WO2024013741A1 - Topical tapinarof composition for treating skin disorders - Google Patents

Topical tapinarof composition for treating skin disorders Download PDF

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Publication number
WO2024013741A1
WO2024013741A1 PCT/IL2023/050720 IL2023050720W WO2024013741A1 WO 2024013741 A1 WO2024013741 A1 WO 2024013741A1 IL 2023050720 W IL2023050720 W IL 2023050720W WO 2024013741 A1 WO2024013741 A1 WO 2024013741A1
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WO
WIPO (PCT)
Prior art keywords
surfactant
another embodiment
composition
amount
tapinarof
Prior art date
Application number
PCT/IL2023/050720
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French (fr)
Inventor
Moshe Arkin
Danil FINKEL-MOISEEV
Hila HAKAK DJERBI
Karine Neimann
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Sol-Gel Technologies Ltd.
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Application filed by Sol-Gel Technologies Ltd. filed Critical Sol-Gel Technologies Ltd.
Publication of WO2024013741A1 publication Critical patent/WO2024013741A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Definitions

  • a topical cream composition comprising tapinarof or a pharmaceutically acceptable salt thereof and uses thereof for treating skin disorders.
  • Tapinarof (3,5-dihydroxy-4-isopropyl-trans-stilbene) is a pharmaceutical active agent investigated for the treatment of atopic dermatitis, psoriasis and psoriatic disorders (Zang YN, et al., Int J Clin Pharmacol Ther. 2016 Feb; 54(2):87-95).
  • the 3,5-dihydroxy-4-isopropyl-stilbene is also known as benvitimod.
  • Tapinarof is a first-in-class drug, whose mechanism is not yet fully understood.
  • Tapinarof is being developed by Glaxo Smith Kline (Stiefel, a GSK company) and Dermavant as a topical drug for treatment of mild to moderate plaque psoriasis and atopic dermatitis. It was shown in both mouse models and in vitro human skin studies to inhibit specific proinflammatory mediators, including interleukin-6 and interleukin- 17 A, and enhance skin barrier function (J Invest Dermatol. 2017 Oct; 137[10]:2110-9).
  • Acne is a chronic inflammatory disease of the pilosebaceous unit resulting from androgen- induced increased sebum production, altered keratinization, inflammation, and bacterial colonisation of hair follicles on the face, neck, chest, and back by Propionib acterium acnes (P. acnes). Although early colonisation with P. acnes and family history might have important roles in the disease, exactly what triggers acne and how treatment affects the course of the disease remains unclear (Williams H.C. et al., The Lancet, Vol.379. Jan 2012, pp. 361-372).
  • Topical therapies including benzoyl peroxide, retinoids, and antibiotics when used in combination usually improve control of mild to moderate acne, but suffer from side-effects.
  • Treatment with combined oral contraceptives can help women with acne. Patients with more severe inflammatory acne usually need oral antibiotics combined with topical benzoyl peroxide to decrease antibiotic-resistant organisms.
  • Oral isotretinoin is the most effective therapy and is used early in severe disease, but its use is limited by teratogenicity and other side-effects.
  • Rosacea is a chronic skin disease that affects more than 16 million Americans. The cause of rosacea is still unknown, and there is no cure. However, research has allowed doctors to find ways to treat the condition by minimizing its symptoms (Cynthia Cobb, Healthline May 21, 2018). [010] There are four subtypes of rosacea. Each subtype has its own set of symptoms. It is possible to have more than one subtype of rosacea at a time.
  • Rosacea typical symptom is small, red, pus-filled bumps on the skin that are present during flare-ups. Typically, rosacea affects only skin on the nose, cheeks, and forehead.
  • Flare-ups often occur in cycles. This means that one will experience symptoms for weeks or months at a time, the symptoms will go away, and then return.
  • Subtype one known as erythematotelangiectatic rosacea (ETR) is associated with facial redness, flushing, and visible blood vessels.
  • ETR erythematotelangiectatic rosacea
  • Subtype two, papulopustular (or acne) rosacea is associated with acne-like breakouts, and often affects middle-aged women.
  • Subtype three known as rhinophyma, is a rare form associated with thickening of the skin on your nose. It usually affects men and is often accompanied by another subtype of rosacea.
  • Subtype four is known as ocular rosacea, and its symptoms are centered on the eye area.
  • Dermatitis is a group of diseases resulting in skin inflammation, itchiness, red skin and rash.
  • the dermatitis group of diseases includes atopic dermatitis (AD), allergic contact dermatitis, irritant contact dermatitis and stasis dermatitis.
  • Atopic dermatitis is the most common type of dermatitis.
  • PN is characterized by hyperkeratotic excoriated papulonodular (itchy) lesions that show symmetrical distribution on the extensor surfaces of the body and/or extremities, the numbers of which range from several to hundreds (Akarsu, S. et al. An Bras Dermatol . 2018;93(5):671-9.). It is a rare disease and is one of the most difficult conditions in terms of determining its etiology and treatment among chronic skin diseases.
  • Hidradenitis suppurativa also known as acne inversa, is a long-term chronic skin disease whose present treatment options are often unsatisfactory. HS has a profound effect on patient’s quality of life (QoL). Alavi A. et al., reviewed QoL aspects of this disease in an article titled “Quality-of-Life Impairment in Patients with Hidradenitis Suppurativa” Am J Clin Dermatol . 2015
  • the clinical picture of HS includes solitary nodules, diffuse, painful abscesses, malodorous drainage, sinus tract formation and scarring.
  • a topical cream composition comprising from about 1% w/w to about 2% w/w tapinarof or a pharmaceutically acceptable salt thereof and less than 1% w/w surfactant.
  • the surfactant is ionic or non ionic.
  • the surfactant is anionic.
  • a topical cream composition comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, and optionally from about 0.01% to about 1% w/w an anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • a method of treating a skin disorder in a patient in need thereof comprises administering to said patient the topical cream composition provided herein, wherein said skin disorder is selected from the group consisting from psoriasis, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus (e.g.
  • alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and extensive pyodermas, acne, rosacea, atopic dermatitis, prurigo nodularis and hidradenitis suppurativa.
  • Figure 1 depicts epidermal thickness in human xenograft psoriasis model in SCID mice following treatment with the tapinarof cream or dexamethasone vs. vehicle.
  • Figure 2 depicts epidermal thickness in human xenograft psoriasis model in SCID mice following treatment with the tapinarof cream A or cream D vs dexamethasone.
  • Figure 3 depicts proliferation index in human xenograft psoriasis model in SCID mice following treatment with the tapinarof cream A or cream D vs dexamethasone.
  • a topical cream composition comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof and less than 1% w/w surfactant.
  • the surfactant is non-ionic.
  • the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is cationic.
  • a topical cream composition comprising from about 1% w/w to about 2 % w/w tapinarof or a pharmaceutically acceptable salt thereof and less than 1% w/w surfactant.
  • this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 1% w/w to about 20% surfactant, and optionally from about 0.01% to about 1% w/w an anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is cationic.
  • the present invention provides a composition comprising tapinarof with lower concentrations of less than 1% of surfactant that provides stable formulations that are effective and safe and do not cause any irritations.
  • These formulations contain non-ionic surfactants of less than 1% or non-irritant ionic surfactants, at concentrations of less than 1% or higher.
  • the present invention also provides tapinarof compositions containing non-irritatant ionic surfactants, at concentrations of less than 1% or higher.
  • the ionic surfactant is anionic.
  • the ionic surfactant is cationic.
  • an anionic surfactant is selected from the group consisting of alkyl sulfates (e.g., sodium lauryl sulfate, ammonium lauryl sulfate and ammonium laureth sulfate); sulfosuccinates (e g., disodium lauryl sulfosuccinate, disodium laureth sulfosuccinate, sodium dioctyl sulfosuccinate and their mixtures with sulfonic acids and lauramidopropyl betaine; alkyl benzene sulfonates (e.g., sodium tosylate, cumene sulfonate, toluene sulfonic acid, xylene sulfonic acid, cumene sulfonic acid and salts (e.g., sodium, potassium, calcium, ammonium) thereof); acyl methyl taurates (e.g., sodium, potassium, calcium, ammoni
  • the anionic surfactant comprises Carbomer Copolymer Type B (Pemulen®TR-l), sodium lauryl sulfate, sodium dodecyl sulfate, or dioctyl sodium sulfosuccinate (docusate sodium).
  • the anionic surfactant is Carbomer Copolymer Type B (Pemulen®TR-l).
  • the anionic surfactant is sodium lauryl sulfate.
  • the anionic surfactant is docusate sodium.
  • a cationic surfactant is selected from the group consisting of quaternary ammonium compounds (e.g., benzalkonium chloride, stearalkonium chloride, centrimonium chloride, and trimethyl ammonium methyl sulfates).
  • quaternary ammonium compounds e.g., benzalkonium chloride, stearalkonium chloride, centrimonium chloride, and trimethyl ammonium methyl sulfates.
  • non-ionic surfactant comprises polysorbate 80, sorbitan monooleate, polysorbate 20, polysorbate 60, cetearyl alcohol, glyceryl oleate, glyceryl stearate, ethoxylated fatty alcohol, ethers, PEG castor oils, PEG esters, PEG 100 stearate, propylene glycol esters (e.g. propylene glycol laurate, propylene glycol palmitostearate, propylene glycol ricinoleate and propylene glycol stearate), glyceryl esters and derivatives (e.g.
  • Sorbitan derivatives e.g. polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, sorbitan isostearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate and sorbitan tri stearate
  • fatty alcohols e.g.
  • emulsifying waxes e.g. mixture of cetearyl alcohol and polysorbate 60 or “Pol a wax NFTM, and pol oxamers or combination thereof.
  • the composition provided herein further comprises from about 0.1% to about 4% w/w gelling agent. In some embodiments, the composition provided herein comprises from about 0.01% to about 1% w/w anti-oxidant.
  • the composition provided herein comprises from about 0.1% w/w to about 20% w/w surfactant. In some embodiments, the composition provided herein comprises less than 5% w/w of the surfactant. In some embodiments, the composition provided herein comprises less than 1% w/w of the surfactant. In other embodiments, the surfactant is in an amount of about 5% w/w to about 20% w/w. In other embodiments, the surfactant is in an amount of about 10% w/w to about 20% w/w. In other embodiments, the surfactant is in an amount of about 15% w/w to about 20% w/w.
  • the surfactant is in an amount of about 5% w/w to about 10% w/w. In other embodiments, the surfactant is in an amount of about 5% w/w. In other embodiments, the surfactant is in an amount of about 1% w/w to about 5% w/w. In other embodiments, the composition comprises the surfactant in an amount of about 0.1% to about 5% w/w. In other embodiments, the surfactant is in an amount of about 0.1% to about 4% w/w. In other embodiments, the surfactant is in an amount of about 0.1% to about 3% w/w. In other embodiments, the surfactant is in an amount of about 0.1% to about 2% w/w.
