Compositions and formulations for the use of PK inhibitors to prevent, treat, and ameliorate skin conditions, diseases, and disorders - Patents.com

Abstract

Provided herein are compositions comprising ruboxistaurin free base, and methods of use thereof, for treating skin conditions.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 344,422, filed May 20, 2022, U.S. Provisional Patent Application No. 63 / 399,946, filed August 22, 2022, and U.S. Provisional Patent Application No. 63 / 489,697, filed March 10, 2023, the contents of which are incorporated by reference in their entireties. [Background technology]

[0002] Hyperpigmentation is a commonly diagnosed disorder in which dark spots occur on the skin. This skin darkening occurs in response to the excess production or irregular distribution of melanin, a brown pigment produced by melanocytes in various skin layers, followed by skin inflammation. Hyperpigmentation includes various skin discoloration disorders such as melasma, post-inflammatory hyperpigmentation, freckles, and lentigines. Skin color changes are the result of intrinsic factors and external insults to the skin, including hormonal changes, inflammation, injury, acne, eczema, drug side effects, sun damage, etc. Skin hyperpigmentation can affect any race or gender, but is mostly prevalent in patients with skin of color and in women.

[0003] Currently, the most commonly used treatment for hyperpigmentation is hydroquinone, either alone or in combination with other drugs. Hydroquinone is toxic to melanocytes and therefore nonselectively inhibits melanin synthesis. Products containing hydroquinone are minimally effective at safe low concentrations and toxic at higher concentrations, sometimes resulting in permanent pigment loss or skin hyperpigmentation leading to histological melanosis. Topical application of the selective PKC inhibitor bisindolylmaleimide in a guinea pig model has been shown to inhibit UV-induced neo-melanogenesis. Summary of the Invention

[0004] The following formula:

[0005] [ka] The PKC-β inhibitor, referred to herein as ruboxistaurin or ruboxistaurin mesylate (also referred to herein as "methanesulfonic acid salt") monohydrate, represented by the formula:

[0006] Common solvents used to formulate other small molecule compounds do not solubilize the specific PK inhibitors described herein, including but not limited to, ruboxistaurin free base, or ruboxistaurin salts (e.g., ruboxistaurin mesylate monohydrate), for use in clinically or aesthetically acceptable compositions. Thus, there is an urgent need to develop topical compositions comprising the PK inhibitors described herein, including but not limited to, ruboxistaurin free base, or ruboxistaurin salts (e.g., ruboxistaurin mesylate monohydrate), that can be delivered topically with reduced skin irritation to treat skin disorders such as hyperpigmentation.

[0007] In a first aspect, the present disclosure provides a composition comprising:

[0008] [ka] or an acceptable salt thereof, and an excipient, a) organic solvents and / or penetration enhancers; b) antioxidants; c) a gelling agent, or d) alcohol, or a combination thereof; The organic solvent, and / or penetration enhancer, antioxidant, alcohol, and gelling agent are defined and described herein. The composition may be formulated with 0.1% or 0.8% ruboxistaurin free base, ruboxistaurin mesylate monohydrate, or other salts. Optionally, the composition is administered once or twice daily. Optionally, the composition is administered for about 12 weeks to about 6 months. Optionally, the composition is administered for about 4 weeks to about 8 weeks. Optionally, the composition is administered for about 8 weeks to about 12 weeks.

[0009] In a second aspect, the present disclosure provides a method for producing a pharmaceutical composition comprising:

[0010] [ka] or an acceptable salt thereof, and propylene glycol, 2-(2-ethoxyethoxy)ethanol, hydroxypropylcellulose, polyethylene glycol, an antioxidant, and alcohol. The composition may be formulated with 0.1% or 0.8% ruboxistaurin free base, ruboxistaurin mesylate monohydrate, or other salts. The composition may be formulated with 0.08% to 0.8% ruboxistaurin mesylate monohydrate, ruboxistaurin free base, or other salts. Optionally, the composition is administered once or twice daily. Optionally, the composition is administered for about 12 weeks to about 6 months. Optionally, the composition is administered for about 4 weeks to about 8 weeks. Optionally, the composition is administered for about 8 weeks to about 12 weeks.

[0011] In a third aspect, the disclosure provides a method of treating a skin disease, condition, or disorder in a subject in need of such treatment, comprising administering to the subject a composition described herein. In some aspects, the disclosure further provides a method of treating a hair or hair follicle disease or disorder. The composition may be formulated with 0.08% to 0.8% of a PK inhibitor, including but not limited to ruboxistaurin free base, or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate). Optionally, the composition is administered once or twice daily. Optionally, the composition is applied to 0.01% to 100% of the body surface area. Optionally, the composition is administered for about 12 weeks to about 6 months. Optionally, the composition is administered for about 4 weeks to about 8 weeks. Optionally, the composition is administered for about 8 weeks to about 12 weeks.

[0012] In a fourth aspect, the 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 oxygen exposure, together with instructions for use. The composition can be formulated with 0.1% or 0.8% ruboxistaurin free base, ruboxistaurin mesylate monohydrate, or other salts. The composition can be formulated with 0.08% to 0.8% ruboxistaurin, ruboxistaurin mesylate monohydrate, or other salts. Optionally, the composition is administered once or twice daily. Optionally, the composition is administered for about 12 weeks to about 6 months. Optionally, the composition is administered for about 4 weeks to about 8 weeks. Optionally, the composition is administered for about 8 weeks to about 12 weeks. [Brief description of the drawings]

[0013] [Figure 1] Microscopic appearance of A) NA21, B) NA16, C) NA17, D) NA25, and E) NA26 after 2 months of storage at 25° C. (400x magnification, unpolarized). [Figure 2A]FIG. 1 shows the percentage of subjects with an IDGA score of -1 (slightly milder than untreated controls) on the dorsum of the hand over 12 weeks of treatment with ruboxistaurin mesylate monohydrate gel 0.8% w / w, hydroquinone 4% w / w, or vehicle (**p<0.01). [Figure 2B] FIG. 1 shows the percentage of subjects with an IDGA score of -1 (slightly less severe than untreated controls) on the upper volar arm over 12 weeks of treatment with ruboxistaurin mesylate monohydrate gel 0.8% w / w, hydroquinone 4% w / w, or vehicle (* indicates p<0.05). [Figure 3A] FIG. 1 shows the percentage of subjects with an IDGA score of -2 (moderately milder than untreated controls) on the dorsum of the hand over 12 weeks of treatment with ruboxistaurin mesylate monohydrate gel 0.8% w / w, hydroquinone 4% w / w, or vehicle (* indicates p<0.05). [Figure 3B] FIG. 14. Percentage of subjects with an IDGA score of −2 (moderately milder than untreated controls) on the upper volar arm over 12 weeks of treatment with ruboxistaurin mesylate monohydrate gel 0.8% w / w, hydroquinone 4% w / w, or vehicle. [Figure 4A] FIG. 1 shows the percentage of subjects with dorsal solar lentigines treated with ruboxistaurin mesylate monohydrate gel 0.8% w / w who have an IDGA value of −2, −1, 0, or 1. [Figure 4B] FIG. 11 shows the percentage of subjects treated with ruboxistaurin mesylate monohydrate gel 0.8% w / w on the volar arm with IDGA values ​​of −2, −1, 0, or 1. [Figure 4C] FIG. 11: Percentage of all subjects at all time points with dorsal solar lentigines treated with ruboxistaurin mesylate monohydrate gel 0.8% w / w and with IDGA values ​​of −2, −1, 0, or 1. [Figure 4D] FIG. 11: Percentage of all subjects at all time points treated with ruboxistaurin mesylate monohydrate gel 0.8% w / w on the volar arm with IDGA values ​​of −2, −1, 0, or 1. [Figure 5A]FIG. 1 shows the change in colorimetric values ​​(measured by visit value to screening value) for subjects with dorsal hand lentigines treated with ruboxistaurin mesylate monohydrate gel 0.8% w / w compared to untreated sites, with positive values ​​indicating a decrease in pigment (* is p<0.05, *** is p<0.001). [Figure 5B] FIG. 1 shows the change in colorimetric values ​​(measured by visit value - screening value) for subjects with lentigines on the upper volar arm treated with ruboxistaurin mesylate monohydrate gel 0.8% w / w compared to untreated sites, with positive values ​​indicating a decrease in pigment. [Figure 5C] FIG. 1 shows the change in colorimetric values ​​(measured by visit value to screening value) for all subjects whose dorsal hand lentigines were treated with ruboxistaurin mesylate monohydrate gel 0.8% w / w at all time points compared to untreated sites; positive values ​​indicate a decrease in pigment (* is p<0.05, *** is p<0.001). [Figure 5D] FIG. 1 shows the change in colorimetric values ​​(measured by visit value - screening value) for all subjects at all time points where lentigines on the upper volar arm were treated with ruboxistaurin mesylate monohydrate gel 0.8% w / w compared to untreated sites; positive values ​​indicate a decrease in pigment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] overview Protein kinase C (PKC or PRKC) is an intracellular signaling molecule that can regulate many vascular functions, including permeability, vasodilatory release, endothelial activation, and growth factor signaling. Protein kinase C is a family of isozymes that includes at least 12 members whose β-isoforms have been associated with the development of diabetic microvascular complications and the production of melanin. In the skin, PKC-β expression is what leads to melanin production and pigmentation in human skin and is thought to be restricted to melanocytes. Inhibition of PKC-β, and the subsequent inhibition of melanin production, is an attractive and selective target in the treatment of hyperpigmentation. While the normal redistribution and increased production of melanin following exposure to ultraviolet (UV) radiation can be beneficial, excessive or uneven production of melanin can result in hyperpigmentation that gives rise to undesirable conditions such as melasma, lentigines, PIH, and other pigmentary 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 for activity. Inhibitors of PKC-β have been shown to reduce melanogenesis.

[0015] Provided herein are compositions comprising ruboxistaurin free base, ruboxistaurin mesylate, or an acceptable salt thereof, and methods of using these compositions to treat a skin disease, condition, or disorder. In some embodiments, the compositions are administered topically, thereby treating a skin disease, condition, or disorder. In some embodiments, the skin disease, condition, or disorder includes hyperpigmentation, hypopigmentation, dyschromia, melasma, post-inflammatory hyperpigmentation or hypopigmentation, discoid lupus erythematosus, erythema, phytophotodermatitis, lentigines (e.g., facial age spots), nevi, nevus spilus, acanthosis nigricans, burn-associated hyperpigmentation or hypopigmentation, drug-induced hyperpigmentation or hypopigmentation (e.g., sulfonamide-, tetracycline-, NSAID-, barbiturate-, and carbamazepine-induced hyperpigmentation), injury-associated hyperpigmentation or hypopigmentation, primary biliary cirrhosis-associated hyperpigmentation or hypopigmentation, Addison's disease-associated hyperpigmentation or hypopigmentation, In some embodiments, the disease, condition, or disorder may include, but is not limited to, skin pigmentation, hemochromatosis-associated hyperpigmentation or hypopigmentation, hyperthyroidism-associated hyperpigmentation or hypopigmentation, melanocytic nevi, freckles, seborrheic keratosis, skin cancer-associated hyperpigmentation or hypopigmentation, infection-associated hyperpigmentation or hypopigmentation (e.g., tinea versicolor, erythrasma, erythrasma), eczema, photocontact, photoallergy, or phototoxic dermatitis, ichthyosis, pigmented spots or nevus spilus associated with neurofibromatosis, or hyperpigmentation or hypopigmentation associated with extreme ultraviolet (UV) radiation exposure, e.g., a reaction to sun exposure or sunburn, or a combination of two or more thereof. In some embodiments, the disease, condition, or disorder includes cosmetic indications, including skin lightening, skin brightening, skin tone evenness, skin normal night, phototraumatic hyperpigmentation, or polychromatic pigmentation. In some embodiments, this also includes vitiligo or other depigmenting diseases and evening out skin pigmentation irregular conditions resulting from pigmentation disorders. The disease may also be a hair or hair follicle disease, disease, or disorder, such as hypertrichosis / hirsutism and hair pigmentation. In particular, the composition is useful for treating hyperpigmentation disorders and pigmentation disorders.

[0016] definition The abbreviations used herein have their conventional meaning within the chemical and biological arts.

[0017] "Alkylene glycol" refers to a compound having the formula H-[O-alkylene]-OH, where the alkylene group has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. In some embodiments, alkylene glycol is C 2-6 In some embodiments, C is an alkylene glycol. 2-6 The alkylene glycol is propylene glycol (1,2-propanediol).

[0018] "Dialkylene glycol" is HO-(alkylene-O) 2 —H, where the alkylene group has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. In some embodiments, the dialkylene glycol is di-(C 2-6 In some embodiments, di-(C 2-6 The alkylene) glycol is dipropylene glycol. Dipropylene glycol can include one or more isomers, such as 4-oxa-2,6-heptanediol, 2-(2-hydroxy-propoxy)-propan-1-ol, 2-(2-hydroxy-1-methyl-ethoxy)-propan-1-ol, and 3,3'-oxybis(propan-1-ol).

[0019] "Polyethylene glycol" is a HO-(CH 2 CH 2 O) nIt refers to a polymer having the formula -OH. Suitable polyethylene glycols may have a free hydroxyl group at each end of the polymer molecule or may have one or more hydroxyl groups etherified with a lower alkyl, e.g., methyl, group. Also suitable are derivatives of polyethylene glycol having an esterifiable carboxy group. The polyethylene glycols useful in the present invention may be polymers of any chain length or molecular weight and may include branching. In some embodiments, the average molecular weight of the polyethylene glycol is about 200 to about 9000. In some embodiments, the average molecular weight of the polyethylene glycol is about 200 to about 5000. In some embodiments, the average molecular weight of the polyethylene glycol is about 200 to about 900. In some embodiments, the average molecular weight of the polyethylene glycol is about 400. Suitable polyethylene glycols include, but are not limited to, PEG 200, PEG 300, PEG 400, PEG 600, and PEG 900. The number following the "PEG" in the name refers to the average molecular weight of the polymer.

[0020] "USP / NF grade, Ph.Eur. grade, BP grade, JP grade, etc." excipients refer to excipients that meet or exceed the requirements of the United States Pharmacopeia / National Formulary (USP / NF), European Pharmacopoeia, British Pharmacopoeia, and Japanese Pharmacopoeia, respectively (e.g., propylene glycol, glycerol, polyethylene glycols such as PEG200 and PEG400, etc.).

[0021] "Highly purified" excipients refer to excipients from which impurities have been removed. High purification removes polar impurities (including potentially reactive primary and secondary oxidation products) from the excipient without altering its chemical composition. Removal of these impurities reduces the excipient's interactions with the active pharmaceutical ingredient (API) and subsequent API degradation, helping to maintain the stability of both the drug and the final composition or formulation. Additionally, removal of these impurities can minimize cellular irritation, making it ideal for various drug administration routes. The highly purified excipients of the present invention include highly purified propylene glycol.

[0022] "Highly purified propylene glycol" or "SR propylene glycol" refers to highly purified propylene glycol that can enhance drug activity and composition (or formulation) stability. In some embodiments, the SR propylene glycol has a purity of about 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% or more. In some embodiments, the SR propylene glycol has a purity of about 99.8% or 99.9% or more.

[0023] "Transcutol" is a compound of the formula: CH 3 CH 2 OCH 2 CH 2 OCH 2 CH 2 It is represented by OH and has the preferred IUPAC name 2-(2-ethoxyethoxy)ethanol. Other names for 2-(2-ethoxyethoxy)ethanol include diethylene glycol monoethyl ether (abbreviated DGME or DEGEE), diethylene glycol ethyl ether (abbreviated DEGEE), ethyldiglycol, dioxytol, 3,6-dioxa-1-octanol, Carbitol, Carbitol cellosolve, Polysolv DE, or Dowanal DE. Transcutol includes "Transcutol P", "Transcutol CG", and "Transcutol HP".

[0024] "Transcutol P" refers to a high purity grade of 2-(2-ethoxyethoxy)ethanol. "Transcutol CG" refers to a specific grade of 2-(2-ethoxyethoxy)ethanol, which is a potent solubilizer and efficacy booster used in the cosmetic and pharmaceutical industries. "Transcutol HP" refers to a highly purified grade of 2-(2-ethoxyethoxy)ethanol, which can enhance drug activity and composition (or formulation) stability. In some embodiments, Transcutol P, CG, or HP is about 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% pure or greater. In some embodiments, Transcutol P or HP is 99.8% or less pure. In one embodiment, Transcutol HP is about 99.90% pure.

[0025] "Fatty alcohol" refers to a primary alcohol with a long aliphatic chain that is saturated or unsaturated. Fatty alcohols can also range from as few as 4-6 carbons to as many as 22-26 carbons. Fatty alcohols include, but are not limited to, capric alcohol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, palmitoleic alcohol (unsaturated), heptadecyl alcohol, stearyl alcohol, oleyl alcohol (unsaturated), nonadecyl alcohol, arachidyl alcohol, heneicosyl alcohol, behenyl alcohol, erucyl alcohol (unsaturated), and lignoceryl alcohol.

[0026] "Aliphatic ester" or "fatty acid ester" refers to a type of ester resulting from the combination of a fatty acid and an alcohol. When the alcohol is polyethylene glycol, the aliphatic ester refers to a polyoxyethylene aliphatic ester or a polyoxyethylene fatty acid ester.

[0027] "Aliphatic ether" refers to a type of ether resulting from the combination of an aliphatic alcohol with a secondary alcohol. When the secondary alcohol is polyethylene glycol, the aliphatic ether refers to a polyoxyethylene aliphatic ether.

[0028] "Polysorbate" refers to a type of aliphatic ester derived from ethoxylated sorbitan (a polyethylene glycol derivative of sorbitol) with fatty acids. Examples of polysorbates include polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), and polysorbate 80 (polyoxyethylene (20) sorbitan monooleate). Suitable polysorbates include, but are not limited to, the Tween™ series (available from Uniqema), including Tween 20 (polyoxyethylene (20) sorbitan monolaurate), Tween 40 (polyoxyethylene (20) sorbitan monopalmitate), Tween 60 (polyoxyethylene (20) sorbitan monostearate), and Tween 80 (polyoxyethylene (20) sorbitan monooleate). Other suitable polysorbates include those listed in Handbook of pharmaceutical excipients, (2006), 5th Edition, by RC Rowe and PJ Shesky, which is incorporated herein by reference in its entirety.

[0029] "Glyceride" refers to a fatty ester when the alcohol component is glycerol. The glyceryl fatty ester (or glyceride) produced can be a monoglyceride, diglyceride, or triglyceride. A "monoglyceride" is a glyceride consisting of one fatty acid chain covalently bonded to a glycerol molecule by an ester bond. A "diglyceride" is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule by an ester bond. A "triglyceride" is a glyceride consisting of three fatty acid chains covalently bonded to a glycerol molecule by ester bonds.

[0030] "Salt" refers to an acid salt or base salt of the compound of the present invention.Typical examples of pharmaceutically acceptable salts are mineral acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (such as acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts, and quaternary ammonium (such as methyl iodide, ethyl iodide, etc.) salts.It is understood that pharmaceutically acceptable salts are non-toxic.Additional information regarding 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.

[0031] "Solvate" refers to a compound provided herein or a salt thereof that further comprises 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.

[0032] "Hydrate" refers to a compound that is complexed with water molecules. The compounds of the invention can be complexed with 1 / 2 water molecules or with 1-10 water molecules.

[0033] A "composition" or "formulation," as used herein, is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product that results directly or indirectly from combining the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means that the carrier, diluent, or excipient must be compatible with the other ingredients of the composition (or formulation) and not deleterious to the recipient thereof.

[0034] For any one of the topical compositions described herein, the water content refers to the total weight including the pH adjusting solution (if present) (e.g., a 0.1 M, 0.5 M, or 1 M solution of citric acid in water), ethanol (if the ethanol is not absolute ethanol), and the portion from the final QS100 (QS stands for quantity).

[0035] "Relative purity of a compound in a topical formulation" refers to the purity of a compound (e.g., a PK inhibitor described herein, including but not limited to, ruboxistaurin free base, or ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate)) at a certain time point (e.g., week 8) stored under stress conditions (e.g., 40°C) or under normal storage conditions (e.g., room temperature or 25°C) compared to the initial purity of the compound at time zero (i.e., day 0). In all cases, the relative purity of a compound at time zero (i.e., day 0) is set as 100%.

[0036] "About" refers to a range of values ​​that includes a particular value, which values ​​one of ordinary skill in the art would consider to be reasonably similar to the particular value. In some embodiments, the term "about" refers to within a standard deviation using measurements generally accepted in the art. In some embodiments, about refers to a range that covers + / - 10% of the particular value. In some embodiments, about refers to the particular value.

[0037] "Substantially free of..." means that the composition is free of di-(C 2-6It refers to a composition that contains 1% by weight or less of other excipients, such as polyethylene glycols (e.g., PEG 200 and / or PEG 400) and / or C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 -OH (e.g., 2-(2-ethoxyethoxy)ethanol or Transcutol HP) contains impurities including ethylene glycol and / or diethylene glycol. Polyethylene glycol (e.g., PEG200 and / or PEG400) and / or C 1-3 Alkyl-(OCH 2 CH 2 ) 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 impurities. In some embodiments, polyethylene glycol (e.g., PEG200 and / or PEG400) and / or C 1-3 Alkyl-(OCH 2 CH 2 ) 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 impurities.

[0038] "Inhibition," "inhibits," and "inhibitor" refer to a compound or method that prohibits a particular action or function.

[0039] "Administering" refers to providing a composition or formulation to a subject (e.g., a patient, such as a human patient) via a desired route, such as topical administration. Topical administration can include applying the composition to a surface of the subject, such as the subject's skin, in the form of, for example, a gel, ointment, lotion, foam, emollient, or as a component of a patch, tape, film, wafer, or bandage. The area to which the composition is applied can vary based on, for example, the condition of the subject, as well as the characteristics of the composition (e.g., form, drug loading, etc.).

[0040] "Treat," "treating," and "treatment" refer to indications of success in treating or ameliorating an injury, condition, or disease, including any objective or subjective parameter, such as remission, remission, reducing symptoms or making the patient more tolerant of the injury, condition, or disease, slowing the rate of regression or wasting, being less wasting at the end of regression, improving the physical or mental health of the patient, etc. Treating or ameliorating symptoms can be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric testing, and / or a psychiatric evaluation.

[0041] "Patient" or "subject" refers to an organism suffering from or susceptible to a disease or disorder that can be treated by administration of the pharmaceutical compositions provided herein. Non-limiting examples include humans, other mammals, cows, rats, mice, dogs, cats, primates, goats, sheep, cows, deer, and other non-mammalian animals. In some embodiments, the patient or subject is a human.

[0042] "Therapeutically effective amount" refers to an amount of a compound or pharmaceutical composition effective for treating or ameliorating a specified disease or disorder, or for exhibiting a detectable therapeutic or inhibitory effect. The exact amount will depend on the purpose of treatment and can be ascertained by those skilled in the art using known techniques (see, for example, Pharmaceutical Dosage Forms by Lieberman (vols. 1-3, 1992); The Art, Science and Technology of Pharmaceutical Compounding by Lloyd (1999); Dosage Calculations by Pickar (1999); and Remington: The Science and Practice of Pharmacy, 20th ed., 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0043] "A," "an," or "a(n)," when used herein in reference to substituents or "substituent groups," 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, where 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, where each substituent is optionally different.

[0044] composition I. Composition In a first aspect, the present disclosure provides a composition. The composition includes a PK inhibitor as described herein, including but not limited to ruboxistaurin free base, ruboxistaurin salt (e.g., ruboxistaurin mesylate salt or another acceptable salt thereof), and one or more excipients. As will be appreciated, some of the one or more excipients of the compositions described herein can have multiple functions. For example, a given substance can function as both a solvent and an enhancer, both an antioxidant and a stabilizer, both an emulsifier and a surfactant, both an emulsifier and a thickener, etc. In some such cases, the function of a given substance can be considered as one, even though its properties may allow for multiple functions. The composition can be formulated with 0.1% or 0.8% of a PK inhibitor, including but not limited to ruboxistaurin free base, or ruboxistaurin salt (e.g., ruboxistaurin mesylate salt monohydrate). The composition may be formulated with 0.08% or 0.8% w / w of ruboxistaurin free base, ruboxistaurin mesylate monohydrate, or other salts. Optionally, the composition is administered once or twice daily. Optionally, the composition is administered for about 12 weeks to about 6 months. Optionally, the composition is administered for about 4 weeks to about 8 weeks. Optionally, the composition is administered for about 8 weeks to about 12 weeks.

[0045] In some embodiments, examples of PK inhibitors as used herein include ruboxistaurin mesylate monohydrate, ruboxistaurin free base, or acceptable salts thereof;

[0046] [ka] or a pharma- ceutically acceptable salt thereof.

[0047] Non-limiting examples of excipients include organic solvents and / or one or more additional agents, such as penetration enhancers, antioxidants, gelling agents, and alcohols or wetting agents. In some compositions, one of the one or more excipients includes an organic solvent and includes one or more organic solvents, such as 1, 2, 3, 4, or 5 organic solvents. In some compositions, one of the one or more excipients includes a penetration enhancer and includes one or more penetration enhancers, such as 1, 2, 3, 4, or 5 penetration enhancers. In some cases, the organic solvent is a penetration enhancer. In some compositions, one of the one or more excipients includes an antioxidant and includes one or more antioxidants, such as 1, 2, 3, 4, or 5 antioxidants. In some compositions, one of the one or more excipients includes a gelling agent and includes one or more gelling agents, such as 1, 2, 3, 4, or 5 gelling agents. In some compositions, one of the one or more excipients includes one or more additional agents, such as alcohol. In some compositions, alcohol is a humectant.

[0048] In some embodiments, the composition includes an organic solvent and / or a penetration enhancer. The organic solvent may be a penetration enhancer. In some embodiments, the composition includes an organic solvent or a penetration enhancer. Non-limiting examples of compositions include an organic solvent and / or a penetration enhancer, and one or more additional excipients. The one or more additional excipients may be an antioxidant. The one or more additional excipients may be an alcohol. The one or more additional excipients may be a gelling agent. The one or more additional excipients may include an antioxidant, an alcohol, a gelling agent, or two or more thereof. The one or more additional excipients may include an antioxidant, an alcohol, and a gelling agent.

[0049] In some embodiments, the composition includes an antioxidant. A non-limiting example of a composition includes an antioxidant and one or more additional excipients. The one or more additional excipients may be an organic solvent and / or a penetration enhancer. The one or more additional excipients may be an alcohol. The one or more additional excipients may be a gelling agent. The one or more additional excipients may include an organic solvent and / or a penetration enhancer, an alcohol, a gelling agent, or two or more thereof. The one or more additional excipients may include an organic solvent and / or a penetration enhancer, an alcohol, and a gelling agent.

[0050] In some embodiments, the composition includes a gelling agent. A non-limiting example of the composition includes a gelling agent and one or more additional excipients. The one or more additional excipients may be an antioxidant. The one or more additional excipients may be an alcohol. The one or more additional excipients may be an organic solvent and / or a penetration enhancer. The one or more additional excipients may include an antioxidant, an alcohol, an organic solvent and / or a penetration enhancer, or two or more thereof. The one or more additional excipients may include an antioxidant, an alcohol, and an organic solvent and / or a penetration enhancer.

[0051] In some embodiments, the composition includes an alcohol. A non-limiting example of the composition includes a solvent and one or more additional excipients. The one or more additional excipients may be a penetration enhancer. The one or more additional excipients may be an antioxidant. The one or more additional excipients may be a gelling agent. The one or more additional excipients may include an antioxidant, a penetration enhancer, a gelling agent, or two or more thereof. The one or more additional excipients may include an antioxidant, a penetration enhancer, and a gelling agent.

