrative examples of pharmaceutically acceptable salts are inorganic acid (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts, quaternary ammonium (methyl iodide, ethyl iodide, etc.) salts.

[0269] In any of the compositions described herein, the PK inhibitor (such as, but not limited to, rubostat free base or rubostat salt (eg, rubostat mesylate monohydrate)) may be in the form of a solvate or a hydrate or a mixture thereof.

[0270] In any of the compositions described herein, Rubostar may be a free base (FB) or a salt such as Rubostar mesylate monohydrate (MM), or a mixture thereof.

[0271] In some embodiments, the PK inhibitor (such as, but not limited to, rubostar free base or rubostar salt (e.g., rubostar mesylate monohydrate)) is present in the composition in an amount of about 0.08% to 10.0%, 0.5% to 5.0%, 0.5% to 2.0%, or about 1.0% by weight. In some embodiments, the PK inhibitor (such as, but not limited to, rubostar free base or rubostar salt (e.g., rubostar mesylate monohydrate)) is present in an amount of about 0.5% to 5.0%, 0.5% to 2.0%, or about 1.0% by weight. In some embodiments, the PK inhibitor (such as, but not limited to, rubostar free base or rubostar salt (e.g., rubostar mesylate monohydrate)) is present in an amount of about 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1.0% of the composition. In some embodiments, the PK inhibitor (such as, but not limited to, rubostar free base or rubostar salt (e.g., rubostar mesylate monohydrate)) is present in an amount of about 0.5% to 2.0%, or about 0.8% by weight. In some embodiments, the compound is present in an amount of about 0.8% by weight. The composition can be formulated with 0.1% w / w, 0.12% w / w, or 0.8% w / w of rubostar mesylate monohydrate, 0.08% w / w, 0.1% w / w, or 0.64% w / w of rubostar free base or other salts thereof. In some cases, the composition is administered once or twice a day. In some cases, the composition is administered for about 12 weeks to about 6 months. In some cases, the composition is administered for about 4 weeks to about 8 weeks. In some cases, the composition is administered for about 8 weeks to about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.64% of Rubostar free base or its salt and is applied twice a day for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.64% of Rubostar free base or its salt and is applied twice a day for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.8% of Rubostar mesylate monohydrate or its salt and is applied twice a day for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.8% of Rubostar mesylate monohydrate or its salt and is applied twice a day for about 4 to about 8 weeks.

[0272] III-4. Implementation Plan

[0273] In some embodiments, the composition comprises a PK inhibitor (such as, but not limited to, rubostat free base or a rubostat salt (e.g., rubostat mesylate monohydrate)), and one or more excipients selected from the group consisting of: a) an organic solvent and / or a penetration enhancer (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH); b) an antioxidant; c) an alcohol; and d) a gelling agent. In some embodiments, the composition comprises a PK inhibitor (such as, but not limited to, rubustard free base or rubustard salt (e.g., rubustard mesylate monohydrate)), and two or more excipients selected from the following: a) an organic solvent and / or a penetration enhancer (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH and / or PEG); b) an antioxidant; c) an alcohol; and d) a gelling agent. In some embodiments, the composition comprises a PK inhibitor (such as, but not limited to, rubustard free base or rubustard salt (e.g., rubustard mesylate monohydrate)), and three or more excipients selected from the following: a) an organic solvent and / or a penetration enhancer (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH and / or PEG); b) an antioxidant; c) an alcohol; and d) a gelling agent. In some embodiments, the composition comprises a PK inhibitor (such as, but not limited to, rubustard free base or rubustard salt (e.g., rubustard mesylate monohydrate) or an acceptable salt thereof), and four or more excipients selected from the following: an organic solvent and / or a penetration enhancer (e.g., a) C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH and / or PEG); b) an antioxidant; c) an alcohol; and f) a gelling agent. In some embodiments, the composition comprises a PK inhibitor (such as, but not limited to, rubustard free base or rubustard salt (e.g., rubustard mesylate monohydrate) or an acceptable salt thereof), and five or more excipients selected from the following: a) an organic solvent and / or a penetration enhancer (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5-OH and / or PEG); b) an antioxidant; c) an alcohol; and d) a gelling agent. In some embodiments, the composition comprises a PK inhibitor (such as, but not limited to, rubustard free base or rubustard salt (e.g., rubustard mesylate monohydrate) or an acceptable salt thereof), and a) an organic solvent and / or a penetration enhancer (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH and / or PEG); b) antioxidant; c) alcohol; and d) gelling agent. In some cases, the organic solvent and / or penetration enhancer includes C 2-6 In some cases, the organic solvent and / or penetration enhancer comprises C 1-3 Alkyl-(OCH2CH2) 1-5 -OH. In some cases, the organic solvent and / or penetration enhancer comprises PEG. In some cases, the organic solvent and / or penetration enhancer comprises C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5-OH and PEG. In some cases, the antioxidant includes BHT. In some cases, the antioxidant includes BHA. In some cases, the antioxidant includes BHT and / or BHA. In some cases, the alcohol includes glycerol. In some cases, the gelling agent includes HPC. In some cases, the gelling agent includes PEG. In some cases, the gelling agent includes HPC and PEG. The composition can be formulated with 0.1% w / w or 0.12% w / w or 0.8% w / w of Rubusta mesylate monohydrate, 0.08% w / w or 0.1% w / w or 0.64% w / w of Rubusta free base or their other salts. In some cases, the composition is applied once or twice a day. In some cases, the composition is applied for about 12 weeks to about 6 months. In some cases, the composition is applied for about 4 weeks to about 8 weeks. In some cases, the composition is applied for about 8 weeks to about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.64% of Rubostar free base or its salt, applied twice a day, for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.64% of Rubostar free base or its salt, applied twice a day, for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.64% of Rubostar free base or its salt, applied twice a day, for about 8 to about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.64% of Rubostar free base or its salt, applied twice a day, for about 12 weeks to about 6 months. In a non-limiting embodiment, the composition is formulated with 0.1% or 0.08% of Rubostar free base or its salt, applied twice a day, for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.1% or 0.08% of Rubostar free base or its salt, applied twice a day, for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.1% or 0.08% of Rubostar free base or its salt, applied twice a day, for about 8 to about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.1% or 0.08% of Rubostar free base or its salt, applied twice a day, for about 12 weeks to about 6 months. In a non-limiting embodiment, the composition is formulated with 0.8% of Rubostar mesylate monohydrate, applied twice a day, for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.8% of Rubostar free base or its salt, applied twice a day, for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.8% of Rubostar free base or its salt, applied twice a day, for about 8 to about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.8% of Rubostar free base or its salt, applied twice a day, for about 12 weeks to about 6 months. In a non-limiting embodiment, the composition is formulated at 0.1% or 0.12% of Rubustadine mesylate monohydrate and is administered twice daily for about 12 weeks.In a non-limiting embodiment, the composition is formulated with 0.1% or 0.12% of Rubostar free base or a salt thereof and is administered twice daily for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.1% or 0.12% of Rubostar free base or a salt thereof and is administered twice daily for about 8 to about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.1% or 0.12% of Rubostar free base or a salt thereof and is administered twice daily for about 12 weeks to about 6 months.

[0274] In some embodiments, the composition comprises a PK inhibitor (such as, but not limited to, rubostat free base or a rubostat salt (e.g., rubostat mesylate monohydrate)), and an organic solvent and / or a penetration enhancer (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH and / or PEG). In some embodiments, the composition comprises a PK inhibitor (such as, but not limited to, rubostat free base or rubostat salt (e.g., rubostat mesylate monohydrate)), and a) an organic solvent and / or a penetration enhancer (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH and / or PEG); and b) an antioxidant. In some embodiments, the composition comprises a PK inhibitor (such as, but not limited to, rubustard free base or rubustard salt (e.g., rubustard mesylate monohydrate) or an acceptable salt thereof), and a) an organic solvent and / or a penetration enhancer (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH and / or PEG); b) an antioxidant; and c) a gelling agent. In some embodiments, the composition comprises a PK inhibitor (such as, but not limited to, rubustard free base or rubustard salt (e.g., rubustard mesylate monohydrate)), and a) an organic solvent and / or a penetration enhancer (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH and / or PEG); b) an antioxidant; c) an alcohol; and d) a gelling agent. In some embodiments, the composition comprises a PK inhibitor rubustard (such as, but not limited to, rubustard free base or a rubustard salt (e.g., rubustard mesylate monohydrate)), and a) an organic solvent and / or a penetration enhancer (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5-OH and / or PEG); b) an alcohol; and c) a gelling agent. In some embodiments, the composition comprises a PK inhibitor (such as, but not limited to, rubustard free base or rubustard salt (e.g., rubustard mesylate monohydrate)), and a) an organic solvent and / or a penetration enhancer (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH and / or PEG); and b) an alcohol. In some embodiments, the composition comprises a PK inhibitor (such as, but not limited to, rubustard free base or rubustard salt (e.g., rubustard mesylate monohydrate)), and a) an organic solvent and / or a penetration enhancer (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH and / or PEG); and b) a gelling agent. In some embodiments, the composition comprises a PK inhibitor (such as, but not limited to, rubostar free base or rubostar salt (e.g., rubostar mesylate monohydrate)), and a) an antioxidant; b) an alcohol; and c) a gelling agent. In some embodiments, the composition comprises a PK inhibitor (such as, but not limited to, rubostar free base or rubostar salt (e.g., rubostar mesylate monohydrate)), and a) an antioxidant; and b) an alcohol. In some embodiments, the composition comprises a PK inhibitor (such as, but not limited to, rubostar free base or rubostar salt (e.g., rubostar mesylate monohydrate)), and a) an antioxidant; and b) a gelling agent. In some embodiments, the composition comprises a PK inhibitor (such as, but not limited to, rubostar free base or rubostar salt (e.g., rubostar mesylate monohydrate)), and a) an alcohol; and b) a gelling agent. In some embodiments, the composition comprises a PK inhibitor (such as, but not limited to, rubostar free base or a rubostar salt (e.g., rubostar mesylate monohydrate)), and an alcohol. In some embodiments, the composition comprises an antioxidant. In some embodiments, the composition comprises a PK inhibitor (such as, but not limited to, rubostar free base or a rubostar salt (e.g., rubostar mesylate monohydrate)), and a gelling agent. In some cases, the organic solvent and / or penetration enhancer comprises C 2-6 In some cases, the organic solvent and / or penetration enhancer comprises C 1-3 Alkyl-(OCH2CH2) 1-5 -OH. In some cases, the organic solvent and / or penetration enhancer comprises PEG. In some cases, the organic solvent and / or penetration enhancer comprises C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5-OH and PEG. In some cases, the antioxidant includes BHT. In some cases, the antioxidant includes BHA. In some cases, the antioxidant includes BHT and / or BHA. In some cases, the alcohol includes glycerol. In some cases, the gelling agent includes HPC. In some cases, the gelling agent includes PEG. In some cases, the gelling agent includes HPC and PEG. The composition can be formulated with 0.1% w / w to 0.8% w / w of Rubusta mesylate monohydrate, 0.08% w / w to 0.64% w / w of Rubusta free alkali or their other salts. In some cases, the composition is applied once or twice a day. In some cases, the composition is applied for about 12 weeks to about 6 months. In some cases, the composition is applied for about 4 weeks to about 8 weeks. In some cases, the composition is applied for about 8 weeks to about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.64% of Rubusta free alkali or its salt, applied twice a day, for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.64% of Rubosta free base or its salt, applied twice a day, for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.08% to 0.1% of Rubosta free base or its salt, applied twice a day, for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.08% to 0.1% of Rubosta free base or its salt, applied twice a day, for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.8% of Rubosta mesylate monohydrate or its salt, applied twice a day, for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.8% of Rubosta mesylate monohydrate or its salt, applied twice a day, for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.1% or 0.12% of Rubosta mesylate monohydrate or its salt, applied twice a day, for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.1% or 0.12% of Rubustadine mesylate monohydrate or a salt thereof and is administered twice daily for about 4 to about 8 weeks.

[0275] In some embodiments, the present disclosure provides a composition (A) comprising a PK inhibitor (such as, but not limited to, rubostat free base or rubostat salt (e.g., rubostat mesylate monohydrate)), and one or more of the following excipients:

[0276] a) Organic solvents and / or penetration enhancers (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH and / or PEG);

[0277] b) antioxidants;

[0278] c) alcohol; and

[0279] d) Gelling agent.

[0280] In some cases, the compound, organic solvent and / or penetration enhancer, antioxidant, alcohol and / or gelling agent are as described herein. In some cases, the organic solvent and / or penetration enhancer comprises C 2-6 In some cases, the organic solvent and / or penetration enhancer comprises C 1-3 Alkyl-(OCH2CH2) 1-5 -OH. In some cases, the organic solvent and / or penetration enhancer comprises PEG. In some cases, the organic solvent and / or penetration enhancer comprises C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5-OH and PEG. In some cases, the antioxidant includes BHT. In some cases, the antioxidant includes BHA. In some cases, the antioxidant includes BHT and / or BHA. In some cases, the alcohol includes glycerol. In some cases, the gelling agent includes HPC. In some cases, the gelling agent includes PEG. In some cases, the gelling agent includes HPC and PEG. The composition can be formulated with 0.1% w / w to 0.8% w / w of Rubusta mesylate monohydrate, 0.08% w / w to 0.64% w / w of Rubusta free base or other salts thereof. In some cases, the composition is applied once or twice a day. In some cases, the composition is applied for about 12 weeks to about 6 months. In some cases, the composition is applied for about 4 weeks to about 8 weeks. In some cases, the composition is applied for about 8 weeks to about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.08% w / w or 0.1% w / w or 0.64% of a PK inhibitor, such as, but not limited to, rubostar free base or rubostar salt (e.g., rubostar mesylate monohydrate), and is administered twice a day for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.08% w / w or 0.1% w / w or 0.64% of a PK inhibitor, such as, but not limited to, rubostar free base or rubostar salt (e.g., rubostar mesylate monohydrate), and is administered twice a day for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.1% w / w or 0.12% w / w or 0.8% w / w of a PK inhibitor, such as, but not limited to, rubostar free base or rubostar salt (e.g., rubostar mesylate monohydrate), and is administered twice a day for about 12 weeks. In non-limiting embodiments, the composition is formulated with 0.1% w / w or 0.12% w / w or 0.8% w / w of a PK inhibitor, such as, but not limited to, rubostat free base or a rubostat salt (e.g., rubostat mesylate monohydrate), and is administered twice daily for about 4 to about 8 weeks.

[0281] In some embodiments of composition (A), antioxidants are not present in the composition.

[0282] In some embodiments of composition (A), one or more of the antioxidants are present in the composition. In some embodiments of composition (A), the antioxidant is present in the composition. In some cases, the antioxidant comprises BHT. In some cases, the antioxidant comprises BHA. In some cases, the antioxidant consists of BHT and / or BHA.

[0283] In some embodiments, the present disclosure provides a composition (B) comprising a PK inhibitor (such as, but not limited to, rubostat free base or rubostat salt (e.g., rubostat mesylate monohydrate)), and excipients a), b), c) and d):

[0284] a) Organic solvents and / or penetration enhancers (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH and / or PEG);

[0285] b) antioxidants;

[0286] c) alcohol; and

[0287] d) Gelling agent.

[0288] In some cases, the compound, organic solvent and / or penetration enhancer, antioxidant, solvent and / or gelling agent are as described herein. In some cases, the organic solvent and / or penetration enhancer comprises C 2-6 In some cases, the organic solvent and / or penetration enhancer comprises C 1-3 Alkyl-(OCH2CH2) 1-5 -OH. In some cases, the organic solvent and / or penetration enhancer comprises PEG. In some cases, the organic solvent and / or penetration enhancer comprises C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5-OH and PEG. In some cases, the antioxidant includes BHT. In some cases, the antioxidant includes BHA. In some cases, the antioxidant includes BHT and / or BHA. In some cases, the alcohol includes glycerol. In some cases, the gelling agent includes HPC. In some cases, the gelling agent includes PEG. In some cases, the gelling agent includes HPC and PEG. The composition can be formulated with 0.1% w / w to 0.8% w / w of Rubusta mesylate monohydrate, 0.08% w / w to 0.64% w / w of Rubusta free alkali or their other salts. In some cases, the composition is applied once or twice a day. In some cases, the composition is applied for about 12 weeks to about 6 months. In some cases, the composition is applied for about 4 weeks to about 8 weeks. In some cases, the composition is applied for about 8 weeks to about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.64% of Rubusta free alkali or its salt, applied twice a day, for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.64% of Rubosta free base or its salt, applied twice a day, for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.08% to 0.1% of Rubosta free base or its salt, applied twice a day, for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.08% to 0.1% of Rubosta free base or its salt, applied twice a day, for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.8% of Rubosta mesylate monohydrate or its salt, applied twice a day, for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.8% of Rubosta mesylate monohydrate or its salt, applied twice a day, for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.1% or 0.12% of Rubosta mesylate monohydrate or its salt, applied twice a day, for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.1% or 0.12% of Rubustadine mesylate monohydrate or a salt thereof and is administered twice daily for about 4 to about 8 weeks.

[0289] In some embodiments, the present disclosure provides a composition (C) comprising a PK inhibitor (such as, but not limited to, rubostat free base or rubostat salt (e.g., rubostat mesylate monohydrate)), and excipients a), b), and d):

[0290] a) Organic solvents and / or penetration enhancers (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH and / or PEG);

[0291] b) antioxidants; and

[0292] d) Gelling agent.

[0293] In some cases, the compound, organic solvent and / or penetration enhancer, antioxidant and / or gelling agent are as described herein. The composition can be formulated with 0.1% w / w to 0.8% w / w of Rubosta mesylate monohydrate, 0.08% w / w to 0.64% w / w of Rubosta free alkali or their other salts. In some cases, the composition is applied once or twice a day. In some cases, the composition is applied for about 12 weeks to about 6 months. In some cases, the composition is applied for about 4 weeks to about 8 weeks. In some cases, the composition is applied for about 8 weeks to about 12 weeks. In non-limiting embodiments, the composition is formulated with 0.64% of a PK inhibitor, such as, but not limited to, Rubosta free alkali or Rubosta salt (e.g., Rubosta mesylate monohydrate), applied twice a day for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.64% of a PK inhibitor, such as, but not limited to, rubostar free base or rubostar salt (e.g., rubostar mesylate monohydrate), and is administered twice a day for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.08% to 0.1% of rubostar free base or its salt, and is administered twice a day for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.08% to 0.1% of rubostar free base or its salt, and is administered twice a day for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.8% of rubostar mesylate monohydrate or its salt, and is administered twice a day for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.8% of rubostar mesylate monohydrate or its salt, and is administered twice a day for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.1% or 0.12% of Rubostar mesylate monohydrate or a salt thereof and is administered twice daily for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.1% or 0.12% of Rubostar mesylate monohydrate or a salt thereof and is administered twice daily for about 4 to about 8 weeks.

[0294] In some embodiments, the present disclosure provides a composition (D) comprising a PK inhibitor (such as, but not limited to, rubostat free base or rubostat salt (e.g., rubostat mesylate monohydrate)), and excipients a), b), and c):

[0295] a) Organic solvents and / or penetration enhancers (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH and / or PEG);

[0296] b) antioxidants; and

[0297] c) Alcohol.

[0298] In some cases, the compound, organic solvent and / or penetration enhancer, antioxidant and / or alcohol are as described herein. The composition can be formulated with 0.1% w / w to 0.8% w / w of Rubosta mesylate monohydrate, 0.08% w / w to 0.64% w / w of Rubosta free alkali or their other salts. In some cases, the composition is applied once or twice a day. In some cases, the composition is applied for about 12 weeks to about 6 months. In some cases, the composition is applied for about 4 weeks to about 8 weeks. In some cases, the composition is applied for about 8 weeks to about 12 weeks. In non-limiting embodiments, the composition is formulated with 0.64% of a PK inhibitor, such as, but not limited to, Rubosta free alkali or Rubosta salt (e.g., Rubosta mesylate monohydrate), applied twice a day, for about 12 weeks. In non-limiting embodiments, the composition is formulated with 0.64% of Rubosta free alkali or its salt, applied twice a day, for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.08% to 0.1% of Rubosta free base or its salt, applied twice a day for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.08% to 0.1% of Rubosta free base or its salt, applied twice a day for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.8% of Rubosta mesylate monohydrate or its salt, applied twice a day for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.8% of Rubosta mesylate monohydrate or its salt, applied twice a day for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.1% or 0.12% of Rubosta mesylate monohydrate or its salt, applied twice a day for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.1% or 0.12% of Rubosta mesylate monohydrate or its salt, applied twice a day for about 4 to about 8 weeks.

[0299] In some embodiments, the organic solvent and / or penetration enhancer of any of compositions (A), (B), (C) and / or (D) comprises C present in the composition in an amount of about 10% to about 40%, about 10% to about 30%, or about 20% by weight. 2-6 In some embodiments, C 2-6 The alkylene glycol is present in an amount of about 10% to about 30%. In some embodiments, C 2-6 The alkylene glycol is present in an amount of about 15% to about 25%. In some embodiments, C 2-6 The alkylene glycol is present in an amount of about 20% by weight.

[0300] In some embodiments, C of any of compositions (A), (B), (C) and / or (D) 2-6 Alkylene glycol is C 2-6 In some embodiments, C 2-6 The alkylene glycol is present in the composition in a total amount of about 10% to about 60%, about 20% to about 40%, or about 34% by weight. 2-6 The alkylene glycol is present in a total amount of about 20% to about 40%. 2-6 The alkylene glycol is present in an amount of about 25% to about 35%. In some embodiments, C 2-6 The alkylene glycol is present in an amount of about 34% by weight.

[0301] In some embodiments, the organic solvent and / or penetration enhancer of any of compositions (A), (B), (C) and / or (D) comprises C present in an amount of about 30% to about 70%, about 40% to about 60%, or about 47% by weight. 1-3 Alkyl-(OCH2CH2) 1-5 -OH. In some embodiments, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH is present in an amount of about 30% to about 70% by weight. 1-3 Alkyl-(OCH2CH2) 1-5 -OH is present in an amount of about 40% to about 60% by weight. 1-3 Alkyl-(OCH2CH2) 1-5 -OH is present in an amount of about 47% by weight.

[0302] In some embodiments, the alcohol is present in an amount of about 10% to about 30%, about 10% to about 20%, or about 15% by weight of any one of compositions (A), (B), (C) and / or (D). In some embodiments, the alcohol is present in an amount of about 10% to about 30%. In some embodiments, the alcohol is present in an amount of about 10% to about 20%. In some embodiments, the alcohol is present in an amount of about 15% by weight. In some cases, the alcohol comprises glycerol.

[0303] In some embodiments, the gelling agent of any one of compositions (A), (B) and / or (C) is present in an amount of about 1% to about 4% or about 3% by weight, and the composition has a viscosity of about 5,000 cP to about 30,000 cP. In some embodiments, the gelling agent is present in an amount of about 1% to about 4% or about 3% by weight, and the composition has a viscosity of about 10,000 cP to about 30,000 cP. In some embodiments, the gelling agent is present in an amount of about 1% to about 3% or about 2% by weight, and the composition has a viscosity of about 15,000 cP to about 30,000 cP. In some embodiments, the gelling agent is present in an amount of about 1% to about 4% or about 5% by weight, and the composition has a viscosity of about 20,000 cP to about 30,000 cP. In some cases, the gelling agent includes PEG. In some cases, the gelling agent includes HPC and PEG.

[0304] In some embodiments, the organic solvent and / or penetration enhancer of any of compositions (A), (B), (C) and / or (D) comprises C 2-6 Alkylene glycol, and C 2-6 The alkylene glycol is propylene glycol; the organic solvent and / or penetration enhancer comprises C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, and C 1-3 Alkyl-(OCH2CH2) 1-5 -OH is 2-(2-ethoxyethoxy)ethanol; and the gelling agent is hydroxypropylcellulose. In some embodiments of any one of compositions (A), (B), (C) and (D), the organic solvent and / or the penetration enhancer comprises C 2-6 Alkylene glycol, and C 2-6 The alkylene glycol is polyethylene glycol; the organic solvent and / or penetration enhancer comprises C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, and C 1-3 Alkyl-(OCH2CH2) 1-5 -OH is 2-(2-ethoxyethoxy)ethanol; and the gelling agent is hydroxypropylcellulose.

[0305] In some embodiments, composition (A1) comprises a PK inhibitor (such as, but not limited to, rubostat free base or a rubostat salt (e.g., rubostat mesylate monohydrate)), and one or more of the following excipients:

[0306] a) propylene glycol, polyethylene glycol and / or 2-(2-ethoxyethoxy)ethanol;

[0307] b) butylated hydroxytoluene and / or butylated hydroxyanisole;

[0308] c) glycerol and / or alcohol; and

[0309] d) Hydroxypropyl cellulose.

[0310] In some cases, the compounds, propylene glycol, polyethylene glycol and / or 2-(2-ethoxyethoxy)ethanol, butylated hydroxytoluene and / or butylated hydroxyanisole, glycerol and / or an alcohol solvent, and / or hydroxypropyl cellulose are as described herein.

[0311] In some embodiments, composition (B1) comprises a PK inhibitor (such as, but not limited to, rubostat free base or rubostat salt (e.g., rubostat mesylate monohydrate)), and excipients a), b), c), and d):

[0312] a) propylene glycol, polyethylene glycol and / or 2-(2-ethoxyethoxy)ethanol;

[0313] b) butylated hydroxytoluene and / or butylated hydroxyanisole;

[0314] c) glycerol and / or alcohol; and

[0315] d) Hydroxypropyl cellulose.

