WO2019113475A1 - Topical ointment formulations and their use in treating skin conditions - Google Patents

Abstract

Embodiments herein are directed to topical compositions comprising PEG 400, PEG 4000, white petrolatum, vitamin E, glycerol monostearate/glycerides, isopropyl myristate, and water. Embodiments herein are directed to topical compositions comprising PEG 400, PEG 4000, white petrolatum, vitamin E, glycerol monostearate/glycerides, isopropyl myristate, water and a topically active therapeutic agent. The topical compositions may be used to treat a variety of skin conditions, including atopic dermatitis.

Description

TOPICAL OINTMENT FORMULATIONS AND THEIR USE IN TREATING SKIN

CONDITIONS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the priority benefit under 35 U.S.C. 119(e) of U.S. Provisional Application No. 62/595,915 filed December 7, 2017 and U.S. Provisional Application No. 62/695,461 filed July 9, 2018, each disclosure of which is incorporated by reference in their entireties.

SUMMARY OF THE INVENTION

[0001] Embodiments herein are directed to topical compositions comprising PEG 400, PEG 4000, white petrolatum, vitamin E, glycerol monostearate/glycerides, isopropyl myri state, and water.

[0002] Embodiments herein are directed to topical compositions comprising PEG 400, PEG 4000, white petrolatum, vitamin E, glycerol monostearate/glycerides, isopropyl myristate, water, and a therapeutically effective amount of a topically active therapeutic agent.

[0003] Some embodiments herein are directed to methods of treating skin conditions in a patient in need thereof comprising topically applying a topical composition comprising PEG 400, PEG 4000, white petrolatum, vitamin E, glycerol monostearate/glycerides, isopropyl myristate, and water.

[0004] Some embodiments herein are directed to methods of treating skin conditions in a patient in need thereof comprising topically applying a topical composition comprising PEG 400, PEG 4000, white petrolatum, vitamin E, glycerol monostearate/glycerides, isopropyl myristate, wate, and a therapeutically effective amount of a topically active therapeutic agent.

DESCRIPTION OF THE DRAWINGS

[0002] For a fuller understanding of the nature and advantages of the present invention, reference should be had to the following detailed description taken in connection with the accompanying drawings, in which:

[0003] FIG. 1 provides the response in IGA (0/1 + 2 point improvement) at week 4 in the ITT population. [0004] FIG. 2 provides the response in IGA (0/1 + 2 point improvement) at week 4 in the PPS population.

[0005] FIG. 3 provides the response in IGA (0/1) at week 4 in the ITT population.

[0006] FIG. 4 provides the response in IGA (0/1) at week 4 in the PPS population.

[0007] FIG. 5 provides the IGA response (0/1 + 2 point improvement) kinetics in the ITT population.

[0008] FIG. 6 provides the IGA response (0/1 + 2 point improvement) kinetics in the PPS population.

[0009] FIG. 7 shows the EASI % improvement from baseline and the week 4 EASI % improvement in the ITT population.

[0010] FIG. 8 provides data of EASI 50/75/90 responders at week 4 for the ITT population.

[0011] FIG. 9 provides data of EASI 50/75/90 responders at week 4 for the PPS population.

[0012] FIG. 10 shows the improvement in NRS (itch) from baseline in the ITT population.

[0013] FIG. 11 shows the improvement in NRS (itch) from baseline at week 4 in the ITT population.

[0014] FIG. 12 shows the improvement in NRS (itch) from baseline at week 4 in the PPS population.

[0015] FIG. 13 shows the BSA % improvement from baseline and the week 4 BSA % improvement in the ITT population.

DETAILED DESCRIPTION

[0016] This invention is not limited to the particular processes, compositions, or methodologies described, as these may vary. The terminology used in the description is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of the present invention. ETnless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. All publications mentioned herein are incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. [0017] It must be noted that, as used herein, and in the appended claims, the singular forms“a,” “an,” and“the” include plural reference unless the context clearly dictates otherwise.

[0018] As used herein, the term“about” means plus or minus 10% of the numerical value of the number with which it is being used. Therefore, about 50% means in the range of 45% to 55%.

[0019] “Administering” when used in conjunction with a composition means to administer a composition to a patient whereby it positively impacts the tissue to which it is targeted, e.g. the skin. “Administering” a composition may be accomplished by, for example, topical administration, or in combination with other known techniques. Administering may be self-administration, wherein the subject in need of such treatment administers a composition or administering may be by a medical or other health care professional or a caretaker of the subject in need of such treatment.

[0020] The term“adolescent” as used herein is a human that is about 12 years of age to less than 18 years of age.

[0021] The term“patient” and“subject” are interchangeable and may be taken to mean any human which may be treated with compounds of the present invention. In some embodiments, the patient or subject is an adult, adolescent, child or infant. In some embodiments, the patient or subject is an adult, 18 years old or greater. In some embodiments, the patient or subject is an adolescent, ages 12-17 years old. In some embodiments, the patient or subject is a pediatric individual, ages 2-11 years old.

[0022] As used herein, the terms “comprising,” “comprise,” “comprises,” and “comprised” are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0023] As used herein, the term“consists of’ or“consisting of’ means that the composition or method includes only the elements, steps, or ingredients specifically recited in the particular embodiment or claim.

[0024] As used herein, the term“consisting essentially of’ or“consists essentially of’ means that the composition or method includes only the specified materials or steps and those that do not materially affect the basic and novel characteristics of the claimed invention.

[0025] Specific embodiments disclosed herein may be further limited in the claims using“consisting of’ or“consisting essentially of’ language, rather than“comprising”. In other words, though embodiments described herein use the phrase “comprising” or “comprises,” any embodiment described herein can be replaced with “consisting of’/“consists of’ or“consisting essentially of’/“consists essentially of.”

[0026] The term“dermatitis” is used to refer to a group of skin conditions which result in inflammation of the skin and is characterized by itchiness, red skin and a rash. Included in this group are atopic dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, stasis dermatitis, seborrheic dermatitis, chronic dermatitis, and eczema.

[0027] The term “Geleol™ refers to glyceryl monostearate or glycerol monostearate/glycerides.

[0028] The term “therapeutically effective amount” refers to an amount of a composition, of the embodiments described herein, necessary or sufficient to achieve the desired effect. For example, in some embodiments, the desired effect may include, without limitation, medically therapeutic, cosmetically therapeutic and/or prophylactic treatment, as appropriate.

[0029] The terms“exfoliative keratolysis” or“keratolysis exfoliative” refer to a skin condition which is characterized by dry skin and superficial, air-filled blisters. These blisters can be peeled off very easily and will leave reddish, tender areas.

[0030]“Follicular hyperkeratinization” plays a key role in the pathogenesis of acne, cells of the follicle become cohesive and do not shed normally onto the skin's surface and results in a microcomedone.

[0031] The term“ichthyosis” refers to a genetic skin disorder characterized by dry, thickened, and scaly skin.

[0032] In each of the embodiments disclosed herein, the compositions and methods may be utilized with or on a subject in need of such treatment, which may also be referred to as“in need thereof.” As used herein, the phrase“in need thereof’ means that the subject has been identified as having a need for the particular method or treatment and that the treatment has been given to the subject for that particular purpose.

[0033] The terms“keratosis follicularis” or“Darier's disease” refer to a genetic disorder characterized by dark crusty patches on the skin, sometimes containing pus.

[0034] The term“lichen simplex chronicus” refers to a skin disorder characterized by chronic itching and scratching. The constant scratching causes thick, leathery, darkened, (lichenified) skin.

[0035] The term“lichen planus” refers to a disease characterized by itchy reddish- purple polygon-shaped skin lesions on the lower back, wrists, and ankles. [0036] As used herein, the term“pharmaceutically acceptable” and grammatical variations thereof, as they refer to carriers, diluents, excipients, and reagents or other ingredients of the composition, represent that the materials used in the final composition are not irritating or otherwise harmful to the patient in general and to the skin, in particular, and preferably are pleasant and well tolerated with respect to general appearance, pH, color, smell and texture (feel), that they are not, for example, unacceptably sticky (tacky), oily or drying, and that they do spread easily, absorb into the skin at an acceptable rate of absorption.

[0037] The term“pityriasis rubra pilaris” refers to a group of chronic disorders characterized by reddish orange, scaling plaques and keratotic follicular papules. Symptoms may include reddish-orange patches on the skin, severe flaking, uncomfortable itching, thickening of the skin on the feet and hands, and thickened bumps around hair follicles.

[0038] The term “psoriasis” refers to the autoimmune disease characterized by patches of abnormal skin which is red, itchy and scaly. There are five main types of psoriasis: plaque, guttate, inverse, pustular, and erythrodermic.

[0039] The terms“pruritus” or“prurigo” refer to the severe itching of the skin due to a variety of ailments.

[0040] The term“palmoplantar pustulosis” refers to a chronic pustular condition affecting the palms and soles.

[0041] The term “rosacea” refers to a skin condition characterized by redness, pimples, swelling, and small, superficial dilated blood vessels.

[0042] The term“sebaceous adenomas” refers to a small bump on the skin, when many small bumps appear it is referred to as“sebaceous hyperplasia.”

[0043] The term“sebaceous gland” includes unilobular or multilobular glands that secrete sebum. Sebaceous glands include pilosebaceous units, fordyce spots, Meibomian glands, glands of the Zeiss and Montgomery areolar tubercles.

[0044] The phrase“disorder associated with sebaceous glands” includes diseases, conditions and symptoms related to sebaceous gland. Disorders associated with sebaceous glands include acne, seborrhea, sebaceoma, sebaceous carcinoma, seborrheic dermatitis, sebaceous cysts, sebaceous adenoma and sebaceous hyperplasia.

[0045] The terms“sebostasis” or“xerosis” refer to the cessation of sebum production resulting in dry skin.

[0046] The term“seborrhea” includes oily skin. [0047] The term “seborrheic dermatitis” includes inflammatory skin disorders characterized by scaly, flaky, itchy, and red skin and includes seborrheic dermatitis caused by fungal, genetic, environmental, hormonal and immune function disorders.

[0048] The term “sebaceous cysts” include steatocystoma simplex (e.g., simple sebaceous duct cyst and solitary steatocystoma) and steatocystoma multiplex (e.g., epidermal polycystic disease and sebocystomatosis).