[0052] II.PK inhibitors In some embodiments, the compositions comprise a PK inhibitor as described herein that prevents, inhibits, or reduces melanin production by inhibiting or modulating a protein kinase. In some embodiments, the compositions inhibit or modulate a protein kinase, including but not limited to protein kinase C, protein kinase C alpha, protein kinase C beta, protein kinase B, and / or protein kinase A. In some embodiments, the compositions inhibit or modulate a protein kinase, including but not limited to PKC alpha, PKC beta, PKC beta. 1 , PKCβ 2 , PKCδ, PKCε, PKCθ, PKCζ, PKCγ, PKCλ, PKCμ, PKCι, PKCη. In some embodiments, the composition inhibits or modulates PRKCA, PKCα, PRKCB, PKCβ, PRKCG, PKCγ, PRKCD, PKCσ, PRKCQ, PKCθ, PRKCE, PKCε, PRKCH, PKCη, PRKCI, PKCζ, PRKCZ, PKCι. In some embodiments, the compound described herein inhibits or modulates 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.

[0053] 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 PKCβ inhibitor. 1 and / or PKCβ 2In some embodiments, the PKC beta inhibitor comprises ruboxistaurin free base or a salt thereof. In some embodiments, the ruboxistaurin free base or a salt thereof is ruboxistaurin free base. In some embodiments, the ruboxistaurin or a salt thereof is ruboxistaurin mesylate monohydrate, ruboxistaurin hydrochloride, ruboxistaurin sulfate, ruboxistaurin tartrate, ruboxistaurin succinate, ruboxistaurin acetate, or ruboxistaurin phosphate.

[0054] The disclosure features a PKC-β inhibitor for use in treating a disease or disorder (e.g., a hyperpigmentation condition) described herein. In some embodiments, the PKC-β inhibitor comprises a bis-indolylmaleimide, a phthalimide, or a derivative thereof. In some embodiments, the PKC-β inhibitor has formula (I):

[0055] [ka] or a pharma- ceutically acceptable salt, stereoisomer, racemate, or solvate thereof, wherein

[0056] W is -O-, -S-, -S(O)-, -S(O) 2 -, -C(O)-, C 2 -C 6 Alkylene, substituted alkylene, C 2 -C 6 Alkenylene, substituted alkenylene, aryl, aryl(CH 2 ) m O, heterocyclyl, heterocyclyl(CH 2 ) m O, -NR 3 -, -N(O)R 3 -, -C(O)NH-, or -NHC(O)-;

[0057] Each of X and Y is independently C 1 -C 4alkylene, substituted alkylene, or X, Y, and W combine to form -(CH 2 ) n -AA- is formed,

[0058] R 1 are each independently hydrogen, halo, or C 1 -C 4 Alkyl, Hydroxyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkyl, Nitro, -NR 4 R 5 , or -NHC(O)(C 1 -C 4 alkyl),

[0059] R 2 is hydrogen, -CH 3 C(O), -NH 2 or hydroxyl,

[0060] R 3 is hydrogen, (CH 2 ) m Aryl, C 1 -C 4 Alkyl, -C(O)O(C 1 -C 4 alkyl), -C(O)NR 4 R 5 , -(C=NH)NH 2 , -S(O)(C 1 -C 4 alkyl), -S(O) 2 (NR 4 R 5 ), or -S(O) 2 (C 1 -C 4 alkyl),

[0061] R 4 and R 5 are each independently hydrogen, C 1 -C 4 alkyl, phenyl, benzyl, or R 4 and R 5together with the nitrogen to which they are attached form a saturated or unsaturated five- or six-membered ring,

[0062] AA is an amino acid residue,

[0063] m is independently 0, 1, 2, or 3;

[0064] Each n is independently 2, 3, 4, or 5.

[0065] 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.

[0066] In some embodiments, R 1 and R 2 is independently hydrogen. In some embodiments, each of X and Y is 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 2is independently hydrogen; each of X and Y is independently alkylene or substituted alkylene; W is substituted alkylene, -O-, -S-, -C(O)NH-, -NHC(O)-, or NR 3 It is.

[0067] In some embodiments, the compound of formula (I) has the formula (Ia):

[0068] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein

[0069] Z is -(CH 2 ) p -or-(CH 2 ) p -O-(CH 2 ) p and

[0070] R 6 is hydroxyl, -SH, C 1 -C 4 Alkyl, (CH 2 ) m Aryl, -NH(aryl), N(CH 3 )(CF 3 ), NH(CF 3 ), or -NR 4 R 5 and

[0071] R 4 is hydrogen or C 1 -C 4 is alkyl,

[0072] R 5 is hydrogen, C 1 -C 4 alkyl, or benzyl;

[0073] p is 0, 1, or 2;

[0074] Each m is independently 2 or 3.

[0075] In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, Z is CH 2 In some embodiments, R 6 NH 2 , NH(CF 3 ), or N(CH 3 ) 2 In some embodiments, Z is CH 2 and R 6 NH 2 , NH(CF 3 ), or N(CH 3 ) 2 In some embodiments, m is 2 and Z is CH 2 and R 6 NH 2 , NH(CF 3 ), or N(CH 3 ) 2 It is.

[0076] In another embodiment, the compound of formula (I) has the formula (Ib):

[0077] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein

[0078] Z is -(CH 2 ) p - and

[0079] R 6 is N(CH 3 )(CF 3 ), NH(CF 3 ), or -NR 4 R 5 and

[0080] R 4 and R 5 Each of 1 -C4 is alkyl,

[0081] R 5 is hydrogen, C 1 -C 4 alkyl, or benzyl;

[0082] p is 0, 1, or 2;

[0083] Each m is independently 2 or 3.

[0084] 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 -NR 4 R 5 and R 4 and R 5 Each of the following is independently C 1 -C 4 Alkyl (e.g., CH 3 In some embodiments, R 6 is N(CH 3 ) 2 In some embodiments, m is 2 and p is 1. In some embodiments, m is 2, p is 1, and R 6 is N(CH 3 ) 2 It is.

[0085] In other embodiments, the compound of formula (I) has the formula (Ic):

[0086] [ka] Compounds of

[0087] or a pharma- ceutically acceptable salt, stereoisomer, racemate, or solvate thereof, wherein R 6 is N(CH 3 )(CF 3 ), NH(CF 3), or -NR 4 R 5 (It is.)

[0088] In some embodiments, R 6 -NR 4 R 5 and R 4 and R 5 Each of the following is independently C 1 -C 4 Alkyl (e.g., CH 3 In some embodiments, R 6 is N(CH 3 ) 2 It is.

[0089] In another embodiment, the compound of formula (I) has the formula (Id):

[0090] [ka] Compounds of

[0091] 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(metheno)dibenzo[e,k]pyrrolo[3,4-h][1,2,13]oxadiazacyclohexadecin-18,20-dione, e.g., ruboxistaurin, or a pharmaceutically acceptable salt, stereoisomer, racemate, or solvate thereof.

[0092] In another embodiment, the compound of formula (I) has the formula (Ie):

[0093] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein A is N(CH 3 ) 2In some embodiments, the compound of formula (Ie) is a 9-[(dimethylamino)methyl]-6,7,10,11-tetrahydro-9H,18H-5,21:12,17-di(metheno)dibenzo[e,k]pyrrolo[3,4-h][1,2,13]oxadiazacyclohexadecin-18,20-dione salt, e.g., a ruboxistaurin salt, or a pharma- ceutically acceptable salt, stereoisomer, racemate, or solvate thereof.

[0094] 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 their salts.In some embodiments, A is acetic acid, benzoic acid, citric acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, methanesulfonic acid, tartaric acid, or their salts.In some embodiments, A is methanesulfonic acid or its salts.

[0095] In another embodiment, the compound of formula (I) has the formula (If):

[0096] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0097] 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(metheno)dibenzo[e,k]pyrrolo[3,4-h][1,2,13]oxadiazacyclohexadecin-18,20-dione mesylate, e.g., ruboxistaurin mesylate, or a pharmaceutically acceptable salt, stereoisomer, racemate, or solvate thereof.

[0098] The compounds of formula (I), (e.g., compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), or (If)) exist as solvates, for example, solvates with water (i.e., hydrates), methanol, ethanol, dimethylformamide, ethyl acetate, and the like. Mixtures of solvates may also be prepared. The source of the solvate may be from a solvent encountered during the preparation of the compound, for example, a solvent of purification (e.g., crystallization), or a solvent in the preparation of purification (e.g., crystallization), or adventitious to such a solvent. In one embodiment, the compounds of formula (I), (e.g., compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), or (If)) exist as a monohydrate or trihydrate solvate.

[0099] In some embodiments, the PKC-β inhibitor of formula (I) may 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 (If-2):

[0100] [ka] or a pharma- ceutically 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(metheno)dibenzo[e,k]pyrrolo[3,4-h][1,2,13]oxadiazacyclohexadecin-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(metheno)dibenzo[e,k]pyrrolo[3,4-h][1,2,13]oxadiazacyclohexadecin-18,20-dione mesylate (e.g., formula (If-2)) or (9R)-9[(dimethylamino)methyl]-6,7,10,11-tetrahydro-9H,18H-5,21:12,17-di(metheno)dibenzo[e,k]pyrrolo[3,4-h][1,2,13]oxadiazacyclohexadecin-18,20-dione mesylate (e.g., formula (If-3))

[0113] ruboxistaurin mesylate, or a pharmaceutically acceptable salt, stereoisomer, racemate, or solvate thereof.

[0101] The preparation of compounds of formula (I) (e.g., compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (If-1), or (If-2)) may be accomplished by the methods described in U.S. Pat. Nos. 5,552,396 and 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)) may also be accomplished using other protocols or methods known to those of skill in the art.

[0102] In some embodiments, the PKC-β inhibitor has formula (II):

[0103] [ka] or a pharma- ceutically acceptable salt, stereoisomer, racemate, or solvate thereof, wherein

[0104] R 1 are each independently hydrogen, halo, or C 1 -C 4 Alkyl, Hydroxyl, C 1 -C 4 Alkoxy, haloalkyl, nitro, NR 4 R 5 , or -NHC(O)(C 1 -C 4 alkyl),

[0105] R 2 is hydrogen, -CH 3 C(O), -NH 2 or hydroxyl,

[0106] R 4 and R 5 are each independently hydrogen, C 1 -C 4 alkyl, phenyl, benzyl, or R 4 and R 5together with the nitrogen to which they are attached form a saturated or unsaturated five- or six-membered ring,

[0107] R 7 is hydrogen or C 1 -C 4 is alkyl,

[0108] R 8 Each is one or more R 9 cycloalkyl or heterocyclyl optionally substituted with

[0109] R 9 Each is one or more R 10 Optionally substituted with C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 haloalkyl, halo, cyano, nitro, aryl, arylalkyl, heteroaryl, or heteroarylalkyl;

[0110] R 10 are independently halo, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 haloalkyl, cyano, or nitro;

[0111] Each m is independently 0, 1, 2, or 3.

[0112] In some embodiments, each m is 0.

[0113] In some embodiments, R 2 is hydrogen.

[0114] In some embodiments, R 7 is C 1 -C 4In some embodiments, R is an alkyl group (e.g., methyl or ethyl). 7 is methyl.

[0115] In some embodiments, R 8 is heterocyclyl. In some embodiments, R 8 is a nitrogen-containing heterocyclyl. In some embodiments, R 8 is a 6-membered nitrogen-containing heterocyclyl. In some embodiments, R 8 is piperidinyl (e.g., 1,4-piperidinyl).

[0116] In some embodiments, R 9 is heteroarylalkyl. In some embodiments, R 9 (CH 2 ) n -pyridyl, and n is 1, 2, 3, or 4. In some embodiments, R 9 (CH 2 )-pyridyl. In some embodiments, R 9 is 2-(CH 2 )-pyridyl.

[0117] In some embodiments, the compound of formula (II) has the formula (IIa):

[0118] [ka] Compounds of

[0119] or a pharma- ceutically acceptable salt, stereoisomer, racemate, or solvate thereof, wherein:

[0120] R 2 is hydrogen, -CH 3 C(O), -NH 2 or hydroxyl,

[0121] R 7 is hydrogen or C 1 -C 4 is alkyl,

[0122] R 9 is C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 haloalkyl, halo, cyano, or nitro;

[0123] R 9a Each is one or more R 10 aryl, arylalkyl, heteroaryl, or heteroarylalkyl optionally substituted with

[0124] R 10 are independently halo, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 It is haloalkyl, cyano, or nitro.

[0125] In some embodiments, each m is 0.

[0126] In some embodiments, R 2 is hydrogen.

[0127] In some embodiments, R 7 is C 1 -C 4 In some embodiments, R is an alkyl group (e.g., methyl or ethyl). 7 is methyl.

[0128] In some embodiments, R 9a is heteroarylalkyl. In some embodiments, R 9a (CH 2 ) n -pyridyl, and n is 1, 2, 3, or 4. In some embodiments, R 9a (CH 2 )-pyridyl. In some embodiments, R 9ais 2-(CH 2 )-pyridyl.

[0129] In some embodiments, the compound of formula (II) has the formula (IIb):

[0130] [ka] Compounds of

[0131] or a pharma- ceutically acceptable salt, stereoisomer, racemate, or solvate thereof, wherein:

[0132] R 9a Each is one or more R 10 aryl, arylalkyl, heteroaryl, or heteroarylalkyl optionally substituted with

[0133] R 10 are independently halo, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 haloalkyl, cyano, or nitro;

[0134] In some embodiments, R 9a is heteroarylalkyl. In some embodiments, R 9a (CH 2 ) n -pyridyl, and n is 1, 2, 3, or 4. In some embodiments, R 9a (CH 2 )-pyridyl. In some embodiments, R 9a is 2-(CH 2 )-pyridyl.

[0135] In some embodiments, the PKC-β inhibitor of formula (II) has the formula (IIc):

[0136] [ka] Compounds of

[0137] 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)), e.g., 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.

[0138] In some embodiments, the PKC-β inhibitor has formula (III):

[0139] [ka] Compounds of

[0140] or a pharma- ceutically acceptable salt, stereoisomer, racemate, or solvate thereof, wherein:

[0141] X 1 and X 2 Each of the groups independently represents -O-, -NR 4 -, or -S-,

[0142] A 1 and A 2 is independently aryl or heteroaryl, each of which is selected from one or more R 9 and optionally substituted with

[0143] R 2 is hydrogen, -CH 3 C(O), -NH 2 or hydroxyl,

[0144] R 4 is hydrogen or C 1 -C 4 is alkyl,

[0145] R 9 is C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 It is haloalkyl, halo, cyano, or nitro.

[0146] In some embodiments, X 1 and X 2 One of them is independently -NR 4 In some embodiments, X 1 and X 2 Each of the is independently -NR 4 In some embodiments, X 1 and X 2 Each of is independently -NH-.

[0147] In some embodiments, A 1 and A 2 In some embodiments, one of A is independently aryl. 1 and A 2 Each of A is independently aryl. 1 and A 2 Each of A is independently phenyl. 1 and A 2 Each of the is independently one R 9 In some embodiments, A is phenyl substituted with 1 and A 2 Each of the groups independently has one R 9 In some embodiments, R 9 is halo (e.g., fluoro).

[0148] In some embodiments, the PKC-β inhibitor has formula (IIIa):

[0149] [ka] Compounds of

[0150] or a pharma- ceutically acceptable salt, stereoisomer, racemate, or solvate thereof, wherein:

[0151] X 1 and X 2 Each of the groups independently represents -O-, -NR 4 -, or -S-,

[0152] R 2 is hydrogen, -CH 3 C(O), -NH 2 or hydroxyl,

[0153] R 4 is hydrogen or C 1 -C 4 is alkyl,

[0154] R 9a and R 9b Each of the 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 It is haloalkyl, halo, cyano, or nitro.

[0155] In some embodiments, X 1 and X 2 One of them is independently -NR 4 In some embodiments, X 1 and X 2 Each of the is independently -NR 4 In some embodiments, X 1 and X 2 Each of is independently -NH-.

[0156] In some embodiments, each phenyl ring has one R 9a and one R 9b In some embodiments, each phenyl ring is substituted with one R 9a and one R 9b In some embodiments, R 9a and R 9b In some embodiments, one of R 9a and R 9b Each of is halo (eg, fluoro).

[0157] In some embodiments, the PKC-β inhibitor of formula (III) is represented by formula (IIIb):

[0158] [ka] Compounds of

[0159] Or its pharmaceutically acceptable salt, stereoisomer, racemate, or solvate. In some embodiments, the PKC-β inhibitor (e.g., compound of formula (III)) is 5,6-bis(4-fluorophenoxy)isoindoline-1,3-dione (e.g., formula (IIIb)), e.g., CGP53353, CG53353, or its pharmaceutically acceptable salt, stereoisomer, racemate, or solvate.

[0160] Other PKCβ inhibitors disclosed herein include, for example, the PKCβ inhibitors described in Protein Kinase C-β Activates Tyrosinase by Phosphorylating Serine Residues in Its Cytoplasmic Domain, by Park et al. (1999), JBC Vol. 274, No. 23, Issue of June 4, pp. 16470-16478, and The receptor for activated C-kinase-I (RACK-I) anchors activated PKC-β on melanosomes, by Park et al. (2004), Journal of Cell Science 117(16) pp. 3659. Exemplary PKC beta pseudosubstrates include, for example, amino acids comprising, consisting essentially of, and consisting of the amino acid sequence Glu-Asp-Tyr-His-Ser-Leu-Tyr-Gln-Ser-His-Leu (SEQ ID NO: 1). PKC beta pseudosubstrates having at least 75%, 80%, 85%, 90%, 95%, 99% homology to SEQ ID NO: 1 are also contemplated.

[0161] III-1. Excipients A. Organic Solvents and / or Penetration Enhancers In some embodiments, the composition comprises an organic solvent and / or a penetration enhancer. Optionally, the composition comprises an organic solvent. Optionally, the organic solvent comprises a penetration enhancer. Optionally, the composition comprises an organic solvent and a penetration enhancer. The organic solvent may be the penetration enhancer. The penetration enhancer may be an organic solvent. Suitable solvents and / or penetration enhancers include C 2-6 Alkylene glycols (e.g., propylene glycol), di-(C 2-6 (alkylene) glycols (e.g., dipropylene glycol), C 1-3 Alkyl-(OCH 2 CH2 ) 1-5 Examples of suitable permeation enhancers include, but are not limited to, glycerol, ethyl ethers such as ethyl ether, ... 2-6 Alkylene glycol (C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 -OH, polyethylene glycol, glycerol, aliphatic alcohols, aliphatic esters, aliphatic ethers, or combinations thereof.

[0162] In some embodiments, the compositions herein comprise two or more organic solvents and / or penetration enhancers. For example, in some embodiments, the compositions comprise a first organic solvent and / or penetration enhancer and a second organic solvent and / or penetration enhancer. Optionally, the first organic solvent and / or penetration enhancer comprises an organic solvent. Optionally, the first organic solvent and / or penetration enhancer comprises a penetration enhancer. Optionally, the first organic solvent and / or penetration enhancer is an organic solvent and a penetration enhancer. Optionally, the second organic solvent and / or penetration enhancer comprises an organic solvent. Optionally, the second organic solvent and / or penetration enhancer comprises a penetration enhancer. Optionally, the second organic solvent and / or penetration enhancer is an organic solvent and a penetration enhancer. In some embodiments, the compositions herein comprise two, three, four, or five organic solvents and / or penetration enhancers.

[0163] Non-limiting examples of organic solvents include C 2-6 Alkylene glycol (e.g., propylene glycol), C 2-6 Alcohol, di-(C 2-6(alkylene) glycols (e.g., dipropylene glycol), C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 -OH (e.g., 2-(2-ethoxyethoxy)ethanol or Transcutol P), polyethylene glycols (e.g., PEG 200 and / or PEG 400), glycerol, fatty alcohols (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 is 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 -OH, Polyethylene glycol, C 2-6 In some embodiments, the solvent comprises an alcohol, glycerol, an aliphatic alcohol, an aliphatic ester, or an aliphatic ether, or a combination of two or more thereof. 2-6 Alkylene glycol, C 2-6 Alcohol or C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 In some embodiments, the solvent comprises C 2-6 In some embodiments, the solvent comprises C 2-6 In some embodiments, the solvent is a C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 In some embodiments, the solvent comprises C 2-6 Alcohol and C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 In some embodiments, the solvent comprises C 2-6 Alcohol and C 2-6In some embodiments, the composition comprises a mixture of C alkylene glycol. 2-6 Alcohol and C. 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 Includes mixtures with -OH.

[0164] Non-limiting examples of penetration enhancers include C 2-6 Alkylene glycol (e.g., propylene glycol), C 2-6 Alcohol, di-(C 2-6 (alkylene) glycols (e.g., dipropylene glycol), C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 -OH (e.g., 2-(2-ethoxyethoxy)ethanol or Transcutol P), polyethylene glycols (e.g., PEG 200 and / or PEG 400), glycerol, fatty alcohols (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 is C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 -OH, Polyethylene glycol, C 2-6 In some embodiments, the penetration enhancer comprises an alcohol, glycerol, a fatty alcohol, a fatty ester, or a fatty ether, or a combination of two or more thereof. 2-6 Alkylene glycol, C 2-6 Alcohol or C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 In some embodiments, the penetration enhancer comprises C 2-6In some embodiments, the penetration enhancer comprises C 2-6 In some embodiments, the penetration enhancer is C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 In some embodiments, the penetration enhancer comprises C 2-6 Alcohol and C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 In some embodiments, the penetration enhancer comprises C 2-6 Alcohol and C 2-6 In some embodiments, the composition comprises a mixture of C alkylene glycol. 2-6 Alcohol and C. 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 Includes mixtures with -OH.

[0165] In some embodiments, the organic solvent and / or penetration enhancer is C 2-6 Alkylene glycol and / or C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 In some embodiments, the second organic solvent and / or the penetration enhancer comprises C 2-6 In some embodiments, the organic solvent and / or penetration enhancer comprises C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 In some embodiments, the organic solvent and / or the penetration enhancer comprises C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 In some embodiments, the organic solvent and / or the penetration enhancer comprises C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2 CH 2 ) 1-5 In some embodiments, the composition comprises a mixture of C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 Contains -OH.

[0166] In some embodiments, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 -OH is 2-(2-ethoxyethoxy)ethanol (e.g., Transcutol P). 2-6 The alkylene glycol is propylene glycol.

[0167] In some embodiments, the organic solvent and / or penetration enhancer comprises propylene glycol and / or 2-(2-ethoxyethoxy)ethanol. In some embodiments, the organic solvent and / or penetration enhancer comprises propylene glycol. In some embodiments, the organic solvent and / or penetration enhancer comprises 2-(2-ethoxyethoxy)ethanol. In some embodiments, the organic solvent and / or penetration enhancer comprises propylene glycol and 2-(2-ethoxyethoxy)ethanol. In some embodiments, the organic solvent and / or penetration enhancer comprises a mixture of propylene glycol and 2-(2-ethoxyethoxy)ethanol. In some embodiments, the composition comprises propylene glycol and 2-(2-ethoxyethoxy)ethanol.

[0168] In some embodiments, the organic solvent and / or penetration enhancer is C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 In some embodiments, the second organic solvent and / or the penetration enhancer comprises C 2-6In some embodiments, the organic solvent and / or penetration enhancer comprises C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 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-(OCH 2 CH 2 ) 1-5 In some embodiments, the organic solvent and / or the penetration enhancer comprises C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 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-(OCH 2 CH 2 ) 1-5 In some embodiments, the organic solvent and / or penetration enhancer comprises C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 -OH, and polyethylene glycol.

[0169] In some embodiments, the organic solvent and / or penetration enhancer comprises polyethylene glycol (PEG). In some embodiments, the polyethylene glycol comprises PEG200, PEG300, PEG400, PEG500, PEG600, PEG700, PEG800, or PEG900, or a combination thereof. In some embodiments, the polyethylene glycol comprises PEG-200 and / or PEG-400. In some embodiments, the polyethylene glycol comprises PEG200. In some embodiments, the polyethylene glycol comprises PEG400. In some embodiments, the polyethylene glycol comprises a mixture of PEG200 and PEG400. In some embodiments, the polyethylene glycol comprises PEG-200 and / or PEG-400. In some embodiments, the organic solvent and / or penetration enhancer comprises PEG200. In some embodiments, the organic solvent and / or penetration enhancer comprises PEG400. In some embodiments, the organic solvent and / or penetration enhancer comprises a mixture of PEG200 and PEG400. In some embodiments, the composition comprises PEG200. In some embodiments, the composition comprises PEG400. In some embodiments, the composition comprises a mixture of PEG 200 and PEG 400. In some embodiments, the polyethylene glycol is highly purified or "SR" polyethylene glycol.

[0170] In some embodiments, the organic solvent and / or penetration enhancer comprises a fatty alcohol. As used herein, the term "fatty alcohol" refers to a fatty alcohol that is saturated or unsaturated. In some embodiments, the fatty alcohol is in a mixture of different fatty alcohols. In some embodiments, the fatty alcohol has an average of about 12-20, 14-20, 12-18, 14-18, or 16-18 carbons. Suitable fatty alcohols include, but are not limited to, capric alcohol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, palmitoleic alcohol, heptadecyl alcohol, stearyl alcohol, oleyl alcohol, nonadecyl alcohol, arachidyl alcohol, heneicosyl alcohol, behenyl alcohol, erucyl alcohol, lignoceryl alcohol, octyldodecanol, and mixtures thereof. In some embodiments, the organic solvent and / or penetration enhancer comprises one or more fatty alcohols selected from capric alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, palmitoleic alcohol, stearyl alcohol, oleyl alcohol, arachidyl alcohol, heneicosyl alcohol, behenyl alcohol, euthyl alcohol, and lignoceryl alcohol. In some embodiments, the organic solvent and / or penetration enhancer comprises octyldodecanol. In some embodiments, the composition comprises octyldodecanol.

[0171] In some embodiments, the organic solvent and / or penetration enhancer comprises a fatty alcohol. In some embodiments, the fatty esters include glyceryl fatty esters, ethylene glycol monoesters and diesters of fatty acids, propylene glycol monoesters and diesters of fatty acids, sorbitan esters, C esters of fatty acids, and the like. 1-6 Alkyl esters or di-(C 1-6 alkyl) esters, or a combination of two or more thereof.

[0172] In some embodiments, the fatty ester is a glyceride. In some embodiments, the glyceride is a monoglyceride, a diglyceride, or a triglyceride. The glyceride may be optionally substituted with a sulfonic acid group, or a pharma- ceutically acceptable salt thereof. Suitable fatty acids from which to derive the fatty acid glyceride include, but are not limited to, those described herein. In some embodiments, the glyceride is a monoglyceride of a fatty acid having 12-18 carbon atoms. In some embodiments, the glyceride is a diglyceride of a fatty acid having 12-18 carbon atoms. In some embodiments, the glyceride is a triglyceride of a fatty acid having 12-18 carbon atoms (e.g., also referred to herein as a medium chain triglyceride). In some embodiments, the organic solvent and / or penetration enhancer comprises a triglyceride of a fatty acid having 12-18 carbon atoms (e.g., also referred to herein as a medium chain triglyceride). In some embodiments, the composition comprises triglycerides of fatty acids having 12 to 18 carbon atoms (eg, also referred to herein as medium chain triglycerides).

[0173] In some embodiments, the aliphatic 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 aliphatic ester is an ethylene glycol monoester, a propylene glycol monoester, or a C alkyl ester of a fatty acid. 1-4 Alkyl esters. Ethylene glycol monoesters, propylene glycol monoesters, and C 1-4 Suitable fatty acids from which to derive any one of the alkyl esters include, but are not limited to, those described herein. In some embodiments, the aliphatic ester is an ethylene glycol monoester, a propylene glycol monoester, or a C 12-18 carbon atom fatty acid. 1-4The fatty acid ester is an alkyl ester. Non-limiting examples of esters of fatty acids include laurate, myristate, palmitate, stearate, and oleate. In some embodiments, the fatty acid ester is isopropyl myristate. In some embodiments, the organic solvent and / or the penetration enhancer comprises isopropyl myristate. In some embodiments, the composition comprises isopropyl myristate.