[0316] In some cases, the compounds, propylene glycol, polyethylene glycol and / or 2-(2-ethoxyethoxy)ethanol, butylated hydroxytoluene and / or butylated hydroxyanisole, glycerol and / or alcohol, and / or hydroxypropylcellulose are as described herein.

[0317] In some embodiments, composition (C1) comprises a PK inhibitor (such as, but not limited to, rubostat free base or a rubostat salt (e.g., rubostat mesylate monohydrate)), and excipients a), b), and c):

[0318] a) propylene glycol, polyethylene glycol and / or 2-(2-ethoxyethoxy)ethanol;

[0319] b) butylated hydroxytoluene and / or butylated hydroxyanisole; and

[0320] c) Hydroxypropyl cellulose.

[0321] In some cases, the compounds, propylene glycol, polyethylene glycol and / or 2-(2-ethoxyethoxy)ethanol, butylated hydroxytoluene and / or butylated hydroxyanisole, and / or hydroxypropylcellulose are as described herein.

[0322] In some embodiments, composition (D1) comprises a PK inhibitor (such as, but not limited to, rubostat free base or rubostat salt (e.g., rubostat mesylate monohydrate)), and excipients a), b), and c):

[0323] a) propylene glycol, polyethylene glycol and / or 2-(2-ethoxyethoxy)ethanol;

[0324] b) butylated hydroxytoluene and / or butylated hydroxyanisole; and

[0325] c) Glycerol and / or alcohol.

[0326] In some cases, the compounds, propylene glycol, polyethylene glycol and / or 2-(2-ethoxyethoxy)ethanol, butylated hydroxytoluene and / or butylated hydroxyanisole, and / or glycerol and / or alcohol are as described herein.

[0327] In some embodiments of any of compositions (A), (B), (C), (D), the antioxidant, if present, is butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, or a combination of two or more thereof. In some embodiments, the antioxidant, when present, is butylated hydroxytoluene and / or butylated hydroxyanisole.

[0328] In some embodiments, the antioxidant of any of compositions (A), (B), (C), (D), (A1), (B1), (C1) and / or (D1), when present, is present in an amount of about 0.01% to about 0.5% or about 0.1% by weight. In some embodiments, the antioxidant, when present, is present in an amount of about 0.01% to about 0.5% by weight. In some embodiments, the antioxidant, when present, is present in an amount of about 0.2% by weight.

[0329] In some embodiments, composition (C1a) comprises a PK inhibitor (such as, but not limited to, rubostat free base or a rubostat salt (e.g., rubostat mesylate monohydrate)), and excipients a), b), c), and d):

[0330] a) propylene glycol and 2-(2-ethoxyethoxy)ethanol;

[0331] b) butylated hydroxytoluene and / or butylated hydroxyanisole;

[0332] c) glycerol and / or polyethylene glycol; and

[0333] d) Hydroxypropyl cellulose.

[0334] In some cases, the compounds, propylene glycol and 2-(2-ethoxyethoxy)ethanol, butylated hydroxytoluene and / or butylated hydroxyanisole, glycerol and / or polyethylene glycol, and / or hydroxypropylcellulose are as described herein.

[0335] In some embodiments, ethanol is present in any of compositions (A1), (B1), (C1) and / or (C1a) in an amount of about 10% to about 30%, about 10% to about 20%, or about 15% by weight. In some embodiments, ethanol is present in an amount of about 10% to about 30% by weight. In some embodiments, ethanol is present in an amount of about 10% to about 20% by weight. In some embodiments, ethanol is present in an amount of about 15% by weight.

[0336] In some embodiments, the polyethylene glycol is present in any of the compositions (A1), (B1), (C1) and / or (C1a) in an amount of about 10% to about 30%, about 10% to about 20%, or about 15% by weight. In some embodiments, the polyethylene glycol is present in an amount of about 10% to about 30% by weight. In some embodiments, the polyethylene glycol is present in an amount of about 10% to about 20% by weight. In some embodiments, the polyethylene glycol is present in an amount of about 14% by weight.

[0337] In some embodiments, glycerol is present in any of compositions (A1), (B1), (C1) and / or (C1a) in an amount of about 10% to about 30%, about 10% to about 20%, or about 15% by weight. In some embodiments, glycerol is present in an amount of about 10% to about 30% by weight. In some embodiments, propylene glycol is present in an amount of about 10% to about 20% by weight. In some embodiments, glycerol is present in an amount of about 15% by weight.

[0338] In some embodiments, 2-(2-ethoxyethoxy)ethanol is present in any of compositions (A1), (B1), (C1) and / or (C1a) in an amount of about 30% to about 50%, about 40% to about 60%, or about 47% by weight. In some embodiments, 2-(2-ethoxyethoxy)ethanol is present in an amount of about 30% to about 50% by weight. In some embodiments, 2-(2-ethoxyethoxy)ethanol is present in an amount of about 40% to about 50% by weight. In some embodiments, 2-(2-ethoxyethoxy)ethanol is present in an amount of about 47% by weight.

[0339] In some embodiments, propylene glycol is present in any of compositions (A1), (B1), (C1) and / or (C1a) in an amount of about 10% to about 30%, or about 20% by weight. In some embodiments, propylene glycol is present in an amount of about 10% to about 30% by weight. In some embodiments, propylene glycol is present in an amount of about 20% by weight.

[0340] In some embodiments, hydroxypropyl cellulose having an average molecular weight of about 700,000Da to about 1,150,000Da is present in any of compositions (A1), (B1), (C1) and / or (C1a) in an amount of about 1% to about 3% or about 2% by weight. In some embodiments, hydroxypropyl cellulose having an average molecular weight of about 700,000Da to about 1,150,000Da is present in an amount of about 1% to about 3% by weight. In some embodiments, hydroxypropyl cellulose having an average molecular weight of about 700,000Da to about 1,150,000Da is present in an amount of about 1% by weight. In some embodiments, hydroxypropyl cellulose having an average molecular weight of about 700,000Da to about 1,150,000Da is present in an amount of about 2% by weight. In some embodiments, hydroxypropyl cellulose is Klucel MF in an amount of about 2% by weight.

[0341] In some embodiments, butylated hydroxytoluene and / or butylated hydroxyanisole are present in the composition (C1a) in an amount of about 0.01% to about 0.5% or about 0.1% by weight. In some embodiments, butylated hydroxytoluene and / or butylated hydroxyanisole are present in an amount of about 0.01% to about 0.2% by weight. In some embodiments, butylated hydroxytoluene is present in an amount of about 0.1% by weight. In some embodiments, butylated hydroxyanisole is present in an amount of about 0.1% by weight.

[0342] In some embodiments, butylated hydroxytoluene is present in composition (C1a) in an amount of about 0.2% by weight. In some embodiments of composition (C1a), butylated hydroxyanisole is present in an amount of about 0.2% by weight.

[0343] In some embodiments of compositions (A), (B), (C), (A1), (B1), (C1), and (C1a), the propylene glycol is super refined propylene glycol.

[0344] In some embodiments of compositions (A), (B), (C), (A1), (B1), (C1), and (C1a), the polyethylene glycol is super refined polyethylene glycol.

[0345] In some embodiments of compositions (A), (B), (C), (A1), (B1), (C1), and (C1a), 2-(2-ethoxyethoxy)ethanol is Transcutol HP having a purity of >99.90%.

[0346] In some embodiments of compositions (A), (B), (C), (A1), (B1), (C1) and (C1a), or any PK inhibitor described herein (e.g., rubostar free base or a salt thereof (e.g., rubostar mesylate monohydrate)), 50-99% by weight of diols, 55%-99% by weight of diols, 60%-99% by weight of diols, 65%-99% by weight of diols, 70%-99% by weight of diols, 75%-99% by weight of diols, 80-99% by weight of diols, 85-99% by weight of diols, 90-99% by weight of diols, or 95-99% by weight of diols. In some embodiments of compositions (A), (B), (C), (A1), (B1), (C1) and (C1a), or any PK inhibitor described herein (e.g., rubostar free base or a salt thereof (e.g., rubostar mesylate monohydrate)), is 80%-95% glycol, 80%-96% glycol or 80%-97% glycol by weight.

[0347] In some embodiments, a PK inhibitor (such as, but not limited to, rubostar free base or a rubostar salt (e.g., rubostar mesylate monohydrate)) is present in one or more of compositions (A), (B), (C), (A1), (B1), (C1) and / or (C1a) in an amount of about 0.5% to about 2% or about 1% by weight. In some embodiments, a PK inhibitor (such as, but not limited to, rubostar free base or a rubostar salt (e.g., rubostar mesylate monohydrate)) is present in an amount of about 0.1% to about 2% by weight. In some embodiments, a PK inhibitor (such as, but not limited to, rubostar free base or a rubostar salt (e.g., rubostar mesylate monohydrate)) is present in an amount of about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1% of the composition. In some embodiments, a PK inhibitor such as, but not limited to, rubostar free base or a rubostar salt (eg, rubostar mesylate monohydrate) is present in an amount of about 0.8% by weight.

[0348] In non-limiting exemplary embodiments herein, the PK inhibitor comprises or is rubostat free base, rubostat mesylate, or rubostat mesylate monohydrate.

[0349] In non-limiting exemplary embodiments herein, the PK inhibitor includes or is rubustard mesylate monohydrate.

[0350] III-5. Form of composition

[0351] Topical compositions that can be used to deliver a compound to an object (e.g., to the skin of an object) include, but are not limited to, foams, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, and suspensions. See, e.g., REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY; (Alfonso R. Gennaro, 19th ed. 1995); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985), which are incorporated herein by reference in their entirety. In some embodiments, the topical composition for delivering a compound is a gel, ointment, lotion, foam, or emollient.

[0352] In some embodiments, the topical composition for delivering the compound is a lotion or cream. Creams and lotions that can be used as topical compositions and their preparation are disclosed in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 282-291 (Alfonso R. Gennaro, 19th edition 1995), the relevant parts of which are hereby incorporated by reference into this article.

[0353] In some embodiments, the surface composition is a gel, for example, a two-phase gel or a single-phase gel. Gel is a semi-solid system composed of a suspension of small inorganic particles or large organic molecules that are penetrated by a liquid. When a gel block comprises a network of small discrete inorganic particles, it is classified as a two-phase gel. A single-phase gel is composed of organic macromolecules, which are uniformly distributed in the liquid so that there is no obvious boundary between the dispersed macromolecules and the liquid. Gels suitable for the present disclosure are disclosed in REMINGTON:THE SCIENCE AND PRACTICE OF PHARMACY 1517-1518 (Alfonso R.Gennaro compiles, the 19th edition 1995), which is hereby incorporated by reference. Other suitable gels for use with the present disclosure are disclosed in U.S. Patent No. 6,387,383 (published on May 14, 2002), 6,517,847 (published on February 11, 2003) and 6,468,989 (published on October 22, 2002).

[0354] In some embodiments, the topical composition is an ointment. An ointment is an oily semisolid with very little, if any, water content. In some cases, an 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, 19th edition 1995).

[0355] In some embodiments, the topical composition can be in the form of a patch, band, film, sheet, wipe, paper, cloth, towel, wet wipes, sponge, foam, mask or bandage comprising a topical composition as described herein. In some embodiments, the patch, band, film, sheet, wipe, paper, cloth, towel, wet wipes, sponge, foam, mask or bandage is in contact with the affected area on the skin. In some embodiments, the patch, band, film, sheet, wipe, paper, cloth, towel, wet wipes, sponge, foam, mask, facial mask, brush, pad, gauze, applicator, cotton ball, roll, swab or bandage is in contact with an area of ​​the subject's skin adjacent to the affected or target area when applied to the subject.

[0356] In some embodiments, topical administration can be in the form of a patch, band, film, sheet, wipe, paper, cloth, towel, wipes, sponge, foam, mask, facial mask, brush, pad, gauze, applicator, cotton ball, roll, swab, or bandage comprising a topical composition as described herein. In some embodiments, the patch, band, film, sheet, wipe, paper, cloth, towel, wipes, sponge, foam, mask, facial mask, brush, pad, gauze, applicator, cotton ball, roll, swab, or bandage is in contact with the affected area on the skin. In some embodiments, the patch, band, film, sheet, wipe, paper, cloth, towel, wipes, sponge, foam, mask, facial mask, brush, pad, gauze, applicator, cotton ball, roll, swab, or bandage is in contact with an area of ​​the subject's skin adjacent to the affected or target area when applied to the subject.

[0357] In some embodiments, the patch, tape, film, sheet, paper, cloth, towel, wipes, sponge, foam, mask, face mask, brush, pad, gauze, applicator, cotton ball, roll, swab, or bandage comprises an adhesive.

[0358] In some embodiments, the topical composition can be applied to the skin or scalp using a tape or film that provides a closed environment. The tape or film can be an adhesive tape, a waterproof tape, or a plastic film (with or without an adhesive layer).

[0359] In some embodiments, the composition is impregnated in a band, paper, cloth, towel, wet wipes, sponge, face mask, foam or film. In some embodiments, the band or film is a band or film containing foam. The holes or interstitial spaces in the foam, paper, cloth, towel, wet wipes, face mask or sponge can be loaded with a composition as described herein. The foam, paper, cloth, towel, wet wipes, face mask or sponge can have an adhesive layer for adhering to skin. If the foam, paper, cloth, towel, wet wipes, face mask or sponge is porous, an external non-porous layer can be provided on the back side of the foam, wipes, paper, cloth, towel, wet wipes, pad, gauze, cotton ball, swab or sponge to enhance the band closure.

[0360] In some embodiments, the composition can be in the form of a sustained release paper, cloth, towel, wipes, sponge, mask, sheet or dot, and can also be made by using a porous foam, can have a certain amount of the composition placed behind the porous foam, and can have a non-porous backing layer placed behind the composition. The non-porous backing layer can have a portion extending beyond the composition containing a PK inhibitor (the PK inhibitor is such as, but not limited to, rubustard free base or rubustard salt (e.g., rubustard mesylate monohydrate)) and a porous layer. The portion can include a certain amount of adhesive to facilitate adhesion of the paper, cloth, towel, wipes, sponge, mask, sheet or dot to the user's skin around the treated area.

[0361] method

[0362] In another aspect, the present disclosure provides a method of treating a skin disease, condition or disorder in a subject in need thereof, the method comprising administering to the subject a composition as described herein.

[0363] In some embodiments, the disease, condition or disorder is a hyperpigmentation disease, condition or disorder.

[0364] In some embodiments, the compositions described herein can be used to treat hyperpigmentation disorders. In some embodiments, hyperpigmentation disorders include, but are not limited to, skin discoloration, melasma, post-inflammatory hyperpigmentation, discoid lupus erythematosus, phytophotodermatitis, lentigo (e.g., age spots), birthmarks, café au lait spots, acanthosis nigricans, burn-related hyperpigmentation, drug-induced hyperpigmentation (e.g., sulfonamides, tetracyclines, NSAIDs, barbiturates, and carbamazepine-induced hyperpigmentation), injury-induced hyperpigmentation, primary biliary cirrhosis-related hyperpigmentation, Addison's disease-related hyperpigmentation, The present invention relates to a kind of hyperpigmentation of the present invention. The present invention relates to a kind of hyperpigmentation of the present invention. The present invention relates to a kind of hyperpigmentation of the present invention. The present invention relates to a kind of hyperpigmentation of the present invention. The present invention relates to a kind of hyperpigmentation of the present invention. The present invention relates to a kind of hyperpigmentation of the present invention. The present invention relates to a kind of hyperpigmentation of the present invention. The present invention relates to a kind of hyperpigmentation of the present invention. The present invention relates to a kind of hyperpigmentation of the present invention. The present invention relates to a kind of hyperpigmentation of the present invention.

[0365] In some embodiments, the disorder or condition is an overgrowth of hair or hair follicles or a condition or disorder of hair or hair follicle pigmentation. In some embodiments, hirsutism / excessive hair or hair pigmentation is a disorder or condition of interest. In some embodiments, the disorder or condition is undesirable overgrowth of hair or hair follicles or undesirable hair pigmentation or hair follicle pigmentation. In some embodiments, the condition or condition is short-term. In some embodiments, the treatment of the condition or condition is short-term. In some embodiments, the effect of the treatment is short-term.

[0366] In some embodiments, the compositions described herein can be used to treat malignant tumors. In some embodiments, the malignant tumor is a malignant melanocytic tumor, a malignant epidermal tumor, a malignant vascular tumor, a malignant metastatic tumor, a malignant fat cell tumor, a malignant sebaceous tumor, or a malignant fibrotic tumor. Malignant tumors include, but are not limited to, melanoma, squamous cell carcinoma, keratoacanthoma, actinic keratosis, basal cell carcinoma, angiosarcoma, Kaposi's sarcoma, cutaneous breast cancer, Merkel cell carcinoma, liposarcoma, sebaceous adenoma, sebaceous gland carcinoma, protuberant dermatofibroma sarcoma, and fibrosarcoma. In some embodiments, the malignant tumor is a melanoma, squamous cell carcinoma, keratoacanthoma, actinic keratosis, basal cell carcinoma, angiosarcoma, Kaposi's sarcoma, cutaneous breast cancer, Merkel cell carcinoma, liposarcoma, sebaceous adenoma, sebaceous gland carcinoma, protuberant dermatofibroma sarcoma, or fibrosarcoma.

[0367] In some embodiments, compositions as described herein can be used to treat benign tumors or skin conditions. In some embodiments, benign tumors are benign vascular tumors, benign fibrotic tumors, benign fat cell tumors, benign sebaceous gland tumors, benign epidermal tumors, benign melanocytic lesions or benign neural tumors. Benign tumors or skin conditions include but are not limited to nodules, benign skin tumors, angiomas (angioma), hemangiomas (hemangioma), pyogenic granulomas, angiofibromas, tuberous sclerosis, angiomyofibroma, angiolipoma, dermatofibroma, fibroma, neurofibroma, scar, scar tissue, keloid, lipoma, soft droop warts, acanthoma nigricans, acanthoma, clear cell acanthoma, acanthosis nigricans, epidermoid cysts, hair cysts, dermoid cysts, melanocytic nevus, epidermal nevus, verrucous epidermal nevus, lentigo-like nevus, café au lait spots, neuromas, Schwannoma (schwannoma) and schwannoma. In some embodiments, the benign tumor is a nodule, a benign skin tumor, angioma, hemangioma, pyogenic granuloma, angiofibroma, tuberous sclerosis, angiomyofibroma, angiolipoma, dermatofibroma, fibroma, neurofibroma, scar, scar tissue, keloid, lipoma, acanthoma nigricans, acanthoma, clear cell acanthoma, acanthosis nigricans, epidermoid cyst, pilaris cyst, dermoid cyst, melanocytic nevus, epidermal nevus, verrucous epidermal nevus, lentigo, café au lait spot, neuroma, schwannoma, or schwannoma.

[0368] In some embodiments, the compositions described herein modulate one or more of aryl hydrocarbon receptor (AHR), aryl hydrocarbon receptor (AHR) transcription factors, CYP1A1, CYP1B1, filaggrin, involucrin, and TGaseI, PXR, IPA, GLP-1, IL-22, 5-HT, CYP2E1, IS, cytochrome P450 enzymes, KLF6, Erα, IA, CD40, CD80, CD86, GSK-3, hedgehog, hedgehog pathway, sulfotransferases, genes involved in immune cell function and differentiation, and / or proteins involved in epidermal differentiation.

[0369] In some embodiments, the compositions described herein can modulate epithelial function; epithelial permeability; mucosal homeostasis; anti-oxidation; anti-inflammation; appetite; insulin secretion; gastric emptying; renal function; uremic toxins; intestinal immune response; skin immune response; mucosal immune response; mucosal reactivity; gastrointestinal motility; autoimmune diseases, cancer, metabolic syndrome, mast cells, B cells, macrophages, antigen presenting cells (APC), Th1 / Th2 cell balance, Th17 and regulatory T cells, immune responses in allergen-induced diseases and infectious diseases.

[0370] In some embodiments, the compositions described herein are applied to the face of a subject. In some embodiments, the compositions described herein are applied to the body of a subject. In some embodiments, the compositions described herein are applied topically to the head, scalp, face, ears, neck, chest, back, inframammary area, arms, legs, hands, fingers, feet, toes, or groin.

[0371] In some embodiments, the compositions described herein are applied to the face of a subject, thereby treating hyperpigmentation of the skin or hair on the face. In some embodiments, the compositions described herein are applied to the body of a subject, thereby treating hyperpigmentation of the skin or hair. In some embodiments, the compositions described herein are topically applied to one or more areas selected from the head, scalp, face, ears, neck, chest, back, inframammary area, arms, legs, hands, feet, and groin, thereby treating hyperpigmentation of the skin or hair in any of these areas.

[0372] In some embodiments, the composition is applied to 0.01% to 100.00% of the body surface area. 1.0% to 90.0% of the body surface area. In some embodiments, the composition is applied to 2.0% to 80.0% of the body surface area. In some embodiments, the composition is applied to 3.0% to 70.0% of the body surface area. In some embodiments, the composition is applied to 5.0% to 60.0% of the body surface area. In some embodiments, the composition is applied to 5.0% to 50.0% of the body surface area. In some embodiments, the composition is applied to 6.0% to 40.0% of the body surface area. In some embodiments, the composition is applied to 7.0% to 30.0% of the body surface area. In some embodiments, the composition is applied to 8.0% to 20.0% of the body surface area. In some embodiments, the composition is applied to 9.0% to 15.0% of the body surface area. In some embodiments, the composition is applied to approximately 10.0% of the body surface area. In some embodiments, the composition is applied to approximately 15.0% of the body surface area. In some embodiments, the composition is applied to about 20.0% of the body surface area.

[0373] In some embodiments, the skin disease, condition or disorder to be alleviated, improved, treated or prevented is hyperpigmentation of skin or hair. In some embodiments, the compositions described herein are applied in an effective amount to achieve a reduction in melanin in the skin of the treatment area. In some embodiments, the compositions described herein are applied in an effective amount to achieve uniformity of skin color of the object. In some embodiments, the compositions described herein are applied in an effective amount to reduce undesirable pigmentation, even skin color, to make the skin monochrome, or to eliminate blemishes or irregular pigmentation in the skin of the object, as measured by colorimetry, digital imaging, other objective measurements or other subjective measurements in the treatment area of ​​the object. In some embodiments, the compositions described herein are applied in an effective amount to achieve a reduction in pigmentation or melanin in the hair produced by the treated hair follicles.

[0374] The compositions disclosed herein can be administered multiple times per day, once per day, multiple times per week, once per week, multiple times per month, or once per month as at least a single dose. In some embodiments, the composition is administered twice per day. In some embodiments, the composition is administered at least twice per week. In some embodiments, the composition is administered at least twice per month. In some embodiments, the composition comprising a compound (i.e., Rubusta free base, Rubusta mesylate monohydrate, or an acceptable salt thereof) in an amount of 0.05% to 10% by weight is administered multiple times per day, once per day, multiple times per week, once per week, twice per week, multiple times per month, once per month, or twice per month as a single dose.

[0375] In some embodiments, the compound is administered in combination with an additional agent (e.g., a therapeutic agent or a cosmetic agent). In some embodiments, one or more additional agents (e.g., a therapeutic agent) are selected from: hydroquinone, indole, indole-based compounds, indole-derived compounds, BIM-1, BIM-2, BIM-3 and BIM-8, bisindole maleimide or its derivatives, protein kinase C inhibitors, protein kinase inhibitors, retinoic acid, corticosteroids, azelaic acid, kojic acid, retinoic acid, glycolic acid, L-ascorbic acid, para-aminobenzoic acid, padimate O, phenylbenzimidazole sulfonic acid, cinoxate, methyl anthranilate, dimethoate, Hydroxybenzone, oxybenzone, avobenzone, octisalate, octocrylene, octyl methoxycinnamate, homosalate, octinoxate, sulisobenzone, triethanolamine salicylate, ecamsule, zinc oxide, titanium dioxide, cosmetic agents, coloring, fragrance, sunscreen, foaming surfactant, vitamins, hydroxy acids, antioxidants, retinoic acid, arbutin 1% (a glycosylated hydroquinone), papermulberry 1%, glabridin 0.5% (licorice extract), Arctostaphylos patula) and Arctostaphylos viscida, aloesin, gentisic acid, flavonoids, hesperidin, ascorbic acid or its derivatives, magnesium ascorbyl phosphate 10%, niacinamide, yeast derivatives, polyphenols, soy protein, kojic acid 1-4% (5-hydroxy-4-pyran-4-one-2-methyl), methoxyphenol 5-20% (4-hydroxyanisole), isopropyl catechol, N-acetyl-4-cysteamine phenol, N-acetyl glucosamine, piceatannol, moisturizing agent, trichloroacetic acid, mercury, 1,4-diol, quinone, benzene-1,4-diol, p-Diphenol, p-Dihydroxyl benzene), hydrochinone, p-hydroxylphenol, hydrochinonium, hydroquinol, tequinol, monobenzyl ether of hydroquinone, and / or cysteamine cream.