[0049] The term“sebaceous hyperplasia” includes enlargement of the sebaceous glands.

[0050] The term“skin” as used herein refers to the organ of the body which protects the subject from environmental irritations, regulates the body’s temperature and allows for external sensations. The“skin” is separated into three layers: the outermost layer called the epidermis which contains melanocytes; the dermis which contains connective tissue, hair follicles and sweat glands; and the deepest subcutaneous layer called the hypodermis which is made up of fat and connective tissue.

[0051] As used herein, the term“topically” and“topical” refers to application of the compositions of the present invention to the surface of the skin and mucous membranes.

[0052]“Topical application” or“topical administration” refers to the delivery of a composition, for treating conditions of the epidermis or dermis, wherein the topical composition is applied to the skin and acts locally and does not have a systemic effect. Topical administration of a drug may often be advantageously applied in, for example, the treatment of various skin disorders.

[0053] As used herein the terms“topical formulations” and“topical compositions” refer to formulations or compositions that may be applied to skin or mucous membranes. Topical formulations or compositions may, for example, be used to confer therapeutic benefit to a patient or cosmetic benefit to a consumer. Such topical formulations or compositions may be provided in the form of a cream, foam, gel, lotion, or ointment.

[0054] The terms“treat,”“treated,” or“treating” as used herein refers to therapeutic treatment, cosmetic treatment and/or prophylactic or preventative measures, wherein the object is to prevent, reduce, eliminate or slow down (lessen) an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results (e.g. decrease acne, comedones, pimples, or breakouts). For the purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of unwanted side effects.

[0055] The term“wart” refers to the small, rough, and hard growths that are similar in color to the rest of the skin caused by caused by infection with a type of human papillomavirus (HPV). A number of types exist including: common warts, plantar warts, filiform warts, and genital warts.

[0056] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention.

[0057] Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g.,“such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0058] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability.

[0059] Embodiments herein are directed to topical compositions comprising PEG 400, PEG 4000, white petrolatum, vitamin E, glycerol monostearate/glycerides, isopropyl myristate, and water. In some embodiments, PEG 400 is at a concentration of about 25% to about 75% by weight of the topical composition. In some embodiments, PEG 4000 is at a concentration of about 15% to about 35% by weight of the topical composition. In some embodiments, white petrolatum is at a concentration of about 1% to about 10% by weight of the topical composition. In some embodiments, vitamin E is at a concentration of about 0.01% to about 5% by weight of the topical composition. In some embodiments, glycerol monostearate/glycerides is at a concentration of about 2% to about 15% by weight of the topical composition. In some embodiments, isopropyl myristate is at a concentration of about 2% to about 25% by weight of the topical composition. In some embodiments, water is at a concentration of about 0.1% to about 10% by weight of the topical composition.

[0060] In certain embodiments, a topical composition comprises PEG 400 at 50.5% by weight, PEG 4000 at 25.0% by weight, white petrolatum at 4.4% by weight, vitamin E at 0.1% by weight, glycerol monostearate/glycerides at 8.0% by weight, isopropyl myristate at 10.0% by weight, and water at 2.0% by weight.

[0061] In certain embodiments, a topical composition comprises PEG 400, PEG 4000, white petrolatum, vitamin E, glycerol monostearate/glycerides, isopropyl myristate, water, and a therapeutically effective amount of a topically active therapeutic agent. In some embodiments, the topically active therapeutic agent is at a concentration of about 0.01% to about 50% by weight of the topical composition. In some embodiments, PEG 400 is at a concentration of about 25% to about 75% by weight of the topical composition. In some embodiments, PEG 4000 is at a concentration of about 15% to about 35% by weight of the topical composition. In some embodiments, white petrolatum is at a concentration of about 1% to about 10% by weight of the topical composition. In some embodiments, vitamin E is at a concentration of about 0.01% to about 5% by weight of the topical composition. In some embodiments, glycerol monostearate/glycerides is at a concentration of about 2% to about 15% by weight of the topical composition. In some embodiments, isopropyl myristate is at a concentration of about 2% to about 25% by weight of the topical composition. In some embodiments, water is at a concentration of about 0.1% to about 10% by weight of the topical composition.

[0062] In certain embodiments, a topical composition comprises PEG 400 at 50.5% by weight, PEG 4000 at 25.0% by weight, white petrolatum at 4.4% by weight, vitamin E at 0.1% by weight, glycerol monostearate/glycerides at 8.0% by weight, isopropyl myristate at 10.0% by weight, water at 2.0% by weight, and the topically active therapeutic agent at 0.5% by weight.

[0063] In some embodiments, the topically active therapeutic agent is selected from the group consisting of topical acne agents, topical anesthetics, topical anti-infectives, topical anti-rosacea agents, topical antibiotics, topical antifungals, topical antihistamines, topical antineoplastics, topical antipsoriatics, topical antivirals, topical astringents, topical debriding agents, topical depigmenting agents, topical non-steroidal anti-inflammatories, topical photochemotherapeutics, topical rubefacient, topical steroids, and any combination thereof. In some embodiments, the topical acne agents is selected from the group consisting of tretinoin, benzoyl peroxide, salicylic acid, erythromycin, clindamycin, azelaic acid, adapalene, dapsone, and any combination thereof. In some embodiments, the topical anesthetics is selected from the group consisting of benzalkonium chloride, lidocaine, prilocaine, benzocaine, pramoxine, dibucaine, and any combination thereof. In some embodiments, the topical anti-infectives is selected from the group consisting of malathion, sinecatechins, ivermectin, acetic acid, spinosad, benzyl alcohol, crotamiton, imiquimod, permethrin, docosansol, and any combination thereof. In some embodiments, the topical anti rosacea agents is selected from the group consisting of azelaic acid, metronidazole, oxymetazoline, brimonidine, and any combination thereof. In some embodiments, the topical antibiotics is selected from the group consisting of sulfacetamide/sulfur sodium, bacitracin, polymyxin b, erythromycin, silver sulfadiazine, retapamulin, mupirocin, neomycin, and any combination thereof. In some embodiments, the topical antifungals is selected from the group consisting of benzoic acid, salicylic acid, undecylenic acid, ketoconazole, nystatin, naftifme, tolnaftate, miconazole, zinc oxide, econazole, ciclopirox, oxiconazole, and any combination thereof. In some embodiments, the topical antihistamines is selected from the group consisting of diphenhydramine, doxepin, and any combination thereof. In some embodiments, the topical antineoplastics is selected from the group consisting of fluorouracil, ingenol, imiquimod, diclofenac, mechlorethamine, and any combination thereof. In some embodiments, the topical antipsoriatics is selected from the group consisting of tazarotene, betamethasone, calcipotriene, tazarotene, calcitriol, and any combination thereof. In some embodiments, the topical antivirals is selected from the group consisting of acyclovir, penciclovir, and any combination thereof. In some embodiments, the topical astringents is selected from the group consisting of calamine, witch hazel, alum, isopropyl alcohol, ethanol, aluminum acetate, aluminum chloride, aluminum sulfate tetradecahydrate, calcium acetate monohydrate, formaldehyde, and any combination thereof. In some embodiments, the topical debriding agents is selected from the group consisting of balsam pern, castor oil, trypsin, collagenase, and any combination thereof. In some embodiments, the topical depigmenting agents is selected from the group consisting of fluocinolone, hydroquinone, tretinoin, hydroquinone, and any combination thereof. In some embodiments, the topical non-steroidal anti-inflammatories is selected from the group consisting of diclofenac, capsaicin, and any combination thereof. In some embodiments, the topical photochemotherapeutics is selected from the group consisting of aminolevulinic acid, methyl aminolevulinate, methoxsalen, and any combination thereof. In some embodiments, the topical rubefacient is selected from the group consisting of camphor, menthol, capsaicin, methyl salicylate, and any combination thereof. In some embodiments, the topical steroids is selected from the group consisting of triamcinolone, fluocinolone, prednicarbate, desonide, betamethasone, halcinonide, hydrocortisone, diflorasone, clobetasol, desoximetasone, clocortolone, and any combination thereof.

[0064] Embodiments herein are directed to a topical composition comprising a therapeutically effective amount of topically active therapeutic agent and pharmaceutically acceptable topical excipients, wherein 90% confidence interval for the ratio of means (population geometric means based on log-transformed data) of the AUC of the topical composition is within 80-125% of the AUC of any one the foregoing topical compositions and the 90% confidence internal for the ratio of means of the C_max of the topical composition is within 70-143% of the C_max of the same foregoing topical composition.

[0065] In embodiments described herein, the topically active therapeutic agent is not methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid (RVT-501), 4-(cyclopropylamino)-2-[4-(4-ethylsulfonylpiperazin-l-yl)anilino]pyrimidine-5- carboxamide (RVT-502), or 2-(4-(4-(6-carbamoyl-3,5-dimethylpyrazin-2- yl)phenyl)cyclohexyl)acetic acid (RVT-503).

[0066] Embodiments herein are directed to methods of treating a skin condition in a patient in need thereof comprising topically applying a topical composition comprising PEG 400, PEG 4000, white petrolatum, vitamin E, glycerol monostearate/glycerides, isopropyl myristate, and water. In certain embodiments, the patient is an adolescent.

[0067] In some embodiments, PEG 400 is at a concentration of about 25% to about 75% by weight of the topical composition. In some embodiments, PEG 4000 is at a concentration of about 15% to about 35% by weight of the topical composition. In some embodiments, white petrolatum is at a concentration of about 1% to about 10% by weight of the topical composition. In some embodiments, vitamin E is at a concentration of about 0.01% to about 5% by weight of the topical composition. In some embodiments, glycerol monostearate/glycerides is at a concentration of about 2% to about 15% by weight of the topical composition. In some embodiments, isopropyl myristate is at a concentration of about 2% to about 25% by weight of the topical composition. In some embodiments, water is at a concentration of about 0.1% to about 10% by weight of the topical composition. [0068] In certain embodiments, the method of treating a skin condition in a patient in need thereof comprises topically applying a topical composition comprising PEG 400 at 50.5% by weight, PEG 4000 at 25.0% by weight, white petrolatum at 4.4% by weight, vitamin E at 0.1% by weight, glycerol monostearate/glycerides at 8.0% by weight, isopropyl myri state at 10.0% by weight, and water at 2.0% by weight.