[0174] In some embodiments, the fatty ester is a sorbitan ester. Suitable fatty acids for deriving the sorbitan ester include, but are not limited to, those described herein. Suitable sorbitan esters include, but are not limited to, the Span™ series (available from Uniqema), including Span 20 (sorbitan monooleate), 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 the penetration enhancer comprises sorbitan monooleate. In some embodiments, the composition comprises sorbitan monooleate.

[0175] In some embodiments, the aliphatic ester is a di-(C 1-4 alkyl) esters (i.e., adipates), di-(C 1-4 In some embodiments, the aliphatic 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.

[0176] In some embodiments, the organic solvent and / or penetration enhancer comprises an aliphatic ether. In some embodiments, the organic solvent and / or penetration enhancer comprises a polyoxyethylene aliphatic ether. In some embodiments, the organic solvent and / or penetration enhancer comprises laureth-4. In some embodiments, the composition comprises laureth-4.

[0177] In some embodiments, the total amount of organic solvent and / or penetration enhancer is present in the composition in an amount of about 60% to about 99% by weight, about 80% to about 99% by weight, about 90% to about 99% by weight, or about 95% to about 99% by weight. In some embodiments, the total amount of organic solvent and / or penetration enhancer is present in the composition in an amount of about 85% by weight. In some embodiments, the total amount of organic solvent and / or penetration enhancer is present in the composition in an amount of about 90% by weight. In some embodiments, the total amount of organic solvent and / or penetration enhancer is present in the composition in an amount of about 96% by weight.

[0178] In some embodiments, the organic solvent and / or penetration enhancer comprises 2-(2-ethoxyethoxy)ethanol. In some embodiments, the composition comprises 2-(2-ethoxyethoxy)ethanol. In some embodiments, the 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of about 40% to about 50% by weight, about 43% to about 49% by weight, about 47 to 49% by weight, or about 47 to 48% by weight. In some embodiments, the 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of about 40% to about 50% by weight, about 43% to about 49% by weight, about 47 to 49% by weight, or about 47 to 48% by weight. In some embodiments, the 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of about 40% to about 50% by weight. In some embodiments, the 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of about 47 to 48% by weight.

[0179] In some embodiments, the organic solvent and / or penetration enhancer comprises propylene glycol. In some embodiments, the composition comprises propylene glycol. In some embodiments, the 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, the 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, the propylene glycol is present in the composition in an amount of about 19-20% by weight.

[0180] In some embodiments, the organic solvent and / or penetration enhancer comprises polyethylene glycol. In some embodiments, the composition comprises polyethylene glycol. In some embodiments, the polyethylene glycol is present in the composition in an amount of about 2-45% by weight, 3-24% by weight, 3-14% by weight, 13-15% by weight, or about 13-14% by weight. In some embodiments, the polyethylene glycol is present in the composition in an amount of about 2-45% by weight, 3-24% by weight, 3-14% by weight, 13-15% by weight, or about 13-14% by weight. In some embodiments, the polyethylene glycol is present in the composition in an amount of about 10% by weight to about 20% by weight. In some embodiments, the polyethylene glycol is present in the composition in an amount of about 13-14% by weight.

[0181] In some embodiments, the organic solvent and / or penetration enhancer comprises propylene glycol and / or 2-(2-ethoxyethoxy)ethanol, and the total amount of propylene glycol and / or 2-(2-ethoxyethoxy)ethanol present in the composition is in an amount of about 50% to about 80% by weight, about 50% to about 70% by weight, or about 67% by weight. In some embodiments, the organic solvent and / or penetration enhancer is propylene glycol and / or 2-(2-ethoxyethoxy)ethanol, and the total amount of propylene glycol and / or 2-(2-ethoxyethoxy)ethanol present in the composition is in an amount of 50% to 80% by weight, 50% to 70% by weight, or about 67% by weight. In some embodiments, the organic solvent and / or penetration enhancer comprises propylene glycol and / or 2-(2-ethoxyethoxy)ethanol, and the total amount of propylene glycol and / or 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of about 50% to 70% by weight. In some embodiments, the organic solvent and / or penetration enhancer comprises propylene glycol and / or 2-(2-ethoxyethoxy)ethanol, and 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.

[0182] In some embodiments, the composition comprises propylene glycol and / or 2-(2-ethoxyethoxy)ethanol, and 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% by weight, about 50% to about 70% by weight, or about 67% by weight. In some embodiments, the composition comprises propylene glycol and / or 2-(2-ethoxyethoxy)ethanol, and the total amount of propylene glycol and / or 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of about 50% to 70% by weight. In some embodiments, the composition comprises propylene glycol and / or 2-(2-ethoxyethoxy)ethanol, and 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.

[0183] In some embodiments, the organic solvent and / or penetration enhancer comprises a mixture of 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 80% by weight, about 50% to about 70% by weight, 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, and the total amount of the mixture is present in the composition in an amount of about 50% to about 80% by weight, about 50% to about 70% by weight, 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, and the total amount of the mixture is present in the composition in an amount of about 50% to about 70% by weight, 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, the total amount of the mixture being 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, the total amount of the mixture being present in the composition in an amount of about 61% by weight.

[0184] In some embodiments, the composition comprises a mixture of polyethylene glycol and 2-(2-ethoxyethoxy)ethanol, the total amount of the mixture is present in the composition in an amount of about 50% to about 80% by weight, about 50% to about 70% by weight, or about 61% by weight. In some embodiments, the composition comprises a mixture of polyethylene glycol and 2-(2-ethoxyethoxy)ethanol, the total amount of the mixture is present in the composition in an amount of about 50% to about 80% by weight, about 50% to about 70% by weight, or about 61% by weight. In some embodiments, the composition comprises a mixture of polyethylene glycol and 2-(2-ethoxyethoxy)ethanol, the total amount of the mixture is present in the composition in an amount of about 50% to about 70% by weight, or about 61% by weight. In some embodiments, the composition comprises a mixture of polyethylene glycol and 2-(2-ethoxyethoxy)ethanol, 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, the total amount of the mixture being present in the composition in an amount of about 61% by weight.

[0185] In some embodiments, the organic solvent and / or penetration enhancer comprises a mixture of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol, the total amount of the mixture being 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, the total amount of the mixture being 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, the total amount of the mixture being 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, the total amount of the mixture being 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, the total amount of the mixture being present in the composition in an amount of about 61% by weight.

[0186] In some embodiments, the composition comprises a mixture of propylene glycol, polyethylene glycol, and 2-(2-ethoxyethoxy)ethanol, the total amount of the mixture being 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, the total amount of the mixture being 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, the total amount of the mixture being 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, the total amount of the mixture being 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, the total amount of the mixture being present in the composition in an amount of about 61% by weight.

[0187] In some embodiments, the organic solvent and / or penetration enhancer comprises propylene glycol and 2-(2-ethoxyethoxy)ethanol. In some embodiments, the composition comprises propylene glycol and 2-(2-ethoxyethoxy)ethanol. In some embodiments, the propylene glycol is present in an amount of about 10% to about 30% by weight of the composition, and the 2-(2-ethoxyethoxy)ethanol is present in an amount of about 40% to about 50% by weight of the composition. In some embodiments, the propylene glycol is present in an amount of about 20% by weight of the composition, and the 2-(2-ethoxyethoxy)ethanol is present in an amount of about 47% by weight of the composition.

[0188] 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, the polyethylene glycol is present in an amount of about 10% to about 20% by weight of the composition, and the 2-(2-ethoxyethoxy)ethanol is present in an amount of about 40% to about 50% by weight of the composition. In some embodiments, the polyethylene glycol is present in an amount of about 14% by weight of the composition, and the 2-(2-ethoxyethoxy)ethanol is present in an amount of about 47% by weight of the composition.

[0189] In some embodiments, the organic solvent and / or penetration enhancer comprises 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, the propylene glycol is present in an amount of about 10% to about 30% by weight of the composition, the polyethylene glycol is present in an amount of about 10% to about 20% by weight of the composition, and the 2-(2-ethoxyethoxy)ethanol is present in an amount of about 40% to about 50% by weight of the composition. In some embodiments, the propylene glycol is present in an amount of about 20% by weight of the composition, the polyethylene glycol is present in an amount of about 14% by weight of the composition, and the 2-(2-ethoxyethoxy)ethanol is present in an amount of about 47% by weight of the composition.

[0190] In some embodiments, the propylene glycol is highly refined propylene glycol.

[0191] In some embodiments, the polyethylene glycol is highly purified polyethylene glycol.

[0192] In some embodiments, the 2-(2-ethoxyethoxy)ethanol is at least about 95%, 96%, 97%, 98%, or 99% pure. In some embodiments, the 2-(2-ethoxyethoxy)ethanol is Transcutol HP. In some embodiments, the 2-(2-ethoxyethoxy)ethanol is at least about 98% or 99% pure, e.g., greater than about 99.90% pure, Transcutol HP.

[0193] In some embodiments, the organic solvent and / or penetration enhancer is C 2-6 In some embodiments, the composition comprises C 2-6 In some embodiments, C 2-6 The alcohol is selected from the group consisting of 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.

[0194] In some embodiments, the composition comprises glycerol in an amount of about 12-24%, 14-20%, 13-17%, 14-16%, or about 14-15% by weight. In some embodiments, the glycerol is present in an amount of about 10% to about 20% by weight. In some embodiments, the glycerol is present in an amount of about 14-15% by weight.

[0195] In some embodiments, the composition comprises ethanol in an amount of about 3-12%, 4-6%, or about 9-11% by weight. In some embodiments, the ethanol is present in an amount of about 5% by weight. In some embodiments, the ethanol is present in an amount of about 10% by weight.

[0196] In some embodiments, the composition is 2-6 In some embodiments, the composition is alcohol-free. In some embodiments, the composition is ethanol-free. In some embodiments, the composition is glycerol-free.

[0197] B. Antioxidants In some embodiments, the composition comprises an antioxidant. In some embodiments, the composition does not comprise an antioxidant. In some embodiments, the composition 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 described herein comprises two, three, four, or five antioxidants.

[0198] 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 comprises butylated hydroxytoluene. In some embodiments, the antioxidant comprises butylated hydroxyanisole. In some embodiments, the antioxidant comprises propyl gallate. In some embodiments, the antioxidant comprises a mixture of butylated hydroxytoluene and butylated hydroxyanisole.

[0199] In some embodiments, the total amount of antioxidants 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 antioxidants is present in an amount of about 0.01% to about 1% by weight, about 0.01% to about 0.5% by weight, or about 0.2% by weight. In some embodiments, any one antioxidant is present in the composition in an amount of about 0.01% to about 1% by weight. In some embodiments, any one antioxidant is present in the composition in an amount of about 0.1% to about 1% by weight. In some embodiments, any one antioxidant is present in the composition in an amount of about 0.1% by weight. In some embodiments, the antioxidant is butylhydroxytoluene in an amount of about 0.01% to about 1% by weight, or about 0.1% by weight of the composition. In some embodiments, the antioxidant comprises butylhydroxytoluene in an amount of about 0.01% to about 1% by weight of the composition. In some embodiments, the antioxidant comprises butylhydroxytoluene in an amount of about 0.1% by weight of the composition. In some embodiments, the antioxidant comprises butyl hydroxyanisole in an amount of about 0.01% to about 1% by weight, or about 0.1% by weight of the composition. In some embodiments, the antioxidant comprises butyl 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% by weight, 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 butyl hydroxytoluene and butyl hydroxyanisole, each present in an amount of about 0.01% to about 1% by weight, or about 0.1% by weight of the composition. In some embodiments, the antioxidant comprises a mixture of butyl hydroxytoluene and butyl hydroxyanisole, each present in an amount of about 0.01% to about 1% by weight, or about 0.1% by weight of the composition. In some embodiments, the antioxidant comprises a mixture of butylated hydroxytoluene and butylated hydroxyanisole, each present in an amount of about 0.1% by weight of the composition.

[0200] C. Alcohol and hydrating agents In some embodiments, the composition includes an additional agent, such as alcohol or a humectant. Suitable agents include C 2-6 Alcohol, C. 2-6 Alkylene glycols (e.g., propylene glycol), di-(C 2-6 (alkylene) glycols (e.g., dipropylene glycol), C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 Examples of suitable glycerols include, but are not limited to, -OH (e.g., 2-(2-ethoxyethoxy)ethanol or Transcutol P), polyethylene glycols (e.g., PEG 200 and / or PEG 400), glycerol, fatty alcohols (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 is 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 -OH, Polyethylene glycol, C 2-6 Includes alcohols, glycerol, fatty alcohols, fatty esters, fatty ethers, and combinations thereof.

[0201] In some embodiments, the agent is 2-6 Alcohol, C. 2-6 Alkylene glycol or C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 In some embodiments, the agent comprises C 2-6 In some embodiments, the agent comprises C 2-6 In some embodiments, the agent is a C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5In some embodiments, the agent comprises a C 2-6 Alcohol and C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 In some embodiments, the agent comprises a C 2-6 Alcohol and C 2-6 In some embodiments, the composition comprises a mixture of C alkylene glycol. 2-6 Alcohol and C. 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 Includes mixtures with -OH.

[0202] In some embodiments, the additional agent is C 2-6 In some embodiments, C 2-6 The alcohol is selected from the group consisting of ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, tert-butanol, glycerol, and combinations thereof. 2-6 The alcohol is glycerol.

[0203] In some embodiments, the composition is 2-6 In some embodiments, the composition is alcohol-free. In some embodiments, the composition is ethanol-free. In some embodiments, the composition is glycerol-free.

[0204] In some embodiments, the composition includes one or more agents, alcohol, or humectants. In some embodiments, the agent is C in an amount of about 5% to 20% by weight, 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 about 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.

[0205] 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, the glycerol is present in an amount of about 10% to about 20% by weight. In some embodiments, the glycerol is present in an amount of about 14-15% by weight.

[0206] In some embodiments, the composition comprises ethanol in an amount of about 3-12%, 4-6%, or 9-11% by weight. In some embodiments, the ethanol is present in an amount of about 5% by weight. In some embodiments, the ethanol is present in an amount of about 10% by weight.

[0207] In some embodiments, the composition is 2-6 In some embodiments, the composition is alcohol-free. In some embodiments, the composition is ethanol-free. In some embodiments, the composition is glycerol-free.

[0208] D. Gelling Agent In some embodiments, the composition comprises a gelling agent. Optionally, 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 herein comprises a first gelling agent and a second gelling agent. In some embodiments, the composition herein comprises two, three, four, or five gelling agents.

[0209] Gelling agents include, for example, hydrophilic and hydroalcoholic gelling agents frequently used in the cosmetic and pharmaceutical industries. Further 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, Sepino P600, polyethylene glycol having an average molecular weight of at least about 2500 Da, and combinations of two or more thereof. In some embodiments, the gelling agent includes Sepino P600. In some embodiments, the gelling agent is Sepino P600. In some embodiments, the gelling agent includes polyethylene glycol having an average molecular weight of about 2500-3500 Da (e.g., PEG 3350). In some embodiments, the gelling agent is polyethylene glycol having an average molecular weight of about 2500-3500 Da (e.g., PEG 3350). In some embodiments, the gelling agent comprises hydroxypropyl cellulose. In some embodiments, the gelling agent is hydroxypropyl cellulose.

[0210] In some embodiments, the gelling agent comprises hydroxypropyl cellulose. In some embodiments, the composition comprises hydroxypropyl cellulose. Optionally, the hydroxypropyl cellulose has an average molecular weight of about 40,000 Daltons (Da), about 80,000 Da, about 100,000 Da, about 140,000 Da, about 180,000 Da, about 280,000 Da, about 370,000 Da, about 700,000 Da, about 850,000 Da, about 1,000,000 Da, about 1,150,000 Da, or 2,500,000 Da. In some embodiments, the hydroxypropyl cellulose has an average molecular weight of about 140,000 Da, about 180,000 Da, about 280,000 Da, about 370,000 Da, about 700,000 Da, about 850,000 Da, about 1,000,000 Da, or about 1,150,000 Da. In some embodiments, the hydroxypropyl cellulose has an average molecular weight of about 700,000 Da, about 850,000 Da, about 1,000,000 Da, or about 1,150,000 Da. In some embodiments, the hydroxypropyl cellulose has an average molecular weight of about 700,000 Da to about 1,150,000 Da.

[0211] Hydroxypropylcelluloses (HPCs) include, for example, Nisso SSL, Nisso SL, Nisso L, Nisso LM, Nisso LMM, Nisso M, Nisso H, Nisso VH, Klucel ELF, Klucel EF, Klucel LF, Klucel JF, Klucel GF, Klucel MF, and Klucel HF.

[0212] Nisso SSL has an average molecular weight of approximately 40,000 Da, Nisso SL has an average molecular weight of approximately 100,000 Da, Nisso L has an average molecular weight of approximately 140,000 Da, Nisso LM has an average molecular weight of approximately 180,000 Da, Nisso LMM has an average molecular weight of approximately 280,000 Da, Nisso M has an average molecular weight of approximately 700,000 Da, Nisso H has an average molecular weight of approximately 1,000,000 Da, and Nisso VH has an average molecular weight of approximately 2,500,000 Da. Suitable particle sizes of Nisso HPC (i.e., Nisso SSL, Nisso SL, Nisso L, Nisso LM, Nisso LMM, Nisso M, Nisso H, and Nisso VH) in the composition include regular powder (e.g., 40 mesh), fine powder (e.g., 100 mesh), and extra fine powder (e.g., 300 mesh). See Technical date sheet for Nisso HPC, which is incorporated herein by reference in its entirety.

[0213] 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.

[0214] Klucel ELF has an average molecular weight of about 40,000 Da, Klucel EF has an average molecular weight of about 80,000 Da, Klucel LF has an average molecular weight of about 95,000 Da, Klucel JF has an average molecular weight of about 140,000 Da, Klucel GF has an average molecular weight of about 370,000 Da, Klucel MF has an average molecular weight of about 850,000 Da, and Klucel HF has an average molecular weight of about 1,150,000 Da. Suitable particle sizes of Klucel HPC in the composition include regular and fine grades. See the Technical date sheet for the Klucel HPC product, which is incorporated herein by reference in its entirety.

[0215] 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.

[0216] 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 the composition, 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 the composition, 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 the composition, 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 the composition, 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 the composition, 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 the composition, in some embodiments, the composition has a viscosity of about 20,000 cP to about 30,000 cP.

[0217] When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of about 5,000 cP to about 100,000 cP. When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of about 5,000 cP to about 50,000 cP. When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of about 5,000 cP to about 40,000 cP. When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of about 5,000 cP to about 30,000 cP. When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of about 10,000 cP to about 30,000 cP. When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of about 15,000 cP to about 30,000 cP. When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of about 20,000 cP to about 30,000 cP.

[0218] In some embodiments, the gelling agent is present in the composition in an amount of about 0.5% to about 30% by weight, while 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, while 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, while 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, while 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, while 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, while 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 about 30% by weight, while the composition has a viscosity of about 20,000 cP to about 30,000 cP.

[0219] In some embodiments, the gelling agent comprises hydroxypropyl cellulose (HPC). In some embodiments, the composition comprises hydroxypropyl cellulose. In some embodiments, the hydroxypropyl cellulose is present in an amount of about 0.5% by weight to about 5% by weight to about 30% by weight, and the composition has a viscosity of about 5,000 cP to about 100,000 cP. When hydroxypropyl cellulose having an average molecular weight of less than about 700,000 Da is used, in some embodiments, the hydroxypropyl cellulose is present in an amount of about 5% by weight 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 hydroxypropyl cellulose is present in an amount of about 0.5% by weight to about 5% by weight, and the composition has a viscosity of about 5,000 cP to about 50,000 cP. In some embodiments, the hydroxypropyl cellulose is present in an amount of about 0.5% by weight to about 5% by weight, and the composition has a viscosity of about 5,000 cP to about 40,000 cP. In some embodiments, hydroxypropyl cellulose is present in an amount of about 0.5% to about 5% by weight, 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% by weight, 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% by weight, 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% by weight, and the composition has a viscosity of about 20,000 cP to about 30,000 cP.

[0220] In some embodiments, the 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. In some embodiments, the 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 5,000 cP to about 50,000 cP. In some embodiments, the 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 5,000 cP to about 40,000 cP. In some embodiments, the 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% by weight to about 2% by weight, and the composition has a viscosity of about 5,000 cP to about 30,000 cP. In some embodiments, the hydroxypropyl cellulose having an average molecular weight of about 700,000 Da to about 1,150,000 Da is present in the composition in an amount of about 0.5% by weight to about 2% by weight, and the composition has a viscosity of about 10,000 cP to about 30,000 cP. In some embodiments, the 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% by weight to about 2% by weight, and the composition has a viscosity of about 15,000 cP to about 30,000 cP. In some embodiments, the 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.

[0221] In some embodiments, the 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.

[0222] III-2. Apparent pH value When the composition is a non-aqueous formulation, the pH value of the composition is the apparent pH value. When the composition contains water, the composition contains a significant amount of other excipients (e.g., C 2-6 The pH value of a partially aqueous solution may be considered to be only an apparent pH value. According to the United States Pharmacopeia (USP) Chapter 791, the apparent pH value of a non-aqueous or partially aqueous solution is expected to vary, and may vary by up to about 1 pH unit. See USP Chapter 791, which is incorporated herein in its entirety.

[0223] In some embodiments, when a pH adjuster is not present in the composition, the composition has an apparent pH value of about 7.5 to about 9.5. In some embodiments, when a pH adjuster is not present in the composition, the composition has an apparent pH value of about 7.5 to about 8.5. In some embodiments, when a pH adjuster is not present in the composition, the composition has an apparent pH value of about 8.5 to about 9.5. In some embodiments, when a pH adjuster is not present in the composition, the composition has an apparent pH value of about 8. In some embodiments, when a pH adjuster is not present in the composition, the composition has an apparent pH value of about 9.

[0224] In some embodiments, when a pH adjuster is present in the composition, the composition has an apparent pH value of about 7 or less. In some embodiments, when a pH adjuster is present in the composition, the composition has an apparent pH value of about 5 to about 7 or about 6 to about 7. In some embodiments, when a pH adjuster is present in the composition, the composition has an apparent pH value of about 6 to about 7.

[0225] III-3.Compound In any one of the compositions described herein, the compound may, in some embodiments, be

[0226] [ka] and PK inhibitors such as, but not limited to, ruboxistaurin free base or ruboxistaurin salts (e.g., ruboxistaurin mesylate monohydrate), represented by any of the formulas:

[0227] In any one of the compositions described herein, the compound can be an acceptable salt of ruboxistaurin free base, ruboxistaurin mesylate monohydrate, or mixtures thereof.Typical examples of pharmaceutically acceptable salts are mineral acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid), organic acid (such as acetic acid, propionic acid, glutamic acid, citric acid), and quaternary ammonium (such as methyl iodide, ethyl iodide).

[0228] In any one of the compositions described herein, the PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), may be in a solvated or hydrated form, or a mixture thereof.

[0229] In any one of the compositions described herein, ruboxistaurin can be the free base (FB) or a salt, such as ruboxistaurin mesylate monohydrate (MM) or a mixture thereof.

[0230] In some embodiments, the PK inhibitor, such as but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin 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, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin 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, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), is present in an amount of about 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1.0% by weight. In some embodiments, the PK inhibitor, such as but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), is present in an amount of about 0.5% to 2.0% by weight, or about 0.8% by weight. In some embodiments, the compound is present in an amount of about 0.8% by weight. The composition may be formulated with 0.1% w / w, 0.12% w / w, or 0.8% w / w ruboxistaurin mesylate monohydrate, 0.08% w / w, 0.1% w / w, or 0.64% w / w ruboxistaurin free base, or other salts. Optionally, the composition is administered once or twice daily. Optionally, the composition is administered for about 12 weeks to about 6 months. Optionally, the composition is administered for about 4 weeks to about 8 weeks. Optionally, the composition is administered for about 8 weeks to about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.64% ruboxistaurin free base or a salt thereof for administration twice daily for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.64% ruboxistaurin free base or a salt thereof for administration twice daily for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.8% ruboxistaurin mesylate monohydrate or a salt thereof for administration twice daily for about 12 weeks.In a non-limiting embodiment, the composition is formulated with 0.8% ruboxistaurin mesylate monohydrate or a salt thereof for administration twice daily for about 4 to about 8 weeks.

[0231] III-4. Embodiment In some embodiments, the compositions include a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), and one or more excipients, including a) an organic solvent and / or a penetration enhancer (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 In some embodiments, the composition comprises a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), and two or more excipients, the excipients being selected from a) an organic solvent and / or a penetration enhancer (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 In some embodiments, the composition comprises a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), and three or more excipients, the excipients being selected from a) an organic solvent and / or a penetration enhancer (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5In some embodiments, the composition comprises a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), or an acceptable salt thereof, and four or more excipients, the excipients being selected from a) an organic solvent and / or a penetration enhancer (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 In some embodiments, the composition comprises a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), or an acceptable salt thereof, and five or more excipients, the excipients being selected from a) an organic solvent and / or a penetration enhancer (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 In some embodiments, the composition comprises a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin 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-(OCH 2 CH 2 ) 1-5 -OH, and / or PEG), b) an antioxidant, c) an alcohol, and d) a gelling agent. Optionally, the second organic solvent and / or penetration enhancer comprises C 2-6 Optionally, the organic solvent and / or penetration enhancer comprises C 1-3 Alkyl-(OCH 2 CH 2 )1-5 Optionally, the organic solvent and / or penetration enhancer comprises octyldodecanol. Optionally, the organic solvent and / or penetration enhancer comprises C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5-OH, and PEG. Optionally, the antioxidant comprises BHT. Optionally, the antioxidant comprises BHA. Optionally, the antioxidant comprises BHT and / or BHA. Optionally, the alcohol comprises glycerol. Optionally, the gelling agent comprises HPC. Optionally, the gelling agent comprises PEG. Optionally, the gelling agent comprises HPC and PEG. The composition may be formulated with 0.1% w / w, or 0.12% w / w, or 0.8% w / w of ruboxistaurin mesylate monohydrate, or 0.08% w / w, or 0.1% w / w, or 0.64% w / w of ruboxistaurin free base, or other salts. Optionally, the composition is administered once or twice daily. Optionally, the composition is administered for about 12 weeks to about 6 months. Optionally, the composition is administered for about 4 weeks to about 8 weeks. Optionally, the composition is administered for about 8 weeks to about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.64% ruboxistaurin free base or a salt thereof for administration twice daily for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.64% ruboxistaurin free base or a salt thereof for administration twice daily for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.64% ruboxistaurin free base or a salt thereof for administration twice daily for about 8 to about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.64% ruboxistaurin free base or a salt thereof for administration twice daily for about 12 weeks to about 6 months. In a non-limiting embodiment, the composition is formulated with 0.1% or 0.08% ruboxistaurin free base or a salt thereof for administration twice daily for about 12 weeks. In non-limiting embodiments, the compositions are formulated with 0.1% or 0.08% ruboxistaurin free base or a salt thereof for administration twice daily for about 4 to about 8 weeks. In non-limiting embodiments, the compositions are formulated with 0.1% or 0.08% ruboxistaurin free base or a salt thereof for administration twice daily for about 8 to about 12 weeks.In non-limiting embodiments, the composition is formulated with 0.1% or 0.08% ruboxistaurin free base or a salt thereof for administration twice daily for about 12 weeks to about 6 months. In non-limiting embodiments, the composition is formulated with 0.8% ruboxistaurin mesylate monohydrate for administration twice daily for about 12 weeks. In non-limiting embodiments, the composition is formulated with 0.8% ruboxistaurin free base or a salt thereof for administration twice daily for about 4 to about 8 weeks. In non-limiting embodiments, the composition is formulated with 0.8% ruboxistaurin free base or a salt thereof for administration twice daily for about 8 to about 12 weeks. In non-limiting embodiments, the composition is formulated with 0.8% ruboxistaurin free base or a salt thereof for administration twice daily for about 12 weeks to about 6 months. In a non-limiting embodiment, the composition is formulated with 0.1% or 0.12% ruboxistaurin mesylate monohydrate or a salt thereof for administration twice daily for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.1% or 0.12% ruboxistaurin mesylate monohydrate or a salt thereof for administration twice daily for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.1% or 0.12% ruboxistaurin mesylate monohydrate or a salt thereof for administration twice daily for about 8 to about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.1% or 0.12% ruboxistaurin mesylate monohydrate or a salt thereof for administration twice daily for about 12 weeks to about 6 months.