[0376] In some embodiments, the additional agent is a sunscreen, sunscreen or filter. The sunscreen, sunscreen or filter can be, but is not limited to, one or more of the following: UVA filter, benzophenone, oxybenzone, sulisobenzone, dioxybenzone, avobenzone, meradinate, disodium phenyl dibenzimidazole tetrasulfonate, diethylaminohydroxy-benzoyl hexyl benzoate, ecamsul, methyl anthranilate, UVB filter, PABA derivative, padimamate O, cinnamate, octinoxate, cinoxate, salicylate, octisalate, homosalate, triethanolamine salicylate, octocrylene, ensolizole, ethylhexyl triazone, broad spectrum filter, ecamsul, Mexoryl SX, Silatriazole, Mexoryl XL, benzyl moxifloxacin, Tinosorb S, and octotriazole (Tinosorb M), octaloxalate, inorganic sunscreen, zinc oxide, titanium dioxide, iron oxide, red veterinary petrolatum, kaolin, calamine, ichthyol, talc, systemic sunscreen, beta-carotene, antimalarial, ascorbic acid, alpha-tocopherol, retinol, selenium, green tea polyphenols, PABA, antihistamines, aspirin, indomethacin, corticosteroids, polyhydroxystearic acid, organic sunscreen 2-ethylhexyl p-methoxycinnamate, 4,4'-tert-butyl methoxydibenzoylmethane, octyl salicylate, terephthalylidene dicamphor sulfonic acid, benzophenone-3. In some embodiments, the sunscreen, sunscreen or filter is selected from one or more of Elta MD (UV sport and UV clear), ISDIN Eryfotona, cetaphil sheer, La-Roche Posay Anthelios and / or supergoop unseen.

[0377] In some embodiments, one or more of the additional agents is a depilatory agent, a bleaching agent, or an anti-aging treatment agent.

[0378] In some embodiments, additional agents may include, but are not limited to, depilatories, potassium or calcium thioglycolate, monothioglycerol, 2-mercaptopropionic acid, monoethanolaminethioglycolic acid, homocysteine, cysteine ​​and glutathione, inhibitors of certain enzymes (such as 5-alpha reductase, ornithine decarboxylase, S-adenosylmethionine decarboxylase, gamma-glutamyl transpeptidase and transglutaminase), endothelin or agonists thereof, thiols, thioglycolic acid and its salts, thiolactic acid and its salts, sulfides, strontium sulfide, calcium thioglycolate, calcium hydroxide, strontium hydroxide, keratolytics, lactic acid, salicylic acid, glycolic acid, citric acid and malic acid.

[0379] In some embodiments, additional agents may include, but are not limited to, hair lighteners, alkaline agents, oxidizing agents, ethanolamine, ammonia, hydrogen peroxide (H2O2), p-phenylenediamine, p-phenylenediamine, diaminobenzene, toluene-2,5-diamine, resorcinol, persulfates, monoethanolamine, sodium sulfite, lime juice, lemon juice, and / or citric acid.

[0380] In some embodiments, the one or more additional agents may include, but are not limited to, one or more of the following: anti-inflammatory drugs, NSAIDs, antimicrobial agents, antibiotics, steroids, antiviral agents, chemotherapeutic agents, alkylating agents, anti-metabolites or anti-microtubule agents, vitamin D derivatives, oxidative compounds, acids, retinoic acid derivatives, keratolytic agents, corticosteroids, immunomodulators, immunomodulators, sunscreens, UV blockers, zinc compounds, retinoic acid, skin discoloration treatments, hyperpigmentation treatments, moisturizers, anti-aging treatments.

[0381] In some embodiments, one or more additional agents are applied topically. In some embodiments, additional agents are applied in conjunction with the compound. In some embodiments, additional agents and the compound are applied to a common area but at different times. In some embodiments, additional agents and the compound are contained in the same unit dosage form. In some embodiments, additional agents and the compound are arranged in different unit dosage forms. In some embodiments, a second or more additional agents are applied. In some embodiments, a second application of the compound is applied. In some embodiments, a third application of the compound is applied.

[0382] In some embodiments, multiple (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, or 15 or more) administrations occur over a seven day period. In some embodiments, multiple (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, or 15 or more) administrations occur over a fourteen day period. In some embodiments, multiple (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, or 15 or more) administrations occur within a twenty-one day period. In some embodiments, multiple (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, or 15 or more) administrations occur within a thirty day period.

[0383] In some embodiments, the compound is administered twice a day, once a day, once every other day, once a week, or once a month. In some embodiments, the compound is administered twice a day, once a day, once every other day, once a week, or once a month for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, or longer. In some embodiments, the compound is administered once a day, twice a day, once every other day, once a week, or once a month for at least 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years. In some embodiments, the compound is administered once a day, twice a day, once every other day, once a week, or once a month for at least 10, 20, 30, 40, 50, 60, 70, 80, 90 years, or for the lifetime of the subject.

[0384] In some embodiments, the subject has been previously treated with the compound, e.g., for at least 1, 6, 12, 24, 36, or 48 months. In some embodiments, the subject has received one or more prior administrations of the compound, e.g., at least 2, 10, 20, 30, 40, 50, 100, 200, 300, or 500 prior administrations of the compound.

[0385] In some embodiments, the composition is applied twice a day for 4 weeks. In some embodiments, the composition is applied twice a day for 5 weeks. In some embodiments, the composition is applied twice a day for 6 weeks. In some embodiments, the composition is applied twice a day for 7 weeks. In some embodiments, the composition is applied twice a day for 8 weeks. In some embodiments, the composition is applied twice a day for 9 weeks. In some embodiments, the composition is applied twice a day for 10 weeks. In some embodiments, the composition is applied twice a day for 11 weeks. In some embodiments, the composition is applied twice a day for 12 weeks. In some embodiments, the composition is applied twice a day for 13 weeks. In some embodiments, the composition is applied twice a day for 14 weeks. In some embodiments, the composition is applied twice a day for 15 weeks. In some embodiments, the composition is applied twice a day for 16 weeks. In some embodiments, the composition is applied twice a day for 17 weeks. In some embodiments, the composition is applied twice a day for 18 weeks. In some embodiments, the composition is applied twice a day for 19 weeks. In some embodiments, the composition is applied twice a day for 20 weeks. In some embodiments, the composition is applied twice a day for 21 weeks. In some embodiments, the composition is administered twice daily for 22 weeks. In some embodiments, the composition is administered twice daily for 23 weeks. In some embodiments, the composition is administered twice daily for 24 weeks. In some embodiments, the composition is 0.8% Rubustadine or a salt thereof.

[0386] In some embodiments, 0.01 g to 100.0 g of the composition is applied daily. In some embodiments, 0.2 g to 50.0 g of the composition is applied daily. In some embodiments, 0.3 g to 20.0 g of the composition is applied daily. In some embodiments, 0.4 g to 15.0 g of the composition is applied daily. In some embodiments, 0.5 g to 10.0 g of the composition is applied daily. In some embodiments, 0.7 g to 7.0 g of the composition is applied daily. In some embodiments, 0.35 g is applied twice a day. In some embodiments, 0.7 g is applied daily. In some embodiments, 0.7 g is applied twice a day. In some embodiments, 1.0 g, 2.0 g, 3.0 g, 4.0 g, 5.0 g, 6.0 g, 7.0 g, 8.0 g, 9.0 g, or 10.0 g is applied once or twice a day. In some embodiments, approximately 36.0 g is applied twice a day.

[0387] In some embodiments, 0.01 g to 100.0 g, 0.2 g to 50.0 g, 0.3 g to 20.0 g, 0.4 g to 15.0 g, 0.5 g to 10.0 g, 0.7 g to 7.0 g, 0.35 g, 0.7 g, 1.0 g, 2.0 g, 3.0 g, 4.0 g, 5.0 g, 6.0 g, 7.0 g, 8.0 g, 9.0 g, 10.0 g, 20.0 g, 30.0 g or about 36.0 g of the composition is applied to 0.1% to 100.0% of the body surface area. In some embodiments, 0.01 g to 100.0 g, 0.2 g to 50.0 g, 0.3 g to 20.0 g, 0.4 g to 15.0 g, 0.5 g to 10.0 g, 0.7 g to 7.0 g, 0.35 g, 0.7 g, 1.0 g, 2.0 g, 3.0 g, 4.0 g, 5.0 g, 6.0 g, 7.0 g, 8.0 g, 9.0 g, 10.0 g, 20.0 g, 30.0 g, or about 36.0 g is applied to 2.0% to 80.0% of the body surface area. In some embodiments, 0.01 g to 100.0 g, 0.2 g to 50.0 g, 0.3 g to 20.0 g, 0.4 g to 15.0 g, 0.5 g to 10.0 g, 0.7 g to 7.0 g, 0.35 g, 0.7 g, 1.0 g, 2.0 g, 3.0 g, 4.0 g, 5.0 g, 6.0 g, 7.0 g, 8.0 g, 9.0 g, 10.0 g, 20.0 g, 30.0 g, or about 36.0 g is applied to 3.0% to 70.0% of the body surface area. In some embodiments, 0.01 g to 100.0 g, 0.2 g to 50.0 g, 0.3 g to 20.0 g, 0.4 g to 15.0 g, 0.5 g to 10.0 g, 0.7 g to 7.0 g, 0.35 g, 0.7 g, 1.0 g, 2.0 g, 3.0 g, 4.0 g, 5.0 g, 6.0 g, 7.0 g, 8.0 g, 9.0 g, 10.0 g, 20.0 g, 30.0 g, or about 36.0 g is applied to 5.0% to 60.0% of the body surface area. In some embodiments, 0.01 g to 100.0 g, 0.2 g to 50.0 g, 0.3 g to 20.0 g, 0.4 g to 15.0 g, 0.5 g to 10.0 g, 0.7 g to 7.0 g, 0.35 g, 0.7 g, 1.0 g, 2.0 g, 3.0 g, 4.0 g, 5.0 g, 6.0 g, 7.0 g, 8.0 g, 9.0 g, 10.0 g, 20.0 g, 30.0 g, or about 36.0 g is applied to 5.0% to 50.0% of the body surface area.In some embodiments, 0.01 g to 100.0 g, 0.2 g to 50.0 g, 0.3 g to 20.0 g, 0.4 g to 15.0 g, 0.5 g to 10.0 g, 0.7 g to 7.0 g, 0.35 g, 0.7 g, 1.0 g, 2.0 g, 3.0 g, 4.0 g, 5.0 g, 6.0 g, 7.0 g, 8.0 g, 9.0 g, 10.0 g, 20.0 g, 30.0 g, or about 36.0 g is applied to 6.0% to 40.0% of the body surface area. In some embodiments, 0.01 g to 100.0 g, 0.2 g to 50.0 g, 0.3 g to 20.0 g, 0.4 g to 15.0 g, 0.5 g to 10.0 g, 0.7 g to 7.0 g, 0.35 g, 0.7 g, 1.0 g, 2.0 g, 3.0 g, 4.0 g, 5.0 g, 6.0 g, 7.0 g, 8.0 g, 9.0 g or 10.0 g is applied to 7.0% to 30.0% of the body surface area. In some embodiments, 0.01 g to 100.0 g, 0.2 g to 50.0 g, 0.3 g to 20.0 g, 0.4 g to 15.0 g, 0.5 g to 10.0 g, 0.7 g to 7.0 g, 0.35 g, 0.7 g, 1.0 g, 2.0 g, 3.0 g, 4.0 g, 5.0 g, 6.0 g, 7.0 g, 8.0 g, 9.0 g, 10.0 g, 20.0 g, 30.0 g, or about 36.0 g is applied to 8.0% to 20.0% of the body surface area. In some embodiments, 0.01 g to 100.0 g, 0.2 g to 50.0 g, 0.3 g to 20.0 g, 0.4 g to 15.0 g, 0.5 g to 10.0 g, 0.7 g to 7.0 g, 0.35 g, 0.7 g, 1.0 g, 2.0 g, 3.0 g, 4.0 g, 5.0 g, 6.0 g, 7.0 g, 8.0 g, 9.0 g, 10.0 g, 20.0 g, 30.0 g, or about 36.0 g is applied to 9.0% to 15.0% of the body surface area. In some embodiments, 0.01 g to 100.0 g, 0.2 g to 50.0 g, 0.3 g to 20.0 g, 0.4 g to 15.0 g, 0.5 g to 10.0 g, 0.7 g to 7.0 g, 0.35 g, 0.7 g, 1.0 g, 2.0 g, 3.0 g, 4.0 g, 5.0 g, 6.0 g, 7.0 g, 8.0 g, 9.0 g, 10.0 g, 20.0 g, 30.0 g, or about 36.0 g is applied to about 10.0% of the body surface area.In some embodiments, 0.01 g to 100.0 g, 0.2 g to 50.0 g, 0.3 g to 20.0 g, 0.4 g to 15.0 g, 0.5 g to 10.0 g, 0.7 g to 7.0 g, 0.35 g, 0.7 g, 1.0 g, 2.0 g, 3.0 g, 4.0 g, 5.0 g, 6.0 g, 7.0 g, 8.0 g, 9.0 g, 10.0 g, 20.0 g, 30.0 g, or about 36.0 g is applied to about 15.0% of the body surface area. In some embodiments, 0.01 g to 100.0 g, 0.2 g to 50.0 g, 0.3 g to 20.0 g, 0.4 g to 15.0 g, 0.5 g to 10.0 g, 0.7 g to 7.0 g, 0.35 g, 0.7 g, 1.0 g, 2.0 g, 3.0 g, 4.0 g, 5.0 g, 6.0 g, 7.0 g, 8.0 g, 9.0 g, 10.0 g, 20.0 g, 30.0 g, or about 36.0 g is applied to about 20.0% of the body surface area.

[0388] In some embodiments, the composition comprises 0.001mg to 10.0g of Rubosta mesylate monohydrate, Rubosta free base or its salt. In some embodiments, 0.01mg to 5.0g of the composition is applied every day. In some embodiments, the composition comprises 0.1mg to 2.0g of Rubosta mesylate monohydrate, Rubosta free base or its salt. In some embodiments, the composition comprises 0.2mg to 1.5g of Rubosta mesylate monohydrate, Rubosta free base or its salt. In some embodiments, the composition comprises 0.5mg to 1.0g of Rubosta mesylate monohydrate, Rubosta free base or its salt. In some embodiments, the composition comprises 0.7mg to 0.7g of Rubosta mesylate monohydrate, Rubosta free base or its salt. In some embodiments, the composition comprises 0.35g. In some embodiments, the composition comprises 0.7g. In some embodiments, the composition comprises 0.7g. In some embodiments, the composition comprises 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 6.0 mg, 7.0 mg, 8.0 mg, 9.0 mg, or 10.0 mg of rubustard mesylate monohydrate, rubustard free base, or a salt thereof.

[0389] In some embodiments, 0.001 mg to 10.0 g, 0.01 mg to 5.0 g, 0.1 mg to 2.0 g, 0.1 mg to 2.0 g, 0.2 mg to 1.5 g, 0.5 mg to 1.0 g, 0.7 mg to 0.7 g, 0.35 mg, 0.7 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 5.6 mg, 6.0 mg, 7.0 mg, 8.0 mg, 9.0 mg or 10.0 mg of rubustard mesylate monohydrate, rubustard free base, or a salt thereof is applied to 0.1% to 100.0% of body surface area. In some embodiments, 0.001 mg to 10.0 g, 0.01 mg to 5.0 g, 0.1 mg to 2.0 g, 0.1 mg to 2.0 g, 0.2 mg to 1.5 g, 0.5 mg to 1.0 g, 0.7 mg to 0.7 g, 0.35 mg, 0.7 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 5.6 mg, 6.0 mg, 7.0 mg, 8.0 mg, 9.0 mg or 10.0 mg of rubustard mesylate monohydrate, rubustard free base, or a salt thereof is applied to 2.0% to 80.0% of the body surface area. In some embodiments, 0.001 mg to 10.0 g, 0.01 mg to 5.0 g, 0.1 mg to 2.0 g, 0.1 mg to 2.0 g, 0.2 mg to 1.5 g, 0.5 mg to 1.0 g, 0.7 mg to 0.7 g, 0.35 mg, 0.7 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 5.6 mg, 6.0 mg, 7.0 mg, 8.0 mg, 9.0 mg or 10.0 mg of rubustard mesylate monohydrate, rubustard free base, or a salt thereof is applied to 3.0% to 70.0% of the body surface area. In some embodiments, 0.001 mg to 10.0 g, 0.01 mg to 5.0 g, 0.1 mg to 2.0 g, 0.1 mg to 2.0 g, 0.2 mg to 1.5 g, 0.5 mg to 1.0 g, 0.7 mg to 0.7 g, 0.35 mg, 0.7 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 5.6 mg, 6.0 mg, 7.0 mg, 8.0 mg, 9.0 mg or 10.0 mg of rubustard mesylate monohydrate, rubustard free base, or a salt thereof is applied to 5.0% to 60.0% of the body surface area.In some embodiments, 0.001 mg to 10.0 g, 0.01 mg to 5.0 g, 0.1 mg to 2.0 g, 0.1 mg to 2.0 g, 0.2 mg to 1.5 g, 0.5 mg to 1.0 g, 0.7 mg to 0.7 g, 0.35 mg, 0.7 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 5.6 mg, 6.0 mg, 7.0 mg, 8.0 mg, 9.0 mg or 10.0 mg of rubustard mesylate monohydrate, rubustard free base, or a salt thereof is applied to 5.0% to 50.0% of the body surface area. In some embodiments, 0.001 mg to 10.0 g, 0.01 mg to 5.0 g, 0.1 mg to 2.0 g, 0.1 mg to 2.0 g, 0.2 mg to 1.5 g, 0.5 mg to 1.0 g, 0.7 mg to 0.7 g, 0.35 mg, 0.7 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 5.6 mg, 6.0 mg, 7.0 mg, 8.0 mg, 9.0 mg or 10.0 mg of rubustard mesylate monohydrate, rubustard free base, or a salt thereof is applied to 6.0% to 40.0% of the body surface area. In some embodiments, 0.001 mg to 10.0 g, 0.01 mg to 5.0 g, 0.1 mg to 2.0 g, 0.1 mg to 2.0 g, 0.2 mg to 1.5 g, 0.5 mg to 1.0 g, 0.7 mg to 0.7 g, 0.35 mg, 0.7 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 5.6 mg, 6.0 mg, 7.0 mg, 8.0 mg, 9.0 mg or 10.0 mg of rubustard mesylate monohydrate, rubustard free base, or a salt thereof is applied to 7.0% to 30.0% of the body surface area. In some embodiments, 0.001 mg to 10.0 g, 0.01 mg to 5.0 g, 0.1 mg to 2.0 g, 0.1 mg to 2.0 g, 0.2 mg to 1.5 g, 0.5 mg to 1.0 g, 0.7 mg to 0.7 g, 0.35 mg, 0.7 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 5.6 mg, 6.0 mg, 7.0 mg, 8.0 mg, 9.0 mg or 10.0 mg of rubustard mesylate monohydrate, rubustard free base, or a salt thereof is applied to 8.0% to 20.0% of the body surface area.In some embodiments, 0.001 mg to 10.0 g, 0.01 mg to 5.0 g, 0.1 mg to 2.0 g, 0.1 mg to 2.0 g, 0.2 mg to 1.5 g, 0.5 mg to 1.0 g, 0.7 mg to 0.7 g, 0.35 mg, 0.7 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 5.6 mg, 6.0 mg, 7.0 mg, 8.0 mg, 9.0 mg or 10.0 mg of rubustard mesylate monohydrate, rubustard free base, or a salt thereof is applied to 9.0% to 15.0% of the body surface area. In some embodiments, 0.001 mg to 10.0 g, 0.01 mg to 5.0 g, 0.1 mg to 2.0 g, 0.1 mg to 2.0 g, 0.2 mg to 1.5 g, 0.5 mg to 1.0 g, 0.7 mg to 0.7 g, 0.35 mg, 0.7 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 5.6 mg, 6.0 mg, 7.0 mg, 8.0 mg, 9.0 mg or 10.0 mg of rubustard mesylate monohydrate, rubustard free base, or a salt thereof is applied to approximately 10.0% of the body surface area. In some embodiments, 0.001 mg to 10.0 g, 0.01 mg to 5.0 g, 0.1 mg to 2.0 g, 0.1 mg to 2.0 g, 0.2 mg to 1.5 g, 0.5 mg to 1.0 g, 0.7 mg to 0.7 g, 0.35 mg, 0.7 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 5.6 mg, 6.0 mg, 7.0 mg, 8.0 mg, 9.0 mg or 10.0 mg of rubustard mesylate monohydrate, rubustard free base, or a salt thereof is applied to approximately 15.0% of the body surface area. In some embodiments, 0.001 mg to 10.0 g, 0.01 mg to 5.0 g, 0.1 mg to 2.0 g, 0.1 mg to 2.0 g, 0.2 mg to 1.5 g, 0.5 mg to 1.0 g, 0.7 mg to 0.7 g, 0.35 mg, 0.7 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 5.6 mg, 6.0 mg, 7.0 mg, 8.0 mg, 9.0 mg or 10.0 mg of rubustard mesylate monohydrate, rubustard free base, or a salt thereof is applied to approximately 20.0% of the body surface area.