  • the surfactant is in an amount of about 0.1% to about 1.5% w/w. In other embodiments, the surfactant is in an amount of about 0.1 to about 1% w/w. In other embodiments, the surfactant is in an amount of about 0.1 to about 0.5% w/w. In other embodiments, the surfactant is in an amount of about 0.1 to about 0.3% w/w. In other embodiments, the surfactant is in an amount of about 0.1 to about 0.2% w/w. In some other embodiments, the surfactant is in an amount of about 0.4 % w/w. In other embodiments, the surfactant is in an amount of about 0.2% to about 0.8 % w/w.
  • the surfactant is ionic. In other embodiments, the surfactant is anionic. In other embodiments, the surfactant is cationic. In other embodiments, the surfactant is non-ionic. In other embodiments, the surfactant is Carbomer Copolymer Type B. In other embodiments, the surfactant is in an amount of about 0.4% w/w Carbomer Copolymer Type B. In other embodiments, the surfactant is in an amount of about 0.2% to about 0.8 % w/w Carbomer Copolymer Type B. In other embodiments, the surfactant is docusate sodium. In other embodiments, the surfactant is sodium lauryl sulfate.
  • the composition provided herein comprises a gelling agent.
  • the composition further comprises an additional gelling agent.
  • the gelling agent and the additional gelling agent are each independently selected from a group consisting of a carbomer, Natrosol hydroxyethylcellulose, starch, pectin, gelatin, agar, alginic acid and salts thereof, carboxymethylcellulose, hydroxypropylmethylcellulose and any combination thereof.
  • the gelling agent or the additional gelling agent is Carbomer Homopolymer Type C (Carbopol®980).
  • the gelling agent or the additional gelling agent is Carbomer Homopolymer Type C (Carbopol ®980), in an amount of about 0.1% to about 4% w/w. In other embodiments, the gelling agent or the additional gelling agent is Carbomer Homopolymer Type C (Carbopol®980), in an amount of 1% w/w, 2%w/w, 3% w/w or 4% w/w.
  • composition provided herein is not a lotion.
  • compositions provided herein does not include DMSO.
  • the gelling agent and/or additional gelling agent is in an amount of about 0.1% to about 4% w/w. In other embodiments, the gelling agent and/or additional gelling agent is in an amount of about 0.1% to about 2% w/w. In other embodiments, the gelling agent and/or additional gelling agent is in an amount of about 0.1% to about 1% w/w. In other embodiments, the gelling agent and/or additional gelling agent is in an amount of about 0.1% to about 0.5% w/w. In other embodiments, the gelling agent and/or additional gelling agent is in an amount of about 0.5% to about 4% w/w.
  • the gelling agent and/or additional gelling agent is in an amount of about 0.5% to about 2% w/w. In other embodiments, the gelling agent and/or additional gelling agent is in an amount of about 0.5% to about 1% w/w. In other embodiments, the gelling agent and/or additional gelling agent is in an amount of about 1% to about 4% w/w. In other embodiments, the gelling agent and/or additional gelling agent is in an amount of about 1% to about 2% w/w.
  • the composition further comprises an additional surfactant.
  • the additional surfactant is in an amount of about 0.1% to about 4% w/w. In other embodiments, the additional surfactant is in an amount of about 0.1% to about 2% w/w. In other embodiments, the additional surfactant is in an amount of about 0.1% to about 1.5% w/w. In other embodiments, the additional surfactant is in an amount of about 0.1% to about 1% w/w. In other embodiments, the additional surfactant is in an amount of about 0.1% to about 0.5% w/w. In other embodiments, the additional surfactant is in an amount of about 0.5% to about 4% w/w.
  • the additional surfactant is in an amount of about 0.5% to about 2% w/w. In another embodiment, the additional surfactant is in an amount of about 0.5% to about 1.5% w/w. In another embodiment, the additional surfactant is in an amount of about 0.5% to about 1% w/w. In another embodiment, the additional surfactant is in an amount of about 1% to about 4% w/w. In another embodiment, the additional surfactant is in an amount of about 1% to about 2% w/w. Each possibility represents a separate embodiment of this invention.
  • the composition further comprises from about 0.1% to about 1.5% w/w preservative.
  • the preservative is selected from benzoic acid, methylparaben, phenoxyethanol, imidurea, chlorocresol, propyl paraben, benzalkonium chloride, benzyl alcohol, imidazolidinyl urea, sodium benzoate, sorbic acid, thimerosal sorbic acid, sodium sorbate, sodium sulfite, ethanol, tocopherols and any combination thereof.
  • the preservative is methylparaben.
  • the preservative is phenoxyethanol.
  • the preservative is a combination of methylparaben and phenoxyethanol. In other embodiments, the preservative is methylparaben in an amount of 0.3% w/w. In other embodiments, the preservative is phenoxyethanol in an amount of 0.5% w/w. In other embodiments, the preservative is a combination of methylparaben in an amount of 0.3% w/w and phenoxyethanol in an amount of 0.5% w/w.
  • the composition further comprises from about 0.1% to about 1.5% w/w preservative.
  • the preservative is in an amount of about 0.1% to about 1% w/w. In other embodiments, the preservative is in an amount of about 0.1% to about 0.5% w/w. In other embodiments, the preservative is in an amount of about 0.5% to about 1.5% w/w. In other embodiments, the preservative is in an amount of about 0.5% to about 1% w/w. In other embodiments, the preservative is in an amount of 0.5%. In other embodiments, the preservative is in an amount of 0.3%.
  • the composition further comprises penetration enhancer.
  • the penetration enhancer is selected from dimethylsulfoxide (DMSO), diethylene glycol monoethyl ether (Transcutol), methyl sulfonylmethane (MSM), propylene glycol, dimethyl isosorbide, oleic acid, oleyl alcohol, ethanol, isopropyl alcohol, a polyethylene glycol, hexylene glycol, glycofurol, isopropyl myristate, glycerin, mono- and di- carboxylic acid esters and any combination thereof.
  • the penetration enhancer is diethylene glycol monoethyl ether (Transcutol).
  • the penetration enhancer is propylene glycol. In other embodiments, the penetration enhancer is diethylene glycol monoethyl ether (Transcutol), in an amount of 5% w/w. In other embodiments, the penetration enhancer is propylene glycol in an amount of 15% w/w. In other embodiments, the penetration enhancer is a combination of diethylene glycol monoethyl ether (Transcutol), in an amount of 5% w/w and propylene glycol in an amount of 15% w/w. In some embodiments, in addition and/or instead said penetration enhancer - water is added to the composition. In another embodiment, the penetration enhancer is not dimethylsulfoxide (DMSO).
  • DMSO dimethylsulfoxide
  • the composition comprises a penetration enhancer in an amount of about 0.1% to about 20% w/w. In other embodiments, the penetration enhancer is in an amount of about 0.1% to about 15% w/w. In other embodiments, the penetration enhancer is in an amount of about 0.1% to about 10% w/w. In other embodiments, the penetration enhancer is in an amount of about 0.1% to about 5% w/w. In other embodiments, the penetration enhancer is in an amount about of 0.1% to about 2% w/w. In other embodiments, the penetration enhancer is in an amount of about 0.1% to about 1% w/w. In other embodiments, the penetration enhancer is in an amount of about 0.1% to about 0.5% w/w.
  • the penetration enhancer is in an amount of about 0.5% to about 20% w/w. In other embodiments, the penetration enhancer is in an amount of about 0.5% to about 15% w/w. In other embodiments, the penetration enhancer is in an amount of about 0.5% to about 10% w/w. In other embodiments, the penetration enhancer is in an amount of about 0.5% to about 5% w/w. In other embodiments, the penetration enhancer is in an amount of about 0.5% to about 2% w/w. In other embodiments, the penetration enhancer is in an amount of about 0.5% to about 1% w/w. In other embodiments, the penetration enhancer is in an amount of about 1% to about 20% w/w.
  • the penetration enhancer is in an amount of about 1% to about 15% w/w. In other embodiments, the penetration enhancer is in an amount of about 1% to about 10% w/w. In other embodiments, the penetration enhancer is in an amount of about 1% to about 5% w/w. In other embodiments, the penetration enhancer is in an amount of about 1% to about 2% w/w. In other embodiments, the penetration enhancer is in an amount of about 2% to about 20% w/w. In other embodiments, the penetration enhancer is in an amount of about 2% to about 15% w/w. In other embodiments, the penetration enhancer is in an amount of about 2% to about 10% w/w.
  • the penetration enhancer is in an amount of about 2% to about 5% w/w. In other embodiments, the penetration enhancer is in an amount of about 5% to about 20% w/w. In other embodiments, the penetration enhancer is in an amount of about 5% to about 15% w/w. In other embodiments, the penetration enhancer is in an amount of about 5% to about 10% w/w. In other embodiments, the penetration enhancer is in an amount of about 10% to about 20% w/w. In other embodiments, the penetration enhancer is in an amount of about 10% to about 15% w/w. In other embodiments, the penetration enhancer is in an amount of about 15% to about 20% w/w.
  • the penetration enhancer is in an amount of 5% w/w, 6% w/w, 7% w/w, 8% w/w, 9% w/w, 10% w/w, 11% w/w, 12% w/w, 13% w/w, 14% w/w, 15% w/w, 16% w/w, 17% w/w, 18% w/w, 19% w/w, 20% w/w or any ranges thereof.
  • the composition further comprises an emollient.
  • the emollient include: coconut fatty acid di ethanol ami de, petrolatum, mineral oil light, castor oil and any combination thereof.
  • the emollient is in a weight of about 0.01 to about 2 % w/w. In one embodiment, the emollient is in a weight of about 0.01 to about 1.5 % w/w. In another embodiment, the emollient is in a weight of about 0.01 to about 1 % w/w. In another embodiment, the emollient is in a weight of about 0.01 to about 0.5 % w/w. In another embodiment, the emollient is in a weight of about 0.01 to about 0.2 % w/w. In another embodiment, the emollient is in a weight of about 0.01 to about 0.1 % w/w.
  • the emollient is in a weight of about 0.1 to about 2 % w/w. In another embodiment, the emollient is in a weight of about 0.1 to about 1.5 % w/w. In another embodiment, the emollient is in a weight of about 0.1 to about 1 % w/w. In another embodiment, the emollient is in a weight of about 0.1 to about 0.5 % w/w. In another embodiment, the emollient is in a weight of about 0.1 to about 0.2 % w/w. In another embodiment, the emollient is in a weight of about 0.2 to about 2 % w/w.