[0232] In some embodiments, the composition comprises a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), and an organic solvent and / or a penetration enhancer (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5In some embodiments, the composition comprises a) a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), a) an organic solvent and / or a penetration enhancer (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 In some embodiments, the composition comprises a) a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), or an acceptable salt thereof, a) an organic solvent and / or a penetration enhancer (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 In some embodiments, the composition comprises a) a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), a) an organic solvent and / or a penetration enhancer (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 In some embodiments, the composition comprises a) a ruboxistaurin PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), a) an organic solvent and / or a penetration enhancer (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5In some embodiments, the composition comprises a) a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), a) an organic solvent and / or a penetration enhancer (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 In some embodiments, the composition comprises a) a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), a) an organic solvent and / or a penetration enhancer (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5In some embodiments, the composition comprises a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), 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, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), a) an antioxidant, and b) an alcohol. In some embodiments, the composition comprises a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), a) an antioxidant, and b) a gelling agent. In some embodiments, the composition comprises a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), a) an alcohol, and b) a gelling agent. In some embodiments, the composition comprises a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin 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, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), and a gelling agent. Optionally, the second organic solvent and / or penetration enhancer is C 2-6 Optionally, the organic solvent and / or penetration enhancer comprises C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 Optionally, the organic solvent and / or penetration enhancer comprises octyldodecanol. Optionally, the organic solvent and / or penetration enhancer comprises C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5-OH, and PEG. Optionally, the antioxidant comprises BHT. Optionally, the antioxidant comprises BHA. Optionally, the antioxidant comprises BHT and / or BHA. Optionally, the alcohol comprises glycerol. Optionally, the gelling agent comprises HPC. Optionally, the gelling agent comprises PEG. Optionally, the gelling agent comprises HPC and PEG. The composition may be formulated with 0.1% w / w to 0.8% w / w of ruboxistaurin mesylate monohydrate, 0.08% w / w to 0.64% w / w of ruboxistaurin free base, or other salts. Optionally, the composition is administered once or twice daily. Optionally, the composition is administered for about 12 weeks to about 6 months. Optionally, the composition is administered for about 4 weeks to about 8 weeks. Optionally, the composition is administered for about 8 weeks to about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.64% ruboxistaurin free base or a salt thereof for administration twice daily for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.64% ruboxistaurin free base or a salt thereof for administration twice daily for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.08% to 0.1% ruboxistaurin free base or a salt thereof for administration twice daily for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.08% to 0.1% ruboxistaurin mesylate monohydrate or a salt thereof for administration twice daily for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.8% ruboxistaurin monohydrate mesylate or a salt thereof for administration twice daily for about 12 weeks. In non-limiting embodiments, the composition is formulated with 0.8% ruboxistaurin mesylate monohydrate or a salt thereof for administration twice daily for about 4 to about 8 weeks. In non-limiting embodiments, the composition is formulated with 0.1% or 0.12% ruboxistaurin monohydrate mesylate or a salt thereof for administration twice daily for about 12 weeks.In non-limiting embodiments, the compositions are formulated with 0.1% or 0.12% ruboxistaurin mesylate monohydrate or a salt thereof for administration twice daily for about 4 to about 8 weeks.

[0233] In some embodiments, the present disclosure provides a composition (A) comprising a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), and one or more of the following excipients: a) organic solvents and / or penetration enhancers (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 -OH, and / or PEG), b) antioxidants; c) Alcohol, and d) Gelling agents.

[0234] Optionally, the compound, organic solvent and / or penetration enhancer, antioxidant, alcohol, and / or gelling agent are as described herein. Optionally, the second organic solvent and / or penetration enhancer is selected from the group consisting of C 2-6 Optionally, the organic solvent and / or penetration enhancer comprises C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 Optionally, the organic solvent and / or penetration enhancer comprises octyldodecanol. Optionally, the organic solvent and / or penetration enhancer comprises C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5-OH, and PEG. Optionally, the antioxidant comprises BHT. Optionally, the antioxidant comprises BHA. Optionally, the antioxidant comprises BHT and / or BHA. Optionally, the alcohol comprises glycerol. Optionally, the gelling agent comprises HPC. Optionally, the gelling agent comprises PEG. Optionally, the gelling agent comprises HPC and PEG. The composition may be formulated with 0.1% w / w to 0.8% w / w of ruboxistaurin mesylate monohydrate, 0.08% w / w to 0.64% w / w of ruboxistaurin free base, or other salts. Optionally, the composition is administered once or twice daily. Optionally, the composition is administered for about 12 weeks to about 6 months. Optionally, the composition is administered for about 4 weeks to about 8 weeks. Optionally, the composition is administered for about 8 weeks to about 12 weeks. In non-limiting embodiments, 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, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate) for administration twice daily for about 12 weeks. In non-limiting embodiments, 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, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate) for administration twice daily for about 4 to about 8 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, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), for administration twice daily 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, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), for administration twice daily for about 4 to about 8 weeks.

[0235] In some embodiments of composition (A), no antioxidant is present in the composition.

[0236] In some embodiments of composition (A), one or more antioxidants are present in the composition. In some embodiments of composition (A), an antioxidant is present in the composition. Optionally, the antioxidant comprises BHT. Optionally, the antioxidant comprises BHA. Optionally, the antioxidant consists of BHT and / or BHA.

[0237] In some embodiments, the present disclosure provides a composition (B) comprising a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), and excipients a), b), c), and d): a) organic solvents and / or penetration enhancers (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 -OH, and / or PEG) b) antioxidants; c) Alcohol, and d) Gelling agents.

[0238] Optionally, the compound, organic solvent and / or penetration enhancer, antioxidant, solvent, and / or gelling agent are as described herein. Optionally, the second organic solvent and / or penetration enhancer is selected from the group consisting of C 2-6 Optionally, the organic solvent and / or penetration enhancer comprises C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 Optionally, the organic solvent and / or penetration enhancer comprises octyldodecanol. Optionally, the organic solvent and / or penetration enhancer comprises C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5-OH, and PEG. Optionally, the antioxidant comprises BHT. Optionally, the antioxidant comprises BHA. Optionally, the antioxidant comprises BHT and / or BHA. Optionally, the alcohol comprises glycerol. Optionally, the gelling agent comprises HPC. Optionally, the gelling agent comprises PEG. Optionally, the gelling agent comprises HPC and PEG. The composition may be formulated with 0.1% w / w to 0.8% w / w of ruboxistaurin mesylate monohydrate, 0.08% w / w to 0.64% w / w of ruboxistaurin free base, or other salts. Optionally, the composition is administered once or twice daily. Optionally, the composition is administered for about 12 weeks to about 6 months. Optionally, the composition is administered for about 4 weeks to about 8 weeks. Optionally, the composition is administered for about 8 weeks to about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.64% ruboxistaurin free base or a salt thereof for administration twice daily for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.64% ruboxistaurin free base or a salt thereof for administration twice daily for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.08% to 0.1% ruboxistaurin free base or a salt thereof for administration twice daily for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.08% to 0.1% ruboxistaurin mesylate monohydrate or a salt thereof for administration twice daily for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.8% ruboxistaurin monohydrate mesylate or a salt thereof for administration twice daily for about 12 weeks. In non-limiting embodiments, the composition is formulated with 0.8% ruboxistaurin mesylate monohydrate or a salt thereof for administration twice daily for about 4 to about 8 weeks. In non-limiting embodiments, the composition is formulated with 0.1% or 0.12% ruboxistaurin monohydrate mesylate or a salt thereof for administration twice daily for about 12 weeks.In non-limiting embodiments, the compositions are formulated with 0.1% or 0.12% ruboxistaurin mesylate monohydrate or a salt thereof for administration twice daily for about 4 to about 8 weeks.

[0239] In some embodiments, the present disclosure provides a composition (C) comprising a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), and excipients a), b), and d): a) organic solvents and / or penetration enhancers (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 -OH, and / or PEG) b) antioxidants, and d) Gelling agents.

[0240] Optionally, the compound, organic solvent and / or penetration enhancer, antioxidant, and / or gelling agent are as described herein. The composition may be formulated with 0.1% w / w to 0.8% w / w of ruboxistaurin mesylate monohydrate, 0.08% w / w to 0.64% w / w of ruboxistaurin free base, or other salts. Optionally, the composition is administered once or twice daily. Optionally, the composition is administered for about 12 weeks to about 6 months. Optionally, the composition is administered for about 4 weeks to about 8 weeks. Optionally, 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 a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), for administration twice daily for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.64% PK inhibitor, such as but not limited to, ruboxistaurin free base or ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate) for twice daily administration for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.08% to 0.1% ruboxistaurin free base or a salt thereof for twice daily administration for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.08% to 0.1% ruboxistaurin mesylate monohydrate or a salt thereof for twice daily administration for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.8% ruboxistaurin monohydrate mesylate or a salt thereof for twice daily administration for about 12 weeks. In non-limiting embodiments, the composition is formulated with 0.8% ruboxistaurin mesylate monohydrate or a salt thereof for administration twice daily for about 4 to about 8 weeks. In non-limiting embodiments, the composition is formulated with 0.1% or 0.12% ruboxistaurin monohydrate mesylate or a salt thereof for administration twice daily for about 12 weeks.In non-limiting embodiments, the compositions are formulated with 0.1% or 0.12% ruboxistaurin mesylate monohydrate or a salt thereof for administration twice daily for about 4 to about 8 weeks.

[0241] In some embodiments, the present disclosure provides a composition (D) comprising a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), and excipients a), b), and c): a) organic solvents and / or penetration enhancers (e.g., C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 -OH, and / or PEG) b) antioxidants, and c) Alcohol. Optionally, the compound, organic solvent and / or penetration enhancer, antioxidant, and / or alcohol are as described herein. The composition may be formulated with 0.1% w / w to 0.8% w / w of ruboxistaurin mesylate monohydrate, 0.08% w / w to 0.64% w / w of ruboxistaurin free base, or other salts. Optionally, the composition is administered once or twice daily. Optionally, the composition is administered for about 12 weeks to about 6 months. Optionally, the composition is administered for about 4 weeks to about 8 weeks. Optionally, 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 a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), for administration twice daily for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.64% ruboxistaurin free base or a salt thereof for administration twice daily for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.08% to 0.1% ruboxistaurin free base or a salt thereof for administration twice daily for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.08% to 0.1% ruboxistaurin mesylate monohydrate or a salt thereof for administration twice daily for about 4 to about 8 weeks. In a non-limiting embodiment, the composition is formulated with 0.8% ruboxistaurin monohydrate mesylate or a salt thereof for administration twice daily for about 12 weeks. In a non-limiting embodiment, the composition is formulated with 0.8% ruboxistaurin mesylate monohydrate or a salt thereof for administration twice daily for about 4 to about 8 weeks. In non-limiting embodiments, the composition is formulated with 0.1% or 0.12% ruboxistaurin monohydrate mesylate or a salt thereof for administration twice daily for about 12 weeks.In non-limiting embodiments, the compositions are formulated with 0.1% or 0.12% ruboxistaurin mesylate monohydrate or a salt thereof for administration twice daily for about 4 to about 8 weeks.

[0242] In some embodiments, the organic solvent and / or penetration enhancer of any one of compositions (A), (B), (C), and / or (D) is present in the composition in an amount of about 10% to about 40% by weight, about 10% to about 30% by weight, or about 20% by weight. 2-6 The alkylene glycol is present in an amount of about 10% to about 30% by weight. 2-6 The alkylene glycol is present in an amount of about 15% to about 25% by weight. 2-6 The alkylene glycol is present in an amount of about 20% by weight.

[0243] In some embodiments, C of any one of compositions (A), (B), (C), and / or (D) 2-6 Alkylene glycol is C 2-6 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. 2-6 The alkylene glycol is present in a total amount of about 20% to about 40% by weight. 2-6 The alkylene glycol is present in an amount of about 25% to about 35% by weight. 2-6 The alkylene glycol is present in an amount of about 34% by weight.

[0244] In some embodiments, the organic solvent and / or penetration enhancer of any one of compositions (A), (B), (C), and / or (D) is present in an amount of about 30% to about 70% by weight, about 40% to about 60% by weight, or about 47% by weight. 1-3 Alkyl-(OCH 2 CH 2 ) 1-5In some embodiments, C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 In some embodiments, C is present in an amount of about 30% to about 70% by weight. 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 In some embodiments, C is present in an amount of about 40% to about 60% by weight. 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 The -OH is present in an amount of about 47% by weight.

[0245] 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% by weight. In some embodiments, the alcohol is present in an amount of about 10% to about 20% by weight. In some embodiments, the alcohol is present in an amount of about 15% by weight. Optionally, the alcohol comprises glycerol.

[0246] In some embodiments, the gelling agent of any one of compositions (A), (B), (C), and / or (D) 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% by weight 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. Optionally, the gelling agent comprises PEG. Optionally, the gelling agent comprises HPC and PEG.

[0247] In some embodiments, the organic solvent and / or penetration enhancer of any one of compositions (A), (B), (C), and / or (D) is 2-6 Contains alkylene glycol, C 2-6 The alkylene glycol is propylene glycol, and the organic solvent and / or penetration enhancer is C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 -OH and C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 In some embodiments of any one of compositions (A), (B), (C), and / or (D), the organic solvent and / or the penetration enhancer is C 2-6 Contains alkylene glycol, C 2-6 The alkylene glycol is propylene glycol, and the organic solvent and / or penetration enhancer is C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 -OH and C 1-3 Alkyl-(OCH 2 CH 2 ) 1-5 -OH is 2-(2-ethoxyethoxy)ethanol and the gelling agent is hydroxypropyl cellulose.

[0248] In some embodiments, composition (A1) comprises a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), and one or more of the following excipients: a) propylene glycol, polyethylene glycol, and / or 2-(2-ethoxyethoxy)ethanol; b) butylated hydroxytoluene and / or butylated hydroxyanisole, c) glycerol and / or alcohol, and d) Hydroxypropyl cellulose. Optionally, the compound, propylene glycol, polyethylene glycol, and / or 2-(2-ethoxyethoxy)ethanol, butylhydroxytoluene and / or butylhydroxyanisole, glycerol and / or alcohol solvent, and / or hydroxypropylcellulose are as described herein.

[0249] In some embodiments, composition (B1) comprises a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), and excipients a), b), c), and d): a) propylene glycol, polyethylene glycol, and / or 2-(2-ethoxyethoxy)ethanol; b) butylated hydroxytoluene and / or butylated hydroxyanisole, c) glycerol and / or alcohol, and d) Hydroxypropyl cellulose. Optionally, the compounds, propylene glycol, polyethylene glycol, and / or 2-(2-ethoxyethoxy)ethanol, butylhydroxytoluene and / or butylhydroxyanisole, glycerol and / or alcohol, and / or hydroxypropylcellulose are as described herein.

[0250] In some embodiments, composition (C1) comprises a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), and excipients a), b), and c): a) propylene glycol, polyethylene glycol, and / or 2-(2-ethoxyethoxy)ethanol; b) butylated hydroxytoluene and / or butylated hydroxyanisole, and c) Hydroxypropyl cellulose. Optionally, the compounds, propylene glycol, polyethylene glycol, and / or 2-(2-ethoxyethoxy)ethanol, butylhydroxytoluene and / or butylhydroxyanisole, and / or hydroxypropylcellulose are as described herein.

[0251] In some embodiments, composition (D1) comprises a PK inhibitor, such as, but not limited to, ruboxistaurin free base or ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), and excipients a), b), and c): a) propylene glycol, polyethylene glycol, and / or 2-(2-ethoxyethoxy)ethanol; b) butylated hydroxytoluene and / or butylated hydroxyanisole, and c) Glycerol and / or alcohol. Optionally, the compounds, propylene glycol, polyethylene glycol, and / or 2-(2-ethoxyethoxy)ethanol, butylhydroxytoluene and / or butylhydroxyanisole, and / or glycerol and / or alcohol are as described herein.

[0252] In some embodiments of any one of compositions (A), (B), (C), and (D), the antioxidant, when present, is butylhydroxytoluene, butylhydroxyanisole, propyl gallate, or a combination of two or more thereof. In some embodiments, the antioxidant, when present, is butylhydroxytoluene and / or butylhydroxyanisole.

[0253] In some embodiments, the antioxidant of any one of compositions (A), (B), (C), (D), (A1), (B1), (C1), and / or (D1), if present, is present in an amount of about 0.01% to about 0.5% by weight or about 0.1% by weight. In some embodiments, the antioxidant, if present, is present in an amount of about 0.01% to about 0.5% by weight. The antioxidant, if present, is present in an amount of about 0.2% by weight.

[0254] In some embodiments, composition (C1a) comprises a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), and excipients a), b), c), and d): a) propylene glycol and 2-(2-ethoxyethoxy)ethanol, b) butylated hydroxytoluene and / or butylated hydroxyanisole, c) glycerol and / or polyethylene glycol, and d) Hydroxypropyl cellulose. Optionally, 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.

[0255] In some embodiments, ethanol is present in any one of compositions (A1), (B1), (C1), and / or (C1a) in an amount of about 10% to about 30% by weight, about 10% to about 20% by weight, 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.

[0256] In some embodiments, polyethylene glycol is present in any one of compositions (A1), (B1), (C1), and / or (C1a) in an amount of about 10% to about 30% by weight, about 10% to about 20% by weight, or about 15% by weight. In some embodiments, polyethylene glycol is present in an amount of about 10% to about 30% by weight. In some embodiments, polyethylene glycol is present in an amount of about 10% to about 20% by weight. In some embodiments, polyethylene glycol is present in an amount of about 14% by weight.

[0257] In some embodiments, glycerol is present in any one of compositions (A1), (B1), (C1), and / or (C1a) in an amount of about 10% to about 30% by weight, about 10% to about 20% by weight, 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.

[0258] In some embodiments, 2-(2-ethoxyethoxy)ethanol is present in any one of compositions (A1), (B1), (C1), and / or (C1a) in an amount of about 30% to about 50% by weight, about 40% to about 60% by weight, 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.

[0259] In some embodiments, propylene glycol is present in any one of compositions (A1), (B1), (C1), and / or (C1a) in an amount of about 10% to about 30% by weight 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.

[0260] In some embodiments, the hydroxypropyl cellulose having an average molecular weight of about 700,000 Da to about 1,150,000 Da is present in any one of compositions (A1), (B1), (C1), and / or (C1a) in an amount of about 1% to about 3% by weight or about 2% by weight. In some embodiments, the hydroxypropyl cellulose having an average molecular weight of about 700,000 Da to about 1,150,000 Da is present in an amount of about 1% to about 3% by weight. In some embodiments, the 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 1% by weight. In some embodiments, the 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 2% by weight. In some embodiments, the hydroxypropyl cellulose is Klucel MF in an amount of about 2% by weight.

[0261] In some embodiments, butyl hydroxytoluene and / or butyl hydroxyanisole are present in composition (C1a) in an amount of about 0.01% to about 0.5% or about 0.1% by weight. In some embodiments, butyl hydroxytoluene and / or butyl hydroxyanisole are present in an amount of about 0.01% to about 0.2% by weight. In some embodiments, butyl hydroxytoluene is present in an amount of about 0.1% by weight. In some embodiments, butyl hydroxyanisole is present in an amount of about 0.1% by weight.

[0262] In some embodiments, butylated hydroxytoluene is present in composition (C1a) in an amount of about 0.2 wt.%. In some embodiments of composition (C1a), butylated hydroxyanisole is present in an amount of about 0.2 wt.%.

[0263] In some embodiments of compositions (A), (B), (C), (A1), (B1), (C1), and (C1a), the propylene glycol is highly refined propylene glycol.

[0264] In some embodiments of compositions (A), (B), (C), (A1), (B1), (C1), and (C1a), the polyethylene glycol is highly purified polyethylene glycol.

[0265] In some embodiments of compositions (A), (B), (C), (A1), (B1), (C1), and (C1a), the 2-(2-ethoxyethoxy)ethanol is Transcutol HP having a purity of greater than 99.90%.

[0266] In some embodiments of compositions (A), (B), (C), (A1), (B1), (C1), and (C1a), any PK inhibitor (e.g., ruboxistaurin free base or a salt thereof (e.g., ruboxistaurin mesylate monohydrate)) composition described herein is 50 to 99% by weight glycol, 55 to 99% by weight glycol, 60 to 99% by weight glycol, 65 to 99% by weight glycol, 70 to 99% by weight glycol, 75 to 99% by weight glycol, 80 to 99% by weight glycol, 85 to 99% by weight glycol, 90 to 99% by weight glycol, or 95 to 99% by weight glycol. In some embodiments of Compositions (A), (B), (C), (A1), (B1), (C1), and (C1a), any PK inhibitor (e.g., ruboxistaurin free base or a salt thereof (e.g., ruboxistaurin mesylate monohydrate)) composition described herein is 80% to 95% by weight glycol, 80% to 96% by weight glycol, or 80% to 97% by weight glycol.

[0267] In some embodiments, a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), is present in Compositions (A), (B), (C), (A1), (B1), (C1), and / or (C1a) in an amount of about 0.5% to 2.0% by weight, or about 1% by weight. In some embodiments, a PK inhibitor, such as, but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), is present in an amount of about 0.1% to 2% by weight. In some embodiments, the PK inhibitor, such as but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin 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% by weight. In some embodiments, the PK inhibitor, such as but not limited to, ruboxistaurin free base or a ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate), is present in an amount of about 0.8% by weight.

[0268] In non-limiting exemplary embodiments herein, the PK inhibitor includes or is ruboxistaurin free base, ruboxistaurin mesylate, or ruboxistaurin mesylate monohydrate.

[0269] In non-limiting exemplary embodiments herein, the PK inhibitor includes or is ruboxistaurin mesylate monohydrate.

[0270] III-5. Form of composition The topical formulations useful for delivering compound to a subject (e.g., the skin of a subject) include, but are not limited to, foam, spray, aerosol, cream, lotion, ointment, gel, solution, emulsion, and suspension.See, for example, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY; (Alfonso R. Gennaro, ed., 19th ed., 1995), and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985), which are incorporated herein by reference in their entirety.In some embodiments, the topical composition used for delivering compound is a gel, ointment, lotion, foam, or emollient.

[0271] In some embodiments, the topical composition used for delivering the compound is a lotion or cream.The cream and lotion that can be used as topical composition and its preparation are disclosed in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, pages 282-291 (edited by Alfonso R. Gennaro, 19th edition, 1995), the relevant part of which is incorporated herein by reference.

[0272] In some embodiments, the topical composition is a gel, for example, a two-phase gel or a single-phase gel. A gel is a semi-solid system consisting of a suspension of small inorganic particles or large organic molecules permeated with a liquid. If a gel mass contains a network of small discrete inorganic particles, it is classified as a two-phase gel. A single-phase gel consists of organic macromolecules distributed uniformly throughout the liquid, such that no clear boundary exists between the dispersed macromolecules and the liquid. Suitable gels for use in the present disclosure are disclosed in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, pages 1517-1517 (edited by Alfonso R. Gennaro, 19th edition, 1995), the relevant portions of which are incorporated herein by reference. Other gels suitable for use with the present disclosure are disclosed in U.S. Pat. Nos. 6,387,383 (issued May 14, 2002), 6,517,847 (issued February 11, 2003), and 6,468,989 (issued October 22, 2002).

[0273] In some embodiments, the topical composition is an ointment. Ointments are oily semi-solids that contain little water. In some examples, ointments are hydrocarbon-based, such as wax, petrolatum, or gelling mineral oil. Ointments suitable for use according to the present disclosure include those disclosed in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, pages 1585-1591 (edited by Alfonso R. Gennaro, 19th edition, 1995).

[0274] In some embodiments, the topical composition may be in the form of a patch, tape, film, wafer, wipe, paper, cloth, towel, towelette, sponge, foam, mask, or bandage that comprises the topical composition described herein.In some embodiments, the patch, tape, film, wafer, wipe, paper, cloth, towel, towelette, sponge, foam, mask, or bandage contacts the affected area of ​​the skin.In some embodiments, the patch, tape, film, wafer, wipe, paper, cloth, towel, towelette, sponge, foam, mask, face mask, brush, pad, gauze, applicator, cotton ball, roll, swab, or bandage contacts the skin area of ​​the subject adjacent to the affected area or target area when applied to the subject.

[0275] In some embodiments, topical administration may be in the form of a patch, tape, film, wafer, wipe, paper, cloth, towel, towelette, sponge, foam, mask, face mask, brush, pad, gauze, applicator, cotton ball, roll, swab, or bandage comprising the topical composition described herein. In some embodiments, the patch, tape, film, wafer, wipe, paper, cloth, towel, towelette, sponge, foam, mask, or bandage contacts the affected area of ​​the skin. In some embodiments, the patch, tape, film, wafer, wipe, paper, cloth, towel, towelette, sponge, foam, mask, face mask, brush, pad, gauze, applicator, cotton ball, roll, swab, or bandage contacts the skin area of ​​the subject adjacent to the affected or target area when applied to the subject.

[0276] In some embodiments, the patch, tape, film, wafer, paper, cloth, towel, towelette, sponge, foam, mask, face mask, brush, pad, gauze, applicator, cotton ball, roll, swab, or bandage comprises an adhesive.

[0277] In some embodiments, the topical composition may be applied to the skin or scalp using a tape or film that provides an occlusive environment. The tape or film may be a bandage, a waterproof bandage, or a plastic film (with or without an adhesive layer).

[0278] In some embodiments, the composition is impregnated into a tape, cloth, towel, towelette, sponge, mask, foam, or film. In some embodiments, the tape or film is a foam-impregnated tape or film. The pores or interstitial spaces in the foam, paper, cloth, towel, towelette, mask, or sponge can be loaded with the composition described herein. The foam, paper, cloth, towel, towelette, mask, or sponge can have an adhesive layer for attachment to the skin. If the foam, paper, cloth, towel, towelette, mask, or sponge is porous, an outer non-porous layer is provided on the back of the foam, wipe, paper, cloth, towel, towelette, pad, gauze, cotton ball, swab, or sponge to enhance the occlusion of the tape.

[0279] In some embodiments, the composition may be in the form of a delayed release paper, cloth, towel, towelette, sponge, mask, wafer, or dot, and may also have a certain amount of the composition disposed on the back of a porous foam, and a non-porous backing layer disposed on the back of the composition. The non-porous backing layer may have a portion that extends beyond the composition and the porous layer, including but not limited to a PK inhibitor, such as ruboxistaurin free base or ruboxistaurin salt (e.g., ruboxistaurin mesylate monohydrate). This portion may include a certain amount of adhesive to facilitate the attachment of the paper, cloth, towel, towelette, sponge, mask, wafer, or dot to the user's skin near the area to be treated.

[0280] method In another aspect, the disclosure provides a method of treating a skin disease, condition, or disorder in a subject in need of such treatment, comprising administering to the subject a composition described herein.

[0281] In some embodiments, the disease, condition, or disorder is a hyperpigmentation disease, condition, or disorder.