[0390] In some embodiments, the composition is applied in an amount of about 0.00001 g / cm2 to about 0.00021 g / cm2. In some embodiments, the composition is applied in an amount of about 0.00001 g / cm2 to about 0.00003 g / cm2, about 0.00001 g / cm2 to about 0.00005 g / cm2, about 0.00001 g / cm2 to about 0.00007 g / cm2, about 0.00001 g / cm2 to about 0.00009 g / cm2, about 0.00001 g / cm2 to about 0.00011 g / cm2, about 0.00001 g / cm2 to about 0.00013 g / cm2, about 0.00001 g / cm2 to about 0.00015 g / cm2, about 0.00001 g / cm2 to about 0.00017 g / cm2, about 0.00001 g / cm2 to about 0.00019 g / cm2, about 0.00001 g / cm2 to about 0.00021 g / cm2, about 0.00003 g / cm2 to about 0.00005 g / cm2, about 0.00003 g / cm2 to about 0.00007 g / cm2, about 0.00003 g / cm2 to about 0.00009 g / cm2, about 0.00003 g / cm2 to about 0.00011 g / cm2, about 0.00003 g / cm2 to about 0.00013 g / cm2, about 0.00003 g / cm2 to about 0.00015 g / cm2, about 0.00003 g / cm2 to about 0.00016 g / cm2, about 0.00003 g / cm2 to about 0.00018 g / cm2 0.00017 g / cm2, about 0.00003 g / cm2 to about 0.00019 g / cm2, about 0.00003 g / cm2 to about 0.00021 g / cm2, about 0.00005 g / cm2 to about 0.00007 g / cm2, about 0.00005 g / cm2 to about 0.00009 g / cm2, about 0.00005 g / cm2 to about 0.00011 g / cm2, about 0.00005 g / cm2 to about 0.00013 g / cm2, about 0.00005 g / cm2 to about 0.00015 g / cm2, about 0.00005 g / cm2 to about 0.00017 g / cm2, about 0 0.00005 g / cm2 to about 0.00019 g / cm2, about 0.00005 g / cm2 to about 0.00021 g / cm2, about 0.00007 g / cm2 to about 0.00009 g / cm2, about 0.00007 g / cm2 to about 0.00011 g / cm2, about 0.00007 g / cm2 to about 0.00013 g / cm2, about 0.00007 g / cm2 to about 0.00015 g / cm2, about 0.00007 g / cm2 to about 0.00017 g / cm2, about 0.00007 g / cm2 to about 0.00019 g / cm2, about 0.00007 g / cm2 to about 0.0.00021g / cm2, about 0.00009g / cm2 to about 0.00011g / cm2, about 0.00009g / cm2 to about 0.00013g / cm2, about 0.00009g / cm2 to about 0.00015g / cm2, about 0.00009g / cm2 to about 0.00017g / cm2, about 0.00009g / cm2 to about 0.00019g / cm2 , about 0.00009 g / cm2 to about 0.00021 g / cm2, about 0.00011 g / cm2 to about 0.00013 g / cm2, about 0.00011 g / cm2 to about 0.00015 g / cm2, about 0.00011 g / cm2 to about 0.00017 g / cm2, about 0.00011 g / cm2 to about 0.00019 g / cm2, about 0.00011 g / cm2 to about 0.00016 g / cm2, about 0.00011 g / cm2 to about 0.00018 g / cm2 cm2 to about 0.00021 g / cm2, about 0.00013 g / cm2 to about 0.00015 g / cm2, about 0.00013 g / cm2 to about 0.00017 g / cm2, about 0.00013 g / cm2 to about 0.00019 g / cm2, about 0.00013 g / cm2 to about 0.00021 g / cm2, about 0.00015 g / cm2 to about 0.0001 7g / cm2, about 0.00015g / cm2 to about 0.00019g / cm2, about 0.00015g / cm2 to about 0.00021g / cm2, about 0.00017g / cm2 to about 0.00019g / cm2, about 0.00017g / cm2 to about 0.00021g / cm2 or about 0.00019g / cm2 to about 0.00021g / cm2 is used. In some embodiments, the composition is applied in an amount of about 0.00001 g / cm2, about 0.00003 g / cm2, about 0.00005 g / cm2, about 0.00007 g / cm2, about 0.00009 g / cm2, about 0.00011 g / cm2, about 0.00013 g / cm2, about 0.00015 g / cm2, about 0.00017 g / cm2, about 0.00019 g / cm2, or about 0.00021 g / cm2. In some embodiments, the composition is applied in an amount of at least about 0.00001 g / cm2, about 0.00003 g / cm2, about 0.00005 g / cm2, about 0.00007 g / cm2, about 0.00009 g / cm2, about 0.00011 g / cm2, about 0.00013 g / cm2, about 0.00015 g / cm2, about 0.00017 g / cm2, or about 0.00019 g / cm2. In some embodiments, the composition is applied in an amount of at most about 0.00003 g / cm2, about 0.00005 g / cm2, about 0.00007 g / cm2, about 0.00009 g / cm2, about 0.00011 g / cm2, about 0.00013 g / cm2, about 0.00015 g / cm2, about 0.00017 g / cm2, or about 0.00019 g / cm2.In some embodiments, the composition is applied in an amount of about 0.0001 g / cm2 to about 0.001 g / cm2. In some embodiments, the composition is from about 0.0001 g / cm2 to about 0.0002 g / cm2, from about 0.0001 g / cm2 to about 0.0003 g / cm2, from about 0.0001 g / cm2 to about 0.0004 g / cm2, from about 0.0001 g / cm2 to about 0.0005 g / cm2, from about 0.0001 g / cm2 to about 0.0006 g / cm2, from about 0.0001 g / cm2 to about 0.0007 g / cm2, from about 0.0001 g / cm2 to about 0.0008 g / cm2, from about 0.0001 g / cm2 to about 0.0009 g / cm2, 9g / cm2, about 0.0001g / cm2 to about 0.001g / cm2, about 0.0002g / cm2 to about 0.0003g / cm2, about 0.0002g / cm2 to about 0.0004g / cm2, about 0.0002g / cm2 to about 0.0005g / cm2, about 0.0002g / cm2 to about 0.0006g / cm2, about 0.0002g / cm2 to about 0.0007g / cm2, about 0.0002g / cm2 to about 0.0008g / cm2, about 0.0002g / cm2 to about 0.0009g / cm2, about 0.0002 g / cm2 to about 0.001 g / cm2, about 0.0003 g / cm2 to about 0.0004 g / cm2, about 0.0003 g / cm2 to about 0.0005 g / cm2, about 0.0003 g / cm2 to about 0.0006 g / cm2, about 0.0003 g / cm2 to about 0.0007 g / cm2, about 0.0003 g / cm2 to about 0.0008 g / cm2, about 0.0003 g / cm2 to about 0.0009 g / cm2, about 0.0003 g / cm2 to about 0.001 g / cm2, about 0.0004 g / cm2 / cm2 to about 0.0005g / cm2, about 0.0004g / cm2 to about 0.0006g / cm2, about 0.0004g / cm2 to about 0.0007g / cm2, about 0.0004g / cm2 to about 0.0008g / cm2, about 0.0004g / cm2 to about 0.0009g / cm2, about 0.0004g / cm2 to about 0.001g / cm2, about 0.0005g / cm2 to about 0.0006g / cm2, about 0.0005g / cm2 to about 0.0007g / cm2, about 0.0005g / cm2 to about 0.0.0008 g / cm2, about 0.0005 g / cm2 to about 0.0009 g / cm2, about 0.0005 g / cm2 to about 0.001 g / cm2, about 0.0006 g / cm2 to about 0.0007 g / cm2, about 0.0006 g / cm2 to about 0.0008 g / cm2, about 0.0006 g / cm2 to about 0.0009 g / cm2, about 0.0006 g / cm2 to about 0.001 g / cm2 cm2, about 0.0007 g / cm2 to about 0.0008 g / cm2, about 0.0007 g / cm2 to about 0.0009 g / cm2, about 0.0007 g / cm2 to about 0.001 g / cm2, about 0.0008 g / cm2 to about 0.0009 g / cm2, about 0.0008 g / cm2 to about 0.001 g / cm2 or about 0.0009 g / cm2 to about 0.001 g / cm2 is used. In some embodiments, the composition is applied in an amount of about 0.0001 g / cm2, about 0.0002 g / cm2, about 0.0003 g / cm2, about 0.0004 g / cm2, about 0.0005 g / cm2, about 0.0006 g / cm2, about 0.0007 g / cm2, about 0.0008 g / cm2, about 0.0009 g / cm2, or about 0.001 g / cm2. In some embodiments, the composition is applied in an amount of at least about 0.0001 g / cm2, about 0.0002 g / cm2, about 0.0003 g / cm2, about 0.0004 g / cm2, about 0.0005 g / cm2, about 0.0006 g / cm2, about 0.0007 g / cm2, about 0.0008 g / cm2, or about 0.0009 g / cm2. In some embodiments, the composition is applied in an amount of up to about 0.0002 g / cm2, about 0.0003 g / cm2, about 0.0004 g / cm2, about 0.0005 g / cm2, about 0.0006 g / cm2, about 0.0007 g / cm2, about 0.0008 g / cm2, about 0.0009 g / cm2, or about 0.001 g / cm2. In some embodiments, the composition is applied in an amount of about 0.001 g / cm2 to about 0.01 g / cm2. In some embodiments, the composition is from about 0.001 g / cm2 to about 0.002 g / cm2, from about 0.001 g / cm2 to about 0.003 g / cm2, from about 0.001 g / cm2 to about 0.004 g / cm2, from about 0.001 g / cm2 to about 0.005 g / cm2, from about 0.001 g / cm2 to about 0.006 g / cm2, from about 0.001 g / cm2 to about 0.007 g / cm2, from about 0.001 g / cm2 to about 0.008 g / cm2, from about 0.001 g / cm2 to about 0.009 g / cm2, from about 0.001 g / cm2 to about 0.01g / cm2, about 0.002g / cm2 to about 0.003g / cm2, about 0.002g / cm2 to about 0.004g / cm2, about 0.002g / cm2 to about 0.005g / cm2, about 0.002g / cm2 to about 0.006g / cm2, about 0.002g / cm2 to about 0.007g / cm2, about 0.002g / cm2 to about 0.008g / cm2, about 0.002g / cm2 to about 0.009g / cm2, about 0.002g / cm2 to about 0.01g / cm2, about 0.003 ... g / cm2, about 0.003 g / cm2 to about 0.005 g / cm2, about 0.003 g / cm2 to about 0.006 g / cm2, about 0.003 g / cm2 to about 0.007 g / cm2, about 0.003 g / cm2 to about 0.008 g / cm2, about 0.003 g / cm2 to about 0.009 g / cm2, about 0.003 g / cm2 to about 0.01 g / cm2, about 0.004 g / cm2 to about 0.005 g / cm2, about 0.004 g / cm2 to about 0.006 g / cm2, about 0.004 g / cm2 to about 0.007 g / cm2, cm2, about 0.004 g / cm2 to about 0.008 g / cm2, about 0.004 g / cm2 to about 0.009 g / cm2, about 0.004 g / cm2 to about 0.01 g / cm2, about 0.005 g / cm2 to about 0.006 g / cm2, about 0.005 g / cm2 to about 0.007 g / cm2, about 0.005 g / cm2 to about 0.008 g / cm2, about 0.005 g / cm2 to about 0.009 g / cm2, about 0.005 g / cm2 to about 0.01 g / cm2, about 0.006 g / cm2 to about 0.007 g / cm2 , about 0.006 g / cm2 to about 0.008 g / cm2, about 0.006 g / cm2 to about 0.009 g / cm2, about 0.006 g / cm2 to about 0.01 g / cm2, about 0.007 g / cm2 to about 0.008 g / cm2, about 0.007 g / cm2 to about 0.009 g / cm2, about 0.007 g / cm2 to about 0.01 g / cm2, about 0.008 g / cm2 to about 0.009 g / cm2, about 0.008 g / cm2 to about 0.01 g / cm2 or about 0.009 g / cm2 to about 0.01 g / cm2 is used. In some embodiments, the composition is present at about 0.001 g / cm2, about 0.002 g / cm2, about 0.003 g / cm2, about 0.004 g / cm2, about 0.005 g / cm2, about 0.006 g / cm2, about 0.007 g / cm2, about 0.008 g / cm2, about 0.009 g / cm2, or about 0.In some embodiments, the composition is applied in an amount of at least about 0.001 g / cm2, about 0.002 g / cm2, about 0.003 g / cm2, about 0.004 g / cm2, about 0.005 g / cm2, about 0.006 g / cm2, about 0.007 g / cm2, about 0.008 g / cm2, or about 0.009 g / cm2. In some embodiments, the composition is applied in an amount of at most about 0.002 g / cm2, about 0.003 g / cm2, about 0.004 g / cm2, about 0.005 g / cm2, about 0.006 g / cm2, about 0.007 g / cm2, about 0.008 g / cm2, about 0.009 g / cm2, or about 0.01 g / cm2. In some embodiments, the composition is applied in an amount of about 0.01 g / cm2 to about 0.1 g / cm2. In some embodiments, the composition is applied in an amount of about 0.01 g / cm2 to about 0.02 g / cm2, about 0.01 g / cm2 to about 0.03 g / cm2, about 0.01 g / cm2 to about 0.04 g / cm2, about 0.01 g / cm2 to about 0.05 g / cm2, about 0.01 g / cm2 to about 0.06 g / cm2, about 0.01 g / cm2 to about 0.07 g / cm2, about 0.01 g / cm2 to about 0.08 g / cm2, about 0.01 g / cm2 to about 0.09 g / cm2, about 0.02 g / cm2 to about 0.03 g / cm2, about 0.02 g / cm2 to about 0.04 g / cm2, about 0.02 g / cm2 to about 0.05 g / cm2, about 0.02 g / cm2 to about 0.06 g / cm2, about 0.02 g / cm2 to about 0.07 g / cm2, about 0.02 g / cm2 to about 0.08 g / cm2, about 0.02 g / cm2 to about / cm2 to about 0.09g / cm2, about 0.01g / cm2 to about 0.1g / cm2, about 0.02g / cm2 to about 0.03g / cm2, about 0.02g / cm2 to about 0.04g / cm2, about 0.02g / cm2 to about 0.05g / cm2, about 0.02g / cm2 to about 0.06g / cm2, about 0.02g / cm2 to about 0.07g / cm2, about 0.02g / cm2 to about 0.08g / cm2, about 0.02 g / cm2 to about 0.09g / cm2, about 0.02g / cm2 to about 0.1g / cm2, about 0.03g / cm2 to about 0.04g / cm2, about 0.03g / cm2 to about 0.05g / cm2, about 0.03g / cm2 to about 0.06g / cm2, about 0.03g / cm2 to about 0.07g / cm2, about 0.03g / cm2 to about 0.08g / cm2, about 0.03g / cm2 to about 0.09g / cm2, about 0. 03g / cm2 to about 0.1g / cm2, about 0.04g / cm2 to about 0.05g / cm2, about 0.04g / cm2 to about 0.06g / cm2, about 0.04g / cm2 to about 0.07g / cm2, about 0.04g / cm2 to about 0.08g / cm2, about 0.04g / cm2 to about 0.09g / cm2, about 0.04g / cm2 to about 0.1g / cm2, about 0.05g / cm2 to about 0.06g / cm2, about 0.0.05 g / cm2 to about 0.07 g / cm2, about 0.05 g / cm2 to about 0.08 g / cm2, about 0.05 g / cm2 to about 0.09 g / cm2, about 0.05 g / cm2 to about 0.1 g / cm2, about 0.06 g / cm2 to about 0.07 g / cm2, about 0.06 g / cm2 to about 0.08 g / cm2, about 0.06 g / cm2 to about 0.09 g / cm2, about 0.05 g / cm2 to about 0.1 g / cm2, about 0.06 g / cm2 to about 0.07 g / cm2, about 0.06 g / cm2 to about 0.08 g / cm2, about 0.06 g / cm2 to about 0.09 g / cm2, about 0 In some embodiments, the composition is applied in an amount of about 0.01 g / cm2, about 0.02 g / cm2, about 0.03 g / cm2, about 0.04 g / cm2, about 0.05 g / cm2, about 0.06 g / cm2, about 0.1 g / cm2, about 0.07 g / cm2, about 0.08 g / cm2, about 0.07 g / cm2, about 0.09 g / cm2, about 0.07 g / cm2 to about 0.1 g / cm2, about 0.08 g / cm2 to about 0.09 g / cm2, about 0.08 g / cm2 to about 0.1 g / cm2, or about 0.09 g / cm2 to about 0.1 g / cm2. In some embodiments, the composition is applied in an amount of about 0.01 g / cm2, about 0.02 g / cm2, about 0.03 g / cm2, about 0.04 g / cm2, about 0.05 g / cm2, about 0.06 g / cm2, about 0.07 g / cm2, about 0.08 g / cm2, about 0.09 g / cm2, or about 0.1 g / cm2. In some embodiments, the composition is applied in an amount of at least about 0.01 g / cm2, about 0.02 g / cm2, about 0.03 g / cm2, about 0.04 g / cm2, about 0.05 g / cm2, about 0.06 g / cm2, about 0.07 g / cm2, about 0.08 g / cm2, or about 0.09 g / cm2. In some embodiments, the composition is applied in an amount of at most about 0.02 g / cm2, about 0.03 g / cm2, about 0.04 g / cm2, about 0.05 g / cm2, about 0.06 g / cm2, about 0.07 g / cm2, about 0.08 g / cm2, about 0.09 g / cm2, or about 0.1 g / cm2. In some embodiments, the composition is applied in an amount of about 0.1 g / cm2 to about 1 g / cm2. In some embodiments, the composition is from about 0.1 g / cm2 to about 0.2 g / cm2, from about 0.1 g / cm2 to about 0.3 g / cm2, from about 0.1 g / cm2 to about 0.4 g / cm2, from about 0.1 g / cm2 to about 0.5 g / cm2, from about 0.1 g / cm2 to about 0.6 g / cm2, from about 0.1 g / cm2 to about 0.7 g / cm2, from about 0.1 g / cm2 to about 0.8 g / cm2, from about 0.1 g / cm2 to about 0.9 g / cm2, from about 0.1 g / cm2 to about 1 g / cm2, from about 0.2 g / cm2 to about 0.3 g / cm2, from about 0.2 g / cm2 to about 0.4 g / cm2, from about 0.2 g / cm2 to about 0.5 g / cm2, from about 0.2 g / cm2 to about 0.6 g / cm2, from about 0.2 g / cm2 to about 0.7 g / cm2, from about 0.2g / cm2 to about 0.8g / cm2, about 0.2g / cm2 to about 0.9g / cm2, about 0.2g / cm2 to about 1g / cm2, about 0.3g / cm2 to about 0.4g / cm2, about 0.3g / cm2 to about 0.5g / cm2, about 0.3g / cm2 to about 0.6g / cm2, about 0.3g / cm2 to about 0.7g / cm2, about 0.3g / cm2 to about 0.8g / cm2 cm2, about 0.3g / cm2 to about 0.9g / cm2, about 0.3g / cm2 to about 1g / cm2, about 0.4g / cm2 to about 0.5g / cm2, about 0.4g / cm2 to about 0.6g / cm2, about 0.4g / cm2 to about 0.7g / cm2, about 0.4g / cm2 to about 0.8g / cm2, about 0.4g / cm2 to about 0.9g / cm2, about 0.4g / cm2 to about 1 g / cm2, about 0.5 g / cm2 to about 0.6 g / cm2, about 0.5 g / cm2 to about 0.7 g / cm2, about 0.5 g / cm2 to about 0.8 g / cm2, about 0.5 g / cm2 to about 0.9 g / cm2, about 0.5 g / cm2 to about 1 g / cm2, about 0.6 g / cm2 to about 0.7 g / cm2, about 0.6 g / cm2 to about 0.8 g / cm2, about 0.6 In some embodiments, the composition is applied in an amount of about 0.1 g / cm2, about 0.2 g / cm2, about 0.3 g / cm2, about 0.4 g / cm2, about 0.5 g / cm2, about 0.6 g / cm2, about 0.7 g / cm2, about 0.8 g / cm2, about 0.9 g / cm2, about 0.7 g / cm2, about 0.8 g / cm2, about 0.9 g / cm2, or about 1 g / cm2. In some embodiments, the composition is applied in an amount of about 0.1 g / cm2, about 0.2 g / cm2, about 0.3 g / cm2, about 0.4 g / cm2, about 0.5 g / cm2, about 0.6 g / cm2, about 0.7 g / cm2, about 0.8 g / cm2, about 0.9 g / cm2, or about 1 g / cm2. In some embodiments, the composition is applied in an amount of at least about 0.1 g / cm2, about 0.2 g / cm2, about 0.3 g / cm2, about 0.4 g / cm2, about 0.5 g / cm2, about 0.6 g / cm2, about 0.7 g / cm2, about 0.8 g / cm2, or about 0.9 g / cm2. In some embodiments, the composition is applied in an amount of at most about 0.2 g / cm2, about 0.3 g / cm2, about 0.4 g / cm2, about 0.5 g / cm2, about 0.6 g / cm2, about 0.7 g / cm2, about 0.8 g / cm2, about 0.9 g / cm2, or about 1 g / cm2.

[0391] In a non-limiting example, the composition is 0.8% Rubostar mesylate monohydrate, 0.64% Rubostar free base, 0.8% Rubostar mesylate monohydrate or a salt thereof, applied twice a day for at least 12 weeks, such as about 12 weeks. Rubostar can be free base. Rubostar can be Rubostar mesylate monohydrate.

[0392] In another non-limiting example, the composition is 0.8% of Rubostar mesylate monohydrate, 0.64% of Rubostar free base or a salt thereof, administered twice a day for about 4 weeks to about 8 weeks, such as about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks or about 8 weeks. The Rubostar free base can be Rubostar mesylate monohydrate.

[0393] In another non-limiting example, the composition is 0.8% Rubostar mesylate monohydrate, 0.64% Rubostar free base or a salt thereof, administered twice daily for about 8 weeks to about 12 weeks, such as about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks or about 12 weeks. The Rubostar free base can be Rubostar mesylate monohydrate.

[0394] In some embodiments, the composition administered is in the form of a gel, cream, ointment, lotion, foam, or emollient.

[0395] In some embodiments, the composition administered is a component of a patch, strip, film, sheet, wipe, paper, cloth, towel, wipes, sponge, mask, wipe, brush, pad, gauze, applicator, cotton ball, roll, swab, or bandage.

[0396] In some embodiments, the subject in need thereof is a human.

[0397] Reagent test kit

[0398] Also provided is a kit for treating a skin disease, condition or illness in a method where the subject needs it, having a composition as described herein in a tube, a flexible aluminum tube or a laminated plastic tube. The kit may include a topical composition comprising a compound (i.e., Rubostar free alkali, Rubostar mesylate monohydrate or its acceptable salt), a second agent or composition, and instructions for providing information about the use of treating skin diseases, conditions or illnesses to a medical care provider. 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 may be provided in the form of a website address where such instructions may be obtained. The unit dose of the compound or topical composition or the second agent or composition provided herein may include such a dosage so that when applied to an object, the treatment or prevention effective level of the compound or topical composition may be maintained at least 1 day at the treatment site of the object.

[0399] In some embodiments, suitable packaging is provided. As used herein, "packaging" includes a solid matrix or material that is conventionally used in systems and can keep the compound provided herein and / or the second dose suitable for application to an object within fixed limits. Such materials include glass and plastic (e.g., polyethylene, polypropylene and polycarbonate) bottles, vials, paper, plastic and plastic-foil laminated envelopes, etc. If electron beam sterilization technology is adopted, the packaging should have a sufficiently low density to allow the contents to be sterilized.

[0400] In some embodiments, packaging is a tube or container that blocks UV light. In some embodiments, the tube or container is opaque. In some embodiments, the tube or container is made of a material that filters UV light and prevents UV light from reaching the product.

[0401] In some embodiments, the packaging minimizes oxygen contacting the product. In some embodiments, the tube or container is vacuum sealed, and after filling the tube or container with the product, any remaining air is removed from the tube or container. In some cases, the air in the head space of the tube or container is replaced with an inert gas. In some cases, the gas is nitrogen.

[0402] Exemplary embodiments

[0403] Exemplary embodiments of the compositions, kits, and methods described herein are described below:

[0404] 1. A composition comprising rubostat free base or rubostat mesylate monohydrate or a salt thereof, and a penetration enhancer and / or an organic solvent.

[0405] 2. The composition according to embodiment 1, wherein the total amount of penetration enhancer and / or organic solvent is from about 62% to about 99% by weight of the composition.

[0406] 3. The composition according to embodiment 1 or embodiment 2, comprising the penetration enhancer.

[0407] 4. A composition according to embodiment 3, wherein the penetration enhancer comprises C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester or fatty ether, or a combination of two or more thereof.

[0408] 5. The composition according to any one of embodiments 1-4, comprising the organic solvent.

[0409] 6. A composition according to embodiment 5, wherein the organic solvent comprises C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester or fatty ether, or a combination of two or more thereof.

[0410] 7. The composition according to embodiment 6, wherein the organic solvent comprises propylene glycol, 2-(2-ethoxyethoxy)ethanol, glycerol or polyethylene glycol, or a combination of two or more thereof.

[0411] 8. A composition according to embodiment 1 or embodiment 2, wherein the penetration enhancer and / or organic solvent comprises C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester or fatty ether, or a combination of two or more thereof.

[0412] 9. The composition of any one of embodiments 1-8, comprising the penetration enhancer.

[0413] 10. The composition of embodiment 9, wherein the penetration enhancer comprises the organic solvent.

[0414] 11. The composition according to embodiment 1, wherein the penetration enhancer and / or organic solvent comprises propylene glycol, 2-(2-ethoxyethoxy)ethanol, glycerol or polyethylene glycol, or a combination of two or more thereof.

[0415] 12. The composition of any one of embodiments 1-11, comprising an emulsifier.

[0416] 13. The composition of embodiment 12, wherein the penetration enhancer and / or organic solvent comprises the emulsifier.

[0417] 14. The composition of embodiment 12 or embodiment 13, wherein the emulsifier comprises cocoyl caprylic caprylate, decyl oleate, diethylene glycol monoethyl ether, dimethyl isosorbide, glyceryl monooleate, isopropyl myristate, medium chain triglycerides (MCT), octyldodecanol, oleyl alcohol, oleyl oleate, polyoxyethylene alkyl ether, polyoxyethylene stearate, propylene glycol monolaurate, propylene glycol, lecithin, cyclodextrin, sodium docusate, glyceryl monostearate, hydrogenated vegetable oil / cottonseed oil / palm kernel oil, MCT, N-methyl-2-pyrrolidone, poloxamer, PEG, polysorbate, PEG castor oil derivative, propylene glycol, polyoxyglycerol esters, sodium lauryl sulfate, sucrose esters or glycerin, or a combination of two or more thereof.

[0418] 15. The composition according to embodiment 1 or embodiment 2, wherein the penetration enhancer and / or organic solvent comprises diethylene glycol monoethyl ether (DGME), propylene glycol, glycerol or polyethylene glycol, or a combination of two or more thereof.

[0419] 16. The composition of embodiment 15, comprising said DGME.

[0420] 17. The composition according to embodiment 16, wherein the DGME is transcutol TM 、transcutolHP TM or transcutol P TM .

[0421] 18. The composition according to embodiment 17, comprising the transcutol HP TM (2-(2-ethoxyethoxy)ethanol).

[0422] 19. The composition of any one of embodiments 16-18, wherein the DGME has a purity of >99.90%.

[0423] 20. The composition of any one of embodiments 1-19, wherein the penetration enhancer and / or organic solvent comprises: (i) DGME present at about 40-50%, about 43-49%, about 47-49%, or about 47-48% by weight of the composition, (ii) PEG present at about 2-45%, about 3-24%, about 3-14%, about 13-15%, or about 13-14% by weight of the composition, (iii) glycerol present at about 12-24%, about 14-20%, about 13-17%, about 14-16%, or about 14-15% by weight of the composition, (iv) about 8-30%, about 9-22%, about 18-23%, about 19-30%, about 20-31%, about 25-32%, about 26-28%, about 29-30%, about 31-32%, about 33-34%, about 35-36%, about 37-38%, about 39-40%, about 41-41%, about 42-43%, about 44-45%, about 46-47%, about 48-49%, about 49-50%, about 50-50%, about 51-52%, about 52-53%, about 53-54%, about 55-56%, about 57-58%, about 58-59%, about 59-60%, about 59-61%, about 59-70%, about 59-71%, about 59-80%, about 59-90%, about 59-81%, about 59-91%, about 59-93%, about 59-83%, about 59-94%, about 59-103%, about 59-115%, about 59-123%, about 59- 22%, about 19-21%, or about 19-20% propylene glycol is present, the combination of (v) (i) and (ii), the combination of (vi) (i) and (iii), the combination of (vii) (i) and (iv), the combination of (viii) (ii) and (iii), the combination of (ix) (ii) and (iv), the combination of (x) (iii) and (iv), the combination of (xi) (i), (ii) and (iii), the combination of (xii) (i), (ii) and (iv), the combination of (xiii) (i), (iii) and (iv), the combination of (xiv) (ii), (iii) and (iv), or the combination of (vx) (i), (ii), (iii) and (iv).

[0424] 21. The composition of any one of embodiments 1-19, wherein the total amount of penetration enhancer and / or organic solvent is present at about 85% to 99% by weight of the composition.

[0425] 22. The composition of any one of embodiments 1-21, further comprising an antioxidant.

[0426] 23. The composition of embodiment 22, wherein the total amount of antioxidant present in the composition is about 0.01%-1% by weight of the composition.

[0427] 24. A composition comprising Rubostar free base or Rubostar mesylate monohydrate or a salt thereof and an antioxidant.

[0428] 25. A composition according to any one of embodiments 22-24, wherein the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, ascorbic acid, alpha-tocopheryl acetate or ascorbyl palmitate, or a combination thereof or two or more thereof.

[0429] 26. The composition of embodiment 24 or 25, wherein the total amount of antioxidant is present in the composition at about 0.2%-0.3% by weight of the composition.

[0430] 27. A composition according to embodiment 24 or 25, wherein the antioxidant comprises butylated hydroxytoluene (BHT) present at about 0.05-0.3%, about 0.1% or about 0.2% by weight of the composition, and / or comprises butylated hydroxyanisole (BHA) present at about 0.05-0.2% or about 0.1% by weight of the composition.