[0069] In certain embodiments, the method of treating a skin condition in a patient in need thereof comprises topically applying a topical composition comprising PEG 400, PEG 4000, white petrolatum, vitamin E, glycerol monostearate/glycerides, isopropyl myristate, water, and a therapeutically effective amount of a topically active therapeutic agent. In certain embodiments, the patient is an adolescent.

[0070] In some embodiments, the topically active therapeutic agent is at a concentration of about 0.01% to about 50% by weight of the topical composition. In some embodiments, PEG 400 is at a concentration of about 25% to about 75% by weight of the topical composition. In some embodiments, PEG 4000 is at a concentration of about 15% to about 35% by weight of the topical composition. In some embodiments, white petrolatum is at a concentration of about 1% to about 10% by weight of the topical composition. In some embodiments, vitamin E is at a concentration of about 0.01% to about 5% by weight of the topical composition. In some embodiments, glycerol monostearate/glycerides is at a concentration of about 2% to about 15% by weight of the topical composition. In some embodiments, isopropyl myristate is at a concentration of about 2% to about 25% by weight of the topical composition. In some embodiments, water is at a concentration of about 0.1% to about 10% by weight of the topical composition.

[0071] In certain embodiments, the method of treating a skin condition in a patient in need thereof comprises topically applying a topical composition comprising PEG 400 at 50.5% by weight, PEG 4000 at 25.0% by weight, white petrolatum at 4.4% by weight, vitamin E at 0.1% by weight, glycerol monostearate/glycerides at 8.0% by weight, isopropyl myristate at 10.0% by weight, water at 2.0% by weight, and the topically active therapeutic agent at 0.5% by weight.

[0072] In some embodiments, the topically active therapeutic agent is selected from the group consisting of topical acne agents, topical anesthetics, topical anti-infectives, topical anti-rosacea agents, topical antibiotics, topical antifungals, topical antihistamines, topical antineoplastics, topical antipsoriatics, topical antivirals, topical astringents, topical debriding agents, topical depigmenting agents, topical non-steroidal anti-inflammatories, topical photochemotherapeutics, topical rubefacient, topical steroids, and any combination thereof. In some embodiments, the topical acne agents is selected from the group consisting of tretinoin, benzoyl peroxide, salicylic acid, erythromycin, clindamycin, azelaic acid, adapalene, dapsone, and any combination thereof. In some embodiments, the topical anesthetics is selected from the group consisting of benzalkonium chloride, lidocaine, prilocaine, benzocaine, pramoxine, dibucaine, and any combination thereof. In some embodiments, the topical anti-infectives is selected from the group consisting of malathion, sinecatechins, ivermectin, acetic acid, spinosad, benzyl alcohol, crotamiton, imiquimod, permethrin, docosansol, and any combination thereof. In some embodiments, the topical anti rosacea agents is selected from the group consisting of azelaic acid, metronidazole, oxymetazoline, brimonidine, and any combination thereof. In some embodiments, the topical antibiotics is selected from the group consisting of sulfacetamide/sulfur sodium, bacitracin, polymyxin b, erythromycin, silver sulfadiazine, retapamulin, mupirocin, neomycin, and any combination thereof. In some embodiments, the topical antifungals is selected from the group consisting of benzoic acid, salicylic acid, undecylenic acid, ketoconazole, nystatin, naftifme, tolnaftate, miconazole, zinc oxide, econazole, ciclopirox, oxiconazole, and any combination thereof. In some embodiments, the topical antihistamines is selected from the group consisting of diphenhydramine, doxepin, and any combination thereof. In some embodiments, the topical antineoplastics is selected from the group consisting of fluorouracil, ingenol, imiquimod, diclofenac, mechlorethamine, and any combination thereof. In some embodiments, the topical antipsoriatics is selected from the group consisting of tazarotene, betamethasone, calcipotriene, tazarotene, calcitriol, and any combination thereof. In some embodiments, the topical antivirals is selected from the group consisting of acyclovir, penciclovir, and any combination thereof. In some embodiments, the topical astringents is selected from the group consisting of calamine, witch hazel, alum, isopropyl alcohol, ethanol, aluminum acetate, aluminum chloride, aluminum sulfate tetradecahydrate, calcium acetate monohydrate, formaldehyde, and any combination thereof. In some embodiments, the topical debriding agents is selected from the group consisting of balsam pern, castor oil, trypsin, collagenase, and any combination thereof. In some embodiments, the topical depigmenting agents is selected from the group consisting of fluocinolone, hydroquinone, tretinoin, hydroquinone, and any combination thereof. In some embodiments, the topical non-steroidal anti-inflammatories is selected from the group consisting of diclofenac, capsaicin, and any combination thereof. In some embodiments, the topical photochemotherapeutics is selected from the group consisting of aminolevulinic acid, methyl aminolevulinate, methoxsalen, and any combination thereof. In some embodiments, the topical rubefacient is selected from the group consisting of camphor, menthol, capsaicin, methyl salicylate, and any combination thereof. In some embodiments, the topical steroids is selected from the group consisting of triamcinolone, fluocinolone, prednicarbate, desonide, betamethasone, halcinonide, hydrocortisone, diflorasone, clobetasol, desoximetasone, clocortolone, and any combination thereof.

[0073] Embodiments herein are directed to a topical composition comprising a therapeutically effective amount of a topically active therapeutic agent and pharmaceutically acceptable topical excipients, wherein 90% confidence interval for the ratio of means (population geometric means based on log-transformed data) of the AUC of the topical composition is within 80-125% of the AUC of any one the foregoing topical compositions and the 90% confidence internal for the ratio of means of the C_max of the topical composition is within 70-143% of the C_max of the same foregoing topical composition.

[0074] In embodiments described herein, the topically active therapeutic agent is not methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid (RVT-501), 4-(cyclopropylamino)-2-[4-(4-ethylsulfonylpiperazin-l-yl)anilino]pyrimidine-5- carboxamide (RVT-502), or 2-(4-(4-(6-carbamoyl-3,5-dimethylpyrazin-2- yl)phenyl)cyclohexyl)acetic acid (RVT-503).

[0075] The topical compositions of the present invention may be formulated by those skilled in the art as liquids, toners, solutions, sprays, emulsions, moisturizers, sunscreens, creams, lotions, masks, suspensions, triturates, gels, jellies, pastes, foams, ointments, shampoos, adhesives, serums, treated clothes or pads and the like. In some embodiments the topical composition is formulated as eye drops, as ear drops, or as a composition which can be applied to the surface of the tooth.

[0076] In embodiments described herein, the topical compositions may be applied to the skin by any means known in the art including, but not limited to, by an aerosol, spray, pump-pack, brush, swab, or other applicator. The applicator may provide either a fixed or variable metered dose application such as a metered dose aerosol, a stored-energy metered dose pump or a manual metered dose pump.

[0077] In embodiments described herein, the topical composition is formulated as to be applied to a site one time a day or multiple times per day.

[0078] In certain embodiments, the skin condition being treated in a patient in need thereof is selected from the group consisting of dermatitis; psoriasis; itchy skin; acne; inflammation and redness of the skin; disorders associated with sebaceous glands; oily skin; dry skin; rosacea; burns; disorders affecting the palms or soles; genetic disorders of the skin; warts; and any combination thereof. In some embodiments, dermatitis is selected from the group consisting of atopic dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, stasis dermatitis, seborrheic dermatitis, chronic dermatitis, eczema, and any combination thereof. In some embodiments, psoriasis is selected from the group consisting of plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, and any combination thereof. In some embodiments, itchy skin is selected from the group consisting of pruritus, prurigo, pityriasis rubra pilaris, lichen simplex chronicus, lichen planus, and any combination thereof. In some embodiments, acne is selected from the group consisting of acne vulgaris, cystic acne, inflammatory acne, non inflammatory acne, and any combination thereof. In some embodiments, inflammation and redness of the skin is selected from the group consisting of seborrheic dermatitis, urticaria eczema, hives, seborrheic eczema, and any combination thereof. In some embodiments, disorders associated with sebaceous glands is selected from the group consisting of acne, follicular hyperkeratinization, sebostasis, sebaceous adenomas, sebaceous hyperplasia, excess sebum production, seborrhea, sebaceoma, sebaceous carcinoma, seborrheic dermatitis, sebaceous cysts, and any combination thereof. In some embodiments, oily skin is seborrhea. In some embodiments, dry skin is selected from the group consisting of sebostasis, ichthyosis, xerosis, and any combination thereof. In some embodiments, burns is sunburn. In some embodiments, disorders affecting the palms or soles is selected from the group consisting of palmoplantar pustulosis, exfoliative keratolysis, and any combination thereof. In some embodiments, genetic disorders of the skin is Darier’s disease.

[0079] In some embodiments, the method of treating atopic dermatitis in a patient in need thereof comprises topically applying a topical composition comprising PEG 400, PEG 4000, white petrolatum, vitamin E, glycerol monostearate/glycerides, isopropyl myristate, and water. In certain embodiments, the patient is an adolescent.

[0080] In some embodiments, PEG 400 is at a concentration of about 25% to about 75% by weight of the topical composition. In some embodiments, PEG 4000 is at a concentration of about 15% to about 35% by weight of the topical composition. In some embodiments, white petrolatum is at a concentration of about 1% to about 10% by weight of the topical composition. In some embodiments, vitamin E is at a concentration of about 0.01% to about 5% by weight of the topical composition. In some embodiments, glycerol monostearate/glycerides is at a concentration of about 2% to about 15% by weight of the topical composition. In some embodiments, isopropyl myristate is at a concentration of about 2% to about 25% by weight of the topical composition. In some embodiments, water is at a concentration of about 0.1% to about 10% by weight of the topical composition.

[0081] In certain embodiments, the method of treating atopic dermatitis in a patient in need thereof comprises topically applying a topical composition comprising PEG 400 at 50.5% by weight, PEG 4000 at 25.0% by weight, white petrolatum at 4.4% by weight, vitamin E at 0.1% by weight, glycerol monostearate/glycerides at 8.0% by weight, isopropyl myri state at 10.0% by weight, and water at 2.0% by weight.