[0282] In some embodiments, the compositions described herein are useful for treating hyperpigmentation disorders. In some embodiments, hyperpigmentation disorders include dyschromia, melasma, postinflammatory hyperpigmentation, discoid lupus erythematosus, phytophotodermatitis, lentigines (e.g., facial age spots), nevi, nevus spilus, acanthosis nigricans, burn-associated hyperpigmentation, drug-induced hyperpigmentation (e.g., sulfonamide-, tetracycline-, NSAID-, barbiturate-, and carbamazepine-induced hyperpigmentation), injury-associated hyperpigmentation, primary biliary cirrhosis-associated hyperpigmentation, Addison's disease-associated hyperpigmentation, and hemochromatosis-associated hyperpigmentation. The disease may include, but is not limited to, hyperpigmentation associated with hyperthyroidism, melanocytic nevi, freckles (ephelids), seborrheic keratosis, skin cancer-associated hyperpigmentation, infection-associated hyperpigmentation (e.g., tinea versicolor, erythrasma), eczema, photocontact, photoallergy, or phototoxic dermatitis, ichthyosis, pigmented spots or flat nevi associated with neurofibromatosis, or hyperpigmentation associated with extreme ultraviolet (UV) radiation exposure, such as a sun exposure or sunburn reaction, or a combination of two or more thereof. The disease may also be a disease, disorder, or disorder of hair or hair follicles, such as hypertrichosis / hypertrichosis and hair pigmentation. The disease may also be unwanted pigmentation of hair or hair follicles, such as hypertrichosis / hypertrichosis and hair pigmentation. In particular, the composition is useful for treating hyperpigmentation disorders and pigmentation disorders.

[0283] In some embodiments, the disorder or disease is excessive growth of hair or hair follicles, or a hair or hair follicle pigmentation disease or disorder. In some embodiments, hypertrichosis / hirsutism or hair pigmentation is the targeted disorder or disease. In some embodiments, the disorder or disease is unwanted excessive growth of hair or hair follicles, or unwanted pigmentation of hair or hair follicles. In some embodiments, the disease or disorder is temporary. In some embodiments, the treatment of the disease or disorder is temporary. In some embodiments, the effects of the treatment are temporary.

[0284] In some embodiments, the compositions described herein are useful for treating malignant tumors. In some embodiments, the malignant tumor is malignant melanocytic tumor, malignant epidermal tumor, malignant vascular tumor, malignant metastatic tumor, malignant adipose tumor, malignant sebaceous tumor, or malignant fibrous tumor. Malignant tumors include, but are not limited to, melanoma, squamous cell carcinoma, keratoacanthoma, actinic keratoses, basal cell carcinoma, angiosarcoma, Kaposi's sarcoma, cutaneous breast cancer, Merkel cell carcinoma, liposarcoma, sebaceoma, sebaceous gland carcinoma, dermatofibroma sarcoma protuberens, and fibrosarcoma. In some embodiments, the malignant tumor is melanoma, squamous cell carcinoma, keratoacanthoma, actinic keratosis, basal cell carcinoma, angiosarcoma, Kaposi's sarcoma, cutaneous carcinoma of the breast, Merkel cell carcinoma, liposarcoma, sebaceous adenoma, sebaceous gland carcinoma, dermatofibrosarcoma protuberans, or fibrosarcoma.

[0285] In some embodiments, the compositions described herein are useful for treating a benign tumor or skin disease, hi some embodiments, the benign tumor is a benign vascular tumor, a benign fibrous tumor, a benign adipocyte tumor, a benign seboma, a benign epidermal tumor, a benign melanocytic lesion, or a benign neural tumor. Benign tumors or skin diseases include, but are not limited to, nodules, benign skin tumors, angiomas, hemangiomas, pyogenic granulomas, fibroangiomas, tuberous sclerosis complex, angiomyofibromas, angiolipomas, dermatofibromas, fibromas, neurofibromas, scars, scar tissue, keloids, lipomas, acicular fibrous soft tissue, melanoacanthomas, acanthomas, clear cell acanthomas, acanthosis nigricans, epidermoid cysts, hairy cysts, dermoid cysts, melanocytic nevus, epidermal nevus, verrucous epidermal nevus, lentigines, nevus spilus, neuromas, schwannomas, and neurinomas. In some embodiments, the benign tumor is a nodule, a benign skin tumor, angioma, angioma, a pyogenic granuloma, a fibroangioma, a tuberous sclerosis complex, angiomyofibroblastoma, angiolipoma, a dermatofibroma, a fibroma, a neurofibroma, a scar, a scar tissue, a keloid, a lipoma, a fibrous apical dermatosis, a melanoacanthoma, acanthoma, acanthoma clear cell acanthoma, acanthosis nigricans, an epidermoid cyst, a pilonidal cyst, a dermoid cyst, a melanocytic nevus, an epidermal nevus, a verrucous epidermal nevus, a lentigo, a nevus spilus, a neuroma, a schwannoma, or a schwannoma.

[0286] In some embodiments, the compositions described herein modulate one or more of the following: aryl hydrocarbon receptor (AHR), aryl hydrocarbon receptor (AHR) transcription factor, 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, sulfotransferase, genes involved in immune cell function and differentiation, and / or proteins involved in epidermal differentiation.

[0287] In some embodiments, the compositions described herein modulate epithelial function, epithelial permeability, mucosal homeostasis, antioxidant, anti-inflammatory, appetite, insulin secretion, gastric emptying, renal function, uremic toxins, gut 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 (APCs), Th1 / Th2 cell balance, Th17, and regulatory T cells, allergen-induced diseases, and immune responses to infectious diseases.

[0288] In some embodiments, the compositions described herein are administered to the face of a subject. In some embodiments, the compositions described herein are administered to the body of a subject. In some embodiments, the compositions described herein are administered locally to the head, scalp, face, ears, neck, chest, back, under the breasts, arms, legs, hands, fingers, feet, toes, or groin.

[0289] In some embodiments, the compositions described herein are administered 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 administered to the body of a subject, thereby treating hyperpigmentation of the skin or hair. In some embodiments, the compositions described herein are administered topically to one or more areas selected from the head, scalp, face, ears, neck, chest, back, under the breasts, arms, legs, hands, feet, and groin, thereby treating hyperpigmentation of the skin or hair in any one of these areas.

[0290] 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 about 10.0% of the body surface area. In some embodiments, the composition is applied to about 15.0% of the body surface area. In some embodiments, the composition is applied to about 20.0% of the body surface area.

[0291] In some embodiments, the skin disease, condition, or disorder to be reduced, ameliorated, treated, or prevented is hyperpigmentation of the skin or hair. In some embodiments, the compositions described herein are administered in an amount effective to achieve a reduction in skin melanin in the treatment area. In some embodiments, the compositions described herein are administered in an amount effective to achieve evenness of skin color in the subject. In some embodiments, the compositions described herein are administered in an amount effective to lighten unwanted pigmentation, even skin tone, even skin color, or eliminate blemishes or irregular pigmentation in the subject's skin as measured by colorimetry, digital imaging, other objective means, or other subjective means on the treatment area of ​​the subject. In some embodiments, the compositions described herein are administered in an amount effective to achieve a reduction in pigmentation or melanin in the hair produced by the treated hair follicles.

[0292] The compositions described herein may be administered as at least a single dose multiple times daily, daily, multiple times weekly, weekly, multiple times monthly, or monthly. In some embodiments, the compositions are administered twice daily. In some embodiments, the compositions are administered at least twice weekly. In some embodiments, the compositions are administered at least twice monthly. In some embodiments, a composition comprising a compound (i.e., ruboxistaurin free base, ruboxistaurin mesylate monohydrate, or an acceptable salt thereof) in an amount of 0.05% to 10% by weight is administered as a single dose multiple times daily, daily, multiple times weekly, weekly, twice weekly, multiple times monthly, monthly, or twice monthly.

[0293] In some embodiments, the compound is administered in combination with an additional agent, for example a therapeutic or cosmetic agent. In some embodiments, the one or more additional agents, e.g., therapeutic agents, are selected from the following: hydroquinone, indole, indole-based compounds, indole-derived compounds, BIM-1, BIM-2, BIM-3, and BIM-8, bisindolylmaleimide or derivatives thereof, protein kinase C inhibitors, protein kinase inhibitors, tretinoin, corticosteroids, azaleic acid, kojic acid, retinoids, glycolic acid, L-ascorbic acid, p-aminobenzoic acid, padimate O, phenylbenzimidazole sulfonic acid, cinoxate, menthyl anthranilate, dioxybenzone, oxybenzone, avobenzone, octisalate, octocrylene, octyl methoxycinnamate, homosalate, octinoxate, sulisobenzone, trolamine salicylate, ecamsule, zinc oxide, titanium dioxide, cosmetic agents, pigments, fragrances, sunscreens, foam surfactants (lathering surfactant), Vitamins, Hydroxy Acids, Antioxidants, Retinoids, Arbutin 1% (Glycosylated Hydroquinone), Paper Mulberry 1%, Glabridin 0.5% (Licorice Extract), Arctostaphylos patula and Arctostaphylos Viscida, Aloesin, Gentisic Acid, Flavonoids, Hesperidin, Ascorbic Acid or Derivatives, Magnesium Ascorbyl Phosphate 10%, Niacinamide, Yeast Derivative, Polyphenols, Soy Protein, Kojic Acid 1-4% (5-Hydroxy-4-pyran-4-one-2-methyl), Mequinol 5-20% (4-Hydroxyanisole), Isopropyl Catechol, N-Acetyl-4-Cysteaminylphenol, N-Acetyl Glucosamine, Piceatannol, Moisturizers, Trichloroacetic Acid, Mercury, 1,4-Benzenediol, Quinole, Benzene-1,4-Diol, p-Diphenol, p-Dihydroxybenzene, Hydroquinone, p-Hydroxyphenol, Hydroquinonium, Hydroquinol, Tequinol, Monobenzyl Ether of Hydroquinone, and / or Cysteamine Cream.

[0294] In some embodiments, the additional agent is a sunscreen, sun blocker, or sun filter. The sunscreen, sun blocker, or sun filter may be a UVA filter, benzophenone, oxybenzone, sulisobenzone, dioxybenzone, avobenzone, melazimate, bisdisulizole disodium, diethylaminohydroxy-benzoylhexylbenzoate, ecamsule, methyl anthranilate, UVB filter, PABA derivative, padimate O, cinnamate, octinoxate, cinoxate, salicylate, octisalate, homosalate, trolamine salicylate, octocrylene, ensulizole, ethylhexyl triazone, broad antibacterial spectrum filter, ecamsule, The sunscreen may be one or more of, but is not limited to, Sul, Mexoryl SX, Silatriazole, Mexoryl XL, Bemotrizinol, Tinosorb S, Bisoctrizole (Tinosorb M), Octisalate, inorganic sunscreens, zinc oxide, titanium dioxide, iron oxide, red veterinary petrolatum, kaolin, calamine, ichthammol, talc, systemic sunscreens, beta-carotene, antimalarials, ascorbic acid, alpha-tocopherol, retinol, selenium, green tea polyphenols, PABA, antihistamines, aspirin, indomethacin, corticosteroids, polyhydroxystearic acid, organic sunscreens 2-ethylhexyl p-methoxycinnamate, 4,4'-t-butyl methoxydibenzoylmethane, octyl salicylate, terephthalylidene dicamphor sulfonic acid, benzophenone-3. In some embodiments, the sunscreen, sun blocker, or sun 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.

[0295] In some embodiments, one or more of the additional agents is a hair removing agent, a bleaching agent, or an anti-aging treatment.

[0296] In some embodiments, the additional agents may include, but are not limited to, agents having a depilatory effect, potassium or calcium thioglycolate, thioglycerol, 2-mercaptopropionic acid, monoethanolamine thioglycolate, 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 an agonist thereof, thiols, thioglycolic acid and its salts, thiolactic acid and its salts, sulfides, strontium sulfide, calcium thioglycolate, calcium hydroxide, strontium hydroxide, keratolytic agents, lactic acid, salicylic acid, glycolic acid, citric acid, and malic acid.

[0297] In some embodiments, the additional agents may include, but are not limited to, hair lightening agents, alkalizing agents, oxidizing agents, ethanolamine, ammonia, hydrogen peroxide (H2O2), p-phenylenediamine, p-phenylenediamine, diaminobenzene, toluene-2,5-diamine, resorcinol, persulfates, monoethanolamine, sodium hydrosulfite, lime juice, lemon juice, and / or citric acid.

[0298] In some embodiments, the one or more additional agents can include, but are not limited to, one or more of an anti-inflammatory agent, an NSAID, an antibacterial agent, an antibiotic, a steroid, an antiviral agent, a chemotherapeutic agent, an alkylating agent, an antimetabolite, or an anti-microtubule agent, a vitamin D derivative, an oxidizing compound, an acid, a retinoid derivative, a keratolytic agent, a corticosteroid, an immunoregulatory agent, an immunomodulatory component, a sunscreen, a UV blocker, a zinc compound, a retinoid, a pigmentation disorder treatment, a hyperpigmentation treatment, a moisturizer, and an anti-aging treatment.

[0299] In some embodiments, the one or more additional agents are administered locally. In some embodiments, the additional agent is applied together with the compound. In some embodiments, the additional agent and the compound are applied to a common area at different times. In some embodiments, the additional agent and the compound are included in the same unit dosage form. In some embodiments, the additional agent and the compound are located in different unit dosage forms. In some embodiments, a second or multiple additional agents are administered. In some embodiments, a second administration of the compound is administered. In some embodiments, a third administration of the compound is administered.

[0300] In some embodiments, multiple doses, such as 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, are administered in a 7 day period. In some embodiments, multiple doses, such as 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, are administered in a 14 day period. In some embodiments, multiple doses, such as 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, are administered in a 21 day period. In some embodiments, multiple administrations, 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, are administered in a 30 day period.

[0301] In some embodiments, the compound is administered twice a day, daily, every other day, weekly, or monthly. In some embodiments, the compound is administered twice a day, daily, every other day, weekly, or monthly 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 more. In some embodiments, the compound is administered twice a day, daily, every other day, weekly, or monthly for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years. In some embodiments, the compound is administered twice a day, daily, every other day, weekly, or monthly for at least 10, 20, 30, 40, 50, 60, 70, 80, 90 years, or the life of the subject.

[0302] 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 previous administrations of the compound, e.g., at least 2, 10, 20, 30, 40, 50, 100, 200, 300, or 500 previous administrations of the compound.

[0303] In some embodiments, the composition is administered twice daily for 4 weeks. In some embodiments, the composition is administered twice daily for 5 weeks. In some embodiments, the composition is administered twice daily for 6 weeks. In some embodiments, the composition is administered twice daily for 7 weeks. In some embodiments, the composition is administered twice daily for 8 weeks. In some embodiments, the composition is administered twice daily for 9 weeks. In some embodiments, the composition is administered twice daily for 10 weeks. In some embodiments, the composition is administered twice daily for 11 weeks. In some embodiments, the composition is administered twice daily for 12 weeks. In some embodiments, the composition is administered twice daily for 13 weeks. In some embodiments, the composition is administered twice daily for 14 weeks. In some embodiments, the composition is administered twice daily for 15 weeks. In some embodiments, the composition is administered twice daily for 16 weeks. In some embodiments, the composition is administered twice daily for 17 weeks. In some embodiments, the composition is administered twice daily for 18 weeks. In some embodiments, the composition is administered twice daily for 19 weeks. In some embodiments, the composition is administered twice daily for 20 weeks. In some embodiments, the composition is administered twice daily 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% ruboxistaurin or a salt thereof.

[0304] 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 daily. In some embodiments, 0.7 g is applied daily. In some embodiments, 0.7 g is applied twice daily. 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 daily. In some embodiments, about 36.0 g is applied twice daily.

[0305] 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.

[0306] In some embodiments, the composition comprises 0.001 mg to 10.0 g of ruboxistaurin mesylate monohydrate, ruboxistaurin free base, or a salt thereof. In some embodiments, 0.01 mg to 5.0 g of the composition is applied daily. In some embodiments, the composition comprises 0.1 mg to 2.0 g of ruboxistaurin mesylate monohydrate, ruboxistaurin free base, or a salt thereof. In some embodiments, the composition comprises 0.2 mg to 1.5 g of ruboxistaurin mesylate monohydrate, ruboxistaurin free base, or a salt thereof. In some embodiments, the composition comprises 0.5 mg to 1.0 g of ruboxistaurin mesylate monohydrate, ruboxistaurin free base, or a salt thereof. In some embodiments, the composition comprises 0.7 mg to 0.7 g of ruboxistaurin mesylate monohydrate, ruboxistaurin free base, or a salt thereof. In some embodiments, the composition comprises 0.35 g. In some embodiments, the composition comprises 0.7 g. In some embodiments, the composition comprises 0.7 g. 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 ruboxistaurin mesylate monohydrate, ruboxistaurin free base, or a salt thereof.

[0307] 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 ruboxistaurin mesylate monohydrate, ruboxistaurin free base, or a salt thereof is applied to 0.1% to 100.0% 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 ruboxistaurin mesylate monohydrate, ruboxistaurin 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 ruboxistaurin mesylate monohydrate, ruboxistaurin 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 ruboxistaurin mesylate monohydrate, ruboxistaurin 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 ruboxistaurin mesylate monohydrate, ruboxistaurin 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 ruboxistaurin mesylate monohydrate, ruboxistaurin 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 ruboxistaurin mesylate monohydrate, ruboxistaurin 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 ruboxistaurin mesylate monohydrate, ruboxistaurin 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 ruboxistaurin mesylate monohydrate, ruboxistaurin 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 ruboxistaurin mesylate monohydrate, ruboxistaurin free base, or a salt thereof is applied to about 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 ruboxistaurin mesylate monohydrate, ruboxistaurin free base, or a salt thereof is applied to about 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 ruboxistaurin mesylate monohydrate, ruboxistaurin free base, or a salt thereof is applied to about 20.0% of the body surface area.

[0308] 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 0.00018 g / cm2, about 0.00001 g / cm2 to about 0.00019 g / cm2, about 0.00001 g / cm2 to about 0.00020 g / cm2, about 0.00001 g / cm2 to about 0.00021 g / cm2, about 0.00001 g / cm2 to about 0.00022 g / cm2, about 0.00001 g / cm2 to about 0.00023 g / cm2, about 0.00001 g / cm2 to about 0.00024 g / cm2, about 0.00001 g / cm2 to about 0.00025 g / cm2, about 0.00001 g / cm2, about 0.00001g / cm2 to about 0.00019g / cm2, about 0.00001g / cm2 to about 0.00021g / cm2, about 0.00003g / cm2 to about 0.00005g / cm2, about 0.00003g / cm2 to about 0.00007g / cm2, about 0 .00003g / cm2 ~ approx. 0.00009g / cm2, approx. 0.00003g / cm2 ~ approx. 0.00011g / cm2, approx. 0.00003g / cm2 ~ approx. 0.00013g / cm2, approx. 0.00003g / cm2 ~ approx. 0.00015g / cm2, approx. 0.00003 g / cm2 ~ approx. 0.00017g / cm2, approx. 0.00003g / cm2 ~ approx. 0.00019g / cm2, approx. 0.00003g / cm2 ~ approx. 0.00021g / cm2, approx. 0.00005g / cm2 ~ approx. 0.00007g / cm2, approx. 0.00005g / cm2 ~0.00009g / cm2, approximately 0.00005g / cm2~0.00011g / cm2, approximately 0.00005g / cm2~0.00013g / cm2, approximately 0.00005g / cm2~0.00015g / cm2, approximately 0.00005g / cm2~0.00 017g / cm2, about 0.00005g / cm2 to about 0.00019g / cm2, about 0.00005g / cm2 to about 0.00021g / cm2, about 0.00007g / cm2 to about 0.00009g / cm2, about 0.00007g / cm2 to about 0.00011g / c m2, about 0.00007g / cm2 to about 0.00013g / cm2, about 0.00007g / cm2 to about 0.00015g / cm2, about 0.00007g / cm2 to about 0.00017g / cm2, about 0.00007g / cm2 to about 0.00019g / cm2, about 0.00007g / cm2 ~ approx. 0.00021g / cm2, approx. 0.00009g / cm2 ~ approx. 0.00011g / cm2, approx. 0.00009g / cm2 ~ approx. 0.00013g / c m2, about 0.00009g / cm2 to about 0.00015g / cm2, about 0.00009g / cm2 to about 0.00017g / cm2, about 0.00009g / cm2 to about 0.00 019g / cm2, approx. 0.00009g / cm2 ~ approx. 0.00021g / cm2, approx. 0.00011g / cm2 ~ approx. 0.00013g / cm2, approx. 0.00011g / cm2 ~0.00015g / cm2, approx. 0.00011g / cm2~0.00017g / cm2, approx. 0.00011g / cm2~0.00019g / cm2, approx. 0.0001 1g / cm2 ~ approx. 0.00021g / cm2, approx. 0.00013g / cm2 ~ approx. 0.00015g / cm2, approx. 0.00013g / cm2 ~ approx. 0.00017g / cm2, approx. 0.00013g / cm2~Approx. 0.00019g / cm2, Approx. 0.00013g / cm2~Approx. 0.00021g / cm2, Approx. 0.00015g / cm2~Approx. 0.00017g / cm2, about 0.00015 g / cm2 to about 0.00019 g / cm2, about 0.00015 g / cm2 to about 0.00021 g / cm2, about 0.00017 g / cm2 to about 0.00019 g / cm2, about 0.00017 g / cm2 to about 0.00021 g / cm2, or about 0.00019 g / cm2 to about 0.00021 g / cm2. 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 least about 0.The composition is applied in an amount of 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 about 0.0001 g / cm2 to about 0.001 g / cm2. In some embodiments, the composition is about 0.0001 g / cm to about 0.0002 g / cm, about 0.0001 g / cm to about 0.0003 g / cm, about 0.0001 g / cm to about 0.0004 g / cm, about 0.0001 g / cm to about 0.0005 g / cm, about 0.0001 g / cm to about 0.0006 g / cm, about 0.0001 g / cm to about 0.0007 g / cm, about 0.0001 g / cm to about 0.0008 g / cm, about 0.0001g / cm2~Approx. 0.0009g / cm2, Approx. 0.0001g / cm2~Approx. 0.001g / cm2, Approx. 0.0002g / cm2~Approx. 0.0003g / cm2, Approx. 0.0002g / cm2~Approx. 0.0004g / c m2, 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 0.000 8g / cm2, about 0.0002g / cm2 to about 0.0009g / cm2, about 0.0002g / cm2 to about 0.001g / cm2, about 0.0003g / cm2 to about 0.0004g / cm2, about 0.0003g / cm2 to about 0 .0005g / cm2, about 0.0003g / cm2 to about 0.0006g / cm2, about 0.0003g / cm2 to about 0.0007g / cm2, about 0.0003g / cm2 to about 0.0008g / cm2, about 0.0003g / c m2 ~ approx. 0.0009g / cm2, approx. 0.0003g / cm2 ~ approx. 0.001g / cm2, approx. 0.0004g / cm2 ~ approx. 0.0005g / cm2, approx. 0.0004g / cm2 ~ approx. 0.0006g / cm2, approx. 0.000 4g / cm2 ~ approx. 0.0007g / cm2, approx. 0.0004g / cm2 ~ approx. 0.0008g / cm2, approx. 0.0004g / cm2 ~ approx. 0.0009g / cm2, approx. 0.0004g / cm2 ~ approx. 0.001g / cm2, approx.0005g / cm2~Approx. 0.0006g / cm2, Approx. 0.0005g / cm2~Approx. 0.0007g / cm2, Approx. 0.0005g / cm2~Approx. 0.0008g / cm2, Approx. 0.0005g / cm2~Approx. 0.0009g / c m2, about 0.0005g / cm2 to about 0.001g / cm2, about 0.0006g / cm2 to about 0.0007g / cm2, about 0.0006g / cm2 to about 0.0008g / cm2, about 0.0006g / cm2 to about 0.00 0.0007 g / cm2 to about 0.0009 g / cm2, about 0.0007 g / cm2 to 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 0.0009 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. 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 at 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 applied at up to about 0.001 g / cm2 to about 0.002 g / cm2, about 0.001 g / cm2 to about 0.003 g / cm2, about 0.001 g / cm2 to about 0.004 g / cm2, about 0.001 g / cm2 to about 0.005 g / cm2, about 0.001g / cm2 ~ approx. 0.006g / cm2, approx. 0.001g / cm2 ~ approx. 0.007g / cm2, approx. 0.001g / cm2 ~ approx. 0.008g / cm2, approx. 0.001g / cm2 ~ approx. 0.009g / cm2, approx. 0.001g / cm2 ~ approx. 0.01g / cm2, approx. 0.002 g / cm2~about 0.003g / cm2, about 0.002g / cm2~about 0.004g / cm2, about 0.002g / cm2~about 0.005g / cm2, about 0.002g / cm2~about 0.006g / cm2, about 0.002g / cm2~about 0.007g / cm2, about 0.002g / c m2~about 0.008g / cm2, about 0.002g / cm2~about 0.009g / cm2, about 0.002g / cm2~about 0.01g / cm2, about 0.003g / cm2~about 0.004g / cm2, about 0.003g / cm2~about 0.005g / cm2, about 0.003g / cm2~about 0.006g / cm2, about 0.003g / cm2 to about 0.007g / cm2, about 0.003g / cm2 to about 0.008g / cm2, about 0.003g / cm2 to about 0.009g / cm2, about 0.003g / cm2 to about 0.01g / cm2, about 0.004g / cm2 to about 0.00 5g / cm2, about 0.004g / cm2 to about 0.006g / cm2, about 0.004g / cm2 to about 0.007g / cm2, about 0.004g / cm2 to about 0.008g / cm2, about 0.004g / cm2 to about 0.009g / cm2, about 0.004g / cm2 to about 0.01g / c m2, about 0.005g / cm2 to about 0.006g / cm2, about 0.005g / cm2 to about 0.007g / cm2, about 0.005g / cm2 to about 0.008g / cm2, about 0.005g / cm2 to about 0.009g / cm2, about 0.005g / cm2 to about 0.01g / cm2, about In some embodiments, the composition is applied in an amount of 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 0.006 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. In some embodiments, the composition is applied in an amount of about 0.0.001 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 0.01 g / cm2. In some embodiments, the composition is applied in an amount of at least about 0.00. The composition is applied in an amount of about 1 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 up to 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 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 ... cm2 ~ approx. 0.09g / cm2, approx. 0.01g / cm2 ~ approx. 0.1g / cm2, approx. 0.02g / cm2 ~ approx. 0.03g / cm2, approx. 0.02g / cm2 ~ approx. 0.04g / cm2, approx. 0.02g / c m2 ~ approx. 0.05g / cm2, approx. 0.02g / cm2 ~ approx. 0.06g / cm2, approx. 0.02g / cm2 ~ approx. 0.07g / cm2, approx. 0.02g / cm2 ~ approx. 0.08g / cm2, approx. 0.02g / cm 2~Approx. 0.09g / cm2, Approx. 0.02g / cm2~Approx. 0.1g / cm2, Approx. 0.03g / cm2~Approx. 0.04g / cm2, Approx. 0.03g / cm2~Approx. 0.05g / cm2, Approx. 0.03g / cm2 ~0.06g / cm2, approximately 0.03g / cm2~0.07g / cm2, approximately 0.03g / cm2~0.08g / cm2, approximately 0.03g / cm2~0.09g / cm2, approximately 0.03g / cm2~ Approx. 0.1g / cm2, Approx. 0.04g / cm2~Approx. 0.05g / cm2, Approx. 0.04g / cm2~Approx. 0.06g / cm2, Approx. 0.04g / cm2~Approx. 0.07g / cm2, Approx. 0.04g / cm2~Approx. 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 0.05g / cm2 to about 0.07g / cm2, about 0.05g / cm2 to about 0.08g / cm2, about 0.05g / cm2 to about 0.09g / cm2, about 0.05g / cm2 to about 0.1g / cm2, about 0 .06g / cm2~Approx. 0.07g / cm2, Approx. 0.06g / cm2~Approx. 0.08g / cm2, Approx. 0.06g / cm2~Approx. 0.09g / cm2, Approx. 0.06g / cm2~ The composition is applied in an amount of about 0.1 g / cm2, about 0.07 g / cm2 to about 0.08 g / cm2, about 0.07 g / cm2 to 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 about 0.1 g / cm2 to about 0.2 g / cm2, about 0.1 g / cm2 to about 0.3 g / cm2, about 0.1 g / cm2 to about 0.4 g / cm2, about 0.1 g / cm2 to about 0.5 g / cm2, about 0.1 g / cm2 to about 0.6 g / cm2, about 0.1 g / cm2 to about 0.7 g / cm2. 2, about 0.1g / cm2~about 0.8g / cm2, about 0.1g / cm2~about 0.9g / cm2, about 0.1g / cm2~about 1g / cm2, about 0.2g / cm2 cm2 ~ approx. 0.3g / cm2, approx. 0.2g / cm2 ~ approx. 0.4g / cm2, approx. 0.2g / cm2 ~ approx. 0.5g / cm2, approx. 0.2g / cm2 ~ approx. 0.6g / cm2, about 0.2g / cm2 to about 0.7g / cm2, 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, 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 / c m2, 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 / cm 2, about 0.4g / cm2~about 1g / cm2, about 0.5g / cm2~about 0.6g / cm2, about 0.5g / cm2~about 0.7g / cm2, about 0.5g / cm2~about 0.8g / cm2, Approx. 0.5g / cm2 ~ approx. 0.9g / cm2, approx. 0.5g / cm2 ~ approx. 1g / cm2, approx. 0.6g / cm2 ~ approx. 0.7g / cm2, approx. 0.6g / cm2 ~ approx. 0.8g / cm2, approx. 0 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 0.7 g / cm2, about 0.9 g / cm2, about 0.7 g / cm2, about 0.8 g / cm2, about 0.9 g / cm2, about 0.8 g / cm2, about 1 g / cm2, or 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.