[0431] 28. The composition of any one of embodiments 1-27, further comprising an alcohol.

[0432] 29. The composition of embodiment 28, wherein the total amount of alcohol is present in the composition at about 62%-99% by weight of the composition.

[0433] 30. A composition comprising Rubostar free base or Rubostar mesylate monohydrate or a salt thereof and an alcohol.

[0434] 31. The composition of any one of embodiments 28-30, wherein the alcohol comprises a C2-6 alcohol.

[0435] 32. A composition according to any one of embodiments 28-31, wherein the alcohol comprises glycerol, ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol or tert-butanol, or a combination of two or more thereof.

[0436] 33. The composition of any one of embodiments 30-32, wherein the total amount of alcohol is present in the composition at about 85%-99% by weight of the composition.

[0437] 34. A composition according to any of embodiments 30-32, wherein the alcohol comprises: (i) DGME present at about 40-50%, about 43-49%, about 47-49%, or about 47-48% by weight of the composition, (ii) PEG present at about 2-45%, about 3-24%, about 3-14%, about 13-15%, or about 13-14% by weight of the composition, (iii) glycerol present at about 12-24%, about 14-20%, about 13-17%, about 14-16%, or about 14-15% by weight of the composition, (iv) about 8-30%, about 9-22%, about 18-22%, about 19-30%, about 20-25%, about 26-27%, about 28-30%, about 29-30%, about 30-40%, about 31-31%, about 32-33%, about 34-35%, about 36-37%, about 38-39%, about 39-40%, about 41-42%, about 43-44%, about 45-45%, about 46-47%, about 48-49%, about 49-50%, about 50-50%, about 51-52%, about 52-53%, about 53-54%, about 55-56%, about 56-57%, about 57-58%, about 58-59%, about 59-60%, about 59-61%, about 59-70%, about 59-71%, about 59-80%, about 59-90%, about 59-81%, about 59-91%, about 59-83%, about 59-93%, about 59-94%, about 59-103%, about 59- 19-21% or about 19-20% propylene glycol is present, (v) a combination of (i) and (ii), a combination of (vi) (i) and (iii), a combination of (vii) (i) and (iv), a combination of (viii) (ii) and (iii), a combination of (ix) (ii) and (iv), a combination of (x) (iii) and (iv), a combination of (xi) (i), (ii) and (iii), a combination of (xii) (i), (ii) and (iv), a combination of (xiii) (i), (iii) and (iv), a combination of (xiv) (ii), (iii) and (iv), or a combination of (vx) (i), (ii), (iii) and (iv).

[0438] 35. The composition of any one of embodiments 1-34, further comprising a gelling agent.

[0439] 36. The composition of embodiment 35, wherein the gelling agent is about 16%-75% or about 18%-56% by weight of the composition.

[0440] 37. A composition comprising rubostar free base, rubostar mesylate monohydrate or a salt thereof and a gelling agent.

[0441] 38. The composition of any one of embodiments 35-37, wherein the gelling agent comprises hydroxypropyl cellulose, hydroxyethyl cellulose, carbopol, carbomer, or carboxymethyl cellulose, or a combination of two or more thereof.

[0442] 39. The composition according to embodiment 38, wherein the hydroxypropyl cellulose (HPC) is HPC GF, HPC CF or HPC HF, or a combination of two or more thereof.

[0443] 40. A composition according to any one of embodiments 37 to 39, wherein the gelling agent comprises: (i) glycerol present at about 12-24%, about 14-20%, about 13-17%, about 14-16%, or about 14-15% by weight of the composition, (ii) PEG present at about 2-45%, about 3-24%, about 3-14%, about 13-15%, or about 13-14% by weight of the composition, (iii) HPC present at about 0.5%-4% or about 1-3% by weight of the composition, (iv) a combination of (i) and (ii), (v) a combination of (i) and (iii), (vi) a combination of (ii) and (iii), or (vii) a combination of (i), (ii), and (iii).

[0444] 41. The composition of any one of embodiments 37-39, wherein the gelling agent has an average molecular weight of about 700,000 Da to 1,150,000 Da.

[0445] 42. A composition comprising rubostar free base or rubostar mesylate monohydrate or a salt thereof, a penetration enhancer and / or an organic solvent and an antioxidant.

[0446] 43. The composition of embodiment 42, wherein the total amount of penetration enhancer and / or organic solvent is from about 62% to about 99% by weight of the composition.

[0447] 44. The composition of embodiment 42 or embodiment 43, comprising the penetration enhancer.

[0448] 45. A composition according to embodiment 44, wherein the penetration enhancer comprises C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester or fatty ether, or a combination of two or more thereof.

[0449] 46. ​​The composition of any one of embodiments 42-45, comprising the organic solvent.

[0450] 47. A composition according to embodiment 46, wherein the organic solvent comprises C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester or fatty ether, or a combination of two or more thereof.

[0451] 48. The composition of embodiment 47, wherein the organic solvent comprises propylene glycol, 2-(2-ethoxyethoxy)ethanol, glycerol or polyethylene glycol, or a combination of two or more thereof.

[0452] 49. A composition according to embodiment 42 or embodiment 43, wherein the penetration enhancer and / or organic solvent comprises C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester or fatty ether, or a combination of two or more thereof.

[0453] 50. The composition of any one of embodiments 42-49, comprising the penetration enhancer.

[0454] 51. The composition of embodiment 50, wherein the penetration enhancer comprises the organic solvent.

[0455] 52. The composition of embodiment 42, wherein the penetration enhancer and / or organic solvent comprises propylene glycol, 2-(2-ethoxyethoxy)ethanol, glycerol or polyethylene glycol, or a combination of two or more thereof.

[0456] 53. The composition of any one of embodiments 42-52, comprising an emulsifier.

[0457] 54. The composition of embodiment 53, wherein the penetration enhancer and / or organic solvent comprises the emulsifier.

[0458] 55. The composition of embodiment 53 or embodiment 54, wherein the emulsifier comprises cocoyl caprylate, decyl oleate, diethylene glycol monoethyl ether, dimethyl isosorbide, glyceryl monooleate, isopropyl myristate, MCT, octyldodecanol, oleyl alcohol, oleyl oleate, polyoxyethylene alkyl ether, polyoxyethylene stearate, propylene glycol monolaurate, propylene glycol, lecithin, cyclodextrin, sodium docusate, glyceryl monostearate, hydrogenated vegetable oil / cottonseed oil / palm kernel oil, MCT, N-methyl-2-pyrrolidone, poloxamer, PEG, polysorbate, PEG castor oil derivative, propylene glycol, polyoxyglycerol esters, sodium lauryl sulfate, sucrose esters or glycerin, or a combination of two or more thereof.

[0459] 56. The composition of embodiment 42 or embodiment 43, wherein the penetration enhancer and / or organic solvent comprises diethylene glycol monoethyl ether (DGME), propylene glycol, glycerol or polyethylene glycol, or a combination of two or more thereof.

[0460] 57. A composition according to embodiment 56, comprising the DGME.

[0461] 58. The composition according to embodiment 57, wherein the DGME is transcutol TM 、transcutolHP TM or transcutol P TM .

[0462] 59. The composition according to embodiment 58, comprising the transcutol HP TM (2-(2-ethoxyethoxy)ethanol).

[0463] 60. The composition of any one of embodiments 57-59, wherein the DGME has a purity of >99.90%.

[0464] 61. The composition of any one of embodiments 42-60, wherein the penetration enhancer and / or organic solvent comprises: (i) DGME present at about 40-50%, about 43-49%, about 47-49%, or about 47-48% by weight of the composition, (ii) PEG present at about 2-45%, about 3-24%, about 3-14%, about 13-15%, or about 13-14% by weight of the composition, (iii) glycerol present at about 12-24%, about 14-20%, about 13-17%, about 14-16%, or about 14-15% by weight of the composition, (iv) about 8-30%, about 9-22%, about 18-23%, about 19-30%, about 20-31%, about 25-32%, about 26-28%, about 29-30%, about 31-32%, about 33-34%, about 35-36%, about 37-38%, about 39-40%, about 41-41%, about 42-43%, about 44-45%, about 46-47%, about 48-49%, about 49-50%, about 50-50%, about 51-52%, about 52-53%, about 53-54%, about 55-56%, about 57-58%, about 58-59%, about 59-60%, about 59-61%, about 59-70%, about 59-71%, about 59-80%, about 59-90%, about 59-81%, about 59-91%, about 59-83%, about 59-93%, about 59-94%, about 59-103%, about 59-115%, about 59-123%, about 59 22%, about 19-21%, or about 19-20% propylene glycol is present, the combination of (v) (i) and (ii), the combination of (vi) (i) and (iii), the combination of (vii) (i) and (iv), the combination of (viii) (ii) and (iii), the combination of (ix) (ii) and (iv), the combination of (x) (iii) and (iv), the combination of (xi) (i), (ii) and (iii), the combination of (xii) (i), (ii) and (iv), the combination of (xiii) (i), (iii) and (iv), the combination of (xiv) (ii), (iii) and (iv), or the combination of (vx) (i), (ii), (iii) and (iv).

[0465] 62. The composition of any one of embodiments 42-60, wherein the total amount of penetration enhancer and / or organic solvent is present at about 85% to 99% by weight of the composition.

[0466] 63. A composition according to any one of embodiments 42-62, wherein the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, ascorbic acid, alpha-tocopheryl acetate or ascorbyl palmitate, or a combination of two or more thereof.

[0467] 64. A composition according to any one of embodiments 42-63, wherein the total amount of antioxidant is present at about 0.01% to 15% or about 0.2% to 0.3% by weight of the composition.

[0468] 65. A composition according to any of embodiments 42-63, wherein the antioxidant comprises butylated hydroxytoluene (BHT) present at about 0.05-0.3%, about 0.1% or about 0.2% by weight of the composition, and / or comprises butylated hydroxyanisole (BHA) present at about 0.05-0.2% or about 0.1% by weight of the composition.

[0469] 66. A composition comprising Rubostar or Rubostar mesylate or a salt thereof, a penetration enhancer and / or an organic solvent, one or more antioxidants and an alcohol.

[0470] 67. The composition of embodiment 66, wherein the penetration enhancer and / or organic solvent is from about 62% to about 99% by weight of the composition.

[0471] 68. The composition of embodiment 66 or embodiment 67, comprising the penetration enhancer.

[0472] 69. A composition according to embodiment 68, wherein the penetration enhancer comprises C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester or fatty ether, or a combination of two or more thereof.

[0473] 70. The composition of any one of embodiments 66-69, comprising the organic solvent.

[0474] 71. A composition according to embodiment 70, wherein the organic solvent comprises C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester or fatty ether, or a combination of two or more thereof.

[0475] 72. The composition of embodiment 71, wherein the organic solvent comprises propylene glycol, 2-(2-ethoxyethoxy)ethanol, glycerol or polyethylene glycol, or a combination of two or more thereof.

[0476] 73. A composition according to embodiment 66 or embodiment 67, wherein the penetration enhancer and / or organic solvent comprises C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester or fatty ether, or a combination of two or more thereof.

[0477] 74. The composition of any one of embodiments 66-73, comprising the penetration enhancer.

[0478] 75. The composition of embodiment 74, wherein the penetration enhancer comprises the organic solvent.

[0479] 76. The composition of embodiment 66 or embodiment 67, wherein the penetration enhancer and / or organic solvent comprises propylene glycol, 2-(2-ethoxyethoxy)ethanol, glycerol or polyethylene glycol, or a combination of two or more thereof.

[0480] 77. The composition of any one of embodiments 66-76, comprising an emulsifier.

[0481] 78. The composition of embodiment 77, wherein the penetration enhancer and / or organic solvent comprises the emulsifier.

[0482] 79. The composition of embodiment 77 or embodiment 78, wherein the emulsifier comprises cocoyl caprylic caprylate, decyl oleate, diethylene glycol monoethyl ether, dimethyl isosorbide, glyceryl monooleate, isopropyl myristate, MCT, octyldodecanol, oleyl alcohol, oleyl oleate, polyoxyethylene alkyl ether, polyoxyethylene stearate, propylene glycol monolaurate, propylene glycol, lecithin, cyclodextrin, sodium docusate, glyceryl monostearate, hydrogenated vegetable oil / cottonseed oil / palm kernel oil, MCT, N-methyl-2-pyrrolidone, poloxamer, PEG, polysorbate, PEG castor oil derivative, propylene glycol, polyoxyglycerol esters, sodium lauryl sulfate, sucrose esters or glycerin, or a combination of two or more thereof.

[0483] 80. The composition of embodiment 66 or embodiment 67, wherein the penetration enhancer and / or organic solvent comprises diethylene glycol monoethyl ether (DGME), propylene glycol, glycerol or polyethylene glycol, or a combination of two or more thereof.

[0484] 81. The composition of embodiment 80, comprising said DGME.

[0485] 82. The composition according to embodiment 81, wherein the DGME is transcutol TM、transcutolHP TM or transcutol P TM .

[0486] 83. A composition according to embodiment 82, comprising the transcutol HP TM (2-(2-ethoxyethoxy)ethanol).

[0487] 84. The composition of any one of embodiments 81-83, wherein the DGME has a purity of >99.90%.

[0488] 85. The composition of any one of embodiments 66-84, wherein the penetration enhancer and / or organic solvent comprises: (i) DGME present at about 40-50%, about 43-49%, about 47-49%, or about 47-48% by weight of the composition, (ii) PEG present at about 2-45%, about 3-24%, about 3-14%, about 13-15%, or about 13-14% by weight of the composition, (iii) glycerol present at about 12-24%, about 14-20%, about 13-17%, about 14-16%, or about 14-15% by weight of the composition, (iv) about 8-30%, about 9-22%, about 18-23%, about 19-30%, about 20-31%, about 25-32%, about 26-28%, about 29-30%, about 31-32%, about 33-34%, about 35-36%, about 37-38%, about 39-40%, about 41-41%, about 42-43%, about 44-45%, about 46-47%, about 48-49%, about 49-50%, about 50-50%, about 51-52%, about 52-53%, about 53-54%, about 55-56%, about 57-58%, about 58-59%, about 59-60%, about 59-61%, about 59-70%, about 59-71%, about 59-80%, about 59-90%, about 59-81%, about 59-91%, about 59-83%, about 59-93%, about 59-94%, about 59-103%, about 59-115%, about 59-123%, about 59 22%, about 19-21%, or about 19-20% propylene glycol is present, the combination of (v) (i) and (ii), the combination of (vi) (i) and (iii), the combination of (vii) (i) and (iv), the combination of (viii) (ii) and (iii), the combination of (ix) (ii) and (iv), the combination of (x) (iii) and (iv), the combination of (xi) (i), (ii) and (iii), the combination of (xii) (i), (ii) and (iv), the combination of (xiii) (i), (iii) and (iv), the combination of (xiv) (ii), (iii) and (iv), or the combination of (vx) (i), (ii), (iii) and (iv).

[0489] 86. The composition of any one of embodiments 66-84, wherein the total amount of penetration enhancer and / or organic solvent is present in 85% to 99% by weight of the composition.

[0490] 87. A composition according to any one of embodiments 66-86, wherein the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, ascorbic acid, alpha-tocopheryl acetate or ascorbyl palmitate, or a combination thereof or two or more thereof.

[0491] 88. A composition according to any one of embodiments 66-87, wherein the total amount of antioxidant is present in the composition at about 0.01% to 1% or about 0.2% to 0.3% by weight of the composition.

[0492] 89. A composition according to any of embodiments 66-87, wherein the antioxidant comprises butylated hydroxytoluene (BHT) present at about 0.05-0.3%, about 0.1% or about 0.2% by weight of the composition, and / or comprises butylated hydroxyanisole (BHA) present at about 0.05-0.2% or about 0.1% by weight of the composition.

[0493] 90. The composition of any one of embodiments 66-89, wherein the alcohol comprises a C2-6 alcohol.

[0494] 91. The composition of any one of embodiments 66-89, wherein the alcohol comprises glycerol, ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, or tert-butanol.

[0495] 92. The composition of any one of embodiments 66-91, wherein the alcohol is present in the composition at about 62%-99% or about 85%-99% by weight of the composition.

[0496] 93. A composition according to any of embodiments 66-91, wherein the alcohol comprises: (i) DGME present at about 40-50%, about 43-49%, about 47-49%, or about 47-48% by weight of the composition, (ii) PEG present at about 2-45%, about 3-24%, about 3-14%, about 13-15%, or about 13-14% by weight of the composition, (iii) glycerol present at about 12-24%, about 14-20%, about 13-17%, about 14-16%, or about 14-15% by weight of the composition, (iv) about 8-30%, about 9-22%, about 18-22%, about 19-30%, about 20-25%, about 26-27%, about 28-30%, about 29-30%, about 30-30%, about 31-31%, about 32-33%, about 34-35%, about 36-37%, about 38-39%, about 39-40%, about 30-40%, about 31-31%, about 32-33%, about 33-34%, about 35-36%, about 37-38%, about 38-39%, about 39-40%, about 30-40%, about 31-33%, about 33-35%, about 35-36%, about 38-39%, about 39-40%, about 31-33%, about 33-33%, about 35 19-21% or about 19-20% propylene glycol is present, (v) a combination of (i) and (ii), a combination of (vi) (i) and (iii), a combination of (vii) (i) and (iv), a combination of (viii) (ii) and (iii), a combination of (ix) (ii) and (iv), a combination of (x) (iii) and (iv), a combination of (xi) (i), (ii) and (iii), a combination of (xii) (i), (ii) and (iv), a combination of (xiii) (i), (iii) and (iv), a combination of (xiv) (ii), (iii) and (iv), or a combination of (vx) (i), (ii), (iii) and (iv).

[0497] 94. A composition comprising rubostar free base or rubostar mesylate monohydrate or a salt thereof, a penetration enhancer and / or an organic solvent and an alcohol.

[0498] 95. The composition of embodiment 94, wherein the total amount of penetration enhancer and / or organic solvent is from about 62% to about 99% by weight of the composition.

[0499] 96. The composition of embodiment 94 or embodiment 95, comprising the penetration enhancer.

[0500] 97. A composition according to embodiment 96, wherein the penetration enhancer comprises C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester or fatty ether, or two or more thereof.

[0501] 98. The composition of any one of embodiments 94-97, comprising the organic solvent.

[0502] 99. A composition according to embodiment 98, wherein the organic solvent comprises C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester or fatty ether, or two or more thereof.

[0503] 100. The composition of embodiment 99, wherein the organic solvent comprises propylene glycol, 2-(2-ethoxyethoxy)ethanol, glycerol or polyethylene glycol, or a combination of two or more thereof.

[0504] 101. A composition according to embodiment 94 or embodiment 95, wherein the penetration enhancer and / or organic solvent comprises C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester or fatty ether, or a combination of two or more thereof.

[0505] 102. The composition of any one of embodiments 94-101, comprising the penetration enhancer.

[0506] 103. The composition of embodiment 102, wherein the penetration enhancer comprises the organic solvent.

[0507] 104. The composition of embodiment 94, wherein the penetration enhancer and / or organic solvent comprises propylene glycol, 2-(2-ethoxyethoxy)ethanol, glycerol or polyethylene glycol, or a combination of two or more thereof.

[0508] 105. The composition of any one of embodiments 94-104, comprising an emulsifier.

[0509] 106. The composition of embodiment 105, wherein the penetration enhancer and / or organic solvent comprises the emulsifier.

[0510] 107. The composition of embodiment 105 or embodiment 106, wherein the emulsifier comprises cocoyl caprylic caprylate, decyl oleate, diethylene glycol monoethyl ether, dimethyl isosorbide, glyceryl monooleate, isopropyl myristate, MCT, octyldodecanol, oleyl alcohol, oleyl oleate, polyoxyethylene alkyl ether, polyoxyethylene stearate, propylene glycol monolaurate, propylene glycol, lecithin, cyclodextrin, sodium docusate, glyceryl monostearate, hydrogenated vegetable oil / cottonseed oil / palm kernel oil, MCT, N-methyl-2-pyrrolidone, poloxamer, PEG, polysorbate, PEG castor oil derivative, propylene glycol, polyoxyglycerol esters, sodium lauryl sulfate, sucrose esters or glycerin, or a combination of two or more thereof.

[0511] 108. The composition of embodiment 94 or embodiment 95, wherein the penetration enhancer and / or organic solvent comprises diethylene glycol monoethyl ether (DGME), propylene glycol, glycerol or polyethylene glycol, or a combination of two or more thereof.

[0512] 109. The composition of embodiment 108, comprising said DGME.

[0513] 110. The composition according to embodiment 109, wherein the DGME is Transcutol TM 、TranscutolHP TM or Transcutol P TM .

[0514] 111. The composition according to embodiment 110, comprising the Transcutol HP TM (2-(2-ethoxyethoxy)ethanol).

[0515] 112. The composition of any one of embodiments 109-111, wherein the DGME has a purity of >99.90%.

[0516] 113. The composition of any one of embodiments 94-112, wherein the penetration enhancer and / or organic solvent comprises: (i) DGME present at about 40-50%, about 43-49%, about 47-49%, or about 47-48% by weight of the composition, (ii) PEG present at about 2-45%, about 3-24%, about 3-14%, about 13-15%, or about 13-14% by weight of the composition, (iii) glycerol present at about 12-24%, about 14-20%, about 13-17%, about 14-16%, or about 14-15% by weight of the composition, (iv) about 8-30%, about 9-22%, about 18-24%, about 19-30%, about 20-30%, about 25-20%, about 26-27%, about 28-30%, about 29-30%, about 31-31%, about 32-33%, about 34-35%, about 36-37%, about 38-39%, about 39-40%, about 30-40%, about 31-41%, about 32-43%, about 33-33%, about 35-36%, about 37-38%, about 38-39%, about 39-41%, about 31-43%, about 33-33%, about 35-35%, about 36-35%, about 38-39%, about 39-40%, about 31-43%, about 33-33%, about 35-33%, about 33-33%, about 35 -22%, about 19-21%, or about 19-20% propylene glycol present, the combination of (v)(i) and (ii), the combination of (vi)(i) and (iii), the combination of (vii)(i) and (iv), the combination of (viii)(ii) and (iii), the combination of (ix)(ii) and (iv), the combination of (x)(iii) and (iv), the combination of (xi)(i), (ii), and (iii), the combination of (xii)(i), (ii), and (iv), the combination of (xiii)(i), (iii), and (iv), the combination of (xiv)(ii), (iii), and (iv), or the combination of (vx)(i), (ii), (iii), and (iv).

[0517] 114. The composition of any one of embodiments 94-112, wherein the total amount of penetration enhancer and / or organic solvent is present at about 85% to 99%, 50% to 80%, 50% to 70%, or about 60% by weight of the composition.

[0518] 115. The composition of any one of embodiments 94-114, wherein the alcohol comprises a C2-6 alcohol.

[0519] 116. The composition of any one of embodiments 94-115, wherein the alcohol comprises glycerol, ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, or tert-butanol.

[0520] 117. The composition of any one of embodiments 94-116, wherein the alcohol is present in the composition at about 62%-99% or about 85-99% by weight of the composition.

[0521] 118. A composition according to any of embodiments 94-117, wherein the alcohol comprises: (i) DGME present at about 40-50%, about 43-49%, about 47-49%, or about 47-48% by weight of the composition, (ii) PEG present at about 2-45%, about 3-24%, about 3-14%, about 13-15%, or about 13-14% by weight of the composition, (iii) glycerol present at about 12-24%, about 14-20%, about 13-17%, about 14-16%, or about 14-15% by weight of the composition, (iv) about 8-30%, about 9-22%, about 18-22%, about 19-30%, about 20-25%, about 26-27%, about 28-30%, about 29-30%, about 30-30%, about 31-31%, about 32-33%, about 34-35%, about 36-37%, about 38-39%, about 39-40%, about 30-40%, about 31-41%, about 32-43%, about 33-33%, about 35-36%, about 37-38%, about 38-39%, about 39-41%, about 31-43%, about 33-33%, about 35-33%, about 36-35%, about 38-39%, about 39-40%, about 33-33%, about 35 about 19-21% or about 19-20% propylene glycol is present, (v) a combination of (i) and (ii), (vi) a combination of (i) and (iii), (vii) a combination of (i) and (iv), (viii) a combination of (ii) and (iii), (ix) a combination of (ii) and (iv), (x) a combination of (iii) and (iv), (xi) (i), (ii) and (iii), (xii) (i), (ii) and (iv), (xiii) (i), (iii) and (iv), (xiv) (ii), (iii) and (iv), or (vx) (i), (ii), (iii) and (iv).

[0522] 119. A composition comprising Rubostar free base or Rubostar mesylate monohydrate or a salt thereof, an antioxidant and an alcohol.

[0523] 120. The composition of embodiment 119, wherein the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, ascorbic acid, alpha-tocopheryl acetate, or ascorbyl palmitate, or a combination thereof or two or more thereof.

[0524] 121. The composition of embodiment 119 or 120, wherein the total amount of antioxidant is present in the composition at about 0.01% to 1% or about 0.2% to 0.3% by weight of the composition.

[0525] 122. A composition according to embodiment 119 or 120, wherein the antioxidant comprises butylated hydroxytoluene (BHT) present at about 0.05-0.3%, about 0.1% or about 0.2% by weight of the composition, and / or comprises butylated hydroxyanisole (BHA) present at about 0.05-0.2% or about 0.1% by weight of the composition.

[0526] 123. The composition of any one of embodiments 119-122, wherein the alcohol comprises a C2-6 alcohol.

[0527] 124. The composition of any one of embodiments 119-123, wherein the alcohol comprises glycerol, ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, or tert-butanol.