  • the emollient is in a weight of about 0.2 to about 1.5 % w/w. In another embodiment, the emollient is in a weight of about 0.2 to about 1 % w/w. In another embodiment, the emollient is in a weight of about 0.2 to about 0.5 % w/w. In another embodiment, the emollient is in a weight of about 0.5 to about 2 % w/w. In another embodiment, the emollient is in a weight of about 0.5 to about 1.5 % w/w. In another embodiment, the emollient is in a weight of about 0.5 to about 1 % w/w.
  • the emollient is in a weight of about 1 to about 2 % w/w. In another embodiment, the emollient is in a weight of about 1.5 to about 2 % w/w. In another embodiment, the emollient is in a weight of about 1 to about 1.5 % w/w.
  • the composition further comprises a chelating agent.
  • a chelating agent include: ethylenediaminetetraacetic acid (EDTA), nitrolotriacetic acid (NTA) and citric acid.
  • the chelating agent is in a weight of about 0.01 to about 2 % w/w. In one embodiment, the chelating agent is in a weight of about 0.01 to about 1.5 % w/w. In another embodiment, the chelating agent is in a weight of about 0.01 to about 1 % w/w. In another embodiment, the chelating agent is in a weight of about 0.01 to about 0.5 % w/w. In another embodiment, the chelating agent is in a weight of about 0.01 to about 0.2 % w/w. In another embodiment, the chelating agent is in a weight of about 0.01 to about 0.1 % w/w.
  • the chelating agent is in a weight of about 0.1 to about 2 % w/w. In another embodiment, the chelating agent is in a weight of about 0.1 to about 1.5 % w/w. In another embodiment, the chelating agent is in a weight of about 0.1 to about 1 % w/w. In another embodiment, the chelating agent is in a weight of about 0.1 to about 0.5 % w/w. In another embodiment, the chelating agent is in a weight of about 0.1 to about 0.2 % w/w. In another embodiment, the chelating agent is in a weight of about 0.2 to about 2 % w/w.
  • the chelating agent is in a weight of about 0.2 to about 1.5 % w/w. In another embodiment, the chelating agent is in a weight of about 0.2 to about 1 % w/w. In another embodiment, the chelating agent is in a weight of about 0.2 to about 0.5 % w/w. In another embodiment, the chelating agent is in a weight of about 0.5 to about 2 % w/w. In another embodiment, the chelating agent is in a weight of about 0.5 to about 1.5 % w/w. In another embodiment, the chelating agent is in a weight of about 0.5 to about 1 % w/w.
  • the chelating agent is in a weight of about 1 to about 2 % w/w. In another embodiment, the chelating agent is in a weight of about 1.5 to about 2 % w/w. In another embodiment, the chelating agent is in a weight of about 1 to about 1.5 % w/w. In another embodiment, the chelating agent is in a weight of 0.1 % w/w.
  • the composition further comprises a pH adjusting agent.
  • the pH adjusting agent include: sodium hydroxide, potassium hydroxyide, hydrochloric acid, sodium acetate, acetic acid, ammonium acetate, ammonium sulfate, ammoniu hydroxide, arginine, aspartic acid and salts thereof, bicarbonate salts, carbonate salts, citric acid and salts thereof, diethanolamine, glycine, lysine, boric acid and salts thereof and phosphate salts.
  • the pH adjusting agent is in a weight of about 0.01 to about 5 % w/w. In one embodiments the pH adjusting agent is in a weight of about 0.01 to about 2 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.01 to about 1.5 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.01 to about 1 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.01 to about 0.5 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.01 to about 0.2 % w/w.
  • the pH adjusting agent is in a weight of about 0.01 to about 0.1 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.1 to about 5 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.1 to about 2 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.1 to about 1.5 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.1 to about 1 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.1 to about 0.5 % w/w.
  • the pH adjusting agent is in a weight of about 0.1 to about 0.2 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.2 to about 5 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.2 to about 2 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.2 to about 1.5 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.2 to about 1 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.2 to about 0.5 % w/w.
  • the pH adjusting agent is in a weight of about 0.5 to about 5 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.5 to about 2 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.5 to about 1.5 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.5 to about 1 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 1 to about 5 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 1 to about 2 % w/w.
  • the pH adjusting agent is in a weight of about 1.5 to about 2 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 1 to about 1.5 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 1.5 to about 5 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 2 to about 5 % w/w. In another embodiment, the pH adjusting agent is in a weight of 1 % w/w.
  • the purity of the tapinarof is greater than 97%. In some embodiments, the purity of the tapinarof is greater than 98%. In some embodiments, the purity of the tapinarof is greater than 99%. In some embodiments, the purity of the tapinarof is greater than 99.5%. In some embodiments, the purity of the tapinarof is between 97% and 99.99%. In some embodiments, the purity of the tapinarof is between 99% and 99.99%.
  • the composition comprises tapinarof in an amount of about 0.25% to about 10% w/w. In other embodiments, the tapinarof is in an amount of about 0.25% to about 5% w/w. In other embodiments, the tapinarof is in an amount of about 0.25% to about 2% w/w. In other embodiments, the tapinarof is in an amount of about 0.25% to about 1% w/w. In other embodiments, the tapinarof is in an amount of about 0.25% to about 0.5% w/w. In other embodiments, the tapinarof is in an amount of about 0.5% to about 10% w/w.
  • the tapinarof is in an amount of about 0.5% to about 5% w/w. In other embodiments, the tapinarof is in an amount of about 0.5% to about 2% w/w. In another embodiment, the tapinarof is in an amount of about 0.5% to about 1% w/w. In other embodiments, the tapinarof is in an amount of about 1% to about 10% w/w. In another embodiment, the tapinarof is in an amount of about 1% to about 5% w/w. In other embodiments, the tapinarof is in an amount of about 1% to about 2% w/w. In other embodiments, the tapinarof is in an amount of about 2% to about 10% w/w.
  • the tapinarof is in an amount of about 2% to about 5% w/w. In other embodiments, the tapinarof is in an amount of about 5% to about 10% w/w. In other embodiments, the tapinarof is in an amount of 1.5% w/w. In other embodiments, the tapinarof is in an amount of 1 % w/w. In other embodiments the tapinarof is in an amount from about 1% w/w to about 2% w/w.
  • the tapinarof is in an amount of 0.75% w/w, 1% w/w, 2% w/w, 3% w/w, 4% w/w, 5% w/w, 6% w/w, 7% w/w, 8% w/w, 9% w/w, 10% w/w or any ranges thereof.
  • the composition comprises from about 0.01% to about 1% w/w an anti-oxidant.
  • the anti-oxidant is selected from the group consisting from butylated hydroxy toluene (BHT), parabens, propyl gallate, ascorbic acid, flavones, flavanones, flavonols, stilbenoids, gallic acid, cinnamic acid, ellagic acid, salicylic acid, curcumin, eugenol, citric acid, tocopherol, vitamin E, tocopherol polyethylene glycol succinate (TPGS), and any combination thereof.
  • the anti-oxidant is butylated hydroxy toluene (BHT).
  • the anti-oxidant is butylated hydroxy toluene (BHT), in an amount of 0.1% w/w.
  • the composition comprises from about 0.01% to about 1% w/w an anti-oxidant.
  • the anti-oxidant is in an amount of about 0.01% to about
  • the anti-oxidant is in an amount of about 0.01% to about 0.05% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.01% to about 0.1% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.01% to about 0.2% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.01% to about 0.5% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.02% to about 1% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.02% to about 0.05% w/w.
  • the anti-oxidant is in an amount of about 0.02% to about 0.1% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.02% to about 0.2% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.02% to about 0.5% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.05% to about 1% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.05% to about 0.1% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.05% to about 0.2% w/w.
  • the anti-oxidant is in an amount of about 0.05% to about 0.5% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.1% to about 1% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.1% to about 0.2% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.1% to about 0.5% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.2% to about 0.5% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.2% to about 1% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.5% to about 1% w/w. In other embodiments, the anti-oxidant is in an amount of 0.5%. In another embodiment, the anti-oxidant is in an amount of 0.1%.
  • compositions provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.
  • compositions suitable for administration of the active agents include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.
  • the active agents may be formulated as the sole pharmaceutically active agent in the composition or may be combined with other active agents.
  • the active agents are included in the carrier in an amount sufficient to exert a therapeutically useful effect.
  • emollient or lubricating vehicles that help hydrate the skin are more preferred than volatile vehicles, such as ethanol, that dry the skin.
  • suitable bases or vehicles for preparing compositions for use with human skin are petrolatum, petrolatum plus volatile silicones, lanolin, cold cream and hydrophilic ointment.
  • Suitable pharmaceutically and dermatologically acceptable vehicles are organic in nature or an aqueous emulsion and capable of having the selected compound or compounds, which may be micronized, dispersed, suspended or dissolved therein.
  • the vehicle may include pharmaceutically-acceptable emollients, moisturizers, including lactic acid, ammonium lactate and urea, skin penetration enhancers, coloring agents, fragrances, emulsifiers, thickening agents, vegetable oils, essential oils, zinc oxide and solvents.
  • the composition according to the invention is a cream.
  • a fatty or oily phase in an aqueous phase (O/W) or conversely (W/O)
  • the composition can be in a form of suspensions or emulsions of soft, semi-liquid or solid consistency of a cream, or alternatively multiple emulsions (W/O/W or O/W/O), microemulsions, microcapsules, microparticles or vesicular dispersions of ionic and/or nonionic type, or wax/aqueous phase dispersions.
  • the composition according to the invention is a cream or an emulsion.
  • this invention provides a method of treating a skin disorder in a patient in need thereof, said method comprises administering to said patient the topical cream composition as described herein, wherein said skin disorder is selected from psoriasis, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus (e.g.
  • alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and extensive pyodermas, acne, rosacea, atopic dermatitis, prurigo nodularis and hidradenitis suppurativa.
  • the acne is selected from acne vulgaris, papulopustular acne and nodular acne.
  • the rosacea is selected from erythematotelangiectatic rosacea, papulopustular rosacea, rhinophyma rosacea and ocular rosacea.
  • this invention provides a method of treating a skin disorder in a patient in need thereof, said method comprises administering to said patient the topical cream composition comprising from about 1% w/w to about 2% w/w tapinarof or a pharmaceutically acceptable salt thereof and less than 1% w/w surfactant; wherein said skin disorder is selected from psoriasis, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus (e.g.
  • alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and extensive pyodermas, acne, rosacea, atopic dermatitis, prurigo nodularis and hidradenitis suppurativa.
  • the surfactant is ionic or non-ionic.
  • the surfactant is anionic.
  • the surfactant is cationic.
  • this invention provides a method of treating a skin disorder in a patient in need thereof, said method comprises administering to said patient the topical cream composition comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof and less than 1% w/w surfactant; wherein said skin disorder is selected from psoriasis, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus (e.g.
  • alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and extensive pyodermas, acne, rosacea, atopic dermatitis, prurigo nodularis and hidradenitis suppurativa.
  • the surfactant is ionic or non-ionic.
  • the surfactant is anionic.
  • the surfactant is cationic.
  • this invention provides a method of treating a skin disorder in a patient in need thereof, said method comprises administering to said patient the topical cream composition comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, and optionally from about 0.01% to about 1% w/w an anti-oxidant, wherein the surfactant is ionic; wherein said skin disorder is selected from psoriasis, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus (e.g.
  • alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and extensive pyodermas, acne, rosacea, atopic dermatitis, prurigo nodularis and hidradenitis suppurativa.
  • the surfactant is anionic.
  • the surfactant is cationic.
  • the methods and compositions provided herein are for use in the treatment of atopic eczema. In some embodiments, the methods and compositions provided herein are for use in the treatment of seborrheic eczema. In some embodiments, the methods and compositions provided herein are for use in the treatment of lichen simplex. In some embodiments, the methods and compositions provided herein are for use in the treatment of sunburn, pruritus (e.g. in the genitoanal region). In some embodiments, the methods and compositions provided herein are for use in the treatment of alopecia areata. In some embodiments, the methods and compositions provided herein are for use in the treatment of hypertrophic scars.
  • the methods and compositions provided herein are for use in the treatment of discoid lupus erythematosus. In some embodiments, the methods and compositions provided herein are for use in the treatment of follicular and extensive pyodermas. In some embodiments, the methods and compositions provided herein are for use in the treatment of acne. In some embodiments, the methods and compositions provided herein are for use in the treatment of rosacea. In some embodiments, the methods and compositions provided herein are for use in the treatment of atopic dermatitis. In some embodiments, the methods and compositions provided herein are for use in the treatment of prurigo nodularis. In some embodiments, the methods and compositions provided herein are for use in the treatment of hidradenitis suppurativa.
  • Dosage frequencies can be gradually attenuated over time and maintained at a steady dose suitable for long-term - six months, 1 year, 5 years, 10 years or more, up to lifelong administration to control the symptoms of the hidradenitis suppurativa.
  • dosage administration can begin at from twice a day, to once a day, to two times a week, to once a week, to once every two weeks or less frequent than once every two weeks.
  • the frequency of administration can be determined empirically. Exemplary frequencies are once daily, twice daily, weekly, bi-weekly or monthly.
  • Typical administration frequencies of the topical combination compositions of this invention are once daily and twice daily.
  • Dosage frequencies can be gradually attenuated over time and maintained at a steady dose suitable for long-term - six months, 1 year, 5 years, 10 years or more, up to lifelong administration to control the symptoms of said skin disorders.
  • dosage administration can begin at from twice a day, to once a day, to two times a week, to once a week, to once every two weeks or less frequent than once every two weeks.
  • kits containing the compositions of this invention optionally including instructions for administration.
  • the combinations include, for example, the compositions as provided herein. Additionally, provided herein are kits containing the above-described combinations and optionally instructions for administration by topical, transdermal, or other routes, depending on the composition to be delivered.
  • compositions provided herein can be packaged as articles of manufacture containing packaging material, a composition provided herein, and a label that indicates that the composition is for treating the skin disorders/diseases described hereinabove, and is formulated for topical delivery.
  • packaging materials for use in packaging pharmaceutical products are well known to those of skill in the art.
  • Examples of pharmaceutical packaging materials include, but are not limited to bottles, tubes, containers, application syringes and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
  • a topical cream composition comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, and less than 1% w/w surfactant.
  • the surfactant is ionic or non-ionic.
  • a topical cream composition comprising from about from about 1% w/w to about 2% w/w tapinarof or a pharmaceutically acceptable salt thereof, and less than 1% w/w surfactant.
  • the surfactant is ionic or non-ionic.
  • a topical cream composition comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, and optionally from about 0.01% to about 1% w/w an antioxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is cationic.
  • a topical cream composition comprising from about 1% w/w to about 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, and optionally from about 0.01% to about 1% w/w an antioxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is cationic.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate or docusate sodium.
  • this invention provides a topical cream composition, comprising 1% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, and optionally from about 0.01% to about 1% w/w an anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the surfactant is anionic.
  • the surfactant is cationic.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR- 1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising 1% w/w tapinarof or a pharmaceutically acceptable salt thereof, and less than 1% w/w surfactant.
  • the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is non-ionic.
  • this invention provides a topical cream composition, comprising 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, and less than 1% w/w surfactant.
  • the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is non-ionic.
  • this invention provides a topical cream composition, comprising from about 1% w/w to about 2% w/w tapinarof or a pharmaceutically acceptable salt thereof, less than 1% w/w surfactant and from about 0.1% to about 4% w/w gelling agent.
  • the surfactant is ionic or non-ionic.
  • the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is selected from the group consisting of Carbomer Copolymer Type B, polysorbate 80, sorbitan monooleate, polysorbate 20, PEG 100 stearate, polysorbate 60, sodium dodecyl sulfate,
  • this invention provides a topical cream composition, comprising from about 1% w/w to about 2% w/w tapinarof or a pharmaceutically acceptable salt thereof, less than 1% w/w surfactant wherein the surfactant is ionic.
  • this invention provides a topical cream composition, comprising from about 1% w/w to about 2% w/w tapinarof or a pharmaceutically acceptable salt thereof, less than 1% w/w surfactant wherein the surfactant is non-ionic.
  • the surfactant is selected from the group consisting of Carbomer Copolymer Type B, polysorbate 80, sorbitan monooleate, polysorbate 20, PEG 100 stearate,
  • the surfactant is selected from the group consisting of Carbomer Copolymer Type B, polysorbate 80, sorbitan monooleate, polysorbate 20, PEG 100 stearate
  • the surfactant is selected from the group consisting of Carbomer Copolymer Type B, polysorbate 80, sorbit
  • this invention provides a topical cream composition, comprising from about 1% w/w to about 2% w/w tapinarof or a pharmaceutically acceptable salt thereof, less than 1% w/w surfactant, from about 0.1% to about 4% w/w gelling agent and from about 0.01% to about 1% w/w antioxidant.
  • the surfactant is ionic or non-ionic.
  • the surfactant is ionic.
  • the surfactant is anionic.
  • this invention provides a topical cream composition, comprising from about 1% w/w to about 2% w/w tapinarof or a pharmaceutically acceptable salt thereof, less than 1% w/w surfactant and from about 0.01% to about 1% w/w anti-oxidant.
  • the surfactant is ionic or non-ionic.
  • the surfactant is ionic.
  • the surfactant is anionic.
  • this invention provides a topical cream composition, comprising 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, and optionally from about 0.01% to about 1% w/w an anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the surfactant is less than 1% w/w.
  • the surfactant is anionic.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, and optionally from about 0.01% to about 1% w/w an anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the surfactant is less than 1% w/w.
  • the surfactant is anionic.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising 1% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, and optionally from about 0.01% to about 1% w/w an anti-oxidant, wherein the surfactant is ionic. .
  • the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w.
  • the surfactant is less than 1% w/w. In another embodiment, the surfactant is anionic. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising 1% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w gelling agent and optionally from about 0.01% to about 1% w/w an anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is Carbomer Copolymer Type B or docusate sodium
  • the gelling agent is Carbomer Homopolymer Type C (Carbopol®980).
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w.
  • this invention provides a topical cream composition, comprising 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w gelling agent and optionally from about 0.01% to about 1% w/w an anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is Carbomer Copolymer Type B or docusate sodium
  • the gelling agent is Carbomer Homopolymer Type C (Carbopol®980).
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w.
  • this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w gelling agent and optionally from about 0.01% to about 1% w/w an anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof, and the gelling agent is Carbomer Homopolymer Type C (Carbopol®980).
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w.
  • this invention provides a topical cream composition, comprising 1% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w gelling agent, an additional gelling agent and optionally from about 0.01% to about 1% w/w an anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the surfactant is less than 1% w/w.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w gelling agent, an additional gelling agent and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the surfactant is less than 1% w/w.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w gelling agent, an additional gelling agent and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the surfactant is less than 1% w/w.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising 1% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w gelling agent, an additional gelling agent and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic, and the gelling agent is Carbomer Homopolymer Type C (Carbopol®980).
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the surfactant is less than 1% w/w.
  • the surfactant is anionic.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w gelling agent, an additional gelling agent and from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic, and the gelling agent is Carbomer Homopolymer Type C (Carbopol®980).
  • the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the surfactant is less than 1% w/w.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w gelling agent, an additional gelling agent and from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic, and the gelling agent is Carbomer Homopolymer Type C (Carbopol®980).
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the surfactant is less than 1% w/w.
  • the surfactant is anionic.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 4% w/w additional gelling agent and from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the surfactant is less than 1% w/w.
  • the surfactant is anionic.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 4% w/w additional gelling agent and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the surfactant is less than 1% w/w.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 4% w/w additional gelling agent and optionally from about 0.01% to about 1% w/w antioxidant, wherein the surfactant is ionic, and the gelling agent is Carbomer Homopolymer Type C (Carbopol®980). In another embodiment the surfactant is anionic.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w.
  • this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 4% w/w additional gelling agent and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic, and the gelling agent is Carbomer Homopolymer Type C (Carbopol®980).
  • the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the surfactant is less than 1% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, an additional surfactant, , and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the surfactant is less than 1% w/w.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, an additional surfactant, and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the surfactant is less than 1% w/w.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof from about 0.1% w/w to about 20% surfactant, an additional surfactant, from about 0.1% to about 4% w/w gelling agent, and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic, and the gelling agent is Carbomer Homopolymer Type C (Carbopol®980).
  • the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the surfactant is less than 1% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, an additional surfactant, from about 0.1% to about 4% w/w gelling agent, and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic, and the gelling agent is Carbomer Homopolymer Type C (Carbopol®980).
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the surfactant is less than 1% w/w.
  • the surfactant is anionic.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, an additional surfactant, from about 0.1% to about 4% w/w gelling agent, an additional gelling agent and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w.
  • the gelling agent is Carbomer Homopolymer Type C (Carbopol®980).
  • the additional gelling agent is in amount of from about 0.1% to about 4% w/w.
  • the additional surfactant is in amount of from about 0.1% to about 4% w/w.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, an additional surfactant, from about 0.1% to about 4% w/w gelling agent, an additional gelling agent and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w.
  • the gelling agent is Carbomer Homopolymer Type C (Carbopol®980).
  • the additional gelling agent is in amount of from about 0.1% to about 4% w/w.