[0309] In a non-limiting example, the composition is 0.8% ruboxistaurin mesylate monohydrate, 0.64% ruboxistaurin free base, 0.8% ruboxistaurin mesylate monohydrate, or a salt thereof, administered twice daily for at least 12 weeks, e.g., about 12 weeks. The ruboxistaurin can be free base. The ruboxistaurin can be ruboxistaurin mesylate monohydrate.

[0310] In another non-limiting example, the composition is 0.8% ruboxistaurin mesylate monohydrate, 0.64% ruboxistaurin free base, or a salt thereof, administered twice daily for about 4 weeks to about 8 weeks, e.g., about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or about 8 weeks. The ruboxistaurin free base can be ruboxistaurin mesylate monohydrate.

[0311] In another non-limiting example, the composition is 0.8% ruboxistaurin mesylate monohydrate, 0.64% ruboxistaurin free base, or a salt thereof, administered twice daily for about 8 weeks to about 12 weeks, e.g., about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, or about 12 weeks. The ruboxistaurin free base can be ruboxistaurin mesylate monohydrate.

[0312] In some embodiments, the composition administered is in the form of a gel, cream, ointment, lotion, foam, or emollient.

[0313] In some embodiments, the composition administered is a component of a patch, tape, film, wafer, wipe, paper, cloth, towel, towelette, sponge, mask, wipe, brush, pad, gauze, applicator, cotton ball, roll, swab, or bandage.

[0314] In some embodiments, the subject in need of the composition is a human.

[0315] kit Also provided is a kit for use in a method of treating a skin disease, illness, or disorder in a subject in need of treatment with the composition described herein in a tube, flexible aluminum tube, or laminated plastic tube. The kit can include a topical composition containing a compound (i.e., ruboxistaurin free base, ruboxistaurin mesylate monohydrate, or an acceptable salt thereof), a second agent or composition, and instructions that provide information to a medical professional on how to use the composition to treat a skin disease, illness, or disorder. The instructions can be provided in printed form, or in the form of an electronic or digital medium such as a floppy disk, CD, or DVD, a data storage device, a flash drive, or in the form of a website address where such instructions can be obtained. A unit dose of the compound or topical composition provided herein, or the second agent or composition, can include a dosage amount that, when administered to a subject, can maintain a therapeutically or prophylactically effective level of the compound or topical composition at the treatment site of the subject for at least one day.

[0316] In some embodiments, suitable packaging is provided.As provided herein, "packaging" includes solid matrix or material that is conventionally used in systems and can hold the compound provided herein and / or the second agent suitable for administration to a subject within a fixed limit.Such materials include glass and plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, and plastic foil laminated envelopes, etc.When e-beam sterilization technology is utilized, the packaging must be of low density so as to allow sterilization of the contents.

[0317] In some embodiments, the packaging is a tube or container that blocks UV light. In some embodiments, the tube or container is transparent. In some embodiments, the tube or container is made of a material that filters UV light, preventing UV light from reaching the product.

[0318] In some embodiments, the packaging minimizes the contact of oxygen with the product. In some embodiments, the tube or container is vacuum sealed, and any remaining air is removed from the tube or packaging container after the tube or container is filled with the product. In some cases, the air in the head space of the tube or container is replaced with an inert gas. In some cases, the inert gas is nitrogen.

[0319] Exemplary embodiments Described below are exemplary embodiments of the compositions, kits, and methods described herein.

[0320] 1. A composition comprising ruboxistaurin free base or ruboxistaurin mesylate monohydrate, or a salt thereof, and a penetration enhancer and / or an organic solvent.

[0321] 2. The composition of 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.

[0322] 3. The composition of embodiment 1 or 2, comprising a penetration enhancer.

[0323] 4. The composition of embodiment 3, wherein the penetration enhancer further comprises a C2-6 alkylene glycol, a C1-3 alkyl-(OCH2CH2)1-5-OH, a polyethylene glycol, glycerol, a fatty alcohol, a fatty ester, or a fatty ether, or a combination of two or more thereof.

[0324] 5. The composition of any one of embodiments 1 to 4, comprising an organic solvent.

[0325] 6. The composition of embodiment 5, wherein the organic solvent further comprises a C2-6 alkylene glycol, a C1-3 alkyl-(OCH2CH2)1-5-OH, a polyethylene glycol, glycerol, an aliphatic alcohol, an aliphatic ester, or an aliphatic ether, or a combination of two or more thereof.

[0326] 7. The composition of 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.

[0327] 8. The composition of embodiment 1 or 2, wherein the penetration enhancer and / or organic solvent comprises a C2-6 alkylene glycol, a C1-3 alkyl-(OCH2CH2)1-5-OH, a polyethylene glycol, glycerol, a fatty alcohol, a fatty ester, or a fatty ether, or a combination of two or more thereof.

[0328] 9. The composition of any one of embodiments 1 to 8, comprising a penetration enhancer.

[0329] 10. The composition of embodiment 9, wherein the penetration enhancer comprises an organic solvent.

[0330] 11. The composition of 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.

[0331] 12. The composition of any one of the preceding embodiments, comprising an emulsifier.

[0332] 13. The composition of embodiment 12, wherein the penetration enhancer and / or organic solvent comprises an emulsifier.

[0333] 14. The composition of embodiment 12 or 13, wherein the emulsifier comprises Cocoylcaprylocaprate, 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, Docusate Sodium, Glyceryl Monostearate, Hydrogenated Vegetable Oil / Cottonseed Oil / Palm Kernel Oil, MCT, N-Methyl-2-Pyrrolidone, Poloxamer, PEG, Polysorbate, PEG Castor Oil Derivatives, Propylene Glycol, Polyoxylglycerides, Sodium Lauryl Sulfate, Sucrose Esters, or Glycerol, or a combination of two or more thereof.

[0334] 15. The composition of embodiment 1 or 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.

[0335] 16. The composition of embodiment 15, comprising DGME.

[0336] 17. The composition of embodiment 16, wherein DGME is transcutol™, transcutol HP™, or transcutol P™.

[0337] 18. The composition of embodiment 17, comprising transcutol HP™ (2-(2-ethoxyethoxy)ethanol).

[0338] 19. A composition according to any one of embodiments 16 to 18, wherein the purity of DGME is greater than 99.90%.

[0339] 20. The penetration enhancer and / or organic solvent is (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 19-21%, or about 19-20% by weight of the composition. 20. The composition of any one of embodiments 1-19, comprising a polyethylene glycol comprising: (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) a combination of (i), (ii) and (iii); (xii) a combination of (i), (ii) and (iv); (xiii) a combination of (i), (iii) and (iv); (xiv) a combination of (ii), (iii) and (iv); or (vx) a combination of (i), (ii), (iii) and (iv).

[0340] 21. The composition of any one of embodiments 1-19, wherein the total amount of penetration enhancer and / or organic solvent is present in an amount from about 85% to about 99% by weight of the composition.

[0341] 22. The composition of any one of embodiments 1 to 21, further comprising an antioxidant.

[0342] 23. The composition of embodiment 22, wherein the total amount of antioxidants is about 0.01% to 1% by weight of the composition.

[0343] 24. A composition comprising ruboxistaurin free base or ruboxistaurin mesylate monohydrate, or a salt thereof, and an antioxidant.

[0344] 25. The composition of 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 of two or more thereof.

[0345] 26. The composition of embodiment 24 or 25, wherein the total amount of antioxidants is about 0.2% to 0.3% by weight of the composition.

[0346] 27. The composition of 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 butylated hydroxyanisole (BHA) present at about 0.05-0.2%, or about 0.1% by weight of the composition.

[0347] 28. The composition of any one of embodiments 1 to 27, further comprising an alcohol.

[0348] 29. The composition of embodiment 28, wherein the total amount of alcohol is about 62% to 99% by weight of the composition.

[0349] 30. A composition comprising ruboxistaurin free base or ruboxistaurin mesylate monohydrate, or a salt thereof, and an alcohol.

[0350] 31. The composition of any one of embodiments 28-30, wherein the alcohol comprises a C2-6 alcohol.

[0351] 32. The composition of 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.

[0352] 33. The composition of embodiment 28, wherein the total amount of alcohol is about 62% to 99% by weight of the composition.

[0353] 34. The alcohol is (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) polyethylene present at about 8-30%, about 9-22%, about 18-22%, about 19-21%, or about 19-20% by weight of the composition; 33. The composition of any one of embodiments 30-32, comprising: glycol; (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) a combination of (i), (ii) and (iii); (xii) a combination of (i), (ii) and (iv); (xiii) a combination of (i), (iii) and (iv); (xiv) a combination of (ii), (iii) and (iv); or (vx) a combination of (i), (ii), (iii) and (iv).

[0354] 35. The composition of any one of embodiments 1 to 34, further comprising a gelling agent.

[0355] 36. The composition of embodiment 35, wherein the gelling agent is about 16% to 75% by weight, or about 18% to 56% by weight of the composition.

[0356] 37. A composition comprising ruboxistaurin free base or ruboxistaurin mesylate monohydrate, or a salt thereof, and a gelling agent.

[0357] 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.

[0358] 39. The composition of embodiment 38, wherein the hydroxypropyl cellulose (HPC) is HPC GF, HPC CF, or HPC HF, or a combination of two or more thereof.

[0359] 40. The composition of any one of embodiments 37-39, wherein 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).

[0360] 41. The composition of any one of embodiments 37 to 39, wherein the average molecular weight of the gelling agent is from about 700,000 Da to about 1,150,000 Da.

[0361] 42. A composition comprising ruboxistaurin free base or ruboxistaurin mesylate monohydrate, or a salt thereof, a penetration enhancer and / or organic solvent, and an antioxidant.

[0362] 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.

[0363] 44. The composition of embodiment 42 or 43, comprising a penetration enhancer.

[0364] 45. The composition of embodiment 44, wherein the penetration enhancer comprises a C2-6 alkylene glycol, a C1-3 alkyl-(OCH2CH2)1-5-OH, a polyethylene glycol, glycerol, a fatty alcohol, a fatty ester, or a fatty ether, or a combination of two or more thereof.

[0365] 46. ​​The composition of any one of embodiments 42-45, comprising an organic solvent.

[0366] 47. The composition of embodiment 46, wherein the organic solvent comprises a C2-6 alkylene glycol, a C1-3 alkyl-(OCH2CH2)1-5-OH, a polyethylene glycol, glycerol, an aliphatic alcohol, an aliphatic ester, or an aliphatic ether, or a combination of two or more thereof.

[0367] 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.

[0368] 49. The composition of embodiment 42 or 43, wherein the penetration enhancer and / or organic solvent comprises a C2-6 alkylene glycol, a C1-3 alkyl-(OCH2CH2)1-5-OH, a polyethylene glycol, glycerol, a fatty alcohol, a fatty ester, or a fatty ether, or a combination of two or more thereof.

[0369] 50. The composition of any one of embodiments 42-49, comprising a penetration enhancer.

[0370] 51. The composition of embodiment 50, wherein the penetration enhancer comprises an organic solvent.

[0371] 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.

[0372] 53. The composition of any one of embodiments 42 to 52, comprising an emulsifier.

[0373] 54. The composition of embodiment 53, wherein the penetration enhancer and / or organic solvent comprises an emulsifier.

[0374] 55. The composition of embodiment 53 or 54, wherein the emulsifier comprises cocoyl caprylocaprate, 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, docusate sodium, glyceryl monostearate, hydrogenated vegetable oil / cottonseed oil / palm kernel oil, MCT, N-methyl-2-pyrrolidone, poloxamer, PEG, polysorbate, PEG castor oil derivative, propylene glycol, polyoxylglycerides, sodium lauryl sulfate, sucrose esters, or glycerol, or a combination of two or more thereof.

[0375] 56. The composition of embodiment 42 or 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.

[0376] 57. The composition of embodiment 56, comprising DGME.

[0377] 58. The composition of embodiment 57, wherein DGME is transcutol™, transcutol HP™, or transcutol P™.

[0378] 59. The composition of embodiment 58, comprising transcutol HP™ (2-(2-ethoxyethoxy)ethanol).

[0379] 60. A composition described in any one of embodiments 57 to 59, wherein the purity of DGME is greater than 99.90%.

[0380] 61. The penetration enhancer and / or organic solvent is (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 19-21%, or about 19-20% by weight of the composition. 61. The composition of any one of embodiments 42-60, comprising polyethylene glycol, (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) a combination of (i), (ii) and (iii), (xii) a combination of (i), (ii) and (iv), (xiii) a combination of (i), (iii) and (iv), (xiv) a combination of (ii), (iii) and (iv), or (vx) a combination of (i), (ii), (iii) and (iv).

[0381] 62. The composition of any one of embodiments 42 to 60, wherein the total amount of penetration enhancer and / or organic solvent is present in an amount from about 85% to about 99% by weight of the composition.

[0382] 63. The composition of 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 of two or more thereof.

[0383] 64. The composition of any one of embodiments 42-63, wherein the total amount of antioxidant is present in an amount of about 0.01% to 15% by weight, or about 0.2% to 0.3% by weight of the composition.

[0384] 65. The composition of any one 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 butylated hydroxyanisole (BHA) present at about 0.05-0.2%, or about 0.1% by weight of the composition.

[0385] 66. A composition comprising ruboxistaurin free base or ruboxistaurin mesylate monohydrate, or a salt thereof, a penetration enhancer and / or organic solvent, one or more antioxidants, and an alcohol.

[0386] 67. The composition of embodiment 66, wherein the total amount of penetration enhancer and / or organic solvent is from about 62% to about 99% by weight of the composition.

[0387] 68. The composition of embodiment 66 or 67, comprising a penetration enhancer.

[0388] 69. The composition of embodiment 68, wherein the penetration enhancer comprises a C2-6 alkylene glycol, a C1-3 alkyl-(OCH2CH2)1-5-OH, a polyethylene glycol, glycerol, a fatty alcohol, a fatty ester, or a fatty ether, or a combination of two or more thereof.

[0389] 70. The composition of any one of embodiments 66-69, comprising an organic solvent.

[0390] 71. The composition of embodiment 70, wherein the organic solvent comprises a C2-6 alkylene glycol, a C1-3 alkyl-(OCH2CH2)1-5-OH, a polyethylene glycol, glycerol, an aliphatic alcohol, an aliphatic ester, or an aliphatic ether, or a combination of two or more thereof.

[0391] 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.

[0392] 73. The composition of embodiment 66 or 67, wherein the penetration enhancer and / or organic solvent comprises a C2-6 alkylene glycol, a C1-3 alkyl-(OCH2CH2)1-5-OH, a polyethylene glycol, glycerol, a fatty alcohol, a fatty ester, or a fatty ether, or a combination of two or more thereof.

[0393] 74. The composition of any one of embodiments 66-73, comprising a penetration enhancer.

[0394] 75. The composition of embodiment 74, wherein the penetration enhancer comprises an organic solvent.

[0395] 76. The composition of embodiment 66 or 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.

[0396] 77. The composition of any one of embodiments 66-76, comprising an emulsifier.

[0397] 78. The composition of embodiment 77, wherein the penetration enhancer and / or organic solvent comprises an emulsifier.

[0398] 79. The composition of embodiment 77 or 78, wherein the emulsifier comprises cocoyl caprylocaprate, 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, docusate sodium, glyceryl monostearate, hydrogenated vegetable oil / cottonseed oil / palm kernel oil, MCT, N-methyl-2-pyrrolidone, poloxamer, PEG, polysorbate, PEG castor oil derivative, propylene glycol, polyoxylglyceride, sodium lauryl sulfate, sucrose esters, or glycerol, or a combination of two or more thereof.

[0399] 80. The composition of embodiment 66 or 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.

[0400] 81. The composition of embodiment 80, comprising DGME.

[0401] 82. The composition of embodiment 81, wherein DGME is transcutol™, transcutol HP™, or transcutol P™.

[0402] 83. The composition of embodiment 82, comprising transcutol HP™ (2-(2-ethoxyethoxy)ethanol).

[0403] 84. A composition described in any one of embodiments 81 to 83, wherein the purity of DGME is greater than 99.90%.

[0404] 85. The penetration enhancer and / or organic solvent is (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 19-21%, or about 19-20% by weight of the composition. 85. The composition of any one of embodiments 66-84, comprising polyethylene glycol, (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) a combination of (i), (ii) and (iii), (xii) a combination of (i), (ii) and (iv), (xiii) a combination of (i), (iii) and (iv), (xiv) a combination of (ii), (iii) and (iv), or (vx) a combination of (i), (ii), (iii) and (iv).

[0405] 86. The composition of any one of embodiments 66-84, wherein the total amount of penetration enhancer and / or organic solvent is present in about 85% to about 99% by weight of the composition.

[0406] 87. The composition of 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 of two or more thereof.

[0407] 88. The composition of any one of embodiments 66 to 87, wherein the total amount of antioxidant is present in the composition in an amount of about 0.01% to 1% by weight, or about 0.2% to 0.3% by weight of the composition.

[0408] 89. The composition of any one 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 butylated hydroxyanisole (BHA) present at about 0.05-0.2%, or about 0.1% by weight of the composition.

[0409] 90. The composition of any one of embodiments 66-89, wherein the alcohol comprises a C2-6 alcohol.

[0410] 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.

[0411] 92. The composition of any one of embodiments 66 to 91, wherein the alcohol is present in the composition in an amount ranging from about 62% to 99% by weight, or from about 85% to 99% by weight of the composition.

[0412] 93. The alcohol is (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) polyethylene present at about 8-30%, about 9-22%, about 18-22%, about 19-21%, or about 19-20% by weight of the composition; 92. The composition of any one of embodiments 66-91, comprising: glycerol; (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) a combination of (i), (ii) and (iii); (xii) a combination of (i), (ii) and (iv); (xiii) a combination of (i), (iii) and (iv); (xiv) a combination of (ii), (iii) and (iv); or (vx) a combination of (i), (ii), (iii) and (iv).

[0413] 94. A composition comprising ruboxistaurin free base or ruboxistaurin mesylate monohydrate, or a salt thereof, a penetration enhancer and / or an organic solvent, and an alcohol.

[0414] 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.

[0415] 96. The composition of embodiment 94 or 95, comprising a penetration enhancer.

[0416] 97. The composition of embodiment 96, wherein the penetration enhancer comprises a C2-6 alkylene glycol, a C1-3 alkyl-(OCH2CH2)1-5-OH, a polyethylene glycol, glycerol, a fatty alcohol, a fatty ester, or a fatty ether, or a combination of two or more thereof.

[0417] 98. The composition of any one of embodiments 94-97, comprising an organic solvent.

[0418] 99. The composition of embodiment 98, wherein the organic solvent comprises a C2-6 alkylene glycol, a C1-3 alkyl-(OCH2CH2)1-5-OH, a polyethylene glycol, glycerol, an aliphatic alcohol, an aliphatic ester, or an aliphatic ether, or a combination of two or more thereof.

[0419] 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.

[0420] 101. The composition of embodiment 94 or 95, wherein the penetration enhancer and / or organic solvent comprises a C2-6 alkylene glycol, a C1-3 alkyl-(OCH2CH2)1-5-OH, a polyethylene glycol, glycerol, a fatty alcohol, a fatty ester, or a fatty ether, or a combination of two or more thereof.

[0421] 102. The composition of any one of embodiments 94-101, comprising a penetration enhancer.

[0422] 103. The composition of embodiment 102, wherein the penetration enhancer comprises an organic solvent.

[0423] 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.

[0424] 105. The composition of any one of embodiments 94 to 104, comprising an emulsifier.

[0425] 106. The composition of embodiment 105, wherein the penetration enhancer and / or organic solvent comprises an emulsifier.

[0426] 107. The composition of embodiment 105 or 106, wherein the emulsifier comprises cocoyl caprylocaprate, 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, docusate sodium, glyceryl monostearate, hydrogenated vegetable oil / cottonseed oil / palm kernel oil, MCT, N-methyl-2-pyrrolidone, poloxamer, PEG, polysorbate, PEG castor oil derivative, propylene glycol, polyoxylglyceride, sodium lauryl sulfate, sucrose esters, or glycerol, or a combination of two or more thereof.

[0427] 108. The composition of embodiment 94 or 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.

[0428] 109. The composition of embodiment 108, comprising DGME.

[0429] 110. The composition of embodiment 109, wherein the DGME is Transcutol™, Transcutol HP™, or Transcutol P™.

[0430] 111. The composition described in embodiment 110, comprising Transcutol HP™ (2-(2-ethoxyethoxy)ethanol).

[0431] 112. A composition described in any one of embodiments 109 to 111, wherein the purity of DGME is greater than 99.90%.

[0432] 113. The penetration enhancer and / or organic solvent is (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 19-21%, or about 19-20% by weight of the composition. The composition of any one of embodiments 94-112, comprising polyethylene glycol, (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) a combination of (i), (ii) and (iii), (xii) a combination of (i), (ii) and (iv), (xiii) a combination of (i), (iii) and (iv), (xiv) a combination of (ii), (iii) and (iv), or (vx) a combination of (i), (ii), (iii) and (iv).

[0433] 114. The composition of any one of embodiments 94 to 112, wherein the total amount of penetration enhancer and / or organic solvent is present in about 85% to 99%, 50% to 80%, 50% to 70%, or about 60% by weight of the composition.

[0434] 115. The composition of any one of embodiments 94-114, wherein the alcohol comprises a C2-6 alcohol.

[0435] 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.

[0436] 117. The composition of any one of embodiments 94 to 116, wherein the alcohol is present in the composition in an amount of about 62% to 99% by weight, or about 85% to 99% by weight of the composition.

[0437] 118. The alcohol is (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) polyethylene present at about 8-30%, about 9-22%, about 18-22%, about 19-21%, or about 19-20% by weight of the composition. 118. The composition of any one of embodiments 94-117, comprising: glycol; (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) a combination of (i), (ii) and (iii); (xii) a combination of (i), (ii) and (iv); (xiii) a combination of (i), (iii) and (iv); (xiv) a combination of (ii), (iii) and (iv); or (vx) a combination of (i), (ii), (iii) and (iv).

[0438] 119. A composition comprising ruboxistaurin free base or ruboxistaurin mesylate monohydrate, or a salt thereof, an antioxidant, and an alcohol.

[0439] 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 of two or more thereof.

[0440] 121. The composition of embodiment 119 or 120, wherein the total amount of antioxidants is present in the composition in an amount of about 0.01% to 1% by weight, or about 0.2% to 0.3% by weight of the composition.

[0441] 122. The composition of 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 butylated hydroxyanisole (BHA) present at about 0.05-0.2%, or about 0.1% by weight of the composition.

[0442] 123. The composition of any one of embodiments 119-122, wherein the alcohol comprises a C2-6 alcohol.

[0443] 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.

[0444] 125. The composition of any one of embodiments 119 to 124, wherein the alcohol is present in the composition in an amount ranging from about 62% to 99% by weight, or from about 85% to 99% by weight of the composition.

[0445] 126. The alcohol is (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; or (iv) polyethylene present at about 8-30%, about 9-22%, about 18-22%, about 19-21%, or about 19-20% by weight of the composition. 125. The composition of any one of embodiments 119-124, comprising a glycol, (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) a combination of (i), (ii) and (iii), (xii) a combination of (i), (ii) and (iv), (xiii) a combination of (i), (iii) and (iv), (xiv) a combination of (ii), (iii) and (iv), or (vx) a combination of (i), (ii), (iii) and (iv).

[0446] 127. A composition comprising ruboxistaurin free base or ruboxistaurin mesylate monohydrate, or a salt thereof, a penetration enhancer and / or organic solvent, an antioxidant, an alcohol, and a gelling agent.

[0447] 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.

[0448] 129. The composition of embodiment 127 or 128, comprising a penetration enhancer.

[0449] 130. The composition of embodiment 129, wherein the penetration enhancer comprises a C2-6 alkylene glycol, a C1-3 alkyl-(OCH2CH2)1-5-OH, a polyethylene glycol, glycerol, a fatty alcohol, a fatty ester, or a fatty ether, or a combination of two or more thereof.

[0450] 131. The composition of any one of embodiments 127-130, comprising an organic solvent.

[0451] 132. The composition of embodiment 131, wherein the organic solvent comprises a C2-6 alkylene glycol, a C1-3 alkyl-(OCH2CH2)1-5-OH, a polyethylene glycol, glycerol, an aliphatic alcohol, an aliphatic ester, or an aliphatic ether, or a combination of two or more thereof.

[0452] 133. The composition of 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.

[0453] 134. The composition of embodiment 127 or 128, wherein the penetration enhancer and / or organic solvent comprises a C2-6 alkylene glycol, a C1-3 alkyl-(OCH2CH2)1-5-OH, a polyethylene glycol, glycerol, a fatty alcohol, a fatty ester, or a fatty ether, or a combination of two or more thereof.

[0454] 135. The composition of any one of embodiments 127-134, comprising a penetration enhancer.

[0455] 136. The composition of embodiment 135, wherein the penetration enhancer comprises an organic solvent.

[0456] 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.

[0457] 138. The composition of any one of embodiments 127-137, comprising an emulsifier.

[0458] 139. The composition of embodiment 138, wherein the penetration enhancer and / or organic solvent comprises an emulsifier.

[0459] 140. The composition of embodiment 138 or 139, wherein the emulsifier comprises cocoyl caprylocaprate, 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, docusate sodium, glyceryl monostearate, hydrogenated vegetable oil / cottonseed oil / palm kernel oil, MCT, N-methyl-2-pyrrolidone, poloxamer, PEG, polysorbate, PEG castor oil derivative, propylene glycol, polyoxylglyceride, sodium lauryl sulfate, sucrose esters, or glycerol, or a combination of two or more thereof.