[0528] 125. The composition of any one of embodiments 119-124, wherein the alcohol is present in the composition at about 62%-99% or about 85-99% by weight of the composition.

[0529] 126. A composition according to any of embodiments 119-124, wherein the alcohol comprises: (i) DGME present at about 40-50%, about 43-49%, about 47-49%, or about 47-48% by weight of the composition, (ii) PEG present at about 2-45%, about 3-24%, about 3-14%, about 13-15%, or about 13-14% by weight of the composition, (iii) glycerol present at about 12-24%, about 14-20%, about 13-17%, about 14-16%, or about 14-15% by weight of the composition, (iv) about 8-30%, about 9-22%, about 18-22%, about 19-30%, about 20-25%, about 21-26%, about 27-28%, about 29-30%, about 31-32%, about 33-34%, about 35-36%, about 37-38%, about 39-40%, about 41-41%, about 42-43%, about 44-45%, about 46-47%, about 48-49%, about 49-50%, about 50-50%, about 51-52%, about 52-53%, about 53-54%, about 55-56%, about 56-57%, about 57-58%, about 58-59%, about 59-60%, about 59-61%, about 59-70%, about 59-71%, about 59-80%, about 59-81%, about 59-90%, about 59-91%, about 59-100%, about 59-110%, about 59-120%, about 59-130%, about 59-1 about 19-21% or about 19-20% propylene glycol is present, (v) a combination of (i) and (ii), (vi) a combination of (i) and (iii), (vii) a combination of (i) and (iv), (viii) a combination of (ii) and (iii), (ix) a combination of (ii) and (iv), (x) a combination of (iii) and (iv), (xi) (i), (ii) and (iii), (xii) (i), (ii) and (iv), (xiii) (i), (iii) and (iv), (xiv) (ii), (iii) and (iv), or (vx) (i), (ii), (iii) and (iv).

[0530] 127. A composition comprising rubostar free base or rubostar mesylate monohydrate or a salt thereof, a penetration enhancer and / or an organic solvent, an antioxidant, an alcohol and a gelling agent.

[0531] 128. The composition of embodiment 127, wherein the total amount of penetration enhancer and / or organic solvent is from about 85% to about 99% by weight of the composition.

[0532] 129. The composition of embodiment 127 or embodiment 128, comprising the penetration enhancer.

[0533] 130. A composition according to embodiment 129, wherein the penetration enhancer comprises C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester or fatty ether, or a combination of two or more thereof.

[0534] 131. The composition of any one of embodiments 127-130, comprising the organic solvent.

[0535] 132. A composition according to embodiment 131, wherein the organic solvent comprises C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester or fatty ether, or a combination of two or more thereof.

[0536] 133. A composition according to embodiment 132, wherein the organic solvent comprises propylene glycol, 2-(2-ethoxyethoxy)ethanol, glycerol or polyethylene glycol, or a combination of two or more thereof.

[0537] 134. A composition according to embodiment 127 or embodiment 128, wherein the penetration enhancer and / or organic solvent comprises C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester or fatty ether, or a combination of two or more thereof.

[0538] 135. The composition of any one of embodiments 127-134, comprising the penetration enhancer.

[0539] 136. The composition of embodiment 135, wherein the penetration enhancer comprises the organic solvent.

[0540] 137. The composition of embodiment 127, wherein the penetration enhancer and / or organic solvent comprises propylene glycol, 2-(2-ethoxyethoxy)ethanol, glycerol or polyethylene glycol, or a combination of two or more thereof.

[0541] 138. The composition of any one of embodiments 127-137, comprising an emulsifier.

[0542] 139. The composition of embodiment 138, wherein the penetration enhancer and / or organic solvent comprises the emulsifier.

[0543] 140. The composition of embodiment 138 or embodiment 139, wherein the emulsifier comprises cocoyl caprylic caprylate, decyl oleate, diethylene glycol monoethyl ether, dimethyl isosorbide, glyceryl monooleate, isopropyl myristate, MCT, octyldodecanol, oleyl alcohol, oleyl oleate, polyoxyethylene alkyl ether, polyoxyethylene stearate, propylene glycol monolaurate, propylene glycol, lecithin, cyclodextrin, sodium docusate, glyceryl monostearate, hydrogenated vegetable oil / cottonseed oil / palm kernel oil, MCT, N-methyl-2-pyrrolidone, poloxamer, PEG, polysorbate, PEG castor oil derivative, propylene glycol, polyoxyglycerol esters, sodium lauryl sulfate, sucrose esters or glycerin, or a combination of two or more thereof.

[0544] 141. The composition of embodiment 127 or embodiment 128, wherein the penetration enhancer and / or organic solvent comprises diethylene glycol monoethyl ether (DGME), propylene glycol, glycerol or polyethylene glycol, or a combination of two or more thereof.

[0545] 142. A composition according to embodiment 141, comprising the DGME.

[0546] 143. The composition according to embodiment 142, wherein the DGME is Transcutol TM 、TranscutolHP TM or Transcutol P TM .

[0547] 144. A composition according to embodiment 143, comprising the Transcutol HP TM (2-(2-ethoxyethoxy)ethanol).

[0548] 145. The composition of any one of embodiments 142-144, wherein the DGME has a purity of >99.90%.

[0549] 146. The composition of any one of embodiments 127-145, wherein the penetration enhancer and / or organic solvent comprises: (i) DGME present at about 40-50%, about 43-49%, about 47-49%, or about 47-48% by weight of the composition, (ii) PEG present at about 2-45%, about 3-24%, about 3-14%, about 13-15%, or about 13-14% by weight of the composition, (iii) glycerol present at about 12-24%, about 14-20%, about 13-17%, about 14-16%, or about 14-15% by weight of the composition, (iv) about 8-30%, about 9-22%, about 11-24%, about 13-17 ... 8-22%, about 19-21%, or about 19-20% propylene glycol is present, the combination of (v) (i) and (ii), the combination of (vi) (i) and (iii), the combination of (vii) (i) and (iv), the combination of (viii) (ii) and (iii), the combination of (ix) (ii) and (iv), the combination of (x) (iii) and (iv), the combination of (xi) (i), (ii) and (iii), the combination of (xii) (i), (ii) and (iv), the combination of (xiii) (i), (iii) and (iv), the combination of (xiv) (ii), (iii) and (iv), or the combination of (vx) (i), (ii), (iii) and (iv).

[0550] 147. The composition of any one of embodiments 127-145, wherein the total amount of penetration enhancer and / or organic solvent is present at about 85% to 99% by weight of the composition.

[0551] 148. A composition according to any one of embodiments 127-147, wherein the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, ascorbic acid, alpha-tocopheryl acetate or ascorbyl palmitate, or a combination thereof or two or more thereof.

[0552] 149. The composition of any one of embodiments 127-148, wherein the total amount of antioxidant is present in the composition at about 0.01% to 1% or about 0.2% to 0.3% by weight of the composition.

[0553] 150. A composition according to any of embodiments 127-149, wherein the antioxidant comprises butylated hydroxytoluene (BHT) present at about 0.05-0.3%, about 0.1% or about 0.2% by weight of the composition, and / or comprises butylated hydroxyanisole (BHA) present at about 0.05-0.2% or about 0.1% by weight of the composition.

[0554] 151. The composition of any one of embodiments 127-150, wherein the alcohol comprises a C2-6 alcohol.

[0555] 152. The composition of any one of embodiments 127-151, wherein the alcohol comprises glycerol, ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, or tert-butanol.

[0556] 153. The composition of any one of embodiments 127-152, wherein the alcohol is present in the composition at about 62%-99% or about 85%-99% by weight of the composition.

[0557] 154. A composition according to any of embodiments 127-152, wherein the alcohol comprises: (i) DGME present at about 40-50%, about 43-49%, about 47-49%, or about 47-48% by weight of the composition, (ii) PEG present at about 2-45%, about 3-24%, about 3-14%, about 13-15%, or about 13-14% by weight of the composition, (iii) glycerol present at about 12-24%, about 14-20%, about 13-17%, about 14-16%, or about 14-15% by weight of the composition, (iv) about 8-30%, about 9-22%, about 18-22%, about 19-30%, about 20-25%, about 21-26%, about 27-28%, about 29-30%, about 31-32%, about 33-34%, about 35-36%, about 37-38%, about 39-40%, about 41-41%, about 42-43%, about 44-45%, about 46-47%, about 48-49%, about 49-50%, about 50-50%, about 51-52%, about 52-53%, about 53-54%, about 55-56%, about 56-57%, about 57-58%, about 58-59%, about 59-60%, about 59-61%, about 59-70%, about 59-71%, about 59-80%, about 59-90%, about 59-81%, about 59-91%, about 59-83%, about 59-93%, about 59-94%, about 59-103%, about 59-115%, about 59-123%, about 19-21% or about 19-20% propylene glycol is present, (v) a combination of (i) and (ii), (vi) a combination of (i) and (iii), (vii) a combination of (i) and (iv), (viii) a combination of (ii) and (iii), (ix) a combination of (ii) and (iv), (x) a combination of (iii) and (iv), (xi) (i), (ii) and (iii), (xii) (i), (ii) and (iv), (xiii) (i), (iii) and (iv), (xiv) (ii), (iii) and (iv), or (vx) (i), (ii), (iii) and (iv).

[0558] 155. The composition of any one of embodiments 127-154, wherein the gelling agent comprises hydroxypropyl cellulose, hydroxyethyl cellulose, carbopol, carbomer, or carboxymethyl cellulose, or a combination of two or more thereof.

[0559] 156. The composition of embodiment 155, wherein the hydroxypropyl cellulose is HPC GF, HPC CF or HPC HF, or a combination of two or more thereof.

[0560] 157. A composition according to any of embodiments 127-156, wherein the gelling agent is present in a total amount of about 16%-75% or about 18%-56% by weight of the composition; and / or the gelling agent comprises: (i) glycerol present in about 12-24%, about 14-20%, about 13-17%, about 14-16% or about 14-15% by weight of the composition, (ii) PEG present in about 2-45%, about 3-24%, about 3-14%, about 13-15% or about 13-14% by weight of the composition, (iii) HPC present in about 0.5%-4% or about 1-3% by weight of the composition, (iv) a combination of (i) and (ii), (v) a combination of (i) and (iii), (vi) a combination of (ii) and (iii), or (vii) a combination of (i), (ii) and (iii).

[0561] 158. A composition according to any one of embodiments 127-157, wherein the gelling agent has an average molecular weight of about 700,000 Da to 1,150,000 Da.

[0562] 159. A composition comprising Rubostar free base or Rubostar mesylate monohydrate or a salt thereof, an antioxidant, an alcohol and a gelling agent.

[0563] 160. The composition of embodiment 159, wherein the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, ascorbic acid, alpha-tocopheryl acetate, or ascorbyl palmitate, or a combination thereof or two or more thereof.

[0564] 161. The composition of embodiment 159 or 160, wherein the total amount of antioxidant is present in the composition at about 0.01% to 1% or about 0.2% to 0.3% by weight of the composition.

[0565] 162. A composition according to embodiment 159 or 160, wherein the antioxidant comprises butylated hydroxytoluene (BHT) present at about 0.05-0.3%, about 0.1% or about 0.2% by weight of the composition, and / or comprises butylated hydroxyanisole (BHA) present at about 0.05-0.2% or about 0.1% by weight of the composition.

[0566] 163. The composition of any one of embodiments 159-162, wherein the alcohol comprises a C2-6 alcohol.

[0567] 164. The composition of any one of embodiments 159-163, wherein the alcohol comprises glycerol, ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, or tert-butanol.

[0568] 165. The composition of any one of embodiments 159-164, wherein the alcohol is present in the composition at about 62%-99% or about 85%-99% by weight of the composition.

[0569] 166. A composition according to any of embodiments 159-164, wherein the alcohol comprises: (i) DGME present in about 40-50%, about 43-49%, about 47-49%, or about 47-48% by weight of the composition, (ii) PEG present in about 2-45%, about 3-24%, about 3-14%, about 13-15%, or about 13-14% by weight of the composition, (iii) glycerol present in about 12-24%, about 14-20%, about 13-17%, about 14-16%, or about 14-15% by weight of the composition, (iv) about 8-30%, about 9-22%, about 18-22%, about 19-30%, about 20-25%, about 21-26%, about 27-28%, about 29-30%, about 31-32%, about 33-34%, about 35-36%, about 37-38%, about 39-40%, about 41-41%, about 42-43%, about 44-45%, about 46-47%, about 48-49%, about 49-50%, about 50-50%, about 51-52%, about 52-53%, about 53-54%, about 55-56%, about 56-57%, about 57-58%, about 58-59%, about 59-60%, about 59-61%, about 59-70%, about 59-71%, about 59-80%, about 59-81%, about 59-90%, about 59-91%, about 59-83%, about 59-93%, about 59-94%, about 59-103%, about 59-115%, about 59-123%, about 19-21% or about 19-20% propylene glycol is present, (v) a combination of (i) and (ii), (vi) a combination of (i) and (iii), (vii) a combination of (i) and (iv), (viii) a combination of (ii) and (iii), (ix) a combination of (ii) and (iv), (x) a combination of (iii) and (iv), (xi) (i), (ii) and (iii), (xii) (i), (ii) and (iv), (xiii) (i), (iii) and (iv), (xiv) (ii), (iii) and (iv), or (vx) (i), (ii), (iii) and (iv).

[0570] 167. A composition according to any one of embodiments 159-166, wherein the gelling agent comprises hydroxypropyl cellulose, hydroxyethyl cellulose, carbopol, carbomer, or carboxymethyl cellulose, or a combination of two or more thereof.

[0571] 168. The composition of embodiment 167, wherein the hydroxypropyl cellulose is HPC GF, HPC CF or HPC HF, or a combination of two or more thereof.

[0572] 169. A composition according to any of embodiments 159-168, wherein the gelling agent is present in a total amount of about 16%-75% or about 18%-56% by weight of the composition; and / or the gelling agent comprises: (i) glycerol present in about 12-24%, about 14-20%, about 13-17%, about 14-16% or about 14-15% by weight of the composition, (ii) PEG present in about 2-45%, about 3-24%, about 3-14%, about 13-15% or about 13-14% by weight of the composition, (iii) HPC present in about 0.5%-4% or about 1-3% by weight of the composition, (iv) a combination of (i) and (ii), (v) a combination of (i) and (iii), (vi) a combination of (ii) and (iii), or (vii) a combination of (i), (ii) and (iii).

[0573] 170. The composition of any one of embodiments 159-169, wherein the gelling agent has an average molecular weight of about 700,000 Da to 1,150,000 Da.

[0574] 171. A composition comprising rubostar free base or rubostar mesylate monohydrate or a salt thereof, a penetration enhancer and / or an organic solvent, an alcohol and a gelling agent.

[0575] 172. The composition of embodiment 171, wherein the total amount of penetration enhancer and / or organic solvent is from about 62% to about 99% by weight of the composition.

[0576] 173. The composition of embodiment 171 or embodiment 172, comprising the penetration enhancer.

[0577] 174. A composition according to embodiment 173, wherein the penetration enhancer comprises C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester or fatty ether, or a combination of two or more thereof.

[0578] 175. The composition of any one of embodiments 171-174, comprising the organic solvent.

[0579] 176. A composition according to embodiment 175, wherein the organic solvent comprises C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester or fatty ether, or a combination of two or more thereof.

[0580] 177. The composition of embodiment 176, wherein the organic solvent comprises propylene glycol, 2-(2-ethoxyethoxy)ethanol, glycerol or polyethylene glycol, or a combination of two or more thereof.

[0581] 178. The composition of embodiment 171 or embodiment 172, wherein the penetration enhancer and / or organic solvent comprises C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester or fatty ether, or a combination of two or more thereof.

[0582] 179. The composition of any one of embodiments 171-178, comprising the penetration enhancer.

[0583] 180. The composition of embodiment 179, wherein the penetration enhancer comprises the organic solvent.

[0584] 181. The composition of embodiment 171, wherein the penetration enhancer and / or organic solvent comprises propylene glycol, 2-(2-ethoxyethoxy)ethanol, glycerol or polyethylene glycol, or a combination of two or more thereof.

[0585] 182. The composition of any one of embodiments 171-181, comprising an emulsifier.

[0586] 183. The composition of embodiment 182, wherein the penetration enhancer and / or organic solvent comprises the emulsifier.

[0587] 184. The composition of embodiment 182 or embodiment 183, wherein the emulsifier comprises cocoyl caprylic caprylate, decyl oleate, diethylene glycol monoethyl ether, dimethyl isosorbide, glyceryl monooleate, isopropyl myristate, MCT, octyldodecanol, oleyl alcohol, oleyl oleate, polyoxyethylene alkyl ethers, polyoxyethylene stearate, propylene glycol monolaurate, propylene glycol, lecithin, cyclodextrin, sodium docusate, glyceryl monostearate, hydrogenated vegetable oil / cottonseed oil / palm kernel oil, MCT, N-methyl-2-pyrrolidone, poloxamer, PEG, polysorbate, PEG castor oil derivative, propylene glycol, polyoxyglycerol esters, sodium lauryl sulfate, sucrose esters or glycerin, or a combination of two or more thereof.

[0588] 185. The composition of embodiment 171 or embodiment 172, wherein the penetration enhancer and / or organic solvent comprises diethylene glycol monoethyl ether (DGME), propylene glycol, glycerol or polyethylene glycol, or a combination of two or more thereof.

[0589] 186. A composition according to embodiment 185, comprising the DGME.

[0590] 187. The composition according to embodiment 186, wherein the DGME is Transcutol TM 、TranscutolHP TM or Transcutol P TM .

[0591] 188. A composition according to embodiment 187, comprising the Transcutol HP TM (2-(2-ethoxyethoxy)ethanol).

[0592] 189. The composition of any one of embodiments 186-188, wherein the DGME has a purity of >99.90%.

[0593] 190. The composition of any one of embodiments 171-189, wherein the penetration enhancer and / or organic solvent comprises: (i) DGME present at about 40-50%, about 43-49%, about 47-49%, or about 47-48% by weight of the composition, (ii) PEG present at about 2-45%, about 3-24%, about 3-14%, about 13-15%, or about 13-14% by weight of the composition, (iii) glycerol present at about 12-24%, about 14-20%, about 13-17%, about 14-16%, or about 14-15% by weight of the composition, (iv) about 8-30%, about 9-22%, about 11-24%, about 13-17 ... 8-22%, about 19-21%, or about 19-20% propylene glycol is present, the combination of (v) (i) and (ii), the combination of (vi) (i) and (iii), the combination of (vii) (i) and (iv), the combination of (viii) (ii) and (iii), the combination of (ix) (ii) and (iv), the combination of (x) (iii) and (iv), the combination of (xi) (i), (ii) and (iii), the combination of (xii) (i), (ii) and (iv), the combination of (xiii) (i), (iii) and (iv), the combination of (xiv) (ii), (iii) and (iv), or the combination of (vx) (i), (ii), (iii) and (iv).

[0594] 191. The composition of any one of embodiments 171-189, wherein the total amount of penetration enhancer and / or organic solvent is present at about 85% to 99% by weight of the composition.

[0595] 192. The composition of any one of embodiments 171-191, wherein the alcohol comprises a C2-6 alcohol.

[0596] 193. The composition of any one of embodiments 171-192, wherein the alcohol comprises glycerol, ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, or tert-butanol.

[0597] 194. The composition of any one of embodiments 171-193, wherein the alcohol is present in the composition at about 62%-99% or about 85%-99% by weight of the composition.

[0598] 195. A composition according to any of embodiments 171-193, wherein the alcohol comprises: (i) DGME present in about 40-50%, about 43-49%, about 47-49%, or about 47-48% by weight of the composition, (ii) PEG present in about 2-45%, about 3-24%, about 3-14%, about 13-15%, or about 13-14% by weight of the composition, (iii) glycerol present in about 12-24%, about 14-20%, about 13-17%, about 14-16%, or about 14-15% by weight of the composition, (iv) about 8-30%, about 9-22%, about 18-22%, about 19-30%, about 20-25%, about 21-26%, about 27-28%, about 29-30%, about 31-31%, about 32-33%, about 34-35%, about 36-37%, about 38-39%, about 39-40%, about 30-40%, about 31-32%, about 32-33%, about 38-39%, about 39-41%, about 30-41%, about 31-33%, about 31-34%, about 38-39%, about 39-42%, about 31-33%, about 31-35%, about 31-3 ... about 19-21% or about 19-20% propylene glycol is present, (v) a combination of (i) and (ii), (vi) a combination of (i) and (iii), (vii) a combination of (i) and (iv), (viii) a combination of (ii) and (iii), (ix) a combination of (ii) and (iv), (x) a combination of (iii) and (iv), (xi) (i), (ii) and (iii), (xii) (i), (ii) and (iv), (xiii) (i), (iii) and (iv), (xiv) (ii), (iii) and (iv), or (vx) (i), (ii), (iii) and (iv).

[0599] 196. A composition according to any one of embodiments 171-195, wherein the gelling agent comprises hydroxypropyl cellulose, hydroxyethyl cellulose, carbopol, carbomer, or carboxymethyl cellulose, or a combination of two or more thereof.

[0600] 197. The composition of embodiment 196, wherein the hydroxypropyl cellulose is HPC GF, HPC CF or HPC HF, or a combination of two or more thereof.

[0601] 198. A composition according to any of embodiments 171-197, wherein the gelling agent is present in a total amount of about 16%-75% or about 18%-56% by weight of the composition; and / or the gelling agent comprises: (i) glycerol present in about 12-24%, about 14-20%, about 13-17%, about 14-16% or about 14-15% by weight of the composition, (ii) PEG present in about 2-45%, about 3-24%, about 3-14%, about 13-15% or about 13-14% by weight of the composition, (iii) HPC present in about 0.5%-4% or about 1-3% by weight of the composition, (iv) a combination of (i) and (ii), (v) a combination of (i) and (iii), (vi) a combination of (ii) and (iii), or (vii) a combination of (i), (ii) and (iii).

[0602] 199. The composition of any one of embodiments 171-198, wherein the gelling agent has an average molecular weight of about 700,000 Da to 1,150,000 Da.

[0603] 200. A composition comprising rubostar free base or rubostar mesylate monohydrate or a salt thereof, a penetration enhancer and / or an organic solvent, an antioxidant and a gelling agent.

[0604] 201. The composition of embodiment 200, wherein the total amount of penetration enhancer and / or organic solvent is from about 62% to about 99% by weight of the composition.

[0605] 202. The composition of embodiment 200 or embodiment 201, comprising the penetration enhancer.

[0606] 203. A composition according to embodiment 202, wherein the penetration enhancer comprises C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester or fatty ether, or a combination of two or more thereof.

[0607] 204. The composition of any one of embodiments 200-203, comprising the organic solvent.

[0608] 205. A composition according to embodiment 204, wherein the organic solvent comprises C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester or fatty ether, or a combination of two or more thereof.

[0609] 206. The composition of embodiment 205, wherein the organic solvent comprises propylene glycol, 2-(2-ethoxyethoxy)ethanol, glycerol or polyethylene glycol, or a combination of two or more thereof.

[0610] 207. A composition according to embodiment 200 or embodiment 201, wherein the penetration enhancer and / or organic solvent comprises C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester or fatty ether, or a combination of two or more thereof.

[0611] 208. The composition of any one of embodiments 200-207, comprising the penetration enhancer.

[0612] 209. The composition of embodiment 208, wherein the penetration enhancer comprises the organic solvent.

[0613] 210. The composition of embodiment 200, wherein the penetration enhancer and / or organic solvent comprises propylene glycol, 2-(2-ethoxyethoxy)ethanol, glycerol or polyethylene glycol, or a combination of two or more thereof.

[0614] 211. The composition of any one of embodiments 200-210, comprising an emulsifier.

[0615] 212. The composition of embodiment 211, wherein the penetration enhancer and / or organic solvent comprises the emulsifier.

[0616] 213. The composition of embodiment 211 or embodiment 212, wherein the emulsifier comprises cocoyl caprylic caprylate, decyl oleate, diethylene glycol monoethyl ether, dimethyl isosorbide, glyceryl monooleate, isopropyl myristate, MCT, octyldodecanol, oleyl alcohol, oleyl oleate, polyoxyethylene alkyl ether, polyoxyethylene stearate, propylene glycol monolaurate, propylene glycol, lecithin, cyclodextrin, sodium docusate, glyceryl monostearate, hydrogenated vegetable oil / cottonseed oil / palm kernel oil, MCT, N-methyl-2-pyrrolidone, poloxamer, PEG, polysorbate, PEG castor oil derivative, propylene glycol, polyoxyglycerol esters, sodium lauryl sulfate, sucrose esters or glycerin, or a combination of two or more thereof.

[0617] 214. The composition of embodiment 200 or embodiment 201, wherein the penetration enhancer and / or organic solvent comprises diethylene glycol monoethyl ether (DGME), propylene glycol, glycerol or polyethylene glycol, or a combination of two or more thereof.

[0618] 215. A composition according to embodiment 214, comprising the DGME.

[0619] 216. The composition according to embodiment 215, wherein the DGME is Transcutol TM 、TranscutolHP TM or Transcutol P TM .

[0620] 217. A composition according to embodiment 216, comprising the Transcutol HP TM (2-(2-ethoxyethoxy)ethanol).

[0621] 218. A composition according to any of embodiments 215-217, wherein the DGME has a purity of >99.90%.