  • the additional surfactant is in amount of from about 0.1% to about 4% w/w.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising 1% w/w or 1.5 % w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w an additional surfactant, from about 0.1% to about 4% w/w gelling agent, and optionally from about 0.01% to about 1% w/w antioxidant, wherein the surfactant is ionic, and the gelling agent is Carbomer Homopolymer Type C (Carbopol®980).
  • the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the surfactant is less than 1% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w an additional surfactant, from about 0.1% to about 4% w/w gelling agent, and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic, and the gelling agent is Carbomer Homopolymer Type C (Carbopol®980). In another embodiment the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w an additional surfactant, from about 0.1% to about 4% w/w gelling agent, an additional gelling agent and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w.
  • the gelling agent is Carbomer Homopolymer Type C (Carbopol®980). In another embodiment, the additional gelling agent is in amount of from about 0.1% to about 4% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w additional surfactant, from about 0.1% to about 4% w/w gelling agent, an additional gelling agent and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w.
  • the gelling agent is Carbomer Homopolymer Type C (Carbopol®980). In another embodiment, the additional gelling agent is in amount of from about 0.1% to about 4% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 1.5% w/w preservative, and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the surfactant is less than 1% w/w.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 1.5% w/w preservative, and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the surfactant is less than 1% w/w.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w gelling agent, an additional gelling agent, from about 0.1% to about 1.5% w/w preservative, and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the surfactant is less than 1% w/w.
  • the additional gelling agent is in amount of from about 0.1% to about 4% w/w.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w gelling agent, an additional gelling agent, from about 0.1% to about 1.5% w/w preservative, and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w.
  • the additional gelling agent is in amount of from about 0.1% to about 4% w/w.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, an additional surfactant, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 1.5% w/w preservative, and from about 0.01% to about 1% w/w antioxidant, wherein the surfactant is ionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the surfactant is less than 1% w/w.
  • the surfactant is anionic.
  • the additional surfactant is in amount of from about 0.1% to about 4% w/w.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, an additional surfactant, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 1.5% w/w preservative, and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w.
  • the additional surfactant is in amount of from about 0.1% to about 4% w/w.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w additional surfactant, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 4% w/w additional gelling agent, from about 0.1% to about 1.5% w/w preservative, and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the composition comprises 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 1.5% w/w preservative, a penetration enhancer and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the composition further comprises an additional gelling agent.
  • the composition further comprises an additional surfactant.
  • the additional gelling agent is in amount of from about 0.1% to about 4% w/w.
  • the additional surfactant is in amount of from about 0.1% to about 4% w/w.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 1.5% w/w preservative, a penetration enhancer and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w.
  • the composition further comprises an additional gelling agent.
  • the composition further comprises an additional surfactant.
  • the additional gelling agent is in amount of from about 0.1% to about 4% w/w.
  • the additional surfactant is in amount of from about 0.1% to about 4% w/w.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
  • this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w additional surfactant, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 4% w/w additional gelling agent, from about 0.1% to about 1.5% w/w preservative, a penetration enhancer and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the surfactant is less than 1% w/w. In another embodiment, the composition comprises 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) or docusate sodium.
  • this invention provides a topical cream composition, comprising 1% w/w or 1.5 % w/w tapinarof or a pharmaceutically acceptable salt thereof from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 1.5% w/w preservative, about 0.1% to about 20% w/w penetration enhancer and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w.
  • the composition further comprises an additional gelling agent.
  • the composition further comprises an additional surfactant.
  • the additional gelling agent is in amount of from about 0.1% to about 4% w/w.
  • the additional surfactant is in amount of from about 0.1% to about 4% w/w.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) or docusate sodium.
  • this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 1.5% w/w preservative, about 0.1% to about 20% w/w penetration enhancer and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the surfactant is less than 1% w/w.
  • the composition further comprises an additional gelling agent.
  • the composition further comprises an additional surfactant.
  • the additional gelling agent is in amount of from about 0.1% to about 4% w/w.
  • the additional surfactant is in amount of from about 0.1% to about 4% w/w.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) or docusate sodium.
  • this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w additional surfactant, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 4% w/w additional gelling agent, from about 0.1% to about 1.5% w/w preservative, about 0.1% to about 20% w/w penetration enhancer and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the composition comprises 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) or docusate sodium.
  • this invention provides a topical cream composition, comprising 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w gelling agent, a penetration enhancer and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the surfactant is less than 1% w/w.
  • the composition further comprises an additional gelling agent.
  • the composition further comprises an additional surfactant.
  • the additional gelling agent is in amount of from about 0.1% to about 4% w/w.
  • the additional surfactant is in amount of from about 0.1% to about 4% w/w.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) or docusate sodium.
  • this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w gelling agent, a penetration enhancer and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the surfactant is less than 1% w/w.
  • the composition further comprises an additional gelling agent.
  • the composition further comprises an additional surfactant.
  • the additional gelling agent is in amount of from about 0.1% to about 4% w/w.
  • the additional surfactant is in amount of from about 0.1% to about 4% w/w.
  • the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) or docusate sodium.
  • this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w additional surfactant, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 4% w/w additional gelling agent, a penetration enhancer and optionally from about 0.01% to about 1% w/w antioxidant, wherein the surfactant is ionic.
  • the surfactant is anionic.
  • the surfactant is in amount of from about 0.1% to about 1.5% w/w.
  • the surfactant is less than 1% w/w. In another embodiment, the composition comprises 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) or docusate sodium.
  • a method of treating a skin disorder in a patient in need thereof comprises administering to said patient the topical cream composition provided herein, wherein said skin disorder is selected from psoriasis, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and extensive pyodermas, acne, rosacea, atopic dermatitis, prurigo nodularis and hidradenitis suppurativa.
  • the composition provided herein is for use in treating a skin disorder in a patient in need thereof, said method comprises administering to said patient the topical cream composition provided herein, wherein said skin disorder is selected from psoriasis, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and extensive pyodermas, acne, rosacea, atopic dermatitis, prurigo nodularis and hidradenitis suppurativa.
  • said skin disorder is selected from psoriasis, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus, alopecia areata, hypertrophic scars
  • the indefinite articles “a” and “an” mean “at least one” or “one or more” unless the context clearly dictates otherwise.
  • the term “treating” or” treatment” includes curing a condition, treating a condition, preventing a condition, treating symptoms of a condition, curing symptoms of a condition, ameliorating symptoms of a condition, treating effects of a condition, ameliorating effects of a condition, and preventing results of a condition.
  • the terms “pharmaceutically active agent” or “active agent” or “active pharmaceutical ingredient” or “API” are interchangeable and mean the ingredient is a pharmaceutical drug which is biological active and is regulatory approved or approvable as such.
  • the term “ingredient” refers to a pharmaceutically acceptable ingredient which is included or is amenable to be included in FDA’s Inactive Ingredient database (IIG). Inactive ingredients sometimes exhibit some therapeutic effects, although they are not drugs.
  • a "pharmaceutical composition” refers to a composition comprising one or more active ingredients with other components such as pharmaceutically acceptable ingredients or excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of an active ingredient to a subject.
  • compositions, method formulation may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.
  • method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
  • mice were established Additionally, 10 psoriatic patients were recruited (six males and four females), ranging from 21 to 66 years (mean age 45 years). All patients had classic plaque psoriasis. Normal skin from one healthy volunteer was obtained for grafting.
  • mice Beige-severe combined immunodeficient mice C.B-17/IcrHsdscid- bg (beige-SCID) mice (weight ⁇ 25 g) were included in this study. Mice were monitored twice a week for vital signs such as weight, food intake, coat, eyes, anal genital areas, discharge/soiling, behavior and criteria related to skin transplantation.
  • PBMC's from the psoriatic patient's blood were isolated and cultured in the presence of a high dose of IL-2; Prospec ,100 U/mL of media- RPMI 1640,10% human AB serum (Sigma, St.Louis,MO), 1% glutamine, 1% antibiotics (media components; Biologicallndustries, Kibbutz Beit Haemeck, Israel) , as previously described (Gilhar A. et al., The beneficial effect of blocking Kvl.3 in the psoriasiform SCID mouse model. J Invest Dermatol. 2011;131 : 118-124; Mattbeck J. et al., IGFBP7 as a potential therapeutic target in Psoriasis.
  • each mouse was injected (intradermally) with 1 x 10 7 IL-2 enriched allogeneic PBMC's from psoriatic patients (1 x 10 7 cells injected/mouse). Cells from different psoriasis patients were equally distributed between treatment groups. Each patient was represented in each treatment group.
  • mice Fourteen days following cells injections, the mice were divided into treatment groups (Table 1, see below ) and treated according to the timeline indicated below (see Scheme 1). Each transplant was equally topically treated (50 pg) by using a sterile spatula.
  • Dexamethasone (D2915, Sigma): was freshly prepared for each administration by dilution in saline to final concentration (50 mg/ml). Dexamethasone serves as a positive control and was administered topically twice daily for 14 days following cells injections (at Day 42 following human skin transplantation) until the end of the study (Day 56).
  • the vehicle was administered topically (50 pg) once daily for 14 days.
  • Skin graft histological assessment was performed (according to the psoriatic criteria including epidermal thickness) using light microscopy, and two observers blindly performed the evaluations.
  • Epidermal thickness was determined using an ocular micrometer at a minimum of 50 points along the epidermis selected to represent points of maximal and minimal thickness. Thickness of the suprapapillary plate was measured similarly at 50 points for each sample. Three slices were examined for each sample.
  • mice comprised 30 mice divided into 3 groups (Table 1; with results found in Tables 2-4) as follows: Group 1: Vehicle; Group 2: Dexamethasone; Group 3: Tapinarof 1%, cream A (cream of Example 1).
  • mice comprised 30 mice divided into 3 groups (Table 5; with results found in Tables 6-9) as follows: Group 1 : dexamethasone; Group 2: Tapinarof 1%', cream D (Table 10); Group 3: Tapinarof 1% , cream A (cream of Example 1);
  • mice treated with dexamethasone showed complete (9/10) recovery from the psoriatic features.
  • these dexamethasone-treated grafts underwent a complete normalization of the skin, including a significant decrease in epidermal thickness compared to the Vehicle cream group (254 ⁇ 59 pm versus 713 ⁇ 293 pm, P ⁇ 0.002) (Tables 2-4, Figure 1).
  • Table 2 Histological evaluation of human skin grafts following treatment
  • Table 3 Histology of treated psoriasis grafts (mean epidermal thickness, scoring, complete recovery/total No grafts)
  • Table 6 Histological evaluation of human skin grafts following treatment
  • Table 7 Histology of treated psoriasis grafts (mean epidermal thickness, scoring, complete recovery/total No grafts)
  • Table 10 - cream D, which is formulation 21 of Tapinarof (1% w/w) in Table 8 of US
  • Table 11 Tapinarof composition with docusate sodium
  • Tapinarof Cream 1% with sodium lauryl sulfate as surfactant
  • Table 13 Tapinarof composition with sodium lauryl sulfate

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Abstract

Provided herein a topical cream composition comprising tapinarof or a pharmaceutically acceptable salt thereof and uses thereof for treating skin disorders.