[0460] 141. The composition of embodiment 127 or 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.

[0461] 142. The composition of embodiment 141, comprising DGME.

[0462] 143. The composition of embodiment 142, wherein the DGME is Transcutol™, Transcutol HP™, or Transcutol P™.

[0463] 144. The composition of embodiment 143, comprising Transcutol HP™ (2-(2-ethoxyethoxy)ethanol).

[0464] 145. A composition described in any one of embodiments 142 to 144, wherein the purity of DGME is greater than 99.90%.

[0465] 146. The penetration enhancer and / or organic solvent is (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 19-21%, or about 19-20% by weight of the composition. 146. The composition of any one of embodiments 127-145, comprising polyethylene glycol, (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) a combination of (i), (ii) and (iii), (xii) a combination of (i), (ii) and (iv), (xiii) a combination of (i), (iii) and (iv), (xiv) a combination of (ii), (iii) and (iv), or (vx) a combination of (i), (ii), (iii) and (iv).

[0466] 147. The composition of any one of embodiments 127-145, wherein the total amount of penetration enhancer and / or organic solvent is present in an amount from about 85% to about 99% by weight of the composition.

[0467] 148. The composition of 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 of two or more thereof.

[0468] 149. The composition of any one of embodiments 127 to 148, wherein the total amount of antioxidant is present in the composition in an amount of about 0.01% to 1% by weight, or about 0.2% to 0.3% by weight of the composition.

[0469] 150. The composition of any one of embodiments 127 to 149, wherein the antioxidant comprises butylated hydroxytoluene (BHT) present at about 0.05 to 0.3%, about 0.1%, or about 0.2% by weight of the composition, and / or butylated hydroxyanisole (BHA) present at about 0.05 to 0.2%, or about 0.1% by weight of the composition.

[0470] 151. The composition of any one of embodiments 127-150, wherein the alcohol comprises a C2-6 alcohol.

[0471] 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.

[0472] 153. The composition of any one of embodiments 127-152, wherein the alcohol is present in the composition in an amount ranging from about 62% to 99% by weight, or from about 85% to 99% by weight of the composition.

[0473] 154. The alcohol is (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; or (iv) polyethylene present at about 8-30%, about 9-22%, about 18-22%, about 19-21%, or about 19-20% by weight of the composition. 153. The composition of any one of embodiments 127-152, comprising a glycol, (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) a combination of (i), (ii) and (iii), (xii) a combination of (i), (ii) and (iv), (xiii) a combination of (i), (iii) and (iv), (xiv) a combination of (ii), (iii) and (iv), or (vx) a combination of (i), (ii), (iii) and (iv).

[0474] 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.

[0475] 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.

[0476] 157. The gelling agent is present in a total amount of about 16% to 75% by weight, or about 18% to 56% by weight of the composition, and / or the gelling agent is (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) glycerol, present in about 2-45%, about 3-24%, about 3-14%, about 13-15%, or about 15-20% by weight of the composition; 157. The composition of any one of embodiments 127-156, comprising: (i) PEG present in about 13-14% by weight, or about 13-14% by weight of the composition; (iii) HPC present in about 0.5-4% by weight, 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).

[0477] 158. The composition of any one of embodiments 127 to 157, wherein the average molecular weight of the gelling agent is from about 700,000 Da to about 1,150,000 Da.

[0478] 159. A composition comprising ruboxistaurin free base or ruboxistaurin mesylate monohydrate, or a salt thereof, an antioxidant, an alcohol, and a gelling agent.

[0479] 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 of two or more thereof.

[0480] 161. The composition of embodiment 159 or 160, wherein the total amount of antioxidants is present in the composition in an amount of about 0.01% to 1% by weight, or about 0.2% to 0.3% by weight of the composition.

[0481] 162. The composition of 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 butylated hydroxyanisole (BHA) present at about 0.05-0.2%, or about 0.1% by weight of the composition.

[0482] 163. The composition of any one of embodiments 159-162, wherein the alcohol comprises a C2-6 alcohol.

[0483] 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.

[0484] 165. The composition of any one of embodiments 159 to 164, wherein the alcohol is present in the composition in an amount ranging from about 62% to 99% by weight, or from about 85% to 99% by weight of the composition.

[0485] 166. The alcohol is (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; or (iv) polyethylene present at about 8-30%, about 9-22%, about 18-22%, about 19-21%, or about 19-20% by weight of the composition. 165. The composition of any one of embodiments 159-164, comprising a glycol, (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) a combination of (i), (ii) and (iii), (xii) a combination of (i), (ii) and (iv), (xiii) a combination of (i), (iii) and (iv), (xiv) a combination of (ii), (iii) and (iv), or (vx) a combination of (i), (ii), (iii) and (iv).

[0486] 167. The composition of 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.

[0487] 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.

[0488] 169. The gelling agent is present in a total amount of about 16% to 75% by weight, or about 18% to 56% by weight of the composition, and / or the gelling agent is (i) glycerol, present in about 12-24% by weight, about 14-20% by weight, about 13-17% by weight, about 14-16% by weight, or about 14-15% by weight of the composition; (ii) glycerol, present in about 2-45% by weight, about 3-24% by weight, about 3-14% by weight, about 13-15% by weight, or about 15-20% by weight of the composition; 169. The composition of any one of embodiments 159-168, comprising: (i) PEG present in about 13-14% by weight, or about 13-14% by weight of the composition; (iii) HPC present in about 0.5-4% by weight, 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).

[0489] 170. The composition of any one of embodiments 159-169, wherein the average molecular weight of the gelling agent is from about 700,000 Da to about 1,150,000 Da.

[0490] 171. A composition comprising ruboxistaurin free base or ruboxistaurin mesylate monohydrate, or a salt thereof, a penetration enhancer and / or organic solvent, an alcohol, and a gelling agent.

[0491] 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.

[0492] 173. The composition of embodiment 171 or 172, comprising a penetration enhancer.

[0493] 174. The composition of embodiment 173, wherein the penetration enhancer comprises a C2-6 alkylene glycol, a C1-3 alkyl-(OCH2CH2)1-5-OH, a polyethylene glycol, glycerol, a fatty alcohol, a fatty ester, or a fatty ether, or a combination of two or more thereof.

[0494] 175. The composition of any one of embodiments 171-174, comprising an organic solvent.

[0495] 176. The composition of embodiment 175, wherein the organic solvent comprises a C2-6 alkylene glycol, a C1-3 alkyl-(OCH2CH2)1-5-OH, a polyethylene glycol, glycerol, an aliphatic alcohol, an aliphatic ester, or an aliphatic ether, or a combination of two or more thereof.

[0496] 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.

[0497] 178. The composition of embodiment 171 or 172, wherein the penetration enhancer and / or organic solvent comprises a C2-6 alkylene glycol, a C1-3 alkyl-(OCH2CH2)1-5-OH, a polyethylene glycol, glycerol, a fatty alcohol, a fatty ester, or a fatty ether, or a combination of two or more thereof.

[0498] 179. The composition of any one of embodiments 171-178, comprising a penetration enhancer.

[0499] 180. The composition of embodiment 179, wherein the penetration enhancer comprises an organic solvent.

[0500] 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.

[0501] 182. The composition of any one of embodiments 171-181, comprising an emulsifier.

[0502] 183. The composition of embodiment 182, wherein the penetration enhancer and / or organic solvent comprises an emulsifier.

[0503] 184. The composition of embodiment 182 or 183, wherein the emulsifier comprises cocoyl caprylocaprate, 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, docusate sodium, glyceryl monostearate, hydrogenated vegetable oil / cottonseed oil / palm kernel oil, MCT, N-methyl-2-pyrrolidone, poloxamer, PEG, polysorbate, PEG castor oil derivative, propylene glycol, polyoxylglyceride, sodium lauryl sulfate, sucrose esters, or glycerol, or a combination of two or more thereof.

[0504] 185. The composition of embodiment 171 or 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.

[0505] 186. The composition of embodiment 185, comprising DGME.

[0506] 187. The composition of embodiment 186, wherein the DGME is Transcutol™, Transcutol HP™, or Transcutol P™.

[0507] 188. The composition of embodiment 187, comprising Transcutol HP™ (2-(2-ethoxyethoxy)ethanol).

[0508] 189. A composition described in any one of embodiments 186 to 188, wherein the purity of DGME is greater than 99.90%.

[0509] 190. The penetration enhancer and / or organic solvent is (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 19-21%, or about 19-20% by weight of the composition. 189. The composition of any one of embodiments 171-189, comprising a polyethylene glycol, (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) a combination of (i), (ii) and (iii), (xii) a combination of (i), (ii) and (iv), (xiii) a combination of (i), (iii) and (iv), (xiv) a combination of (ii), (iii) and (iv), or (vx) a combination of (i), (ii), (iii) and (iv).

[0510] 191. The composition of any one of embodiments 171-189, wherein the total amount of penetration enhancer and / or organic solvent is present in about 85% to about 99% by weight of the composition.

[0511] 192. The composition of any one of embodiments 171-191, wherein the alcohol comprises a C2-6 alcohol.

[0512] 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.

[0513] 194. The composition of any one of embodiments 171 to 193, wherein the alcohol is present in the composition in an amount ranging from about 62% to 99% by weight, or from about 85% to 99% by weight of the composition.

[0514] 195. The alcohol is (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; or (iv) polyethylene present at about 8-30%, about 9-22%, about 18-22%, about 19-21%, or about 19-20% by weight of the composition. 194. The composition of any one of embodiments 171-193, comprising a glycol, (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) a combination of (i), (ii) and (iii), (xii) a combination of (i), (ii) and (iv), (xiii) a combination of (i), (iii) and (iv), (xiv) a combination of (ii), (iii) and (iv), or (vx) a combination of (i), (ii), (iii) and (iv).

[0515] 196. The composition of 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.

[0516] 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.

[0517] 198. The gelling agent is present in a total amount of about 16% to 75% by weight, or about 18% to 56% by weight of the composition, and / or the gelling agent is (i) glycerol, present in about 12-24% by weight, about 14-20% by weight, about 13-17% by weight, about 14-16% by weight, or about 14-15% by weight of the composition; (ii) glycerol, present in about 2-45% by weight, about 3-24% by weight, about 3-14% by weight, about 13-15% by weight, or about 15-20% by weight of the composition; 20. The composition of any one of embodiments 171-197, comprising: (i) PEG present in about 10-15% by weight, or about 13-14% by weight; (ii) HPC present in about 0.5-4% by weight, or about 1-3% by weight of the composition; (iii) a combination of (i) and (ii); (iv) a combination of (i) and (iii); (v) a combination of (i) and (iii); (vi) a combination of (ii) and (iii); or (vii) a combination of (i), (ii) and (iii).

[0518] 199. The composition of any one of embodiments 171 to 198, wherein the average molecular weight of the gelling agent is from about 700,000 Da to about 1,150,000 Da.

[0519] 200. A composition comprising ruboxistaurin free base or ruboxistaurin mesylate monohydrate, or a salt thereof, a penetration enhancer and / or organic solvent, an antioxidant, and a gelling agent.

[0520] 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.

[0521] 202. The composition of embodiment 200 or 201, comprising a penetration enhancer.

[0522] 203. The composition of embodiment 202, wherein the penetration enhancer comprises a C2-6 alkylene glycol, a C1-3 alkyl-(OCH2CH2)1-5-OH, a polyethylene glycol, glycerol, a fatty alcohol, a fatty ester, or a fatty ether, or a combination of two or more thereof.

[0523] 204. The composition of any one of embodiments 200-203, comprising an organic solvent.

[0524] 205. The composition of embodiment 204, wherein the organic solvent comprises a C2-6 alkylene glycol, a C1-3 alkyl-(OCH2CH2)1-5-OH, a polyethylene glycol, glycerol, an aliphatic alcohol, an aliphatic ester, or an aliphatic ether, or a combination of two or more thereof.

[0525] 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.

[0526] 207. The composition of embodiment 200 or 201, wherein the penetration enhancer and / or organic solvent comprises a C2-6 alkylene glycol, a C1-3 alkyl-(OCH2CH2)1-5-OH, a polyethylene glycol, glycerol, an aliphatic alcohol, an aliphatic ester, or an aliphatic ether, or a combination of two or more thereof.

[0527] 208. The composition of any one of embodiments 200-207, comprising a penetration enhancer.

[0528] 209. The composition of embodiment 208, wherein the penetration enhancer comprises an organic solvent.

[0529] 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.

[0530] 211. The composition according to any one of embodiments 200 to 210, comprising an emulsifier.

[0531] 212. The composition of embodiment 211, wherein the penetration enhancer and / or organic solvent comprises an emulsifier.

[0532] 213. The composition of embodiment 211 or 212, wherein the emulsifier comprises cocoyl caprylocaprate, 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, docusate sodium, glyceryl monostearate, hydrogenated vegetable oil / cottonseed oil / palm kernel oil, MCT, N-methyl-2-pyrrolidone, poloxamer, PEG, polysorbate, PEG castor oil derivative, propylene glycol, polyoxylglyceride, sodium lauryl sulfate, sucrose esters, or glycerol, or a combination of two or more thereof.

[0533] 214. The composition of embodiment 200 or 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.

[0534] 215. The composition of embodiment 214, comprising DGME.

[0535] 216. The composition of embodiment 215, wherein the DGME is Transcutol™, Transcutol HP™, or Transcutol P™.

[0536] 217. The composition of embodiment 216, comprising Transcutol HP™ (2-(2-ethoxyethoxy)ethanol).

[0537] 218. A composition described in any one of embodiments 215 to 217, wherein the purity of DGME is greater than 99.90%.

[0538] 219. The penetration enhancer and / or organic solvent is (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 19-21%, or about 19-20% by weight of the composition. The composition of any one of embodiments 200-218, comprising polyethylene glycol, (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) a combination of (i), (ii) and (iii), (xii) a combination of (i), (ii) and (iv), (xiii) a combination of (i), (iii) and (iv), (xiv) a combination of (ii), (iii) and (iv), or (vx) a combination of (i), (ii), (iii) and (iv).

[0539] 220. The composition of any one of embodiments 200-218, wherein the total amount of penetration enhancer and / or organic solvent is present in an amount from about 85% to about 99% by weight of the composition.

[0540] 221. The composition of 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 of two or more thereof.

[0541] 222. The composition of any one of embodiments 200 to 221, wherein the total amount of antioxidant is present in the composition in an amount of about 0.01% to 1% by weight, or about 0.2% to 0.3% by weight of the composition.

[0542] 223. The composition of any one 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 butylated hydroxyanisole (BHA) present at about 0.05-0.2%, or about 0.1% by weight of the composition.

[0543] 224. The composition of 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.

[0544] 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.

[0545] 226. The gelling agent is present in a total amount of about 16% to 75% by weight, or about 18% to 56% by weight of the composition, and / or the gelling agent is (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) glycerol, present in about 2-45%, about 3-24%, about 3-14%, about 13-15%, or about 15-20% by weight of the composition; 226. The composition of any one of embodiments 200-225, comprising: (i) PEG present in about 10-15% by weight, or about 13-14% by weight; (ii) HPC present in about 0.5-4% by weight, 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).

[0546] 227. The composition of any one of embodiments 200 to 226, wherein the average molecular weight of the gelling agent is from about 700,000 Da to about 1,150,000 Da.

[0547] 228. A composition comprising (i) ruboxistaurin free base or ruboxistaurin mesylate monohydrate, or a salt thereof, and (ii) PEG, propylene glycol, 2-(2-ethoxyethoxy)ethanol, butylhydroxytoluene, butylhydroxyanisole, glycerol, or hydroxypropylcellulose, or a combination of two or more thereof.

[0548] 229. The composition of any one of embodiments 1-228, comprising PEG, propylene glycol, 2-(2-ethoxyethoxy)ethanol, butylated hydroxytoluene, butylated hydroxyanisole, glycerol, or hydroxypropylcellulose, or a combination of two or more thereof.

[0549] 230. The composition according to embodiment 228 or 229, which is: (a) to (h).

[0550] (a) PEG is present in an amount of 10% to 30%, 10% to 20%, or about 14% by weight of the composition;

[0551] (b) propylene glycol is present in an amount of 10% to 40%, 15% to 30%, or about 20% by weight of the composition;

[0552] (c) 2-(2-ethoxyethoxy)ethanol is present in an amount of 30% to 70%, 40% to 60%, or about 47% by weight of the composition;

[0553] (d) butylhydroxytoluene is present in an amount of 0.01% to 0.5%, 0.01% to 0.2%, 0.01% to about 0.1%, or about 0.1% by weight of the composition;

[0554] (e) butylated hydroxyanisole is present in an amount of 0.01% to 0.5%, 0.01% to 0.2%, 0.01% to about 0.1%, or about 0.1% by weight of the composition;

[0555] (f) glycerol is present in an amount of 5% to 25%, 10% to 20%, or about 15% by weight of the composition; or

[0556] (g) hydroxypropyl cellulose is present in an amount of 1% to 4% or about 3% by weight of the composition; or

[0557] (h) Any combination of (a) through (g)

[0558] 231. The composition of any one of embodiments 228-230, comprising hydroxypropyl cellulose having an average molecular weight of about 700,000 Da to about 1,150,000 Da.

[0559] 232. The composition of any one of embodiments 228-231, comprising PEG present in an amount of about 14% by weight of the composition.

[0560] 233. The composition of any one of embodiments 228-232, comprising propylene glycol present in an amount of about 20% by weight of the composition.

[0561] 234. The composition of any one of embodiments 228-233, comprising 2-(2-ethoxyethoxy)ethanol present in an amount of about 20% by weight of the composition.

[0562] 235. The composition of any one of embodiments 228-234, comprising butylated hydroxytoluene present in an amount of about 0.1% by weight of the composition.

[0563] 236. The composition of any one of embodiments 228-235, comprising butylated hydroxyanisole present in an amount of about 0.1% by weight of the composition.

[0564] 237. The composition of any one of embodiments 228-236, comprising glycerol present in an amount of about 15% by weight of the composition.

[0565] 238. The composition of any one of embodiments 228-237, comprising hydroxypropylcellulose present in an amount of about 3% by weight of the composition.

[0566] 239. The composition of any one of embodiments 1 to 238, wherein ruboxistaurin free base, ruboxistaurin 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.

[0567] 240. The composition of embodiment 239, wherein the ruboxistaurin free base, ruboxistaurin mesylate monohydrate, or salts thereof are present in an amount of about 1% by weight of the composition.

[0568] 241. The composition of embodiment 239, wherein the ruboxistaurin free base, ruboxistaurin mesylate monohydrate, or salts thereof are present in an amount of about 0.6% by weight of the composition.

[0569] 242. The composition of embodiment 239, wherein the ruboxistaurin free base, ruboxistaurin mesylate monohydrate, or salts thereof are present in an amount of about 0.8% by weight of the composition.

[0570] 243. The composition according to any one of embodiments 1 to 242, formulated as a pharmaceutical composition.

[0571] 244. The composition of any one of embodiments 1 to 242, formulated as a cosmetic composition.

[0572] 245. The composition of any one of embodiments 1 to 242, formulated as a topical pharmaceutical or cosmetic composition.

[0573] 246. The composition of any one of embodiments 1 to 245, in the form of a gel, ointment, cream, lotion, foam, or emollient.

[0574] 247. The composition of any one of embodiments 1 to 245 as a component of a patch, tape, film, cloth strip, towelette, sponge, wafer, mask, wipe, brush, pad, gauze, applicator, cotton ball, roll, swab, or bandage.

[0575] 248. A method of treating a disease, illness, or disorder in a subject in need of such treatment, comprising administering to the subject a composition according to any one of embodiments 1 to 247.

[0576] 249. The disease, illness, or disorder is hyperpigmentation, dyschromia, melasma, postinflammatory hyperpigmentation, discoid lupus erythematosus, erythema, phytophotodermatitis, lentigines (e.g., facial age spots), nevi, nevus spilus, acanthosis nigricans, burn-associated hyperpigmentation, drug-induced hyperpigmentation (e.g., sulfonamide-, tetracycline-, NSAID-, barbiturate-, and carbamazepine-induced hyperpigmentation), traumatic hyperpigmentation, primary biliary cirrhosis-associated hyperpigmentation, Addison's disease-associated hyperpigmentation, hemochromatosis-associated hyperpigmentation, thyroid function disorder, The method of embodiment 248, wherein the skin disease, condition, or disorder comprises hyperpigmentation associated with hyperactivity, melanocytic nevi, freckles (ephelids), seborrheic keratosis, skin cancer-associated hyperpigmentation, infection-associated hyperpigmentation (e.g., tinea versicolor, erythrasma), eczema, photocontact, photoallergic, or phototoxic dermatitis, ichthyosis, pigmented spots or nevi associated with neurofibromatosis, or hyperpigmentation associated with extreme ultraviolet (UV) radiation exposure, e.g., a reaction to sun exposure or tanning, or a combination of two or more thereof.

[0577] 250. The method of embodiment 248, wherein the disease, illness, or disorder comprises a hyperpigmentation disorder.

[0578] 251. The method of embodiment 248, wherein the disease, illness, or disorder comprises hypertrichosis / hirsutism or hair pigmentation.

[0579] 252. The method of any one of embodiments 247-250, wherein the composition is in the form of a gel, ointment, cream, lotion, foam, or emollient.

[0580] 253. The method of any one of embodiments 248-251, wherein the composition is a component of a patch, tape, film, cloth strip, towelette, sponge, wafer, or bandage.

[0581] 254. The method of any one of embodiments 248-253, wherein the composition is administered locally to the head, scalp, face, ears, neck, chest, back, inflamed areas, arms, legs, or groin.

[0582] 255. The method of any one of embodiments 248-254, wherein the composition is administered twice a day.

[0583] 256. The method of any one of embodiments 248-255, wherein the composition is administered for at least 12 weeks.

[0584] 257. The method of any one of embodiments 248-256, wherein the composition is administered for about 12 weeks to about 24 weeks.

[0585] 258. The method of any one of embodiments 248-257, wherein the composition is administered for about 12 weeks.

[0586] 259. The method of any one of embodiments 248-255, wherein the composition is administered for at least 4 weeks.

[0587] 260. The method of any one of embodiments 248-255, wherein the composition is administered for about 4 weeks to about 8 weeks.

[0588] 261. The method of any one of embodiments 248-255, wherein the composition is administered for about 4 weeks to about 6 weeks.

[0589] 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.

[0590] 263. The method of any one of embodiments 248-255, wherein the composition is administered for about 8 weeks to about 12 weeks.

[0591] 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, together with instructions for use.

[0592] 265. A kit comprising the composition of any one of embodiments 1-247 in a container or tube, flexible aluminum tube, or laminated plastic tube, that blocks ultraviolet light from the composition.

[0593] 266. A kit comprising a composition according to any one of embodiments 1 to 247 in a container, tube, or pump, wherein oxygen is prevented from contacting the composition.

[0594] 267. The kit of embodiment 266, wherein the container, tube, or pump is vacuum sealed.

[0595] 268. The kit according to embodiment 267, wherein the headspace of the container, tube or pump is filled with an inert gas to prevent oxidation.

[0596] 269. The kit according to embodiment 268, wherein the gas used is nitrogen. EXAMPLES

[0597] Example 1: Preparation of the composition The topical compositions of the present disclosure can be prepared according to the procedures provided below. Reaction conditions, steps, and reactants not provided in the following procedures will be apparent and known to those skilled in the art.

[0598] The excipients (i.e., organic solvent and / or penetration enhancer, antioxidant, alcohol) were aliquoted and weighed into individual containers to form a mixture. The compound (i.e., ruboxistaurin free base, ruboxistaurin mesylate monohydrate, or an acceptable salt thereof) was added to the mixture to achieve the desired concentration. The gelling agent (e.g., HPC) was then added as appropriate. For some of the compositions, a final second addition of water (if present) was made to titrate the composition to 100% by weight. The final mixture was then thoroughly mixed to form the composition.

[0599] Example 2: Various compositions with / without ruboxistaurin free base, ruboxistaurin mesylate monohydrate, or acceptable salts thereof The following compositions were prepared following the general procedure of Example 1 using the excipients in Tables 1 and 2.

[0600] [Table 1]

[0601] In accordance with Table 1, the following excipient concentrations are provided in exemplary formulations herein (e.g., within about + / - 0.5% of the values ​​in Table 1): about 40-50% Transcutol (e.g., solvent and / or penetration enhancer, alcohol), about 8-12% propylene glycol (e.g., solvent and / or penetration enhancer, alcohol), about 8-12% ethanol (e.g., solvent and / or penetration enhancer, alcohol), about 12-18% glycerol (e.g., solvent and / or penetration enhancer, alcohol, gelling agent), about 12-16% PEG (e.g., solvent and / or penetration enhancer, alcohol, gelling agent), about 0.5%-4% HPC (e.g., gelling agent), about 2-4% Sepino (e.g., gelling agent), about 0.5-2% Carbopol (e.g., gelling agent), and about 0.1-0.3% ascorbic acid (e.g., antioxidant). In this case, each of the excipients may be optional. Optionally, the composition comprises an organic solvent and / or a penetration enhancer, optionally the organic solvent and / or the penetration enhancer is an alcohol and / or a gelling agent, and 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. Optionally, the composition comprises an alcohol, optionally the alcohol is an organic solvent / penetration enhancer and / or a gelling agent, and optionally the total amount of the alcohol in the composition is about 80-100% or about 95-99% of the composition. Optionally, the composition comprises an antioxidant, optionally the total amount of the antioxidant is about 0.1-0.3% or about 0.2% of the composition. Optionally, the composition comprises a gelling agent, optionally the total amount of the gelling agent is about 28-48% of the composition or about 31-32% of the composition. Thus, disclosed herein are compositions comprising a solvent and / or penetration enhancer, an alcohol, a gelling agent, and an antioxidant in the exemplary amounts set forth above, alone and in combination.

[0602] [Table 2]

[0603] According to Table 2, use the following excipient concentrations: about 40-50% Transcutol (e.g., solvent and / or penetration enhancer, alcohol), about 8-12% propylene glycol (e.g., solvent and / or penetration enhancer, alcohol), about 8-12% ethanol (e.g., solvent and / or penetration enhancer, alcohol), about 12-18% glycerol (e.g., solvent and / or penetration enhancer, alcohol, gelling agent), about 12-16% PEG (e.g., solvent and / or penetration enhancer, alcohol, gelling agent), about 0.5% glycerol ... 1-0.3% ascorbic acid (e.g., antioxidant), about 0.05-0.2% BHT (e.g., antioxidant), about 0.05-0.2% BHA (e.g., antioxidant), about 0.025-0.1% propyl gallate (e.g., antioxidant), about 0.001-0.003% alpha-tocopheryl acetate (e.g., antioxidant), about 0.01-0.03% ascorbyl palmitate (e.g., antioxidant) are provided in exemplary formulations herein (e.g., optionally within about + / - 10-20% of the values ​​in Table 2), where each of the excipients may be optional. Optionally, the composition comprises an organic solvent and / or a penetration enhancer, optionally the organic solvent and / or the penetration enhancer is an alcohol and / or a gelling agent, and 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. Optionally, the composition comprises an alcohol, optionally the alcohol is an organic solvent / penetration enhancer and / or a gelling agent, and optionally the total amount of the alcohol in the composition is about 80-100% or about 85-96% of the composition. Optionally, the composition comprises an antioxidant, optionally the total amount of the antioxidant is about 0.3-0.9% or about 0.1-0.3% of the composition. Optionally, the composition comprises a gelling agent, optionally the total amount of the gelling agent is about 24-34% of the composition or about 18-29% of the composition. Thus, disclosed herein are compositions comprising a solvent and / or penetration enhancer, an alcohol, a gelling agent, and an antioxidant in the exemplary amounts set forth above, alone and in combination.