[0622] 219. The composition of any one of embodiments 200-218, wherein the penetration enhancer and / or organic solvent comprises: (i) DGME present at about 40-50%, about 43-49%, about 47-49%, or about 47-48% by weight of the composition, (ii) PEG present at about 2-45%, about 3-24%, about 3-14%, about 13-15%, or about 13-14% by weight of the composition, (iii) glycerol present at about 12-24%, about 14-20%, about 13-17%, about 14-16%, or about 14-15% by weight of the composition, (iv) about 8-30%, about 9-22%, about 11-24%, about 13-17 ... 8-22%, about 19-21%, or about 19-20% propylene glycol is present, the combination of (v) (i) and (ii), the combination of (vi) (i) and (iii), the combination of (vii) (i) and (iv), the combination of (viii) (ii) and (iii), the combination of (ix) (ii) and (iv), the combination of (x) (iii) and (iv), the combination of (xi) (i), (ii) and (iii), the combination of (xii) (i), (ii) and (iv), the combination of (xiii) (i), (iii) and (iv), the combination of (xiv) (ii), (iii) and (iv), or the combination of (vx) (i), (ii), (iii) and (iv).

[0623] 220. The composition of any one of embodiments 200-218, wherein the total amount of penetration enhancer and / or organic solvent is present in about 85% to 99% by weight of the composition.

[0624] 221. A composition according to any one of embodiments 200-220, wherein the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, ascorbic acid, alpha-tocopheryl acetate or ascorbyl palmitate, or a combination thereof or two or more thereof.

[0625] 222. A composition according to any of embodiments 200-221, wherein the total amount of antioxidant is present in the composition at about 0.01% to 1% or about 0.2% to 0.3% by weight of the composition.

[0626] 223. A composition according to any of embodiments 200-221, wherein the antioxidant comprises butylated hydroxytoluene (BHT) present at about 0.05-0.3%, about 0.1% or about 0.2% by weight of the composition, and / or comprises butylated hydroxyanisole (BHA) present at about 0.05-0.2% or about 0.1% by weight of the composition.

[0627] 224. A composition according to any one of embodiments 200-223, wherein the gelling agent comprises hydroxypropyl cellulose, hydroxyethyl cellulose, carbopol, carbomer, or carboxymethyl cellulose, or a combination of two or more thereof.

[0628] 225. The composition of embodiment 224, wherein the hydroxypropyl cellulose is HPC GF, HPC CF or HPC HF, or a combination of two or more thereof.

[0629] 226. A composition according to any of embodiments 200-225, wherein the gelling agent is present in a total amount of about 16%-75% or about 18%-56% by weight of the composition; and / or the gelling agent comprises: (i) glycerol present in about 12-24%, about 14-20%, about 13-17%, about 14-16% or about 14-15% by weight of the composition, (ii) PEG present in about 2-45%, about 3-24%, about 3-14%, about 13-15% or about 13-14% by weight of the composition, (iii) HPC present in about 0.5%-4% or about 1-3% by weight of the composition, (iv) a combination of (i) and (ii), (v) a combination of (i) and (iii), (vi) a combination of (ii) and (iii), or (vii) a combination of (i), (ii) and (iii).

[0630] 227. A composition according to any one of embodiments 200-226, wherein the gelling agent has an average molecular weight of about 700,000 Da to 1,150,000 Da.

[0631] 228. A composition comprising: (i) rubostar free base or rubostar mesylate monohydrate or a salt thereof, and (ii) PEG, propylene glycol, 2-(2-ethoxyethoxy)ethanol, butylated hydroxytoluene, butylated hydroxyanisole, glycerol or hydroxypropylcellulose, or two or more thereof.

[0632] 229. A composition according to any of embodiments 1-228, comprising PEG, propylene glycol, 2-(2-ethoxyethoxy)ethanol, butylated hydroxytoluene, butylated hydroxyanisole, glycerol or hydroxypropylcellulose, or two or more thereof.

[0633] 230. The composition of embodiment 228 or embodiment 229, wherein

[0634] (a) the PEG is present in an amount of 10% to 30%, 10% to 20%, or about 14% by weight of the composition;

[0635] (b) the propylene glycol is present in an amount of 10% to 40%, 15% to 30%, or about 20% by weight of the composition;

[0636] (c) the 2-(2-ethoxyethoxy)ethanol is present in an amount of 30% to 70%, 40% to 60%, or about 47% by weight of the composition;

[0637] (d) the butylated hydroxytoluene is present in an amount of 0.01% to 0.5%, 0.01% to 0.2%, 0.01% to 0.1%, or about 0.1%, by weight of the composition;

[0638] (e) the butylated hydroxyanisole is present in an amount of 0.01% to 0.5%, 0.01% to 0.2%, 0.01% to 0.1%, or about 0.1%, by weight of the composition;

[0639] (f) the glycerin is present in an amount of 5% to 25%, 10% to 20%, or about 15%, by weight of the composition; or

[0640] (g) the hydroxypropyl cellulose is present in an amount of 1% to 4% or about 3% by weight of the composition; or

[0641] (h) Any combination of (a)-(g).

[0642] 231. The composition of any one of embodiments 228-230, comprising the hydroxypropyl cellulose, wherein the hydroxypropyl cellulose has an average molecular weight of about 700,000 Da to 1,150,000 Da.

[0643] 232. The composition of any one of embodiments 228-231, comprising the PEG, wherein the PEG is present in an amount of about 14% by weight of the composition.

[0644] 233. The composition of any one of embodiments 228-232, comprising the propylene glycol, wherein the propylene glycol is present in an amount of about 20% by weight of the composition.

[0645] 234. The composition of any one of embodiments 228-233, comprising the 2-(2-ethoxyethoxy)ethanol, wherein the 2-(2-ethoxyethoxy)ethanol is present in an amount of about 47% by weight of the composition.

[0646] 235. The composition of any one of embodiments 228-234, comprising the butylated hydroxytoluene, wherein the butylated hydroxytoluene is present in an amount of about 0.1% by weight of the composition.

[0647] 236. The composition of any one of embodiments 228-235, comprising the butylated hydroxyanisole, wherein the butylated hydroxyanisole is present in an amount of about 0.1% by weight of the composition.

[0648] 237. A composition according to any one of embodiments 228-236, comprising the glycerol, wherein the glycerol is present in an amount of about 15% by weight of the composition.

[0649] 238. The composition of any one of embodiments 228-237, comprising the hydroxypropyl cellulose, wherein the hydroxypropyl cellulose is present in an amount of about 3% by weight.

[0650] 239. The composition of embodiments 1-238, wherein the rubostar free base, rubostar mesylate monohydrate, or a salt thereof is present in an amount of 0.1% to 10.0%, 0.5% to 5%, 0.5% to 2%, or about 1% by weight of the composition.

[0651] 240. The composition according to embodiment 239, wherein the rubostar free base, rubostar mesylate monohydrate or a salt thereof is present in an amount of about 1% by weight of the composition.

[0652] 241. The composition of embodiment 239, wherein the rubostar free base, rubostar mesylate monohydrate, or a salt thereof is present in an amount of about 0.6% by weight of the composition.

[0653] 242. The composition according to embodiment 239, wherein the rubostar free base, rubostar mesylate monohydrate or a salt thereof is present in an amount of about 0.8% by weight of the composition.

[0654] 243. The composition of any one of embodiments 1 to 242, wherein the composition is formulated as a pharmaceutical composition.

[0655] 244. The composition of any one of embodiments 1 to 242, wherein the composition is formulated as a cosmetic composition.

[0656] 245. The composition of any one of embodiments 1 to 242, wherein the composition is formulated as a topical pharmaceutical composition or a topical cosmetic composition.

[0657] 246. The composition of any one of embodiments 1 to 245, which is in the form of a gel, ointment, cream, lotion, foam or emollient.

[0658] 247. The composition of any one of embodiments 1 to 245, which is a component of a patch, a tape, a film, a cloth, a wipe, a sponge, a sheet, a mask, a wipe, a brush, a pad, a gauze, an applicator, a cotton ball, a roll, a swab, or a bandage.

[0659] 248. A method of treating a disease, condition, or disorder in a subject in need thereof, comprising administering to the subject a composition according to any one of embodiments 1-247.

[0660] 249. The method of embodiment 248, wherein the disease, condition or disorder is a skin disease, condition or disorder comprising: hyperpigmentation, skin discoloration, melasma, post-inflammatory hyperpigmentation, discoid lupus erythematosus, phytophotodermatitis, lentigo (e.g., age spots), birthmarks, café au lait spots, acanthosis nigricans, burn-related hyperpigmentation, drug-induced hyperpigmentation (e.g., sulfonamide, tetracycline, NSAID, barbiturate, and carbamazepine-induced hyperpigmentation), injury-induced hyperpigmentation, primary biliary cirrhosis-related hyperpigmentation, Hyperpigmentation, hyperpigmentation associated with Addison's disease, hyperpigmentation associated with hemochromatosis, hyperpigmentation associated with hyperthyroidism, melanocytic nevi, freckles (spots), seborrheic keratosis, hyperpigmentation associated with skin cancer, hyperpigmentation associated with infection (e.g., tinea versicolor, erythrasma), eczema, photocontact, photoallergic or phototoxic dermatitis, ichthyosis, axillary freckles or café-au-lait spots associated with neurofibromatosis, or hyperpigmentation associated with ultraviolet (UV) radiation exposure (e.g., sun exposure or tanning reaction), or a combination of two or more thereof.

[0661] 250. The method of embodiment 248, wherein the disease, condition or disorder comprises a hyperpigmentation disorder.

[0662] 251. The method of embodiment 248, wherein the disease, condition or disorder comprises hirsutism / excessive hair or hair pigmentation.

[0663] 252. The method of any one of embodiments 247-250, wherein the composition is in the form of a gel, an ointment, a cream, a lotion, a foam, or an emollient.

[0664] 253. The method of any one of embodiments 248-251, wherein the composition is a component of a patch, a tape, a film, a cloth, a wipe, a sponge, a sheet, or a bandage.

[0665] 254. The method according to any one of embodiments 248-253, wherein the composition is applied topically to the head, scalp, face, ears, neck, chest, back, inframammary area, arms, legs, or groin.

[0666] 255. The method of any one of embodiments 248-254, wherein the composition is administered twice daily.

[0667] 256. The method of any one of embodiments 248-255, wherein the composition is administered for at least 12 weeks.

[0668] 257. The method of any one of embodiments 248-256, wherein the composition is administered for about 12 weeks to about 24 weeks.

[0669] 258. The method of any one of embodiments 248-257, wherein the composition is administered for about 12 weeks.

[0670] 259. The method of any one of embodiments 248-255, wherein the composition is administered for at least 4 weeks.

[0671] 260. The method of any one of embodiments 248-255, wherein the composition is administered for about 4 weeks to about 8 weeks.

[0672] 261. The method of any one of embodiments 248-255, wherein the composition is administered for about 4 weeks to about 6 weeks.

[0673] 262. The method of any one of embodiments 248-255, wherein the composition is administered for about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or about 8 weeks.

[0674] 263. The method of any one of embodiments 248-255, wherein the composition is administered for about 8 weeks to about 12 weeks.

[0675] 264. A kit comprising the composition according to any one of embodiments 1 to 247 in a tube, a flexible aluminum tube, or a laminated plastic tube, and instructions for use.

[0676] 265. A kit comprising a composition according to any one of embodiments 1 to 247 in a container or tube, flexible aluminum tube or laminated plastic tube, which blocks ultraviolet light from entering the composition.

[0677] 266. A kit comprising the composition of any one of embodiments 1 to 247 in a container, tube, or pump, wherein oxygen is prevented from contacting the composition.

[0678] 267. The kit of embodiment 266, wherein the container, tube or pump is vacuum sealed.

[0679] 268. The kit of embodiment 266 or embodiment 267, wherein the container, tube or pump headspace is filled with an inert gas to prevent oxidation.

[0680] 269. A kit according to embodiment 268, wherein the gas used is nitrogen.

[0681] Example

[0682] Example 1: Preparation of the composition

[0683] The surface compositions of the present disclosure can be prepared according to the procedures provided below. Reaction conditions, steps and reactants not provided in the following procedures will be apparent and known to those skilled in the art.

[0684] Excipients (i.e., organic solvents and / or penetration enhancers, antioxidants, alcohols) are aliquoted or weighed into separate containers to form a mixture. Compounds (i.e., Rubusta free base, Rubusta mesylate monohydrate or an acceptable salt thereof) are added to the mixture to reach the desired concentration. The gelling agent (e.g., HPC) is then added accordingly. In some of the compositions, a second addition of water (if present) is used last to titrate the composition to 100% by weight. The final mixture is then mixed thoroughly to form the composition.

[0685] Example 2: Various compositions with / without Rubostar free base, Rubostar mesylate monohydrate or acceptable salts thereof.

[0686] The following compositions were prepared according to the general procedure of Example 1 using the excipients of Tables 1 and 2.

[0687] Table 1: Various compositions of solvent systems with and without Rubustadine (PBO = placebo)

[0688]

[0689] According to Table 1, the following concentrations of excipients are provided in the example formulations herein (e.g., within about + / - the values ​​in Table 1): about 40-50% Transcutol (an example solvent and / or penetration enhancer, alcohol), about 8-12% propylene glycol (an example solvent and / or penetration enhancer, alcohol), about 8-12% ethanol (an example solvent and / or penetration enhancer, alcohol), about 12-18% glycerol (an example solvent and / or penetration enhancer, alcohol, gelling agent), about 12-16% PEG (an example solvent and / or penetration enhancer, alcohol, gelling agent), about 0.5%-4% HPC (an example gelling agent), about 2-4% Sepineo (an example gelling agent), about 0.5-2% Carbopol (an example gelling agent), and about 0.1-0.3% ascorbic acid (an example antioxidant); wherein each of the excipients may be optional. In some cases, the composition comprises an organic solvent and / or a penetration enhancer, and optionally the organic solvent and / or the penetration enhancer is an alcohol and / or a gelling agent; wherein optionally, the total amount of the organic solvent and / or the penetration enhancer in the composition is about 80-100%, or about 95-99% of the composition. In some cases, the composition comprises an alcohol, and optionally the alcohol is an organic solvent / penetration enhancer and / or a gelling agent; wherein optionally, the total amount of the alcohol in the composition is about 80-100%, or about 95-99% of the composition. In some cases, the composition comprises an antioxidant; wherein optionally, the total amount of the antioxidant is about 0.1-0.3%, or about 0.2% of the composition. In some cases, the composition comprises a gelling agent; wherein optionally, the total amount of the gelling agent is about 28-48% of the composition, or about 31-32% of the composition. Therefore, disclosed herein are compositions comprising the above-described example amounts of solvents and / or penetration enhancers, alcohols, gelling agents, and antioxidants, both individually and in combination.

[0690] Table 2: Various compositions of Rubustadine mesylate monohydrate in excipients

[0691]

[0692]

[0693] According to Table 2, the following concentrations of excipients are provided in the example formulations herein (e.g., in some cases within about + / - 10-20% of the values ​​in Table 2): about 40-50% Transcutol (example solvent and / or penetration enhancer, alcohol), about 8-12% propylene glycol (example solvent and / or penetration enhancer, alcohol), about 8-12% ethanol (example solvent and / or penetration enhancer, alcohol), about 12-18% glycerol (example solvent and / or penetration enhancer, alcohol, gelling agent), about 12-16% PEG (example solvent); In some cases, the composition comprises an organic solvent and / or a penetration enhancer, an alcohol, a gelling agent), about 0.1-0.3% ascorbic acid (an example antioxidant), about 0.05-0.2% BHT (an example antioxidant), about 0.05-0.2% BHA (an example antioxidant), about 0.025-0.1% propyl gallate (an example antioxidant), about 0.001-0.003% alpha-tocopheryl acetate (an example antioxidant), about 0.01-0.03% ascorbyl palmitate (an example antioxidant); wherein each of the excipients may be optional. In some cases, the composition comprises an organic solvent and / or a penetration enhancer, and optionally the organic solvent and / or the penetration enhancer is an alcohol and / or a gelling agent; wherein optionally, the total amount of the organic solvent and / or the penetration enhancer in the composition is about 80-100% or about 85-96% of the composition. In some cases, the composition comprises an alcohol, and optionally the alcohol is an organic solvent / penetration enhancer and / or gelling agent; wherein optionally, the total amount of alcohol in the composition is about 80-100% or about 85-96% of the composition. In some cases, the composition comprises an antioxidant; wherein optionally, the total amount of antioxidant is about 0.3-0.9% or about 0.1-0.3% of the composition. In some cases, the composition comprises a gelling agent; wherein optionally, the total amount of gelling agent is about 24-34% of the composition or about 18-29% of the composition. Therefore, disclosed herein are compositions comprising the above-described example amounts of solvents and / or penetration enhancers, alcohols, gelling agents, and antioxidants, both individually and in combination.

[0694] Example 3: 14-day explant study

[0695] Overview

[0696] A skin whitening assay was performed to demonstrate the pharmacodynamic activity of formulations containing rubustadine mesylate monohydrate. Method development experiments were performed to evaluate the skin whitening potential of these formulations.

[0697] Method development experiments consisted of single formulations, basolateral treatments, and untreated controls using dark skin. Topical formulations or basolateral treatments were applied daily for 7 days with detergent / water washes before each treatment or media change to prevent formulation accumulation (untreated controls were washed in the same manner).

[0698] Materials & Methods

[0699] For method development research, one surface and one basolateral treatment were used for method development experiments together with untreated controls. Freshly excised skin from dark pigmented donors was obtained and cultured with n=3 according to the long-term explant conditions developed. Explants were cultured for a total of 14 days and the following treatment scheme was utilized: untreated control, basolateral treatment (API in culture medium, once every 48 hours, at 17.7nM), and NA18 applied superficially. Explants were treated for 7 consecutive days and maintained for another 7 days without treatment. Before each treatment, each explant was washed with water / detergent solution. According to the long-term culture procedure, all explants were also washed with water / detergent every 2-3 days during the non-treatment phase. Photos were taken at the 0th day, the 7th day and the 14th day for visual evaluation of the skin whitening effect of the preparation. At the 7th day and the 14th day, multiple groups of samples (n=3) were collected for use in analyzing tyrosinase activity and melanin content using the program outlined in the research plan.

[0700] Results, interpretation and conclusions

[0701] Method development

[0702] Topical treatment with NA18 significantly reduced melanin content (p=0.023) and resulted in visible color changes after 7 days compared to untreated controls, whereas basolateral treatment did not appear to affect melanin content or skin color, likely due to lack of engagement at the target site (epidermis). There were no significant differences in tyrosinase activity in either of the 2 treatment regimens compared to untreated controls.

[0703] Table 3: Mean cumulative melanin concentrations (μg / mg tissue) 7 and 14 days after treatment.

[0704]

[0705] Example 4: Further Optimization of Compositions Containing High Transcutol

[0706] The compositions of Table 2 containing about 47-48% Transcutol P ((2-(2-ethoxyethoxy)ethanol) were further studied with the addition of antioxidants (e.g., butylated hydroxytoluene (BHT) and / or butylated hydroxyanisole (BHA), or propyl gallate), preservatives (e.g., phenoxyethanol), alcohols, gelling agents and / or pH adjusters (e.g., aqueous citric acid solution) and / or preservatives (e.g., phenoxyethanol). Thus, the compositions are shown in Tables 5 and 6.

[0707] Table 5: Compositions including Rubustadine mesylate monohydrate

[0708]

[0709]

[0710] Table 6: Other compositions containing Rubustadine mesylate monohydrate

[0711]

[0712]

[0713] According to Table 5, the following concentrations of excipients are provided in the example formulations herein (e.g., within about + / - 10-20% of the values ​​in Table 5): about 40-50% Transcutol (example solvent and / or penetration enhancer, alcohol), about 8-30% propylene glycol (example solvent and / or penetration enhancer, alcohol), about 12-24% glycerol (example solvent and / or penetration enhancer, alcohol, gelling agent), about 2-30% PEG (example solvent and / or penetration enhancer, alcohol, gelling agent), about 0.5-4% HPC (example gelling agent), about 0.5-2% Carbopol (example gelling agent), about 0.05-0.3% BHT (example antioxidant), and about 0.05-0.2% BHA (example antioxidant); wherein each of the excipients may be optional. In some cases, the composition comprises an organic solvent and / or a penetration enhancer, and optionally the organic solvent and / or the penetration enhancer is an alcohol and / or a gelling agent; wherein optionally, the total amount of the organic solvent and / or the penetration enhancer in the composition is about 80-100% or about 86-99% of the composition. In some cases, the composition comprises an alcohol, and optionally the alcohol is an organic solvent / penetration enhancer and / or a gelling agent; wherein optionally, the total amount of the alcohol in the composition is about 80-100% or about 86%-99% of the composition. In some cases, the composition comprises an antioxidant; wherein optionally, the total amount of the antioxidant is about 0.1-0.5% or about 0.1-0.2% of the composition. In some cases, the composition comprises a gelling agent; wherein optionally, the total amount of the gelling agent is about 16-64% of the composition or about 21-42% of the composition. Therefore, disclosed herein are compositions comprising the above-described example amounts of solvents and / or penetration enhancers, alcohols, gelling agents, and antioxidants, both individually and in combination.

[0714] According to Table 6, the following concentrations of excipients are provided in the example formulations herein (e.g., within about + / - 10-20% of the values ​​in Table 6): about 40-50% Transcutol (an example solvent and / or penetration enhancer, alcohol), about 8-22% propylene glycol (an example solvent and / or penetration enhancer, alcohol), about 3-12% ethanol (an example solvent and / or penetration enhancer, alcohol), about 12-24% glycerol (an example solvent and / or penetration enhancer, alcohol), about 10-25% ethanol (an example solvent and / or penetration enhancer, alcohol), about 15-20% glycerol (an example solvent and / or penetration enhancer, alcohol), about 10-25 ... , gelling agent), about 2-45% PEG (an example solvent and / or a penetration enhancer, an alcohol, a gelling agent), about 0.5-4% HPC (an example gelling agent), about 0.5-2% Carbopol (an example gelling agent), about 0.1-0.3% ascorbic acid (an example antioxidant), about 0.05-0.3% BHT (an example antioxidant), about 0.05-0.2% BHA (an example antioxidant); wherein each of the excipients may be optional. In some cases, the composition comprises an organic solvent and / or a penetration enhancer, and optionally the organic solvent and / or the penetration enhancer is an alcohol and / or a gelling agent; wherein optionally, the total amount of the organic solvent and / or the penetration enhancer in the composition is about 65-100% or about 86-98% of the composition. In some cases, the composition comprises an alcohol, and optionally the alcohol is an organic solvent / penetration enhancer and / or gelling agent; wherein optionally, the total amount of alcohol in the composition is about 65-100% or about 86-98% of the composition. In some cases, the composition comprises an antioxidant; wherein optionally, the total amount of the antioxidant is about 0.2-0.8% or about 0.1-0.2% of the composition. In some cases, the composition comprises a gelling agent; wherein optionally, the total amount of the gelling agent is about 16-76% of the composition or about 22-56% of the composition. Therefore, disclosed herein are compositions comprising the above-described example amounts of solvents and / or penetration enhancers, alcohols, gelling agents, and antioxidants, both individually and in combination.

[0715] According to Tables 1, 2, 5 and 6, the following concentrations of excipients are provided in the example formulations herein (e.g., within about + / - 10-20% of the values ​​in Tables 1, 2, 5 and 6): about 40-50%, about 43-49%, about 47-49%, or about 47-48% Transcutol (an example solvent and / or penetration enhancer, alcohol), about 8-30%, about 9-22%, about 18-22%, about 19-21%, or about 19-20% propylene glycol; Alcohol (Example solvent and / or penetration enhancer, alcohol), about 3-12%, about 4-6%, or about 9-11% ethanol (Example solvent and / or penetration enhancer, alcohol), about 12-24%, about 14-20%, about 13-17%, about 14-16%, or about 14-15% glycerol (Example solvent and / or penetration enhancer, alcohol, gelling agent), about 2-45%, about 3-24%, about 3-14%, about 13-15%, or about 13-14% PE G (Example solvent and / or penetration enhancer, alcohol, gelling agent), about 0.5%-4% or about 1-3% HPC (Example gelling agent), about 2-4% or about 3% Sepineo (Example gelling agent), about 0.5-2% or about 1% Carbopol (Example gelling agent), and about 0.1-0.3% or about 0.2% ascorbic acid (Example antioxidant), about 0.05-0.3% or about 0.1-0.2% BHT (Example antioxidant) activator), about 0.05-0.2% or about 0.1% BHA (an example antioxidant), about 0.025-0.1% or about 0.05% propyl gallate (an example antioxidant), about 0.001-0.003% or about 0.002% alpha-tocopheryl acetate (an example antioxidant), about 0.01-0.03% or about 0.02% ascorbyl palmitate (an example antioxidant); wherein each of the excipients may be optional. In some cases, the composition comprises an organic solvent and / or a penetration enhancer, and optionally the organic solvent and / or the penetration enhancer is an alcohol and / or a gelling agent; wherein optionally, the total amount of the organic solvent and / or the penetration enhancer in the composition is about 62-100% or about 85-99% of the composition. In some cases, the composition comprises an alcohol, and optionally the alcohol is an organic solvent / penetration enhancer and / or gelling agent; wherein optionally, the total amount of alcohol in the composition is about 62-100% or about 85-99% of the composition. In some cases, the composition comprises an antioxidant; wherein optionally, the total amount of antioxidant is about 0.1-0.9% or about 0.2-0.3% of the composition. In some cases, the composition comprises a gelling agent; wherein optionally, the total amount of gelling agent is about 16-76% of the composition or about 18-56% of the composition. Therefore, disclosed herein are compositions comprising the above-described example amounts of solvents and / or penetration enhancers, alcohols, gelling agents, and antioxidants, both individually and in combination.