Description

TOPICAL TAPINAROF COMPOSITION FOR TREATING SKIN DISORDERS
FIELD OF THE INVENTION
[001] Provided herein a topical cream composition comprising tapinarof or a pharmaceutically acceptable salt thereof and uses thereof for treating skin disorders.
BACKGROUND
Tapinarof
[002] Tapinarof (3,5-dihydroxy-4-isopropyl-trans-stilbene) is a pharmaceutical active agent investigated for the treatment of atopic dermatitis, psoriasis and psoriatic disorders (Zang YN, et al., Int J Clin Pharmacol Ther. 2016 Feb; 54(2):87-95). The 3,5-dihydroxy-4-isopropyl-stilbene is also known as benvitimod.
[003] Tapinarof is a first-in-class drug, whose mechanism is not yet fully understood.
[004] Tapinarof is being developed by Glaxo Smith Kline (Stiefel, a GSK company) and Dermavant as a topical drug for treatment of mild to moderate plaque psoriasis and atopic dermatitis. It was shown in both mouse models and in vitro human skin studies to inhibit specific proinflammatory mediators, including interleukin-6 and interleukin- 17 A, and enhance skin barrier function (J Invest Dermatol. 2017 Oct; 137[10]:2110-9).
Acne
[005] Acne is a chronic inflammatory disease of the pilosebaceous unit resulting from androgen- induced increased sebum production, altered keratinization, inflammation, and bacterial colonisation of hair follicles on the face, neck, chest, and back by Propionib acterium acnes (P. acnes). Although early colonisation with P. acnes and family history might have important roles in the disease, exactly what triggers acne and how treatment affects the course of the disease remains unclear (Williams H.C. et al., The Lancet, Vol.379. Jan 2012, pp. 361-372).
[006] There is no ideal treatment for acne. Good quality evidence on comparative effectiveness of common topical and systemic acne therapies is scarce. Topical therapies including benzoyl peroxide, retinoids, and antibiotics when used in combination usually improve control of mild to moderate acne, but suffer from side-effects. Treatment with combined oral contraceptives can help women with acne. Patients with more severe inflammatory acne usually need oral antibiotics combined with topical benzoyl peroxide to decrease antibiotic-resistant organisms. [007] Oral isotretinoin is the most effective therapy and is used early in severe disease, but its use is limited by teratogenicity and other side-effects.
[008] The treatment of acne with the composition of this invention results in reduced side-effects, due to long penetration lag time.
Rosacea (Acne Rosacea)
[009] Rosacea is a chronic skin disease that affects more than 16 million Americans. The cause of rosacea is still unknown, and there is no cure. However, research has allowed doctors to find ways to treat the condition by minimizing its symptoms (Cynthia Cobb, Healthline May 21, 2018). [010] There are four subtypes of rosacea. Each subtype has its own set of symptoms. It is possible to have more than one subtype of rosacea at a time.
[011] Rosacea’s typical symptom is small, red, pus-filled bumps on the skin that are present during flare-ups. Typically, rosacea affects only skin on the nose, cheeks, and forehead.
[012] Flare-ups often occur in cycles. This means that one will experience symptoms for weeks or months at a time, the symptoms will go away, and then return.
[013] The four types of rosacea are:
[014] Subtype one, known as erythematotelangiectatic rosacea (ETR), is associated with facial redness, flushing, and visible blood vessels.
[015] Subtype two, papulopustular (or acne) rosacea, is associated with acne-like breakouts, and often affects middle-aged women.
[016] Subtype three, known as rhinophyma, is a rare form associated with thickening of the skin on your nose. It usually affects men and is often accompanied by another subtype of rosacea.
[017] Subtype four is known as ocular rosacea, and its symptoms are centered on the eye area.
Dermatitis (eczema)
[018] Dermatitis is a group of diseases resulting in skin inflammation, itchiness, red skin and rash. The dermatitis group of diseases includes atopic dermatitis (AD), allergic contact dermatitis, irritant contact dermatitis and stasis dermatitis. Atopic dermatitis is the most common type of dermatitis.
Prurigo Nodularis (PN)
[019] PN is characterized by hyperkeratotic excoriated papulonodular (itchy) lesions that show symmetrical distribution on the extensor surfaces of the body and/or extremities, the numbers of which range from several to hundreds (Akarsu, S. et al. An Bras Dermatol . 2018;93(5):671-9.). It is a rare disease and is one of the most difficult conditions in terms of determining its etiology and treatment among chronic skin diseases.
Hidradenitis suppurativa (HS)
[020] Hidradenitis suppurativa, also known as acne inversa, is a long-term chronic skin disease whose present treatment options are often unsatisfactory. HS has a profound effect on patient’s quality of life (QoL). Alavi A. et al., reviewed QoL aspects of this disease in an article titled “Quality-of-Life Impairment in Patients with Hidradenitis Suppurativa” Am J Clin Dermatol . 2015
Feb;16(l):61-5
[021] The clinical picture of HS includes solitary nodules, diffuse, painful abscesses, malodorous drainage, sinus tract formation and scarring.
[022] The exact cause of hidradenitis suppurativa is still unclear, but it is believed that the underlying mechanism involves dysfunction of the apocrine sweat glands or hair follicles.
[023] There is an unmet need for newer and better treatments for the above mentioned skin disorders.
SUMMARY OF THE INVENTION
[024] In some embodiments provided herein a topical cream composition, comprising from about 1% w/w to about 2% w/w tapinarof or a pharmaceutically acceptable salt thereof and less than 1% w/w surfactant. In another embodiment, the surfactant is ionic or non ionic. In another embodiment, the surfactant is anionic.
[025] In some embodiments, provided herein a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, and optionally from about 0.01% to about 1% w/w an anti-oxidant, wherein the surfactant is ionic. In another embodiment, the surfactant is anionic.
[026] In another embodiment, provided herein a method of treating a skin disorder in a patient in need thereof, said method comprises administering to said patient the topical cream composition provided herein, wherein said skin disorder is selected from the group consisting from psoriasis, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus (e.g. in the genitoanal region), alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and extensive pyodermas, acne, rosacea, atopic dermatitis, prurigo nodularis and hidradenitis suppurativa.
BRIEF DESCRIPTION OF THE DRAWINGS [027] The subj ect mater regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. This invention, however, both as to organization and method of operation, together with objects, features, and advantages thereof, may best be understood by reference to the following detailed description when read with the accompanying drawings in which:
[028] Figure 1 depicts epidermal thickness in human xenograft psoriasis model in SCID mice following treatment with the tapinarof cream or dexamethasone vs. vehicle.
[029] Figure 2 depicts epidermal thickness in human xenograft psoriasis model in SCID mice following treatment with the tapinarof cream A or cream D vs dexamethasone.
[030] Figure 3 depicts proliferation index in human xenograft psoriasis model in SCID mice following treatment with the tapinarof cream A or cream D vs dexamethasone.
[031] It will be appreciated that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, the dimensions of some of the elements may be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements.
DETAILED DESCRIPTION OF THE INVENTION
Topical Tapinarof Compositions
[032] In some embodiments provided herein a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof and less than 1% w/w surfactant. In another embodiment, the surfactant is non-ionic. In another embodiment, the surfactant is ionic. In another embodiment, the surfactant is anionic. In another embodiment, the surfactant is cationic. In another embodiment, the surfactant comprises Carbomer Copolymer Type B, polysorbate 80, sorbitan monooleate, polysorbate 20, PEG 100 stearate, polysorbate 60, sodium dodecyl sulfate, sodium lauryl sulfate, cetearyl alcohol, dioctyl sodium sulfosuccinate (=docusate sodium), glyceryl oleate, glyceryl stearate, poloxamers or combination thereof. [033] In some embodiments provided herein a topical cream composition, comprising from about 1% w/w to about 2 % w/w tapinarof or a pharmaceutically acceptable salt thereof and less than 1% w/w surfactant. In another embodiment, the surfactant is non-ionic. In another embodiment, the surfactant is ionic. In another embodiment, the surfactant is anionic. In another embodiment, the surfactant is cationic. In another embodiment, the surfactant comprises Carbomer Copolymer Type B, polysorbate 80, sorbitan monooleate, polysorbate 20, PEG 100 stearate, polysorbate 60, sodium dodecyl sulfate, sodium lauryl sulfate, cetearyl alcohol, dioctyl sodium sulfosuccinate (=docusate sodium), glyceryl oleate, glyceryl stearate, poloxamers or combination thereof.
[034] In some embodiments, this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 1% w/w to about 20% surfactant, and optionally from about 0.01% to about 1% w/w an anti-oxidant, wherein the surfactant is ionic. In another embodiment, the surfactant is anionic. In another embodiment, the surfactant is cationic.
[035] Other known tapinarof formulations (e.g. see US 10,195,160) contain non-ionic surfactants at concentration of l%-20%. For example in US 10,195,160 the formulations contain more than 7 % (-11.6%, see e.g Table 8 formulation 21) of a non-ionic surfactant. Surfactants are known to be irritant and create sensitivity. It is advisable to use low concentration that is still effective not irritant and will stabilize the formulation. While low concentrations may cause stability problems, it is still advisable to seek formulations with low concentrations of surfactants and provide safe, stable and effective formulation. Surprisingly, the present invention provides a composition comprising tapinarof with lower concentrations of less than 1% of surfactant that provides stable formulations that are effective and safe and do not cause any irritations. These formulations contain non-ionic surfactants of less than 1% or non-irritant ionic surfactants, at concentrations of less than 1% or higher.
[036] In another aspect, the present invention also provides tapinarof compositions containing non-irritatant ionic surfactants, at concentrations of less than 1% or higher. In another embodiment, the ionic surfactant is anionic. In another embodiment, the ionic surfactant is cationic.