[0604] Example 3: 14-day explant study overview Skin lightening assays were performed to demonstrate the pharmacodynamic activity of formulations containing ruboxistaurin mesylate monohydrate. Method development experiments were performed to evaluate the skin lightening potential of these formulations.

[0605] Method development experiments consisted of a single formulation, extrabasal treatments, and an untreated control using dark skin. Topical formulations or extrabasal treatments were applied daily for 7 days, with detergent / water washes prior to each treatment or medium change to prevent formulation build-up (untreated controls were washed in the same manner).

[0606] Materials and Methods In this method development study, one topical and one extrabasal treatment were used in the method development experiments along with an untreated control. Freshly excised skin from darkly pigmented donors was obtained and cultured according to the developed long term explant conditions with n=3. Explants were cultured for a total of 14 days and utilized the following treatment regimes: untreated control, extrabasal treatment (API at 17.7 nM in medium every 48 hours), and topically applied NA18. Explants were treated for 7 consecutive days and maintained without treatment for an additional 7 days. Prior to each treatment, each explant was washed with water / detergent. Following the procedure for long-term culture, all explants were washed with water / detergent every 2-3 days as well during the non-treatment phase. Photographs were taken at 0, 7, and 14 days for visual assessment of the skin lightening effect of the formulations. On days 7 and 14, duplicate samples (n=3) were collected and analyzed for tyrosinase activity and melanin content using procedures outlined in the study protocol.

[0607] Results, interpretation, and conclusions Method development Compared to untreated controls, topical treatment with NA18 significantly reduced melanin content (p=0.023) and caused a visible color change after 7 days, whereas extrabasal treatment appeared to have no effect on melanin content or skin color, likely due to lack of engagement at the target site (epidermis).No significant differences in tyrosinase activity were observed in either of the two treatment regimens compared to untreated controls.

[0608] [Table 3]

[0609] Example 4: Further optimization of compositions containing high amounts of Transcutol The compositions in Table 2 containing approximately 47-48% Transcutol P ((2-(2-ethoxyethoxy)ethanol) were further tested with the addition of antioxidants (e.g., butylated hydroxytoluene (BHT) and / or butylated hydroxyanisole (BHA), or propyl gallate), preservatives (e.g., phenoxyethanol), alcohol, gelling agents, and / or pH adjusters (e.g., aqueous citric acid solution) and / or preservatives (e.g., phenoxyethanol). Accordingly, the compositions are shown in Tables 5 and 6.

[0610] [Table 4]

[0611] [Table 5]

[0612] In accordance with Table 5, the following excipient concentrations are provided in the exemplary formulations herein (e.g., within about + / - 10-20% of the values ​​in Table 5): about 40-50% Transcutol (e.g., solvent and / or penetration enhancer, alcohol), about 8-30% propylene glycol (e.g., solvent and / or penetration enhancer, alcohol), about 12-24% glycerol (e.g., solvent and / or penetration enhancer, alcohol, gelling agent), about 2-30% PEG (e.g., solvent and / or penetration enhancer, alcohol, gelling agent), about 0.5-4% HPC (e.g., gelling agent), about 0.5-2% Carbopol (e.g., gelling agent), about 0.05-0.3% BHT (e.g., antioxidant), and about 0.05-0.2% BHA (e.g., antioxidant). In this case, each of the excipients may be optional. Optionally, the composition comprises an organic solvent and / or a penetration enhancer, optionally the organic solvent and / or the penetration enhancer is an alcohol and / or a gelling agent, and 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. Optionally, the composition comprises an alcohol, optionally the alcohol is an organic solvent / penetration enhancer and / or a gelling agent, and optionally the total amount of the alcohol in the composition is about 80-100% or about 86-99% of the composition. Optionally, the composition comprises an antioxidant, optionally the total amount of the antioxidant is about 0.1-0.5% or about 0.1-0.2% of the composition. Optionally, the composition comprises a gelling agent, optionally the total amount of the gelling agent is about 16-64% of the composition or about 21-42% of the composition. Thus, disclosed herein are compositions comprising a solvent and / or penetration enhancer, an alcohol, a gelling agent, and an antioxidant in the exemplary amounts set forth above, alone and in combination.

[0613] According to Table 6, the following excipient concentrations were used: about 40-50% Transcutol (e.g., solvent and / or penetration enhancer, alcohol), about 8-22% propylene glycol (e.g., solvent and / or penetration enhancer, alcohol), about 3-12% ethanol (e.g., solvent and / or penetration enhancer, alcohol), about 12-24% glycerol (e.g., solvent and / or penetration enhancer, alcohol, gelling agent), about 2-45% PEG (e.g. ... For example, about 0.5-4% HPC (e.g., a gelling agent), about 0.5-2% Carbopol (e.g., a gelling agent), about 0.1-0.3% ascorbic acid (e.g., an antioxidant), about 0.05-0.3% BHT (e.g., an antioxidant), about 0.05-0.2% BHA (e.g., an antioxidant) are provided in exemplary formulations herein (e.g., within about + / - 10-20% of the values ​​in Table 6). In this case, each of the excipients may be optional. Optionally, the composition includes an organic solvent and / or a penetration enhancer, optionally the organic solvent and / or the penetration enhancer is an alcohol and / or a gelling agent, and optionally the total amount of organic solvent and / or penetration enhancer in the composition is about 65-100% or about 86-98% of the composition. Optionally, the composition comprises an alcohol, optionally the alcohol is an organic solvent / penetration enhancer and / or a gelling agent, and optionally the total amount of alcohol in the composition is about 65-100% or about 86-98% of the composition. Optionally, the composition comprises an antioxidant, optionally the total amount of antioxidant is about 0.2-0.8% or about 0.1-0.2% of the composition. Optionally, the composition comprises a gelling agent, optionally the total amount of gelling agent is about 16-76% of the composition or about 22-56% of the composition. Thus, disclosed herein are compositions comprising a solvent and / or penetration enhancer, an alcohol, a gelling agent, and an antioxidant, alone and in combination, in the above exemplary amounts.

[0614] The following excipient concentrations according to Tables 1, 2, 5, and 6: about 40-50%, about 43-49%, about 47-49%, or about 47-48% Transcutol (e.g., solvent and / or penetration enhancer, alcohol), about 8-30%, about 9-22%, about 18-22%, about 19-21%, or about 19-20% Propylene Glycol (e.g., solvent and / or penetration enhancer, alcohol), about 3-12%, about 4-6%, or about 9-12% 1% ethanol (e.g., solvent and / or penetration enhancer, alcohol), about 12-24%, about 14-20%, about 13-17%, about 14-16%, or about 14-15% glycerol (e.g., solvent and / or penetration enhancer, alcohol, gelling agent), about 2-45%, about 3-24%, about 3-14%, about 13-15%, or about 13-14% PEG (e.g., solvent and / or penetration enhancer, alcohol, gelling agent), about 0.5 % to 4% or about 1 to 3% HPC (e.g., a gelling agent), about 2 to 4% or about 3% Sepino (e.g., a gelling agent), about 0.5 to 2% or about 1% Carbopol (e.g., a gelling agent), and about 0.1 to 0.3% or about 0.2% ascorbic acid (e.g., an antioxidant), about 0.05 to 0.3% or about 0.1 to 0.2% BHT (e.g., an antioxidant), about 0.05 to 0.2% or about 0.1% BHA (e.g., an antioxidant), about 0.05 to 0.2% or about 0.1% glycerin ... 0.025-0.1% or about 0.05% propyl gallate (e.g., antioxidant), about 0.001-0.003% or about 0.002% alpha-tocopheryl acetate (e.g., antioxidant), about 0.01-0.03% or about 0.02% ascorbyl palmitate (e.g., antioxidant) are provided in exemplary formulations herein (e.g., within about + / - 10-20% of the values ​​in Tables 1, 2, 5, and 6). In this case, each of the excipients may be optional. Optionally, the composition includes an organic solvent and / or a penetration enhancer, optionally the organic solvent and / or the penetration enhancer is an alcohol and / or a gelling agent, and optionally the total amount of organic solvent and / or penetration enhancer in the composition is about 62-100% or about 85-99% of the composition.Optionally, the composition comprises an alcohol, optionally the alcohol is an organic solvent / penetration enhancer and / or a gelling agent, and optionally the total amount of alcohol in the composition is about 62-100% or about 85-99% of the composition. Optionally, the composition comprises an antioxidant, optionally the total amount of antioxidant is about 0.1-0.9% or about 0.2-0.3% of the composition. Optionally, the composition comprises a gelling agent, optionally the total amount of gelling agent is about 16-76% of the composition or about 18-56% of the composition. Thus, disclosed herein are compositions comprising a solvent and / or penetration enhancer, an alcohol, a gelling agent, and an antioxidant, alone and in combination, in the above exemplary amounts.

[0615] As non-limiting examples, the compositions may contain about 40-50%, about 43-49%, about 47-49%, or about 47-48% Transctol (e.g., solvent and / or penetration enhancer, alcohol), about 2-45%, about 3-24%, about 3-14%, about 13-15%, or about 13-14% PEG (e.g., 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 (e.g., solvent and / or penetration enhancer, alcohol, gelling agent). or penetration enhancer, alcohol, gelling agent), about 8-30%, about 9-22%, about 18-22%, about 19-21%, or about 19-20% propylene glycol (e.g., a solvent and / or penetration enhancer, alcohol), about 0.05-0.3% or about 0.1-0.2% BHT (e.g., an antioxidant), about 0.05-0.2% or about 0.1% BHA (e.g., an antioxidant), 0.5%-4% or about 1-3% HPC (e.g., a gelling agent), or a combination of two or more thereof. As another non-limiting example, the composition may comprise about 47-49% or about 47-48% Transcutol (e.g., solvent and / or penetration enhancer, alcohol), about 13-15% or about 13-14% PEG (e.g., solvent and / or penetration enhancer, alcohol, gelling agent), about 14-16% or about 14-15% glycerol (e.g., solvent and / or penetration enhancer, alcohol, gelling agent), about 19-21% or about 19-20% propylene glycol (e.g., solvent and / or penetration enhancer, alcohol), about 0.05-0.3% or about 0.1-0.2% BHT (e.g., antioxidant), about 0.05-0.2% or about 0.1% BHA (e.g., antioxidant), about 0.5%-4% or about 1-3% HPC (e.g., gelling agent), or a combination of two or more thereof.As another non-limiting example, the composition may include about 47-48% Transcutol (e.g., solvent and / or penetration enhancer, alcohol), about 13-14% PEG (e.g., solvent and / or penetration enhancer, alcohol, gelling agent), about 14-15% glycerol (e.g., solvent and / or penetration enhancer, alcohol, gelling agent), about 19-20% propylene glycol (e.g., solvent and / or penetration enhancer, alcohol), about 0.1-0.2% BHT (e.g., antioxidant), about 0.1% BHA (e.g., antioxidant) 3% HPC (e.g., gelling agent), or a combination of two or more thereof.

[0616] In any of the examples or embodiments herein, ruboxistaurin, ruboxistaurin mesylate, or salts thereof are present in the composition at about 0.1%, about 0.8%, or about 1%.

[0617] Example 5: Short-term stability of the composition of Example 4 The compositions in 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. Parameters evaluated were compound (i.e., ruboxistaurin) content and purity, apparent pH, macroscopic and microscopic observations.

[0618] Compound content and purity The content and purity of ruboxistaurin mesylate monohydrate in the investigational and developmental compositions after storage for up to 5 months are detailed in Tables 7 and 8, respectively.

[0619] Percent recovery compares the response of the drug peak to known concentrations of standards, while percent peak purity (area %) compares the area of ​​the drug peak to the sum of the areas of all peaks in the chromatogram.

[0620] [Table 6-1]

[0621] [Table 6-2]

[0622] [Table 7-1]

[0623] [Table 7-2]

[0624] Note that at t=0, data are presented (for impurity data only) generated from both the originally run HPLC method and the HPLC method with the same gradient but extended to elute BHT. For all other time points, the longer run time HPLC analytical method was utilized.

[0625] At t=0, all drug recovery values ​​were between 98 and 102% of label. Drug purity values ​​were greater than approximately 99% for all formulations. After 4 weeks of storage, data suggest that drug recovery was consistent with t=0 at 25°C and 40°C (i.e., ±5% of 100% of label claim). After 4 weeks of storage at 25°C and 40°C, drug purity was slightly lower (by approximately 0.1% to 0.2% area) for most formulations than that observed at t=0 and 2 weeks. Although this represents a minor downward trend, it represents a significant improvement over the original formulation, with the purity of ruboxistaurin mesylate monohydrate observed to be between 90.57 and 95.08% after 4 weeks of storage at 40°C in non-aqueous gel. It should be noted that formulations containing 0.1% w / w ruboxistaurin mesylate monohydrate (i.e., NA22 and NA28) showed the lowest purity, which may be due to the higher excipient:drug ratio in these formulations compared to the 0.8% w / w drug-loaded formulations.

[0626] Ruboxistaurin mesylate monohydrate recovery was within 100 ± 5% in NA13, NA19, NA22, and NA28 after 5 months of storage, with the exception of NA22 ACT stored at 40°C, which had a recovery of 94.15% of the label claim (consistent with the low purity of the drug observed in this formulation).

[0627] The average peak purity of ruboxistaurin mesylate monohydrate after 5 months ranged from 96.03% area (NA22, 40°C) to 98.90% (NA19, 25°C), but the peak area did not decrease by more than 1.6% in any formulation after storage at 25°C or 40°C. Note that a 1.6% decrease was observed in the formulation with a low drug load (0.1%), NA22, which may be due to the high excipient:drug ratio present in this formulation, as discussed above. A peak purity decrease of 1.5% was observed in formulations with a drug load of approximately 0.8% (e.g., NA13, NA18, and NA19) (NA13, stored at 40°C), while both NA18 and NA19 experienced less than 0.5% purity decrease, with maximum decreases of 0.45% and 0.27% observed for NA18 and NA19, respectively, at both storage conditions. Notably, after 5 months, the individual impurities had % a / a greater than 0.8% after 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 were noticeably smaller in size in the 40° C. samples than in the 25° C. samples. Since such peaks were present in the 25° C. and 40° C. samples at 12 weeks, the data generated at 5 months suggests that degradation products (i.e., peaks at RT 4.2 and RT 5.2) may be further degraded and would not be observed using the current methodology.

[0628] The purity data, along with the drug recovery data, suggest that NA18 and NA19 were the most chemically stable formulations over the 5 month period and, as a result, may represent prime candidates for further development.

[0629] Apparent pH The apparent pH at t=up to 5 months (2-8° C., 25° C., and 40° C.) for compositions with and without ruboxistaurin mesylate monohydrate is shown in Table 9.

[0630] [Table 8]

[0631] At t=0, pH ranged between 5.25 and 7.21 for the placebo formulations and between 4.55 and 4.97 for the active formulations. Notably, the pH of the 0.25% ruboxistaurin mesylate monohydrate formulations was lower than the equivalent 0.1% formulations. pH values ​​for NA18 and NA19 containing 0.8% drug were 4.34 and 3.82, respectively, at t=0 in the previous stability study, demonstrating a trend toward lower pH with higher drug levels. After 12 weeks of storage, the apparent pH remained consistent (i.e., within 0.5 units) to the values ​​reported at t=0 for all formulations.

[0632] Macroscopic Observation At t=0, all active formulations were red in appearance due to the presence of ruboxistaurin mesylate monohydrate, including all placebos, which were colorless in appearance. Notably, formulations with lower concentrations of ruboxistaurin mesylate monohydrate were clear and light in color due to the presence of low concentrations of ruboxistaurin mesylate monohydrate. The NA19 PLB was translucent, which may be due to the nature of the gelling agent. This hypothesis is further supported by the low viscosity of formulation NA19, suggesting that the gelling agent was not fully hydrated.

[0633] No significant changes in macroscopic appearance were observed after 4 weeks of storage. The macroscopic appearance of NA13, NA18, NA19, NA22, and NA28 were evaluated at additional time points at t=12 weeks and 5 months, after which no significant changes in appearance were observed.

[0634] microscopic observation Microscopic appearance and microscopic images (unpolarized and polarized) were accessed for all compositions containing ruboxistaurin mesylate monohydrate and the corresponding vehicle.

[0635] At t=0, no excipient or drug crystals were present in most formulations. Notably, no API was observed in the active formulation, NA25.

[0636] After 2 weeks of storage, the formulations were free of API crystals (except for NA25 at 25° C. and 40° C., and only NA16 at 40° C.). After 4 weeks of storage, no changes were observed in NA13, NA18, NA19, NA20, NA22, and NA28, but suspected API crystals were evident in the following formulations: NA16 (25℃ and 40℃) NA17(25℃) NA21(40℃) NA26 (25℃ and 40℃)

[0637] To confirm the above observations, NA16, NA17, and NA26 formulations were further analyzed for microscopic appearance at storage conditions of 2-8°C and crystals were observed.

[0638] These crystals were suspected to be the API since they were not present in the placebo formulation, however, based on the composition of the active formulation, it is not clear what induces the observed crystallization. For example, NA17 and NA18 share identical formulation compositions with the exception of 0.1% w / w BHA in NA18, and API crystals are only observed in the former.

[0639] At additional time points at t=12 weeks and 5 months, 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.

[0640] Based on the composition of formula NA18, 12 kg GMP batches of 0.8% w / w ruboxistaurin mesylate monohydrate gel (lot no. 910006) and placebo gel (lot no. 910008) were manufactured in bulk, tested in Montebello tubes at 12 g per tube, released, and stabilized at 25° C. / 60% R / H and 40° C. / 75% R / H. The table below presents 6 month data for 0.8% w / w gel lot no. 910006.

[0641] [Table 9-1]

[0642] [Table 9-2]

[0643] After 6 months of storage in accordance with the International Council for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guidance Q1A(R2) on Stability Testing of New Drug Substances and Pharmaceuticals at ambient (25°C / 60% relative humidity) and accelerated (40°C / 75% relative humidity) conditions, the lot remained within specification range from the time of lot release to the most recent time point. However, according to the ICH Q1A(R2) guidance, the 6 month time point at accelerated conditions (40°C / 75% relative humidity) acknowledges significant success in demonstrating stability for this drug formulation, as no further testing is required under these conditions in the guidance. Stability testing at ambient conditions (25°C / 60% relative humidity) is ongoing.

[0644] Example 6: Clinical Trials A randomized, observer-blinded, vehicle-controlled study of the safety and efficacy of 0.1% and 0.8% ruboxistaurin mesylate monohydrate gels administered twice daily with formulations NA10, NA18, NA22, or NA28 vehicle (referred to as "ruboxistaurin gel") vs vehicle gel vs hydroquinone cream on adult sun-exposed and sun-protected skin will be conducted for 12 weeks.

[0645] The objective of this study was to compare the effects of daily application of 0.1% and 0.8% ruboxistaurin gel, 4% hydroquinone cream, and vehicle gel. Efficacy assessments were summarized descriptively by treatment group and visit. The study was a two tranche randomized, observer-blinded, 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 tranche were randomized to one of three groups: (1) a cohort of 0.8% ruboxistaurin gel (applied twice daily for 12 weeks), (2) a cohort of 4% hydroquinone cream (applied twice daily for 12 weeks), or (3) a cohort of vehicle gel. In the second tranche, subjects were randomly assigned to one of two groups: (1) a cohort of 0.1% ruboxistaurin gel or (2) a cohort of vehicle gel. One open-label subgroup included subjects with solar lentigines on the dorsum of the hands who received 0.8% ruboxistaurin gel applied twice daily.

[0646] Approximately 90 subjects who met the inclusion / exclusion criteria were enrolled in two randomization tranches: the first tranche of approximately 45 subjects: 0.8% ruboxistaurin gel, 4% hydroquinone cream, or vehicle gel, and the second tranche of approximately 30 subjects: 0.1% ruboxistaurin gel or vehicle gel. Subjects in the two tranche cohorts received treatment on one upper volar arm and dorsal forearm, and approximately 15 subjects with solar lentigines on the dorsum of the hand were enrolled in a subcohort that received 0.8% ruboxistaurin gel on solar lentigines on one volar arm and dorsal forearm. Each subject in two randomized tranches (first tranche: 0.8% ruboxistaurin gel, 4% hydroquinone cream, or vehicle gel; second tranche: 0.1% ruboxistaurin gel or vehicle gel) had two treatment sites and two contralateral untreated control sites.Subjects in solar lentigo subcohort: For two-way within-subject comparisons, there were two treatment sites using 0.8% ruboxistaurin gel and two contralateral untreated control sites.

[0647] Primary outcome measures included: reduction in pigmentation based on the Melanoma Index (change in L* and ITA colorimetric measurements measured 12 weeks after the first dose) and reduction in pigmentation based on digital imaging (change measured with Canfield RBX software analysis measured 12 weeks after the first dose).

[0648] Secondary outcome measures included: percent change in Investigator Dynamic Grading Assessment (IDGA), percent difference in pigmentation between treated and contralateral percent change in Investigator Dynamic Grading Assessment (IDGA) measured at 2, 4, 6, 8, 10, and 12 weeks from first dose, and percent of subjects with Improved Investigator Dynamic Grading Scale (IDGA), percent of subjects with less pigmentation at the treated and contralateral untreated sites measured at 2, 4, 6, 8, 10, and 12 weeks from first dose.

[0649] Eligibility criteria included: males or females aged 18 years or older; Fitzpatrick Skin Type IV-V with an L* measurement between 57.8 and 46.1 when using a CM-700 colorimeter; able to understand, consent to, and sign the study's Informed Consent Form (ICF); agree to discontinue all medications used to treat hyperpigmentation, treat aging, or exfoliate the skin during the study period (makeup and moisturizers are permitted); agree not to alter sun exposure at work, home, or leisure; technically able and willing to apply the test substance; willing to allow digital photographs of treatment and comparison areas to be taken and stored; additional inclusion criteria for the solar lentigo subcohort: presence of at least four solar lentigines at least 4 mm in diameter on the dorsum of both hands.

[0650] Exclusion criteria included: women with a positive urine pregnancy test or who were pregnant, breastfeeding, or of possible pregnancy who did not consent to using active birth control methods during the study; conditions interfering with UV-tanned skin, particularly other pigmentary disorders including, but not limited to, melasma or vitiligo affecting treatment and comparison sites at baseline; presence of known comorbidities associated with the development of hyperpigmentation (e.g., thyroid, liver, adrenal glands); current attendance at tanning booths or undergoing a...

Claims

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

2. The composition according to claim 1, further comprising propylene glycol, glycerin, or polyethylene glycol, or a combination of two or more of these.

3. The composition according to claim 2, wherein the 2-(2-ethoxyethoxy)ethanol and the propylene glycol, the glycerin, or the polyethylene glycol, or a combination of two or more thereof, constitute about 50% to about 99% by weight of the composition.

4. The composition according to claim 2, wherein the 2-(2-ethoxyethoxy)ethanol and the propylene glycol, the glycerin, or the polyethylene glycol, or a combination of two or more thereof, constitute about 80% to about 99% by weight of the composition.

5. The composition according to claim 1, further comprising C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, glycerol, aliphatic alcohol, aliphatic ester, or aliphatic ether, or a combination of two or more of these.

6. Cocoyl caprylocaprate, 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 The composition according to claim 1, further comprising oil, N-methyl-2-pyrrolidone, poloxamer, polysorbate, PEG castor oil derivative, polyoxyglyceride, sodium lauryl sulfate, sucrose ester, glycerol, ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, tert-butanol, hydroxypropylcellulose, hydroxyethylcellulose, Carbopol, carbomer, or carboxymethylcellulose, or a combination of two or more of these.

7. The composition according to claim 1, further comprising hydroxypropyl cellulose which is HPC GF, HPC CF, or HPC HF, or a combination of two or more thereof.

8. The composition according to claim 6, comprising about 16% to about 75% by weight or about 18% to about 56% by weight of the composition, the hydroxypropyl cellulose, the hydroxyethyl cellulose, the carbopol, the carbomer, or the carboxymethyl cellulose, or a combination of two or more of these.

9. The composition according to claim 1, further comprising an antioxidant.

10. The composition according to claim 9, wherein the antioxidant comprises butylhydroxytoluene, butylhydroxyanisole, propyl gallate, ascorbic acid, alpha-tocopheryl acetate, or ascorbyl palmitate, or a combination of two or more of these.

11. The composition according to claim 9, wherein the antioxidant comprises butylhydroxytoluene and / or butylhydroxyanisole.

12. The composition according to claim 9, wherein the antioxidant comprises about 0.01% to 1% by weight, or about 0.2% to 0.3% by weight of the composition.

13. The composition according to claim 1, wherein the ruboxystaurine mesylate monohydrate is present in an amount of about 0.001% to about 1.0% by weight, about 0.010% to about 1.0% by weight, about 0.1% by weight, or about 0.80% by weight of the composition.

14. The composition according to claim 1, wherein the ruboxystaurine mesylate monohydrate is present in the composition in an amount of about 0.001 mg to about 10 g.

15. A protein kinase C (PKC) inhibitor, 2-(2-ethoxyethoxy)ethanol and Polyethylene glycol (PEG) and Propylene glycol and Glycerin and, Hydroxypropyl cellulose and, One or more antioxidants and A composition containing the following:

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

17. The composition according to claim 15, wherein the PKC inhibitor is a PKCα, PKCβ, PKCβ1, PKCβ2, PKCδ, PKCε, PKCθ, PKCζ, PKCγ, PKCλ, PKCμ, PKCι, or PKCη inhibitor.

18. The composition according to claim 17, wherein the PKC inhibitor comprises a PKCβ inhibitor.

19. The composition according to claim 18, wherein the PKCβ inhibitor comprises ruboxystaurin.

20. The composition according to claim 19, wherein the ruboxystaurin comprises ruboxystaurin mesylate monohydrate or ruboxystaurin-free base.

21. The composition according to claim 19, wherein the ruboxystaurine comprises ruboxystaurine hydrochloride, ruboxystaurine sulfate, ruboxystaurine tartrate, ruboxystaurine succinate, ruboxystaurine acetate, ruboxystaurine phosphate, or another ruboxystaurine salt.

22. The composition according to claim 15, wherein the PKC inhibitor is present in the composition in an amount of about 0.001 mg to about 10 g.

23. The composition according to any one of claims 1 to 22 for use in the treatment of cancer.

24. The composition according to claim 23, wherein the cancer is a malignant tumor.

25. The composition according to claim 23, wherein the cancer is a benign tumor.

26. The composition according to any one of claims 1 to 22 for use in improving immune function.

27. ​​The composition according to any one of claims 1 to 22 for use in the treatment of hyperpigmentation.

28. The composition according to claim 23, wherein the composition is formulated as a gel, ointment, cream, lotion, foam, or emollient.

29. The composition according to claim 23, wherein the composition is administered topically to the head, scalp, face, ears, neck, chest, back, lower breast, arms, legs, or groin, or two or more of these areas.

30. The composition according to claim 23, wherein the composition is administered once a day.

31. The composition according to claim 23, wherein the composition is administered twice a day.

32. The composition according to claim 23, wherein the composition is administered 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.

33. The composition according to claim 23, wherein the composition is a component of a patch, tape, film, cloth, towellet, sponge, wafer, or bandage.

34. The composition is Skin glossing agent, Bleach, Sunscreen, sun blocker, or sun filter, Hair removal cream, Anti-aging treatments, Antimicrobial agents, Anti-inflammatory drugs, or Two or more combinations of those The composition according to claim 23, which is administered together with one or more of the above.

35. The composition according to claim 23, wherein the composition is applied to 0.1% to 100% of the body surface area of ​​the target.

36. The composition according to claim 23, wherein approximately 0.01 g to approximately 100 g of the composition is administered.

37. The composition according to claim 23, wherein the composition is applied in an amount of about 0.00001 g to about 1.0 per cm² of the body surface area of ​​the target.

38. The composition according to claim 23, wherein the composition is applied in an amount of about 0.000175 g per cm² of the body surface area of ​​the target.

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