[0082] In certain embodiments, a method of treating skin conditions in a patient in need thereof comprises topically applying a topical composition comprising PEG 400, PEG 4000, white petrolatum, vitamin E, glycerol monostearate/glycerides, isopropyl myristate, water, and a therapeutically effective amount of a topically active therapeutic agent. In some embodiments, the topically active therapeutic agent is at a concentration of about 0.01% to about 50% by weight of the topical composition. In some embodiments, PEG 400 is at a concentration of about 25% to about 75% by weight of the topical composition. In some embodiments, PEG 4000 is at a concentration of about 15% to about 35% by weight of the topical composition. In some embodiments, white petrolatum is at a concentration of about 1% to about 10% by weight of the topical composition. In some embodiments, vitamin E is at a concentration of about 0.01% to about 5% by weight of the topical composition. In some embodiments, glycerol monostearate/glycerides is at a concentration of about 2% to about 15% by weight of the topical composition. In some embodiments, isopropyl myristate is at a concentration of about 2% to about 25% by weight of the topical composition. In some embodiments, water is at a concentration of about 0.1% to about 10% by weight of the topical composition.

[0083] In certain embodiments, the method of treating atopic dermatitis in a patient in need thereof comprises topically applying a topical composition comprising PEG 400 at 50.5% by weight, PEG 4000 at 25.0% by weight, white petrolatum at 4.4% by weight, vitamin E at 0.1% by weight, glycerol monostearate/glycerides at 8.0% by weight, isopropyl myristate at 10.0% by weight, water at 2.0% by weight, and the topically active therapeutic agent at 0.5% by weight.

[0084] In some embodiments, the topically active therapeutic agent is selected from the group consisting of topical acne agents, topical anesthetics, topical anti-infectives, topical anti-rosacea agents, topical antibiotics, topical antifungals, topical antihistamines, topical antineoplastics, topical antipsoriatics, topical antivirals, topical astringents, topical debriding agents, topical depigmenting agents, topical non-steroidal anti-inflammatories, topical photochemotherapeutics, topical rubefacient, topical steroids, and any combination thereof. In some embodiments, the topical acne agents is selected from the group consisting of tretinoin, benzoyl peroxide, salicylic acid, erythromycin, clindamycin, azelaic acid, adapalene, dapsone, and any combination thereof. In some embodiments, the topical anesthetics is selected from the group consisting of benzalkonium chloride, lidocaine, prilocaine, benzocaine, pramoxine, dibucaine, and any combination thereof. In some embodiments, the topical anti-infectives is selected from the group consisting of malathion, sinecatechins, ivermectin, acetic acid, spinosad, benzyl alcohol, crotamiton, imiquimod, permethrin, docosansol, and any combination thereof. In some embodiments, the topical anti rosacea agents is selected from the group consisting of azelaic acid, metronidazole, oxymetazoline, brimonidine, and any combination thereof. In some embodiments, the topical antibiotics is selected from the group consisting of sulfacetamide/sulfur sodium, bacitracin, polymyxin b, erythromycin, silver sulfadiazine, retapamulin, mupirocin, neomycin, and any combination thereof. In some embodiments, the topical antifungals is selected from the group consisting of benzoic acid, salicylic acid, undecylenic acid, ketoconazole, nystatin, naftifme, tolnaftate, miconazole, zinc oxide, econazole, ciclopirox, oxiconazole, and any combination thereof. In some embodiments, the topical antihistamines is selected from the group consisting of diphenhydramine, doxepin, and any combination thereof. In some embodiments, the topical antineoplastics is selected from the group consisting of fluorouracil, ingenol, imiquimod, diclofenac, mechlorethamine, and any combination thereof. In some embodiments, the topical antipsoriatics is selected from the group consisting of tazarotene, betamethasone, calcipotriene, tazarotene, calcitriol, and any combination thereof. In some embodiments, the topical antivirals is selected from the group consisting of acyclovir, penciclovir, and any combination thereof. In some embodiments, the topical astringents is selected from the group consisting of calamine, witch hazel, alum, isopropyl alcohol, ethanol, aluminum acetate, aluminum chloride, aluminum sulfate tetradecahydrate, calcium acetate monohydrate, formaldehyde, and any combination thereof. In some embodiments, the topical debriding agents is selected from the group consisting of balsam pern, castor oil, trypsin, collagenase, and any combination thereof. In some embodiments, the topical depigmenting agents is selected from the group consisting of fluocinolone, hydroquinone, tretinoin, hydroquinone, and any combination thereof. In some embodiments, the topical non-steroidal anti-inflammatories is selected from the group consisting of diclofenac, capsaicin, and any combination thereof. In some embodiments, the topical photochemotherapeutics is selected from the group consisting of aminolevulinic acid, methyl aminolevulinate, methoxsalen, and any combination thereof. In some embodiments, the topical rubefacient is selected from the group consisting of camphor, menthol, capsaicin, methyl salicylate, and any combination thereof. In some embodiments, the topical steroids is selected from the group consisting of triamcinolone, fluocinolone, prednicarbate, desonide, betamethasone, halcinonide, hydrocortisone, diflorasone, clobetasol, desoximetasone, clocortolone, and any combination thereof.

[0085] Embodiments herein are directed to a topical composition comprising a therapeutically effective amount of topically active therapeutic agent and pharmaceutically acceptable topical excipients, wherein 90% confidence interval for the ratio of means (population geometric means based on log-transformed data) of the AUC of the topical composition is within 80-125% of the AUC of any one the foregoing topical compositions and the 90% confidence internal for the ratio of means of the C_max of the topical composition is within 70-143% of the C_max of the same foregoing topical composition.

[0086] In embodiments described herein, the topically active therapeutic agent is not methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid (RVT-501), 4-(cyclopropylamino)-2-[4-(4-ethylsulfonylpiperazin-l-yl)anilino]pyrimidine-5- carboxamide (RVT-502), or 2-(4-(4-(6-carbamoyl-3,5-dimethylpyrazin-2- yl)phenyl)cyclohexyl)acetic acid (RVT-503).

[0087] In embodiments described herein, the method is directed to applying a topical composition once per day. In embodiments described herein, the method is directed to applying a topical composition multiple times per day. In some embodiments, the topical composition is applied two times per day, three times per day, four times per day, or five times per day. In some embodiments, the topical composition is applied one time in the morning and one time in the evening. In some embodiments, the topical composition is applied every 12 hours, every 11 hours, every 10 hours, every 9 hours, every 8 hours, every 7 hours, every 6 hours, every 5 hours, every 4 hours, every 3 hours, every 2 hours, or every hour.

[0088] In embodiments described herein, the method is directed to applying a topical composition to multiple sites on the skin of the body. For example, the topical composition may be applied over large areas of skin prophylactically or the topical composition may be applied to particular sites in need of treatment. In some embodiments, the topical composition is applied to the skin as a liquid, toner, solution, spray, emulsion, moisturizer, sunscreen, cream, lotion, mask, suspension, triturate, gel, jelly, paste, foam, ointment, shampoo, adhesive, serum, treated cloth or pad. In some embodiments, the topical composition is applied to the eyes as eye drops, placed in the ear canal as ear drops or to the surface of the tooth.

EXAMPLES

[0089] Example 1 : Phase 2 Study of RVT-501 in Adult and Adolescent Subjects with Atopic Dermatitis

[0090] Atopic dermatitis is a chronic inflammatory disease of the skin characterized by intense itch (pruritus) and eczematous lesions. It is one of the most common skin diseases, affecting 10-20% of the population in developed countries. It occurs more commonly in children, affecting 15-30% of the child population, and recent estimates indicate approximately 10% of adults are affected. Of the pediatric population, approximately 60% of patients present in the first year of life, and about 85% of patients present by 5 years old.

[0091] Disease is mild to moderate in most patients, with 70% of all patients, and 80% of children having mild to moderate disease, and 20% of patients having moderate to severe disease, where the clinical features are more intense and relapsing. Many factors, both genetic and environmental, contribute to the pathogenesis of the disease, which is characterized by defects in skin barrier and immune system dysregulation. The skin lesions that result from these defects are itchy, painful, and cause the patient social and psychological harm due to their appearance. Beyond the immediate physical symptoms and psychological manifestations of the AD lesions, the disease has profound secondary effects on the well being of patients. Specifically, pruritus associated with the causes the significant patient discomfort, often leading to sleep deprivation, which manifests also into poor sleep quality in parents of young patients.

[0092] Despite the high prevalence, there are limited current treatment options available for the patients. The first line treatment option for patients with mild-moderate disease is topical corticosteroids, but many patients are steroid refractory and there are significant long-term safety risks associated with their use. Topical calcineurin inhibitors, Elidel and Protopic, are used as a second-line treatment option but have a boxed warning for carcinogenicity risks. Thus, there is a significant unmet medical need for a therapeutic that is both safe and efficacious.

[0093] The diagnosis criteria for atopic dermatitis requires at least three of the following major criteria: pruritus, typical morphology and distribution (Adults: flexural lichenification or linearity, Children and infants: involvement of facial and extensor surfaces), chronic or chronically relapsing dermatitis, or personal or family history of atopy (asthma, allergic rhinitis, atopic dermatitis). As well as at least three of the following minor criteria: xerosis, ichthyosis/keratosis pilaris/palmar hyperlinearity, immediate (type 1) skin test reactivity, elevated serum IgE, early age at onset, tendency to skin infections (Staphylococcus aureus, herpes simplex)/impaired cellular immunity, tendency to nonspecific hand/foot dermatitis, nipple eczema, cheilitis, recurrent conjunctivitis, Dennie-Morgan infraorbital fold, keratoconus, anterior subcapsular cataracts, orbital darkening, facial pallor/erythema, pityriasis alba, anterior neck folds, itch when sweating, intolerance to wool and lipid solvents, perifollicular accentuation, food intolerance, course influenced by environmental/emotional factors, or white demographic/delayed blanch.

[0094] RVT-501, previously known as E6005, is an investigational phosphodiesterase 4 (PDE4) inhibitor. Studies have shown that PDE4 activity is upregulated in atopic dermatitis, resulting in reduced levels of cAMP, ultimately causing protein kinase A (PKA) dependent elevation in pro-inflammatory cytokines. Preclinical and clinical data support that PDE4 inhibition by RVT-501 results in downregulation of disease-related cytokines as well as resultant attenuation in disease severity.