[037] In some embodiments, an anionic surfactant is selected from the group consisting of alkyl sulfates (e.g., sodium lauryl sulfate, ammonium lauryl sulfate and ammonium laureth sulfate); sulfosuccinates (e g., disodium lauryl sulfosuccinate, disodium laureth sulfosuccinate, sodium dioctyl sulfosuccinate and their mixtures with sulfonic acids and lauramidopropyl betaine; alkyl benzene sulfonates (e.g., sodium tosylate, cumene sulfonate, toluene sulfonic acid, xylene sulfonic acid, cumene sulfonic acid and salts (e.g., sodium, potassium, calcium, ammonium) thereof); acyl methyl taurates (e.g., sodium methyl lauroyl taurate and sodium methyl cocoyl taurate); acyl sarcocinates (e.g., sodium lauroyl sarcosinate, sodium cocoyl sarcosinate and sodium myristoyl sarcosinate); isethionates (e.g., sodium butyl isethionate, sodium capryloyl isethionate and sodium lauroyl isethionate); propyl peptide condensates; monoglyceride sulfates; ether sulfonates, fatty' acid salts (e.g., sodium stearoyl lactylate), dioctyl sulfosuccinate, dioctyl sodium sulfosuccinate (=== docusate sodium ), Carbomer Copolymer Type B (Pemulen®TR-l) and polyacrylic acid polymers. [038] In another embodiment, the anionic surfactant comprises Carbomer Copolymer Type B (Pemulen®TR-l), sodium lauryl sulfate, sodium dodecyl sulfate, or dioctyl sodium sulfosuccinate (docusate sodium). In another embodiment, the anionic surfactant is Carbomer Copolymer Type B (Pemulen®TR-l). In another embodiment, the anionic surfactant is sodium lauryl sulfate. In another embodiment, the anionic surfactant is docusate sodium.
[039] In some embodiments, a cationic surfactant is selected from the group consisting of quaternary ammonium compounds (e.g., benzalkonium chloride, stearalkonium chloride, centrimonium chloride, and trimethyl ammonium methyl sulfates).
[040] In another embodiment, non-ionic surfactant comprises polysorbate 80, sorbitan monooleate, polysorbate 20, polysorbate 60, cetearyl alcohol, glyceryl oleate, glyceryl stearate, ethoxylated fatty alcohol, ethers, PEG castor oils, PEG esters, PEG 100 stearate, propylene glycol esters (e.g. propylene glycol laurate, propylene glycol palmitostearate, propylene glycol ricinoleate and propylene glycol stearate), glyceryl esters and derivatives (e.g. glyceryl behenate, glyceryl dibehenate, glyceryl di oleate, glyceryl di stearate, glyceryl isostearate, glyceryl laurate, glyceryl linoleate, glyceryl monostearate, glyceryl oleate, glyceryl palmitate, glyceryl ricinoleate, glyceryl stearate, PEG-23 glyceryl cocoate, PEG-6 caprylic/capric glycerides, PEG-7 glyceryl cocoate, polyglyceryl- 10 diisostearate, polyglyceryl-2 diisostearate, polyglyceryl-3 diisostearate and polyglyceryl -6 di isostearate, PEG-12 glyceryl laurate, PEG-120 glyceryl stearate), polymeric ethers (e.g. poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 184, poloxamer 188, poloxamer 237, poloxamer 331, poloxamer 338 and poloxamer 407). Sorbitan derivatives (e.g. polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, sorbitan isostearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate and sorbitan tri stearate), fatty alcohols (e.g. isostearyl alcohol, caprylyl alcohol, decyl alcohol, lauryl alcohol, myristyl alcohol, behenyl alcohol, lanolin alcohol, arachidyl alcohol, oleyl alcohol, palm alcohol, isocetyl alcohol, cetyl alcohol, stearyl alcohol and cetearyl alcohol), emulsifying waxes (e.g. mixture of cetearyl alcohol and polysorbate 60 or “Pol a wax NF™, and pol oxamers or combination thereof.
[041] In some embodiments, the composition provided herein further comprises from about 0.1% to about 4% w/w gelling agent. In some embodiments, the composition provided herein comprises from about 0.01% to about 1% w/w anti-oxidant.
[042] In some embodiments, the composition provided herein comprises from about 0.1% w/w to about 20% w/w surfactant. In some embodiments, the composition provided herein comprises less than 5% w/w of the surfactant. In some embodiments, the composition provided herein comprises less than 1% w/w of the surfactant. In other embodiments, the surfactant is in an amount of about 5% w/w to about 20% w/w. In other embodiments, the surfactant is in an amount of about 10% w/w to about 20% w/w. In other embodiments, the surfactant is in an amount of about 15% w/w to about 20% w/w. In other embodiments, the surfactant is in an amount of about 5% w/w to about 10% w/w. In other embodiments, the surfactant is in an amount of about 5% w/w. In other embodiments, the surfactant is in an amount of about 1% w/w to about 5% w/w. In other embodiments, the composition comprises the surfactant in an amount of about 0.1% to about 5% w/w. In other embodiments, the surfactant is in an amount of about 0.1% to about 4% w/w. In other embodiments, the surfactant is in an amount of about 0.1% to about 3% w/w. In other embodiments, the surfactant is in an amount of about 0.1% to about 2% w/w. In other embodiments, the surfactant is in an amount of about 0.1% to about 1.5% w/w. In other embodiments, the surfactant is in an amount of about 0.1 to about 1% w/w. In other embodiments, the surfactant is in an amount of about 0.1 to about 0.5% w/w. In other embodiments, the surfactant is in an amount of about 0.1 to about 0.3% w/w. In other embodiments, the surfactant is in an amount of about 0.1 to about 0.2% w/w. In some other embodiments, the surfactant is in an amount of about 0.4 % w/w. In other embodiments, the surfactant is in an amount of about 0.2% to about 0.8 % w/w. In other embodiments, the surfactant is ionic. In other embodiments, the surfactant is anionic. In other embodiments, the surfactant is cationic. In other embodiments, the surfactant is non-ionic. In other embodiments, the surfactant is Carbomer Copolymer Type B. In other embodiments, the surfactant is in an amount of about 0.4% w/w Carbomer Copolymer Type B. In other embodiments, the surfactant is in an amount of about 0.2% to about 0.8 % w/w Carbomer Copolymer Type B. In other embodiments, the surfactant is docusate sodium. In other embodiments, the surfactant is sodium lauryl sulfate.
[043] In some embodiments, the composition provided herein comprises a gelling agent. In some embodiments, the composition further comprises an additional gelling agent. In some embodiments, the gelling agent and the additional gelling agent are each independently selected from a group consisting of a carbomer, Natrosol hydroxyethylcellulose, starch, pectin, gelatin, agar, alginic acid and salts thereof, carboxymethylcellulose, hydroxypropylmethylcellulose and any combination thereof. In other embodiments, the gelling agent or the additional gelling agent is Carbomer Homopolymer Type C (Carbopol®980). In other embodiments, the gelling agent or the additional gelling agent is Carbomer Homopolymer Type C (Carbopol ®980), in an amount of about 0.1% to about 4% w/w. In other embodiments, the gelling agent or the additional gelling agent is Carbomer Homopolymer Type C (Carbopol®980), in an amount of 1% w/w, 2%w/w, 3% w/w or 4% w/w.
[044] In some embodiment, the composition provided herein is not a lotion.
[045] In some embodiments, the compositions provided herein does not include DMSO.
[046] In some embodiments, the gelling agent and/or additional gelling agent is in an amount of about 0.1% to about 4% w/w. In other embodiments, the gelling agent and/or additional gelling agent is in an amount of about 0.1% to about 2% w/w. In other embodiments, the gelling agent and/or additional gelling agent is in an amount of about 0.1% to about 1% w/w. In other embodiments, the gelling agent and/or additional gelling agent is in an amount of about 0.1% to about 0.5% w/w. In other embodiments, the gelling agent and/or additional gelling agent is in an amount of about 0.5% to about 4% w/w. In other embodiments, the gelling agent and/or additional gelling agent is in an amount of about 0.5% to about 2% w/w. In other embodiments, the gelling agent and/or additional gelling agent is in an amount of about 0.5% to about 1% w/w. In other embodiments, the gelling agent and/or additional gelling agent is in an amount of about 1% to about 4% w/w. In other embodiments, the gelling agent and/or additional gelling agent is in an amount of about 1% to about 2% w/w.
[047] In some embodiments, the composition further comprises an additional surfactant. In some embodiments, the additional surfactant comprises Carbomer Copolymer Type B, polysorbate 80, sorbitan monooleate, polysorbate 20, PEG 100 stearate, polysorbate 60, sodium dodecyl sulfate, sodium lauryl sulfate, cetearyl alcohol, dioctyl sodium sulfosuccinate (=docusate sodium), glyceryl oleate, glyceryl stearate or poloxamers or any combination thereof.
[048] In some embodiments, the additional surfactant is in an amount of about 0.1% to about 4% w/w. In other embodiments, the additional surfactant is in an amount of about 0.1% to about 2% w/w. In other embodiments, the additional surfactant is in an amount of about 0.1% to about 1.5% w/w. In other embodiments, the additional surfactant is in an amount of about 0.1% to about 1% w/w. In other embodiments, the additional surfactant is in an amount of about 0.1% to about 0.5% w/w. In other embodiments, the additional surfactant is in an amount of about 0.5% to about 4% w/w. In other embodiments, the additional surfactant is in an amount of about 0.5% to about 2% w/w. In another embodiment, the additional surfactant is in an amount of about 0.5% to about 1.5% w/w. In another embodiment, the additional surfactant is in an amount of about 0.5% to about 1% w/w. In another embodiment, the additional surfactant is in an amount of about 1% to about 4% w/w. In another embodiment, the additional surfactant is in an amount of about 1% to about 2% w/w. Each possibility represents a separate embodiment of this invention.
[049] In some embodiments, the composition further comprises from about 0.1% to about 1.5% w/w preservative. In some embodiments, the preservative is selected from benzoic acid, methylparaben, phenoxyethanol, imidurea, chlorocresol, propyl paraben, benzalkonium chloride, benzyl alcohol, imidazolidinyl urea, sodium benzoate, sorbic acid, thimerosal sorbic acid, sodium sorbate, sodium sulfite, ethanol, tocopherols and any combination thereof. In other embodiments, the preservative is methylparaben. In other embodiments, the preservative is phenoxyethanol. In other embodiments, the preservative is a combination of methylparaben and phenoxyethanol. In other embodiments, the preservative is methylparaben in an amount of 0.3% w/w. In other embodiments, the preservative is phenoxyethanol in an amount of 0.5% w/w. In other embodiments, the preservative is a combination of methylparaben in an amount of 0.3% w/w and phenoxyethanol in an amount of 0.5% w/w.
[050] In some embodiments, the composition further comprises from about 0.1% to about 1.5% w/w preservative. In other embodiments, the preservative is in an amount of about 0.1% to about 1% w/w. In other embodiments, the preservative is in an amount of about 0.1% to about 0.5% w/w. In other embodiments, the preservative is in an amount of about 0.5% to about 1.5% w/w. In other embodiments, the preservative is in an amount of about 0.5% to about 1% w/w. In other embodiments, the preservative is in an amount of 0.5%. In other embodiments, the preservative is in an amount of 0.3%.