[0716] As non-limiting examples, the composition comprises: about 40-50%, about 43-49%, about 47-49%, or about 47-48% Transcutol (an example solvent and / or penetration enhancer, alcohol), about 2-45%, about 3-24%, about 3-14%, about 13-15%, or about 13-14% PEG (an example solvent and / or penetration enhancer, alcohol, gelling agent), about 12-24%, about 14-20%, about 13-17%, about 14-16%, or about 14-15% glycerol (an example solvent and / or penetration enhancer, alcohol, gelling agent), about 12-24%, about 14-20%, about 13-17%, about 14-16%, or about 14-15% about 0.05-0.2% or about 0.1% BHA (an example antioxidant), about 0.5%-4% or about 1-3% HPC (an example gelling agent), or a combination of two or more thereof. As another non-limiting example, the composition comprises: about 47-49% or about 47-48% Transcutol (an example solvent and / or penetration enhancer, alcohol), about 13-15% or about 13-14% PEG (an example solvent and / or penetration enhancer, alcohol, gelling agent), about 14-16% or about 14-15% glycerol (an example solvent and / or penetration enhancer, alcohol, gelling agent), about 19-21% or about 19-20% propylene glycol (an example solvent and / or penetration enhancer, alcohol), about 0.05-0.3% or about 0.1-0.2% BHT (an example antioxidant), about 0.05-0.2% or about 0.1% BHA (an example antioxidant), about 0.5%-4% or about 1-3% HPC (an example gelling agent), or a combination of two or more thereof. As another non-limiting example, the composition comprises: about 47-48% Transcutol (an example solvent and / or penetration enhancer, alcohol), about 13-14% PEG (an example solvent and / or penetration enhancer, alcohol, gelling agent), about 14-15% glycerol (an example solvent and / or penetration enhancer, alcohol, gelling agent), about 19-20% propylene glycol (an example solvent and / or penetration enhancer, alcohol), about 0.1-0.2% BHT (an example antioxidant), about 0.1% BHA (an example antioxidant), about 3% HPC (an example gelling agent), or a combination of two or more thereof.

[0717] In any example or embodiment herein, Rubostar, Rubostar mesylate, or a salt thereof is present in the composition at about 0.1%, about 0.8%, or about 1%.

[0718] Example 5: Short-term stability of the composition of Example 4

[0719] The compositions of Tables 5 and 6 were subjected to short-term physicochemical stability studies after storage for up to 5 months at 25° C. and 40° C. The parameters evaluated were content and purity of the compound (i.e., Rubusta), apparent pH, macroscopic and microscopic observations.

[0720] Content and purity of the compound

[0721] The content and purity of Rubusta mesylate monohydrate in the research and development compositions after storage for up to 5 months are detailed in Tables 7 and 8, respectively.

[0722] Percent recovery (%) compares the response of the drug peak to a standard of known concentration, while percent peak purity (% area) compares the area of ​​the drug peak to the sum of the areas of all peaks in the chromatogram.

[0723] Table 7: Content of Rubusta mesylate monohydrate (% w / w from label claim) at t=0 and after stability testing up to 4 weeks at 25°C and 40°C, mean of n=3 replicates (range in brackets).

[0724]

[0725] Table 7: continued

[0726]

[0727] Table 8: Purity (% a / a) of Rubusta at t=0 and after stability testing up to 4 weeks at 25°C and 40°C, mean of n=3 replicates (range in brackets).

[0728]

[0729] Table 8: continued

[0730]

[0731] It should be noted that data generated from both the HPLC method originally performed and the HPLC method with the same gradient but extended to elute BHT at t=0 are presented (for impurity data only). All other time points employed the HPLC analytical method with the longer run time.

[0732] At t = 0, all drug recovery values ​​were 98-102% of the label. For all formulations, drug purity values ​​were about> 99%. After storage for 4 weeks, the data showed that drug recovery was consistent with t = 0 at 25 ° C and 40 ° C (i.e., 100% ± 5% of the label claim). After storage for 4 weeks at 25 ° C and 40 ° C, for most formulations, drug purity was slightly lower than the drug purity observed at t = 0 and 2 weeks (about 0.1%-0.2% area). Although this represents a slight downward trend, it is a huge improvement over the initial formulation, where for non-aqueous gels, after storage for 4 weeks at 40 ° C, it was observed that the purity of Rubusta mesylate monohydrate was between 90.57% and 95.08%. It should be noted that formulations including 0.1% w / w Rubusta mesylate monohydrate (ie NA22 and NA28) showed the lowest purity and this may be due to the higher excipient:drug ratio in these formulations compared to formulations loaded with 0.8% w / w drug.

[0733] After 5 months of storage, the recoveries of Rubusta mesylate monohydrate were within 100 ± 5% for NA13, NA19, NA22, and NA28, except for NA22 ACT stored at 40 °C, which had a label-claimed recovery of 94.15%, which was consistent with the lower purity of the drug observed from this formulation.

[0734] The average peak purity of Rubusta mesylate monohydrate after 5 months ranged from 96.03% area (NA22, 40°C) to 98.90% (NA19, 25°C), and the peak area did not decrease by more than 1.6% after storage at 25°C or 40°C for any formulation. It should be noted that a decrease of 1.6% was observed for formulation NA22 with a low drug load (0.1%), and as discussed previously, this may be attributed to the higher excipient:drug ratio present in this formulation. For formulations with a drug load of approximately 0.8% (e.g., NA13, NA18, and NA19), a decrease in peak purity of 1.5% was observed (NA13, stored at 40°C), however both NA18 and NA19 showed a decrease in purity of <0.5%, with the maximum decreases observed for NA18 and NA19 being 0.45% and 0.27%, respectively, under both storage conditions. It is noteworthy that no single impurity had a %a / a greater than 0.8% after 5 months storage at either 25°C or 40°C. The peak purity of NA13 stored at 40°C was higher than that observed at 25°C, and the peaks at RT 4.2 and 5.2 in the 40°C sample appeared to be smaller in size than the 25°C sample. Since such peaks were present in the 12-week 25°C and 40°C samples, the data generated at the 5-month time point suggest that the degradation products (i.e., peaks at RT 4.2 and RT5.2) may have further degraded and were not observed using the current methodology.

[0735] The purity data together with the drug recovery data indicated that NA18 and NA19 were the most chemically stable formulations over the 5 month period and therefore may exist as lead candidates for further development.

[0736] Apparent pH

[0737] The apparent pH of compositions with or without Rubusta mesylate monohydrate up to t=5 months (2-8°C, 25°C and 40°C) are presented in Table 9.

[0738] Table 9: Apparent pH of compositions under stability study

[0739]

[0740] At t=0, the pH of the placebo formulations varied between 5.25-7.21, and the pH of the active formulations varied between 4.55-4.97. Notably, the pH of the 0.25% Rubusta mesylate monohydrate formulation was lower than the equivalent 0.1% formulation. In previous stability testing, the pH of NA18 and NA19 containing 0.8% drug had pH values ​​of 4.34 and 3.82 at t=0, respectively, further demonstrating the trend that higher drug levels lead to lower pH. After 12 weeks of storage, the apparent pH of all formulations remained consistent with the values ​​reported at t=0 (i.e., within 0.5 units).

[0741] Macroscopic observation results

[0742] At t=0, all active formulations appeared red due to the presence of Rubostar mesylate monohydrate and all placebos appeared colorless. It is noteworthy that the formulations in which lower concentrations of Rubostar mesylate monohydrate were present were clear and lighter in color due to the presence of lower concentrations of Rubostar mesylate monohydrate. NA19 PLB was translucent and this may be due to the nature of the gelling agent. This hypothesis is further supported by the fact that formulation NA19 had a low viscosity, which indicates that the gelling agent has not been fully hydrated.

[0743] There was no significant change in macroscopic appearance after 4 weeks of storage.Additional time points of t=12 weeks and 5 months were performed where the macroscopic appearance of NA13, NA18, NA19, NA22 and NA28 was assessed, after which there was no significant change in appearance.

[0744] Microscopic observation results

[0745] Microscopic appearance and microscopic images (non-polarized and polarized light) were obtained for all compositions including Rubustadine mesylate monohydrate and the corresponding vehicle.

[0746] At t = 0, no excipients or drug crystals were present in most formulations. Notably, API was observed in the active formulation NA25.

[0747] After 2 weeks of storage, the formulations contained no API crystals (except for NA25 at both 25°C and 40°C and NA16 at 40°C only). After 4 weeks of storage, no changes were observed in NA13, NA18, NA19, NA20, NA22, and NA28, although crystals suspected to be the API were evident in the following formulations:

[0748] NA16 (25℃ and 40℃)

[0749] NA17(25℃)

[0750] NA21(40℃)

[0751] NA26 (25℃ and 40℃)

[0752] To confirm the above observations, the microscopic appearance of NA16, NA17 and NA26 formulations stored at 2-8°C was also analyzed and crystals were observed.

[0753] While these crystals were suspected to be the API, as they were not present in the placebo formulation, it was not obvious what was driving the observed crystallization based on the composition of the active formulation. For example, NA17 and NA18 shared the same formulation composition except for 0.1% w / w BHA in NA18, and API crystals were only observed in the former.

[0754] Additional time points at t = 12 weeks and 5 months were performed where the microscopic appearance of NA13, NA18, NA19, NA22 and NA28 was evaluated after storage at 25° C. and 40° C. NA18, NA10, NA22 and NA28 did not appear to contain drug crystals after 5 months at 2-8° C., 25° C. or 40° C.

[0755] Based on the composition of formulation NA18, 12 kg GMP batches of 0.8% w / w Rubusta mesylate monohydrate gel (batch number 910006) and placebo gel (batch number 910008) were manufactured in batches and filled into Montebello tubes at 12 g per tube, tested and released, and tested for stability at 25°C / 60% R / H and 40°C / 75% R / H. The following table lists the 6-month data for 0.8% w / w gel batch number 910006.

[0756] Table 10: 0.8% w / w Rubustadine Mesylate Monohydrate Clinical Trial Batch Stability Results

[0757]

[0758]

[0759]

[0760] After 6 months of storage per the International Conference on Harmonization (ICH) Guideline Q1A(R2) Stability Testing of New Drug Substances and Drug Products at ambient (25°C / 60% relative humidity) and accelerated (40°C / 75% relative humidity) temperatures and conditions, the batch remained within specifications from batch release to the most recent time point. In addition, per the ICH Q1A(R2) guidance, the 6-month time point under accelerated (40°C / 75% relative humidity) conditions represents a significant success in demonstrating the stability of this drug product formulation, as the guidance does not require further testing under these conditions. Stability testing under ambient (25°C / 60% relative humidity) conditions is ongoing.

[0761] Example 6: Clinical Trial

[0762] A randomized, observer-blind, vehicle-controlled study was conducted on the safety and efficacy of twice-daily application of 0.1% and 0.8% Rubostar mesylate monohydrate gel (referred to as "Rubostar gel") containing excipients of formulations NA10, NA18, NA22, or NA28 vs. vehicle gel vs. hydroquinone cream on sun-exposed and sun-protected skin in adults for 12 weeks.

[0763] The objective of this study was to compare the effects of daily application of 0.1% and 0.8% Rubostar gel, 4% hydroquinone cream, and vehicle gel. Efficacy assessments were summarized descriptively by treatment group and visit. The study was a two-layer randomized, observer-blind, and vehicle-controlled, multiple-dose study in adult subjects with Fitzpatrick skin types IV-V and colorimeter L* measurements between 57.8 and 46.1 as measured by a colorimeter CM-700. Subjects in the first stratum were randomized to one of the following 3 groups: (1) 0.8% Rubostar gel group (applied twice daily for 12 weeks), (2) 4% hydroquinone cream group (applied twice daily for 12 weeks), or (3) vehicle gel group. In the second stratum, subjects were randomized to one of the following 2 groups: (1) 0.1% Rubostar gel or (2) vehicle gel group. An open-label subgroup included subjects with solar lentigo on the dorsum of the hands to receive twice daily applications of 0.8% Rubusta gel.

[0764] Recruited about 90 subjects, it meets the inclusion / exclusion criteria of entering two random layers.The first layer of about 45 subjects: 0.8% Rubusta gel, 4% hydroquinone cream or vehicle gel, and the second layer of about 30 subjects: 0.1% Rubusta gel or vehicle gel).The object in the two-layer group accepts the application to the palm side of the unilateral upper arm and the back of the forearm, and about 15 objects with the back of the hand solar lentigo are recruited in the subgroup, and the subgroup applies 0.8% Rubusta gel to the solar lentigo of the palm side of the unilateral back of the hand and the palm side of the upper arm.Each object in two randomized layers (the first layer: 0.8% Rubusta gel, 4% hydroquinone cream or vehicle gel and the second layer: 0.1% Rubusta gel or vehicle gel) has two treatment sites and two untreated control sites of the contralateral sides. Subjects in the Solar Lentigo Subgroup: Intra-subject ...

Claims

1. A composition comprising a protein kinase C (PKC) inhibitor and 2-(2-ethoxyethoxy)ethanol, wherein the 2-(2-ethoxyethoxy)ethanol is from about 40% to about 50% by weight of the composition.

2. The composition of claim 1, wherein the PKC inhibitor is a PKCα, PKCβ, PKCβ1, PKCβ2, PKCδ, PKCε, PKCθ, PKCζ, PKCγ, PKCλ, PKCμ, PKCι or PKCη inhibitor.

3. The composition of claim 2, wherein the PKC inhibitor comprises a PKCβ inhibitor. The composition of claim 3 , wherein the PKCβ inhibitor comprises rubustard.

5. The composition of claim 4, wherein the Rubostar comprises Rubostar mesylate monohydrate or Rubostar free base.

6. The composition of claim 4, wherein the rubostar comprises rubostar hydrochloride, rubostar sulfate, rubostar tartrate, rubostar succinate, rubostar acetate, rubostar phosphate or another rubostar salt.

7. A composition comprising Rubusta mesylate monohydrate and 2-(2-ethoxyethoxy)ethanol, wherein the 2-(2-ethoxyethoxy)ethanol is from about 40% to about 50% by weight of the composition.

8. The composition according to any one of claims 1 to 6, further comprising propylene glycol, glycerol or polyethylene glycol (eg, PEG 400), or a combination of two or more thereof.

9. The composition of claim 7, wherein the 2-(2-ethoxyethoxy)ethanol and the propylene glycol, glycerol or polyethylene glycol, or a combination of two or more thereof, is from about 50% to about 99% by weight of the composition.

10. The composition of claim 7 or 9, wherein the 2-(2-ethoxyethoxy)ethanol and the propylene glycol, glycerol or polyethylene glycol, or a combination of two or more thereof, is from about 80% to about 99% by weight of the composition.

11. The composition according to any one of claims 1 to 10, further comprising C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, glycerol, fatty alcohol, fatty ester or fatty ether, or a combination of two or more thereof.

12. The composition of any one of claims 1 to 11, further comprising cocoyl caprylic caprate, decyl oleate, dimethyl isosorbide, glyceryl monooleate, isopropyl myristate, medium chain triglycerides (MCT), octyldodecanol, oleyl alcohol, oleyl oleate, polyoxyethylene alkyl ether, polyoxyethylene stearate, propylene glycol monolaurate, lecithin, cyclodextrin, sodium docusate, glyceryl monostearate, hydrogenated vegetable oil, cottonseed oil, palm kernel oil, N-methyl-2-pyrrolidone, poloxamer, polysorbate, PEG castor oil derivative, polyoxyglycerol ester, sodium lauryl sulfate, sucrose ester, glycerol, ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, tert-butanol, hydroxypropyl cellulose, hydroxyethyl cellulose, carbopol, carbomer or carboxymethyl cellulose, or a combination of two or more thereof.

13. The composition according to claim 12, comprising the hydroxypropyl cellulose, wherein the hydroxypropyl cellulose is HPC GF, HPC CF or HPC HF, or a combination of two or more thereof.

14. The composition of claim 13, comprising the hydroxypropyl cellulose, hydroxyethyl cellulose, carbopol, carbomer or carboxymethyl cellulose or a combination of two or more thereof, wherein the hydroxypropyl cellulose, hydroxyethyl cellulose, carbopol, carbomer or carboxymethyl cellulose or a combination of two or more thereof is about 16%-75% or about 18%-56% by weight of the composition.

15. The composition according to any one of claims 1 to 14, further comprising an antioxidant.

16. The composition of claim 15, wherein the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, ascorbic acid, alpha-tocopheryl acetate or ascorbyl palmitate, or a combination thereof or two or more thereof.

17. A composition according to claim 15 or 16, wherein the antioxidant comprises butylated hydroxytoluene and / or butylated hydroxyanisole.

18. A composition according to any one of claims 15 to 17, wherein the antioxidant comprises from about 0.01% to 1%, or from about 0.2% to 0.3%, by weight of the composition.

19. The composition of any one of claims 1 to 18, wherein the PKC inhibitor is about 0.001% to about 1.0%, about 0.010% to about 1.0%, about 0.1%, or about 0.80% by weight of the composition.

20. The composition of any one of claims 1 to 19, wherein the PKC inhibitor is present in the composition in an amount of about 0.001 mg to about 10 g.

21. A composition comprising a protein kinase C (PKC) inhibitor and two or more diols, wherein the composition is 50%-99% by weight of the two or more diols.

22. The composition of claim 21, wherein the PKC inhibitor is a PKCα, PKCβ, PKCβ1, PKCβ2, PKCδ, PKCε, PKCθ, PKCζ, PKCγ, PKCλ, PKCμ, PKCι or PKCη inhibitor.

23. The composition of claim 22, wherein the PKC inhibitor comprises a PKCβ inhibitor.

24. The composition of claim 23, wherein the PKCβ inhibitor comprises rubustard.

25. The composition of claim 24, wherein the Rubostar comprises Rubostar mesylate monohydrate or Rubostar free base.

26. The composition of claim 24, wherein the rubostar comprises rubostar hydrochloride, rubostar sulfate, rubostar tartrate, rubostar succinate, rubostar acetate, rubostar phosphate, or another rubostar salt.

27. A composition comprising Rubostal mesylate monohydrate and two or more diols, wherein the composition is 50% to 99% by weight of the two or more diols.

28. The composition of any one of claims 21 to 26, wherein the two or more glycols comprise 2-(2-ethoxyethoxy)ethanol and one of propylene glycol, glycerol, or polyethylene glycol (e.g., PEG 400).

29. The composition of claim 27, wherein the 2-(2-ethoxyethoxy)ethanol is about 40-50%, about 43-49%, about 47-49%, or about 47-48% by weight of the composition.

30. The composition of any one of claims 21 to 29, wherein the two or more glycols are from about 80% to 99% by weight of the composition.

31. The composition according to any one of claims 21 to 30, further comprising C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, glycerol, fatty alcohol, fatty ester or fatty ether, or a combination of two or more thereof.

32. The composition of any one of claims 21 to 31, further comprising cocoyl caprylic caprate, decyl oleate, dimethyl isosorbide, glyceryl monooleate, isopropyl myristate, medium chain triglycerides (MCT), octyldodecanol, oleyl alcohol, oleyl oleate, polyoxyethylene alkyl ethers, polyoxyethylene stearate, propylene glycol monolaurate, propylene glycol, lecithin, cyclodextrin, docusate sodium, glyceryl monostearate, hydrogenated vegetable oil, cottonseed oil, palm kernel oil, N-methyl-2-pyrrolidone, poloxamer, polysorbate, PEG castor oil derivative, polyoxyglycerol ester, sodium lauryl sulfate, sucrose esters, glycerol, ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, tert-butanol, hydroxypropyl cellulose, hydroxyethyl cellulose, carbopol, carbomer, carboxymethyl cellulose, or a combination of two or more thereof.

33. The composition of claim 32, comprising the hydroxypropyl cellulose, wherein the hydroxypropyl cellulose is HPC GF, HPC CF or HPC HF, or a combination of two or more thereof.

34. The composition of claim 33, comprising the hydroxypropyl cellulose, hydroxyethyl cellulose, carbopol, carbomer or carboxymethyl cellulose, or a combination of two or more thereof, wherein the hydroxypropyl cellulose, hydroxyethyl cellulose, carbopol, carbomer or carboxymethyl cellulose, or a combination of two or more thereof, is about 16%-75% or about 18%-56% by weight of the composition.

35. The composition of any one of claims 21 to 34, further comprising an antioxidant.

36. The composition of claim 35, wherein the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, ascorbic acid, alpha-tocopheryl acetate or ascorbyl palmitate, or a combination thereof or two or more thereof.

37. A composition according to claim 35 or 36, wherein the antioxidant comprises butylated hydroxytoluene and / or butylated hydroxyanisole.

38. The composition of any one of claims 35 to 37, wherein the antioxidant is from about 0.01% to 1%, or from about 0.2% to 0.3%, by weight of the composition.

39. The composition of any one of claims 21 to 38, wherein the PKC inhibitor is about 0.001% to about 1.0%, about 0.010% to about 1.0%, about 0.1%, or about 0.80% by weight of the composition.

40. The composition of any one of claims 21 to 39, wherein the PKC inhibitor is present in the composition in an amount of about 0.001 mg to about 10 g.

41. A composition comprising: Protein kinase C (PKC) inhibitors; 2-(2-ethoxyethoxy)ethanol; Polyethylene glycol (PEG); Propylene glycol; glycerin; Hydroxypropyl cellulose; and One or more antioxidants.

42. The composition of claim 41, wherein: (i) the PKC inhibitor is from about 0.001% to about 1.0%, from about 0.010% to about 1.0%, about 0.1% or about 0.80% by weight of the composition; (ii) the 2-(2-ethoxyethoxy)ethanol is from about 40% to about 50%, from about 43% to about 49%, from about 47% to about 49%, or from about 47% to about 48%, by weight of the composition; (iii) the polyethylene glycol is from about 2% to about 45%, from about 3% to about 24%, from about 3% to about 14%, from about 13% to about 15%, or from about 13% to about 14%, by weight of the composition; (iv) the propylene glycol is from about 8% to about 30%, from about 9% to about 22%, from about 18% to about 22%, from about 19% to about 21%, or from about 19% to about 20%, by weight of the composition; (v) the glycerin is from about 10% to about 20% or about 15% by weight of the composition; (vi) the hydroxypropyl cellulose is from about 1% to about 3% by weight of the composition; (vii) the one or more antioxidants are present at about 0.01% to about 1.0% by weight of the composition; or (viii) two or more selected from (i) to (vii).

43. The composition of claim 41 or 42, wherein the PKC inhibitor is a PKCα, PKCβ, PKCβ1, PKCβ2, PKCδ, PKCε, PKCθ, PKCζ, PKCγ, PKCλ, PKCμ, PKCι or PKCη inhibitor.

44. The composition of claim 43, wherein the PKC inhibitor comprises a PKCβ inhibitor.

45. The composition of claim 44, wherein the PKCβ inhibitor comprises rubustard.

46. ​​The composition of claim 45, wherein the rubostar comprises rubostar mesylate monohydrate or rubostar free base.

47. The composition of claim 45, wherein the rubostar comprises rubostar hydrochloride, rubostar sulfate, rubostar tartrate, rubostar succinate, rubostar acetate, rubostar phosphate, or another rubostar salt.

48. The composition of any one of claims 41 to 47, wherein the PKC inhibitor is present in the composition in an amount of about 0.001 mg to about 10 g.

49. A method of treating cancer comprising administering to a subject in need thereof a composition according to any one of claims 1 to 48.

50. The method of claim 49, wherein the cancer is a malignant tumor.

51. The method of claim 49, wherein the cancer is a benign tumor.

52. A method of improving immune function comprising administering a composition according to any one of claims 1 to 48 to a subject in need thereof.

53. A method of treating hyperpigmentation comprising administering to a subject in need thereof a composition according to any one of claims 1 to 48.

54. The method of any one of claims 49 to 53, wherein the composition is formulated as a gel, ointment, cream, lotion, foam or emollient.

55. The method of any one of claims 49 to 54, wherein the composition is applied topically to the head, scalp, face, ears, neck, chest, back, inframammary area, arms, legs or groin, or two or more thereof.

56. The method of any one of claims 49 to 55, wherein the composition is administered once daily.

57. The method of any one of claims 49 to 55, wherein the composition is administered twice daily.

58. according to the method described in any one of claims 49 to 57, wherein the composition is applied for at least 4 weeks, at least 8 weeks, at least 12 weeks, about 4 weeks to about 6 weeks, about 4 weeks to about 8 weeks, about 8 weeks to about 10 weeks, about 8 weeks to about 12 weeks or about 12 weeks to about 24 weeks.

59. The method of any one of claims 49 to 58, wherein the composition is a component of a patch, tape, film, cloth, wipe, sponge, sheet or bandage.

60. The method of any one of claims 49 to 59, wherein the composition is administered with one or more of: Skin lightener; Bleach; Sunscreens, sunblocks or filters; Depilatory agents; Anti-aging treatments; Antimicrobial agents; or anti-inflammatory agents; or A combination of two or more of them.

61. The method of any one of claims 49 to 60, wherein the composition is applied to 0.1% to 100% of the subject's body surface area.

62. The method of any one of claims 49 to 61, wherein about 0.01 g to about 100 g of the composition is administered.

63. The method according to any one of claims 49 to 62, wherein the composition is present in an amount of 1% to 2% by volume per cm 2 The amount is applied in an amount of about 0.00001 g to about 1.0 g per body surface area of ​​the subject.

64. The method according to any one of claims 49 to 63, wherein the composition is present in an amount of 1% to 2% by volume per cm 2 An amount of about 0.000175 g per body surface area of ​​the subject is applied.

Images