[0095] Eisai Co., Ltd. developed a version of RVT-501 ointment (Formulation B), which was a white petrolatum based composition. Four concentrations (0.01%, 0.03%, 0.1%, 0.2%) of RVT-501 Formulation B were developed. The RVT-501 ointment (Formulation B) was used in nonclinical and clinical studies completed to date (see Section 2.2.2). The degree of efficacy observed in prior clinical studies with the highest concentration RVT-501 0.2% ointment did not appear to reach a maximum; thus, a formulation with an increased concentration of RVT-501 was developed by Eisai (Formulation C) utilizing a polyethylene glycol based composition. Further refinement of this Formulation C by Dermavant Sciences has resulted in a new RVT-501 ointment formulation at two concentrations, RVT-501 0.2% ointment (Formulation C) and RVT-501 0.5% ointment (Formulation C). These two concentrations of formulation C will be used in this study.

[0096] Three studies conducted in adult and pediatric subjects with AD included efficacy endpoints as secondary objectives. In general, these studies showed that RVT-501, at various doses, has dose-related increasing efficacy based on various scoring systems in atopic dermatitis with little to no systemic exposure to RVT-501 or Ml 1 observed.

[0097] Study 001 was a multiple ascending dose study in healthy Japanese male subjects that consisted of an open-label, vehicle-controlled skin irritation period (patch test and photopatch test) and a multiple ascending dose period. The patch/photopatch component of the study was performed using Finn chambers® containing nothing, white petrolatum, vehicle, 0.01%, 0.03%, 0.1% or 0.2% RVT-501 ointment. In the multiple ascending dose component, subjects randomly received vehicle ointment or 0.01%, 0.03%, 0.1% or 0.2% RVT-501 ointment once daily (QD) or twice daily (BID) for up to 11 days (approximately 5 g over approximately 10% BSA). No significant skin or systemic AEs were identified in this study.

[0098] A Phase 1/2 study of RVT-501, Study 101, in Japanese male subjects aged 20 to 64 years with AD, was conducted primarily to evaluate the safety and PK of topical application of RVT-501 ointment (0.01%, 0.03%, 0.1%, and 0.2%) compared with vehicle after application for up to 10 days. Additional exploratory objectives included the efficacy of topical application with these concentrations of RVT-501 ointment in the same population. The severity scores of targeted eczema (SSTE) on the back were significantly reduced at the end of the study compared to baseline, in the 0.03%, 0.1%, and 0.2% RVT-501 ointment groups (P = 0.031 in the 0.1% RVT-501 group, P < 0.001 in the 0.03% and 0.2% RVT-501 groups). The least squares mean difference from vehicle at the end of the study was statistically significant in the 0.2% RVT-501 ointment group (P = 0.003). Similar findings, including dose-dependent efficacy responses, were noted for other efficacy measures such as eczema area and severity index (EASI) and scoring atopic dermatitis (SCORAD) in this study.

[0099] In Study 201, 78 adults aged 20 to 64 with mild to moderate AD encompassing 5 to 30% body surface area (BSA) were randomized 2: 1 to RVT-501 0.2% (n=52) or control (n=26) ointment BID for 4 weeks. All subjects were then continued on RVT-501 0.2% ointment BID for an additional 8 weeks. A total of 72 subjects were exposed to 0.2% RVT-501 ointment in Study 201. Subjects initially receiving RVT-501 0.2% ointment had greater improvements in the Eczema Area and Severity Index (EASI) and Scoring Atopic Dermatitis (SCORAD) scores versus those receiving vehicle, but none of the comparisons of RVT-501 vs. vehicle reached statistical significance at Week 4. Additionally, all subjects generally saw continued trends towards improvement in AD during the 8-week extension phase.

[00100] Study 102 was a Phase 1/2 multicenter, randomized, vehicle-controlled study wherein 62 pediatric subjects aged 2 to 15 years with mild to moderate AD were enrolled in sequential, decreasing-aged cohorts and treated with control ointment, or 0.05% or 0.2% RVT-501 ointment BID for 14 days. Improvements in SSTE and Investigator’s Global Assessment were consistently seen for subjects on RVT-501 0.2% ointment vs. vehicle, but similar improvements were not see with RVT-501 0.05% ointment. Dose-dependent improvements in AD severity were observed, as were improvements in pruritus in a subject cohort that was not on concomitant antihistamine or anti-allergic medication.

[00101] To date, there have been no reports of serious adverse events related to RVT-

501.

[00102] According to the results of Study 001 in healthy adult males and Study 101 in male adults with atopic dermatitis, RVT-501 ointment produced no clinically-significant findings at concentrations of 0.01% to 0.2% RVT-501 in terms of skin irritation (patch test, photopatch test), other adverse events, laboratory values, vital signs, 12-lead electrocardiography, or ophthalmological findings.

[00103] In Study 201, conducted in adult subjects with atopic dermatitis, rates of noteworthy adverse events (e.g., adverse events at the administration site and adverse events involving skin infections) were similar in the vehicle ointment and 0.2% RVT-501 ointment groups during the 4-week randomization stage. In addition, although some adverse events occurred more often in the 0.2% RVT-501 ointment group than in the vehicle ointment group, all were mild or moderate, and tolerability was good. The safety profile for 0.2% RVT-501 ointment applied for 12 weeks was largely the same as that applied for 4 weeks.

[00104] In the 102 Study, conducted in pediatric subjects with atopic dermatitis, repeated application of 0.05% and 0.2% RVT-501 ointment for 2 weeks produced no adverse events considered attributable to the investigational product. Furthermore, there were no other clinically significant findings in terms of other laboratory values, vital signs or 12-lead el ectrocardi ography .

[00105] The safety of repeated administration of RVT-501 ointment has not yet been evaluated beyond 12 weeks in adults or beyond 2 weeks in children.

[00106] The study objectives are to evaluate the safety, pharmacokinetics and efficacy of multiple doses of RVT-501 topical ointment. Prior clinical studies have shown significant efficacy in pediatric patients (Study 102) and positive although nonsignificant efficacy results in adult patients (Study 201) with a 0.2% topical ointment. Preclinical and clinical dose-ranging evidence suggests that higher concentration formulations may result in enhanced efficacy. The primary objective of this study is to evaluate the safety and pharmacokinetics of a 0.5% formulation - a higher concentration formulation than has been used previously - in both adults and adolescents in a BID dosing regimen. A 0.2% BID formulation arm will be included to control for efficacy and safety findings at the previous dose level. [00107] Previous clinical studies with topical ointment doses up to 0.2% BID have shown dose dependent improvement in signs and symptom associated with AD in pediatric and adult populations. In addition, RVT-501 has been well tolerated with few skin related or systemic AEs and has minimal systemic absorption. Preclinical and clinical dose-ranging studies support dosing beyond 0.2%, the highest concentration ointment previously tested. Recently performed skin penetration studies showed an increase in RVT-501 in the skin following topical application of 0.5% ointment compared with the previous 0.2% formulation. Further, radiolabelled pharmacokinetics studies where 14C-RVT-501 was dermally delivered to stripped skin of non-fasted male rats showed that, after a single application, radiolabelled RVT-501 was present in the skin application site 24 hours after administration at 75% of the levels measured after 30 minutes (maximum radioactivity). Thus, both 0.2% and 0.5% topical formulations, BID, will be tested for comparative efficacy in both adults and adolescents.

[00108] Primary Objective: To evaluate the safety and pharmacokinetics of topical RVT-501 in adult and adolescent subjects with atopic dermatitis. Primary endpoints: Plasma concentrations of RVT-501 and Ml l metabolite, pharmacokinetic parameters (if data permit). Frequency and severity of adverse events (local and systemic), laboratory values, vital signs, and ECG. Secondary Objective: To assess the efficacy of topical RVT-501 in adult and adolescent subjects with atopic dermatitis. Secondary endpoints: Efficacy as determined by: Change from baseline in Investigators Global Assessment (IGA), Proportion of subjects who achieve an IGA of 0 or 1 and at least a decrease of 2 point in IGA, Change from baseline in BSA, Change from baseline in Eczema Area and Severity Index (EASI) score, EASI-50 Analysis (50% reduction in EASI score from baseline), Change from baseline in pruritus as measured with the Numeric Rating Scale. Number of Subjects planned: Approximately 150 total of which approximately 90 will be adults (ages 18 to 70) and 60 will be adolescents (ages 12 to 17). Study design: Multi-center, randomized, vehicle-controlled, double-blind trial. Subjects will be randomized (1 : 1 : 1) to the following: RVT-501 0.2% ointment BID x 28 days (30 adults, 20 adolescents), RVT-501 0.5% ointment BID x 28 days (30 adults, 20 adolescents), Vehicle ointment BID x 28 days (30 adults, 20 adolescents). Adult subjects will be enrolled first. After an interim review of the data in 60 adult subjects, adolescent subjects ages (12 to <18) may be enrolled. Duration of the treatment will be for 28 days.

[00109] Criteria for Evaluation: Primary Outcome Measures: Frequency and severity of adverse events (local and systemic), laboratory values, vital signs and ECGs, Plasma concentrations of RVT-501 and Ml l metabolite, and pharmacokinetic parameters (if data permit). Secondary Outcome Measures: Efficacy as determined by the Investigators Global Assessment (IGA), EASI score, and Pruritus score using a visual analog scale. Exploratory: Patient reported outcome measure(s).

[00110] Statistical Methods: Efficacy Analyses: A sample size and power sensitivity analysis was conducted for the efficacy endpoints. Assuming an effect size (defined as difference of mean change from baseline EASI score between treatment groups relative to pooled standard deviation) of 0.7, a sample size of 50 subjects in an active arm and 50 subjects in the combined placebo will provide 93% power at an alpha level of 0.05 (2-sided), based on a 2-sided t-test. The sample size will also allow a difference of 33% between placebo and active treatment in a responder endpoint to be detected with 90% power and a 0.05 significance level assuming the proportion of responders in the placebo group is <=20%. Efficacy endpoints will be summarized and listed by treatment for each age group and both age groups combined; The between-treatment comparisons (active vs placebo and between active dose groups) for continuous efficacy variables will be performed using an analysis of covariance (ANCOVA) model. The between treatment comparisons for the proportion of responders will be compared using a CMH or Chi-square test. Safety Analyses: Adverse events will be mapped to a Medical Dictionary for Regulatory Activities (MedDRA). Treatment emergent adverse events will be summarized by treatment, preferred term and system organ classification. Descriptive summaries of vital signs, ECG parameters, and clinical laboratory results will be presented by study visit and treatment group. Pharmacokinetic Analyses: RVT-501 and Ml l plasma concentrations will be listed by subject, treatment, and time; and will be summarized by treatment and time. The number and percent of subjects with a measurable concentration of either analyte at each time point and any time during the study will be provided.

[00111] Overall Design: This is a multi-center, randomized, vehicle-controlled, double-blind Phase 2 study in adults and adolescent subjects with mild to moderate atopic dermatitis. All subjects will undergo screening procedures within 30 days of enrollment to confirm eligibility. At Day 0 (baseline), eligible subjects will be randomized (1 : 1 : 1) to one of three treatment arms. Subjects will be instructed on how to apply RVT-501 while under the supervision of site personnel in the clinic. Briefly, subjects should apply a thin layer of study medication with their fingertip to all affected areas. Study medication will be dispensed to subjects and will be applied at home as instructed by site personnel between clinic visits. During the treatment period, subjects will apply RVT-501 ointment to affected areas twice a day for 28 days. Subjects will return to the clinic at Day 4 for evaluation, and again at Weeks 1, 2, 3 and 4 for PK, safety and efficacy assessments at the timepoints noted in the Time and Events Table. On clinic visit days (except on Day 4 visit), subjects should apply study drug on-site while under the supervision of site personnel, after efficacy assessments have been completed.

[00112] There will be a follow-up visit 7-10 days following the end of study treatment. A subject’s total participation in the study will include 8 clinic visits over the course of approximately 10 weeks.

[00113] Treatment arms and duration- Treatment Group A: RVT-501 0.2% ointment twice daily x 28 days, Treatment Group B: RVT-501 0.5% ointment twice daily x 28 days, Treatment Group C: Vehicle ointment twice daily x 28 days.

[00114] Table 1 provides the timeline for events throughout the treatment period.

Table 1: Time and Events over treatment period

1. PK samples will be collected pre-dose at week 1 for all subjects. At week 4, PK samples will be collected pre-dose and within 2-4 hours post-dose.

[00115] Atopic Dermatitis Assessments: Efficacy measurement outcomes will include: Investigator Global Assessment (IGA): The Investigator’s Global Assessment (IGA) of Disease Severity will be assessed at every on-site study visit. The IGA is a global assessment of the current state of the disease. It is a 5-point morphological assessment of overall disease severity and will be determined according to the categories described below. In order to be eligible, subjects must have an IGA score of 2 or 3 at Baseline visit (Day 0). Table 2 describes the IGA scores.

Table 2: IGA Scoring Assessment

[00116] Eczema Area and Severity Index (EASI): The Eczema Area and Severity Index (EASI) will be assessed at every study visit. It quantifies the severity of a subject’s atopic dermatitis based on both lesion severity and the percent of BSA affected. The EASI is a composite score ranging from 0-72 that takes into account the degree of erythema, induration/papulation, excoriation, and lichenification (each scored from 0 to 3 separately) for each of four body regions, with adjustment for the percent of BSA involved for each body region and for the proportion of the body region relative to the whole body. A detailed procedure of EASI score calculation is: Four anatomic sites (head, upper extremities, trunk, and lower extremities) are assessed for erythema, induration (papules), excoriation and lichenification as seen on the day of the examination. The severity of each sign is assessed using a 4-point scale: 0 = No symptoms, 1 = Slight or Mild, 2 = Moderate, 3 = Marked or Severe. The area affected by atopic dermatitis within a given anatomic site is estimated as a percentage of the total area of that anatomic site and assigned a numerical value according to the degree of atopic dermatitis involvement as follows: 0 = no involvement, 1 = < 10 %, 2 = 10 to < 30%, 3 = 30 to < 50%, 4 = 50 to < 70%, 5 = 70 to < 90%, 6 = 90 to 100 %. The EASI score is obtained by using the formula:

EASI = 0.1 (E_h + h + E_xh + L_h) A_h + 0.2 (E_u + I_u + E_xu + L_u) A_u + 0.3 (E_t + I_t + E_xt +

Li) A_t + 0.4 (Ei + Ii + E_xi + Li) Ai

Where E, I, Ex, L and A denote erythema, induration, excoriation, lichenification and area, respectively, and h, u, t, and 1 denote head, upper extremities, trunk, and lower extremities, respectively.

[00117] EASI-50 represents the subjects achieving a 50% reduction in EASI score from baseline.

[00118] Body Surface Area (BSA): The BSA affected by Atopic Dermatitis will be evaluated (from 0 to 100%) at every visit. The subjects scalp, palms and soles should be excluded from the calculations at screening and baseline to determine subject’s eligibility. At Day 0 and subsequent visits, BSA of the whole body affected with Atopic Dermatitis will be used to assess efficacy of the study treatment. One subject’s palm (excluding fingers) represents approximately 1%, head 10%, upper extremities 20%, trunk 30%, and lower extremities 40% of his/her total BSA.

[00119] NRS(Numerical Rating Scale) for Pruritus is a validated scale used to quickly assess pruritus severity, where 0 is no itch and 10 is the worst imaginable itch.

[00120] Clinical photography may be performed in a subgroup of subjects at selected study centers that possess the capabilities. This is not required of subjects for participation in the study. Informed consent/assent and photographic release will be required. The photographs may not be referred to by the investigator at any subsequent study visit for the purposes of grading. Photographs will be taken of a representative area of the subject’s disease area. Photographs will be taken at the time points specified in the Time and Events Table. Three photographs of the selected skin area will be taken in a standardized fashion (i.e., same camera, angle, background, distance).

[00121] Patient Reported Symptoms: The subject will assess burning and pruritus at the application site during clinic visits using the following scale: Burning: 0 None (no burning sensation), 1 Mild (Mild burning sensation (not really bothersome)), 2 Moderate (Moderate burning sensation that is somewhat bothersome), 3 Severe (Intense burning sensation that cause a definite discomfort) and Pruritus: 0 None (no itching), 1 Mild (Mild itching sensation (not really bothersome)), 2 Moderate (Moderate itching sensation that is somewhat bothersome), 3 Severe (Intense itching sensation that cause a definite discomfort). This should be completed by the subject prior to other assessments or evaluations by site personnel, where possible.

[00122] Patient Report Outcomes: The Patient Oriented Eczema Measures (POEM - adult version) is a tool used for monitoring atopic dermatitis severity. It focuses on the illness as experienced by the patients. Measurements will be assessed at the time points indicated in Table 1. The full version of POEM is available for free download from the ETniversity of Nottingham at http://www.nottingham.ac.uk/research/groups/cebd/resources/poem.aspx.

[00123] Patient Diary: The self-administered sign and symptom severity diary (which is based on the content of the POEM) assesses the severity of disease-related signs and symptoms. Response options are on an 11 -point NRS and range from 0 (Absent) to 10 (Worst Imaginable). Subjects will be asked to complete the diary each day using a recall period of the past 24 hours where possible. Question 1 of the diary will be used to assess itch. An electronic diary may be utilized.

[00124] Pharmacokinetics: Blood samples for PK analysis of RVT-501 and the Ml l metabolite will be collected at the time points indicated in Table 1. The actual date and time of each blood sample collection will be recorded as well as the date and time of the last dose of study mediation. The timing of PK samples may be altered and/or PK samples may be obtained at additional time points to ensure thorough PK monitoring.

[00125] Table 3 provides the final subject disposition of the current study. Table 4 provides the demographics of the subjects in the current study.

Table 3: Subject Disposition

[1] Percentages based on the number of subjects randomized.

[2] Percentages based on the number of subjects included in the safety population

Table 4: Subject Demographics

[00126] Table 5 provides the summary of adverse events. Table 6 provides a summary of the adverse events by organ class.

Table 5: Summary of Treatment Emergent Adverse Events

[1] Percentages are based on the number of subjects in the Safety population in each treatment group.

[2] Percentages are based on the total number of treatment emergent adverse events reported in each treatment group.

[3] AE that was reported as "related"

[4] When assessing adverse events, refer to the NIH Common Terminology Criteria for Adverse Events (CTCAE), v.4.02, 2009.

Table 6: Summary of Treatment Emergent Adverse Events by Organ Class

[00127] Pharmacokinetics summary: PK samples were collected pre-dose at Weeks 1 and 4, and 2-4 hrs post-dose at Week 4. Only 1 subject (an adolescent) had detectable RVT- 501 above the LLQ (lower limit of quantitation, lng/mL) at l.23ng/mL pre-dose and 2 hrs post-dose on Week 4. Three patients had detectable Ml l exposure with the highest value at l.60ng/mL.

[00128] Results: FIG. 1 provides the response in IGA (0/1 + 2 point improvement) at week 4 in the ITT population. FIG. 2 provides the response in IGA (0/1 + 2 point improvement) at week 4 in the PPS population. Adolescents responded better than adults in both populations.

[00129] FIG. 3 provides the response in IGA (0/1) at week 4 in the ITT population. FIG. 4 provides the response in IGA (0/1) at week 4 in the PPS population. Adolescents responded better than adults in both populations.

[00130] FIG. 5 provides the IGA response (0/1 + 2 point improvement) kinetics in the ITT population. FIG. 6 provides the IGA response (0/1 + 2 point improvement) kinetics in the PPS population. Rapid vehicle response was observed after 2 weeks of treatment. Both ITT and PPS populations exhibit similar time-course curves.

[00131] FIG. 7 shows the EASI % improvement from baseline and the week 4 EASI % improvement in the ITT population. RVT-501 exhibited high vehicle response in improvement in EASI. Minimal separation between arms and age groups at Week 4. Faster response observed in active arms vs. vehicle.

[00132] FIG. 8 provides data of EASI 50/75/90 responders at week 4 for the ITT population. FIG. 9 provides data of EASI 50/75/90 responders at week 4 for the PPS population. Separation was observed in active arms vs. vehicle for EASI50 and EASI 90. Very high vehicle response was observed in ITT and PPS populations.

[00133] FIG. 10 shows the improvement in NRS (itch) from baseline in the ITT population. Rapid response in itch was observed by Week 1 in 0.5% group. High vehicle response was observed as early as Week 2. FIG. 11 shows the improvement in NRS (itch) from baseline at week 4 in the ITT population. FIG. 12 shows the improvement in NRS (itch) from baseline at week 4 in the PPS population. There was no clear difference among arms or age groups. However, there was a surprisingly high vehicle response rate.

[00134] FIG. 13 shows the BSA % improvement from baseline and the week 4 BSA % improvement in the ITT population. Modest separation from vehicle observed vs. active arms across age groups at Week 4. Faster response observed in active arms.

[00135] Conclusions: RVT-501 0.2% and 0.5% ointments were well tolerated. A higher percentage of subjects in the RVT-501 treatment groups achieved an IGA score of 0,1 with at least a 2-point grade improvement (Vehicle=l5. l%, 0.2% RVT-50l=2l.8%, 0.5% RVT-50l=24.5%). Adolescent subjects treated with RVT-501 displayed greater treatment effects. No differences in treatment effect were observed in Adult subjects. Greater improvements in Itch and EASI score were observed in RVT-501 treated subjects in the first 2 weeks of treatment. This differential response between treatment groups decreased during the second 2 weeks.

[00136] Example 2: Evaluating Topical Bioavailabilitv

[00137] Dermatopharmacokinetic (DPK) Studies

[00138] The dermatopharmacokinetic (DPK) approach is comparable to a blood, plasma, urine PK approach applied to the stratum corneum. DPK encompasses drug concentration measurements with respect to time and provides information on drug uptake, apparent steady-state levels, and drug elimination from the stratum corneum based on a stratum corneum concentration-time curve.

[00139] For antiacne drug products, target sites are the hair follicles and sebaceous glands. In this setting, the drug diffuses through the stratum corneum, epidermis, and dermis to reach the site of action. The drug may also follow follicular pathways to reach the sites of action. The extent of follicular penetration depends on the particle size of the active ingredient if it is in the form of a suspension. Tinder these circumstances, the DPK approach is still expected to be applicable because studies indicate a positive correlation between the stratum corneum and follicular concentrations.

[00140] Application and Removal of Test and Reference Products: The treatment areas are marked using a template without disturbing or injuring the stratum comeum/skin. The size of the treatment area will depend on multiple factors including drug strength, analytical sensitivity, the extent of drug diffusion, and exposure time. The stratum corneum is highly sensitive to certain environmental factors. To avoid bias and to remain within the limits of experimental convenience and accuracy, the treatment sites and arms should be randomized. TTptake, steady-state, and elimination phases, as described in more detail below, may be randomized between the right and left arms in a subject. Exposure time points in each phase may be randomized among various sites on each arm. The test and reference products for a particular exposure time point may be applied on sites to minimize differences. Test and reference products should be applied concurrently on the same subjects according to a SOP that has been previously developed and validated. The premarked sites are treated with predetermined amounts of the products (e.g., 5 mg/sq cm) and covered with a nonocclusive guard. Occlusion is used only if recommended in product labeling. Removal of the drug product is performed according to SOPs at the designated time points, using multiple cotton swabs or Q-tips with care to avoid stratum corneum damage. In case of certain oily preparations such as ointments, washing the area with a mild soap may be needed before skin stripping. If washing is carried out, it should be part of an SOP.

[00141] Sites and Duration of Application: The BA/BE study should include measurements of drug uptake into the stratum corneum and drug elimination from skin. Each of these elements is important to establish bioavailability and/or bioequivalence of two products, and each may be affected by the excipients present in the product. A minimum of eight sites should be employed to assess uptake/elimination from each product. The time to reach steady state in the stratum corneum should be used to determine timing of samples. For example, if the drug reaches steady-state in three hours, 0.25, 0.5, 1 and 3 hours posttreatment may be selected to determine uptake and 4, 6, 8 and 24 hours may be used to assess elimination. A zero time point (control site away from test sites) on each subject should be selected to provide baseline data. If the test/reference drug products are studied on both forearms, randomly selected sites on one arm may be designated to measure drug uptake/steady-state. Sites on the contralateral arm may then be designated to measure drug elimination. During drug uptake, both the excess drug removal and stratum corneum stripping times are the same so that the stratum corneum stripping immediately follows the removal of the excess drug. In the elimination phase, the excess drug is removed from the sites at the steady-state time point, and the stratum corneum is harvested at succeeding times over 24 hours to provide an estimate of an elimination phase.

[00142] Collection of Sample: Skin stripping proceeds first with the removal of the first 1-2 layers of stratum corneum with two adhesive tapes strip/disc applications, using a commercially available product (e.g., D-Squame, Transpore). These first two tape-strip(s) contain the generally unabsorbed, as opposed to penetrated or absorbed, drug and therefore should be analyzed separately from the rest of the tape-strips. The remaining stratum corneum layers from each site are stripped at the designated time intervals. This is achieved by stripping the site with an additional 10 adhesive tape-strips. All ten tape strips obtained from a given time point are combined and extracted, with drug content determined using a validated analytical method. The values are generally expressed as amounts/area (e.g., ng/cm²) to maintain uniformity in reported values. Data may be computed to obtain full drug concentration-time profiles, C_max-ss, T_max-ss, and AUCs for the test and reference products.

[00143] Procedure for Skin Stripping:

[00144] To assess drug uptake: Apply the test and/or reference drug products concurrently at multiple sites. After an appropriate interval, remove the excess drug from a specific site by wiping three times lightly with a tissue or cotton swab. Using information from the pilot study, determine the appropriate times of sample collection to assess drug uptake. Repeat the application of adhesive tape two times, using uniform pressure, discarding these first two tape strips. Continue stripping at the same site to collect ten more stratum corneum samples. Care should be taken to avoid contamination with other sites. Repeat the procedure for each site at other designated time points. Extract the drug from the combined ten skin strippings and determine the concentration using a validated analytical method. Express the results as amount of drug per square cm treatment area of the adhesive tape.

[00145] To assess drug elimination: Apply the test and reference drug product concurrently at multiple sites chosen based on the results of the pilot study. Allow sufficient exposure period to reach apparent steady-state level. Remove any excess drug from the skin surface as described previously, including the first two skin strippings. Collect skin stripping samples using ten successive tape strips at time intervals based on the pilot study and analyze them for drug content.

[00146] Metrics and Statistical Analyses: A plot of stratum corneum drug concentration versus a time profile should be constructed to yield stratum corneum metrics of C_max, T_max and AUC. The two one-sided hypotheses at the a= 0.05 level of significance should be tested for AUC and C_max by constructing the 90 percent confidence interval (Cl) for the ratio between the test and reference averages. Individual subject parameters, as well as summary statistics (average, standard deviation, coefficient of variation, 90% Cl) should be reported. For the test product to be BE, the 90 percent Cl for the ratio of means (population geometric means based on log-transformed data) of test and reference treatments should fall within 80-125 percent for AUC and 70- 143 percent for C_maX.

[00147] In vivo Dermal Open Flow Microperfusion

[00148] In dermal open-flow microperfusion (dOFM), a thin, hollow tube is inserted just under the skin surface, running through a section of the skin a few inches wide and then exiting. A liquid similar to body fluid is injected into the tubing; a portion of the tube under the skin is porous, so any drug that has been applied and absorbed through the skin's outer layer enters the flowing liquid, which is then collected for analysis. dOFM can reliably measure the changing amounts of drug in the skin after topical application of a dermatological drug product.

Claims

1. A topical composition comprising PEG 400, PEG 4000, white petrolatum, vitamin E, glycerol monostearate/glycerides, isopropyl myristate, water and optionally a therapeutically effective amount of a topically active therapeutic agent, wherein said agent is not methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4- yl)phenyl]terephthalamic acid (RVT-501), 4-(cyclopropylamino)-2-[4-(4- ethylsulfonylpiperazin-l-yl)anilino]pyrimidine-5-carboxamide (RVT-502), or 2-(4-(4-(6- carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)cyclohexyl)acetic acid (RVT-503).

2. The topical composition of claim 1, wherein PEG 400 is at a concentration of about 25% to about 75% by weight of the topical composition.

3. The topical composition of claim 1, wherein PEG 4000 is at a concentration of about 15% to about 35% by weight of the topical composition.

4. The topical composition of claim 1, wherein white petrolatum is at a concentration of about 1% to about 10% by weight of the topical composition.

5. The topical composition of claim 1, wherein vitamin E is at a concentration of about 0.01% to about 5% by weight of the topical composition.

6. The topical composition of claim 1, wherein glycerol monostearate/glycerides is at a concentration of about 2% to about 15% by weight of the topical composition.

7. The topical composition of claim 1, wherein isopropyl myristate is at a concentration of about 2% to about 25% by weight of the topical composition.

8. The topical composition of claim 1, wherein water is at a concentration of about 0.1% to about 10% by weight of the topical composition.

9. The topical composition of claim 1, wherein PEG 400 is at 50.5% by weight, PEG 4000 is at 25.0% by weight, white petrolatum is at 4.4% by weight, vitamin E is at 0.1% by weight, glycerol monostearate/glycerides is at 8.0% by weight, isopropyl myristate is at 10.0% by weight, and water is at 2.0% by weight.

10. The topical composition of claim 1, wherein the topically active therapeutic agent is present.

11. The topical composition of claim 10, wherein the topically active therapeutic agent is selected from the group consisting of topical acne agents, topical anesthetics, topical anti-infectives, topical anti-rosacea agents, topical antibiotics, topical antifungals, topical antihistamines, topical antineoplastics, topical antipsoriatics, topical antivirals, topical astringents, topical debriding agents, topical depigmenting agents, topical non-steroidal anti-inflammatories, topical photochemotherapeutics, topical rubefacient, topical steroids, and any combination thereof.

12. The topical composition of claim 11, wherein the topical acne agents is selected from the group consisting of tretinoin, benzoyl peroxide, salicylic acid, erythromycin, clindamycin, azelaic acid, adapalene, dapsone, and any combination thereof.

13. The topical composition of claim 11, wherein the topical anesthetics is selected from the group consisting of benzalkonium chloride, lidocaine, prilocaine, benzocaine, pramoxine, dibucaine, and any combination thereof.

14. The topical composition of claim 11, wherein the topical anti- infectives is selected from the group consisting of malathion, sinecatechins, ivermectin, acetic acid, spinosad, benzyl alcohol, crotamiton, imiquimod, permethrin, docosansol, and any combination thereof.

15. The topical composition of claim 11, wherein the topical anti-rosacea agents is selected from the group consisting of azelaic acid, metronidazole, oxymetazoline, brimonidine, and any combination thereof.

16. The topical composition of claim 11, wherein the topical antibiotics is selected from the group consisting of sulfacetamide/sulfur sodium, bacitracin, polymyxin b, erythromycin, silver sulfadiazine, retapamulin, mupirocin, neomycin, and any combination thereof.

17. The topical composition of claim 11, wherein the topical antifungals is selected from the group consisting of benzoic acid, salicylic acid, undecylenic acid, ketoconazole, nystatin, naftifme, tolnaftate, miconazole, zinc oxide, econazole, ciclopirox, oxiconazole, and any combination thereof.

18. The topical composition of claim 11, wherein the topical antihistamines is selected from the group consisting of diphenhydramine, doxepin, and any combination thereof.

19. The topical composition of claim 11, wherein the topical antineoplastics is selected from the group consisting of fluorouracil, ingenol, imiquimod, diclofenac, mechlorethamine, and any combination thereof.

20. The topical composition of claim 11, wherein the topical antipsoriatics is selected from the group consisting of tazarotene, betamethasone, calcipotriene, tazarotene, calcitriol, and any combination thereof.

21. The topical composition of claim 11, wherein the topical antivirals is selected from the group consisting of acyclovir, penciclovir, and any combination thereof.

22. The topical composition of claim 11, wherein the topical astringents is selected from the group consisting of calamine, witch hazel, alum, isopropyl alcohol, ethanol, aluminum acetate, aluminum chloride, aluminum sulfate tetradecahydrate, calcium acetate monohydrate, formaldehyde, and any combination thereof.

23. The topical composition of claim 11, wherein the topical debriding agents is selected from the group consisting of balsam pern, castor oil, trypsin, collagenase, and any combination thereof.

24. The topical composition of claim 11, wherein the topical depigmenting agents is selected from the group consisting of fluocinolone, hydroquinone, tretinoin, hydroquinone, and any combination thereof.

25. The topical composition of claim 11, wherein the topical non-steroidal anti-inflammatories is selected from the group consisting of diclofenac, capsaicin, and any combination thereof.

26. The topical composition of claim 11, wherein the topical photochemotherapeutics is selected from the group consisting of aminolevulinic acid, methyl aminolevulinate, methoxsalen, and any combination thereof.

27. The topical composition of claim 11, wherein the topical rubefacient is selected from the group consisting of camphor, menthol, capsaicin, methyl salicylate, and any combination thereof.

28. The topical composition of claim 11, wherein the topical steroids is selected from the group consisting of triamcinolone, fluocinolone, prednicarbate, desonide, betamethasone, halcinonide, hydrocortisone, diflorasone, clobetasol, desoximetasone, clocortolone, and any combination thereof.

29. A method of treating skin conditions in a patient in need thereof comprising topically applying a topical composition comprising PEG 400, PEG 4000, white petrolatum, vitamin E, glycerol monostearate/glycerides, isopropyl myristate, water and optionally a topically active therapeutic agent, wherein said agent is not methyl N-[3-(6,7- dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid (RVT-501), 4-

(cyclopropylamino)-2-[4-(4-ethylsulfonylpiperazin-l-yl)anilino]pyrimidine-5-carboxamide (RVT-502), or 2-(4-(4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)cyclohexyl)acetic acid (RVT-503).

30. The method of claim 29, wherein PEG 400 is at a concentration of about 25% to about 75% by weight of the topical composition.

31. The method of claim 29, wherein PEG 4000 is at a concentration of about 15% to about 35% by weight of the topical composition.

32. The method of claim 29, wherein white petrolatum is at a concentration of about 1% to about 10% by weight of the topical composition.

33. The method of claim 29, wherein vitamin E is at a concentration of about 0.01% to about 5% by weight of the topical composition.

34. The method of claim 29, wherein glycerol monostearate/glycerides is at a concentration of about 2% to about 15% by weight of the topical composition.

35. The method of claim 29, wherein isopropyl myristate is at a concentration of about 2% to about 25% by weight of the topical composition.

36. The method of claim 29, wherein water is at a concentration of about 0.1% to about 10% by weight of the topical composition.

37. The method of claim 29, wherein PEG 400 is at 50.5% by weight, PEG 4000 is at 25.0% by weight, white petrolatum is at 4.4% by weight, vitamin E is at 0.1% by weight, glycerol monostearate/glycerides is at 8.0% by weight, isopropyl myristate is at 10.0% by weight, and water is at 2.0% by weight.

38. The method of claim 29, wherein the topically active therapeutic agent is present.

39. The method of claim 38, wherein the topically active therapeutic agent is selected from the group consisting of topical acne agents, topical anesthetics, topical anti- infectives, topical anti-rosacea agents, topical antibiotics, topical antifungals, topical antihistamines, topical antineoplastics, topical antipsoriatics, topical antivirals, topical astringents, topical debriding agents, topical depigmenting agents, topical non-steroidal anti inflammatories, topical photochemotherapeutics, topical rubefacient, topical steroids, and any combination thereof.

40. The method of claim 39, wherein the topical acne agents is selected from the group consisting of tretinoin, benzoyl peroxide, salicylic acid, erythromycin, clindamycin, azelaic acid, adapalene, dapsone, and any combination thereof.

41. The method of claim 39, wherein the topical anesthetics is selected from the group consisting of benzalkonium chloride, lidocaine, prilocaine, benzocaine, pramoxine, dibucaine, and any combination thereof.

42. The method of claim 39, wherein the topical anti-infectives is selected from the group consisting of malathion, sinecatechins, ivermectin, acetic acid, spinosad, benzyl alcohol, crotamiton, imiquimod, permethrin, docosansol, and any combination thereof.

43. The method of claim 39, wherein the topical anti-rosacea agents is selected from the group consisting of azelaic acid, metronidazole, oxymetazoline, brimonidine, and any combination thereof.

44. The method of claim 39, wherein the topical antibiotics is selected from the group consisting of sulfacetamide/sulfur sodium, bacitracin, polymyxin b, erythromycin, silver sulfadiazine, retapamulin, mupirocin, neomycin, and any combination thereof.

45. The method of claim 39, wherein the topical antifungals is selected from the group consisting of benzoic acid, salicylic acid, undecylenic acid, ketoconazole, nystatin, naftifme, tolnaftate, miconazole, zinc oxide, econazole, ciclopirox, oxiconazole, and any combination thereof.

46. The method of claim 39, wherein the topical antihistamines is selected from the group consisting of diphenhydramine, doxepin, and any combination thereof.

47. The method of claim 39, wherein the topical antineoplastics is selected from the group consisting of fluorouracil, ingenol, imiquimod, diclofenac, mechlorethamine, and any combination thereof.

48. The method of claim 39, wherein the topical antipsoriatics is selected from the group consisting of tazarotene, betamethasone, calcipotriene, tazarotene, calcitriol, and any combination thereof.

49. The method of claim 39, wherein the topical antivirals is selected from the group consisting of acyclovir, penciclovir, and any combination thereof.

50. The method of claim 39, wherein the topical astringents is selected from the group consisting of calamine, witch hazel, alum, isopropyl alcohol, ethanol, aluminum acetate, aluminum chloride, aluminum sulfate tetradecahydrate, calcium acetate monohydrate, formaldehyde, and any combination thereof.

51. The method of claim 39, wherein the topical debriding agents is selected from the group consisting of balsam pern, castor oil, trypsin, collagenase, and any combination thereof.

52. The method of claim 39, wherein the topical depigmenting agents is selected from the group consisting of fluocinolone, hydroquinone, tretinoin, hydroquinone, and any combination thereof.

53. The method of claim 39, wherein the topical non-steroidal anti inflammatories is selected from the group consisting of diclofenac, capsaicin, and any combination thereof.

54. The method of claim 39, wherein the topical photochemotherapeutics is selected from the group consisting of aminolevulinic acid, methyl aminolevulinate, methoxsalen, and any combination thereof.

55. The method of claim 39, wherein the topical rubefacient is selected from the group consisting of camphor, menthol, capsaicin, methyl salicylate, and any combination thereof.

56. The method of claim 39, wherein the topical steroids is selected from the group consisting of triamcinolone, fluocinolone, prednicarbate, desonide, betamethasone, halcinonide, hydrocortisone, diflorasone, clobetasol, desoximetasone, clocortolone, and any combination thereof.

57. The method of claim 29, wherein the skin condition is selected from the group consisting of dermatitis; psoriasis; itchy skin; acne; inflammation and redness of the skin; disorders associated with sebaceous glands; oily skin; dry skin; rosacea; burns; disorders affecting the palms or soles; genetic disorders of the skin; warts; and any combination thereof.

58. The method of claim 57, wherein dermatitis is selected from the group consisting of atopic dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, stasis dermatitis, seborrheic dermatitis, chronic dermatitis, eczema, and any combination thereof.

59. The method of claim 57, wherein psoriasis is selected from the group consisting of plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, and any combination thereof.

60. The method of claim 57, wherein itchy skin is selected from the group consisting of pruritus, prurigo, pityriasis rubra pilaris, lichen simplex chronicus, lichen planus, and any combination thereof.

61. The method of claim 57, wherein acne is selected from the group consisting of acne vulgaris, cystic acne, inflammatory acne, non-inflammatory acne, and any combination thereof.

62. The method of claim 57, wherein inflammation and redness of the skin is selected from the group consisting of seborrheic dermatitis, urticaria eczema, hives, seborrheic eczema, and any combination thereof.

63. The method of claim 57, wherein disorders associated with sebaceous glands is selected from the group consisting of acne, follicular hyperkeratinization, sebostasis, sebaceous adenomas, sebaceous hyperplasia, excess sebum production, seborrhea, sebaceoma, sebaceous carcinoma, seborrheic dermatitis, sebaceous cysts, and any combination thereof.

64. The method of claim 57, wherein oily skin is seborrhea.

65. The method of claim 57, wherein dry skin is selected from the group consisting of sebostasis, ichthyosis, xerosis, and any combination thereof.

66. The method of claim 57, wherein burns is sunburn.

67. The method of claim 57, wherein disorders affecting the palms or soles is selected from the group consisting of palmoplantar pustulosis, exfoliative keratolysis, and any combination thereof.

68. The method of claim 57, wherein genetic disorders of the skin is Darier’s disease.

69. The method of claim 29, wherein said patient is an adolescent.

70. The method of claim 29, wherein said skin condition is atopic dermatitis.