[051] In some embodiments, the composition further comprises penetration enhancer. In some embodiments, the penetration enhancer is selected from dimethylsulfoxide (DMSO), diethylene glycol monoethyl ether (Transcutol), methyl sulfonylmethane (MSM), propylene glycol, dimethyl isosorbide, oleic acid, oleyl alcohol, ethanol, isopropyl alcohol, a polyethylene glycol, hexylene glycol, glycofurol, isopropyl myristate, glycerin, mono- and di- carboxylic acid esters and any combination thereof. In other embodiments, the penetration enhancer is diethylene glycol monoethyl ether (Transcutol). In other embodiments, the penetration enhancer is propylene glycol. In other embodiments, the penetration enhancer is diethylene glycol monoethyl ether (Transcutol), in an amount of 5% w/w. In other embodiments, the penetration enhancer is propylene glycol in an amount of 15% w/w. In other embodiments, the penetration enhancer is a combination of diethylene glycol monoethyl ether (Transcutol), in an amount of 5% w/w and propylene glycol in an amount of 15% w/w. In some embodiments, in addition and/or instead said penetration enhancer - water is added to the composition. In another embodiment, the penetration enhancer is not dimethylsulfoxide (DMSO).
[052] In some embodiments, the composition comprises a penetration enhancer in an amount of about 0.1% to about 20% w/w. In other embodiments, the penetration enhancer is in an amount of about 0.1% to about 15% w/w. In other embodiments, the penetration enhancer is in an amount of about 0.1% to about 10% w/w. In other embodiments, the penetration enhancer is in an amount of about 0.1% to about 5% w/w. In other embodiments, the penetration enhancer is in an amount about of 0.1% to about 2% w/w. In other embodiments, the penetration enhancer is in an amount of about 0.1% to about 1% w/w. In other embodiments, the penetration enhancer is in an amount of about 0.1% to about 0.5% w/w. In another embodiment other embodiments, the penetration enhancer is in an amount of about 0.5% to about 20% w/w. In other embodiments, the penetration enhancer is in an amount of about 0.5% to about 15% w/w. In other embodiments, the penetration enhancer is in an amount of about 0.5% to about 10% w/w. In other embodiments, the penetration enhancer is in an amount of about 0.5% to about 5% w/w. In other embodiments, the penetration enhancer is in an amount of about 0.5% to about 2% w/w. In other embodiments, the penetration enhancer is in an amount of about 0.5% to about 1% w/w. In other embodiments, the penetration enhancer is in an amount of about 1% to about 20% w/w. In other embodiments, the penetration enhancer is in an amount of about 1% to about 15% w/w. In other embodiments, the penetration enhancer is in an amount of about 1% to about 10% w/w. In other embodiments, the penetration enhancer is in an amount of about 1% to about 5% w/w. In other embodiments, the penetration enhancer is in an amount of about 1% to about 2% w/w. In other embodiments, the penetration enhancer is in an amount of about 2% to about 20% w/w. In other embodiments, the penetration enhancer is in an amount of about 2% to about 15% w/w. In other embodiments, the penetration enhancer is in an amount of about 2% to about 10% w/w. In other embodiments, the penetration enhancer is in an amount of about 2% to about 5% w/w. In other embodiments, the penetration enhancer is in an amount of about 5% to about 20% w/w. In other embodiments, the penetration enhancer is in an amount of about 5% to about 15% w/w. In other embodiments, the penetration enhancer is in an amount of about 5% to about 10% w/w. In other embodiments, the penetration enhancer is in an amount of about 10% to about 20% w/w. In other embodiments, the penetration enhancer is in an amount of about 10% to about 15% w/w. In other embodiments, the penetration enhancer is in an amount of about 15% to about 20% w/w. In other embodiments, the penetration enhancer is in an amount of 5% w/w, 6% w/w, 7% w/w, 8% w/w, 9% w/w, 10% w/w, 11% w/w, 12% w/w, 13% w/w, 14% w/w, 15% w/w, 16% w/w, 17% w/w, 18% w/w, 19% w/w, 20% w/w or any ranges thereof.
[053] In some embodiments, the composition further comprises an emollient. In one embodiment, non-limiting examples of the emollient include: coconut fatty acid di ethanol ami de, petrolatum, mineral oil light, castor oil and any combination thereof.
[054] In some embodiments the emollient is in a weight of about 0.01 to about 2 % w/w. In one embodiment, the emollient is in a weight of about 0.01 to about 1.5 % w/w. In another embodiment, the emollient is in a weight of about 0.01 to about 1 % w/w. In another embodiment, the emollient is in a weight of about 0.01 to about 0.5 % w/w. In another embodiment, the emollient is in a weight of about 0.01 to about 0.2 % w/w. In another embodiment, the emollient is in a weight of about 0.01 to about 0.1 % w/w. In another embodiment, the emollient is in a weight of about 0.1 to about 2 % w/w. In another embodiment, the emollient is in a weight of about 0.1 to about 1.5 % w/w. In another embodiment, the emollient is in a weight of about 0.1 to about 1 % w/w. In another embodiment, the emollient is in a weight of about 0.1 to about 0.5 % w/w. In another embodiment, the emollient is in a weight of about 0.1 to about 0.2 % w/w. In another embodiment, the emollient is in a weight of about 0.2 to about 2 % w/w. In another embodiment, the emollient is in a weight of about 0.2 to about 1.5 % w/w. In another embodiment, the emollient is in a weight of about 0.2 to about 1 % w/w. In another embodiment, the emollient is in a weight of about 0.2 to about 0.5 % w/w. In another embodiment, the emollient is in a weight of about 0.5 to about 2 % w/w. In another embodiment, the emollient is in a weight of about 0.5 to about 1.5 % w/w. In another embodiment, the emollient is in a weight of about 0.5 to about 1 % w/w. In another embodiment, the emollient is in a weight of about 1 to about 2 % w/w. In another embodiment, the emollient is in a weight of about 1.5 to about 2 % w/w. In another embodiment, the emollient is in a weight of about 1 to about 1.5 % w/w.
[055] In some embodiments, the composition further comprises a chelating agent. In one embodiment, non-limiting examples of the chelating agent include: ethylenediaminetetraacetic acid (EDTA), nitrolotriacetic acid (NTA) and citric acid.
[056] In some embodiments the chelating agent is in a weight of about 0.01 to about 2 % w/w. In one embodiment, the chelating agent is in a weight of about 0.01 to about 1.5 % w/w. In another embodiment, the chelating agent is in a weight of about 0.01 to about 1 % w/w. In another embodiment, the chelating agent is in a weight of about 0.01 to about 0.5 % w/w. In another embodiment, the chelating agent is in a weight of about 0.01 to about 0.2 % w/w. In another embodiment, the chelating agent is in a weight of about 0.01 to about 0.1 % w/w. In another embodiment, the chelating agent is in a weight of about 0.1 to about 2 % w/w. In another embodiment, the chelating agent is in a weight of about 0.1 to about 1.5 % w/w. In another embodiment, the chelating agent is in a weight of about 0.1 to about 1 % w/w. In another embodiment, the chelating agent is in a weight of about 0.1 to about 0.5 % w/w. In another embodiment, the chelating agent is in a weight of about 0.1 to about 0.2 % w/w. In another embodiment, the chelating agent is in a weight of about 0.2 to about 2 % w/w. In another embodiment, the chelating agent is in a weight of about 0.2 to about 1.5 % w/w. In another embodiment, the chelating agent is in a weight of about 0.2 to about 1 % w/w. In another embodiment, the chelating agent is in a weight of about 0.2 to about 0.5 % w/w. In another embodiment, the chelating agent is in a weight of about 0.5 to about 2 % w/w. In another embodiment, the chelating agent is in a weight of about 0.5 to about 1.5 % w/w. In another embodiment, the chelating agent is in a weight of about 0.5 to about 1 % w/w. In another embodiment, the chelating agent is in a weight of about 1 to about 2 % w/w. In another embodiment, the chelating agent is in a weight of about 1.5 to about 2 % w/w. In another embodiment, the chelating agent is in a weight of about 1 to about 1.5 % w/w. In another embodiment, the chelating agent is in a weight of 0.1 % w/w.
[057] In some embodiments, the composition further comprises a pH adjusting agent. In one embodiment, non limiting examples of the pH adjusting agent include: sodium hydroxide, potassium hydroxyide, hydrochloric acid, sodium acetate, acetic acid, ammonium acetate, ammonium sulfate, ammoniu hydroxide, arginine, aspartic acid and salts thereof, bicarbonate salts, carbonate salts, citric acid and salts thereof, diethanolamine, glycine, lysine, boric acid and salts thereof and phosphate salts.
[058] In some embodiments the pH adjusting agent is in a weight of about 0.01 to about 5 % w/w. In one embodiments the pH adjusting agent is in a weight of about 0.01 to about 2 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.01 to about 1.5 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.01 to about 1 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.01 to about 0.5 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.01 to about 0.2 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.01 to about 0.1 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.1 to about 5 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.1 to about 2 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.1 to about 1.5 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.1 to about 1 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.1 to about 0.5 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.1 to about 0.2 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.2 to about 5 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.2 to about 2 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.2 to about 1.5 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.2 to about 1 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.2 to about 0.5 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.5 to about 5 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.5 to about 2 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.5 to about 1.5 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 0.5 to about 1 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 1 to about 5 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 1 to about 2 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 1.5 to about 2 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 1 to about 1.5 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 1.5 to about 5 % w/w. In another embodiment, the pH adjusting agent is in a weight of about 2 to about 5 % w/w. In another embodiment, the pH adjusting agent is in a weight of 1 % w/w.
[059] In some embodiments, the purity of the tapinarof is greater than 97%. In some embodiments, the purity of the tapinarof is greater than 98%. In some embodiments, the purity of the tapinarof is greater than 99%. In some embodiments, the purity of the tapinarof is greater than 99.5%. In some embodiments, the purity of the tapinarof is between 97% and 99.99%. In some embodiments, the purity of the tapinarof is between 99% and 99.99%.
[060] In some embodiments, the composition comprises tapinarof in an amount of about 0.25% to about 10% w/w. In other embodiments, the tapinarof is in an amount of about 0.25% to about 5% w/w. In other embodiments, the tapinarof is in an amount of about 0.25% to about 2% w/w. In other embodiments, the tapinarof is in an amount of about 0.25% to about 1% w/w. In other embodiments, the tapinarof is in an amount of about 0.25% to about 0.5% w/w. In other embodiments, the tapinarof is in an amount of about 0.5% to about 10% w/w. In other embodiments, the tapinarof is in an amount of about 0.5% to about 5% w/w. In other embodiments, the tapinarof is in an amount of about 0.5% to about 2% w/w. In another embodiment, the tapinarof is in an amount of about 0.5% to about 1% w/w. In other embodiments, the tapinarof is in an amount of about 1% to about 10% w/w. In another embodiment, the tapinarof is in an amount of about 1% to about 5% w/w. In other embodiments, the tapinarof is in an amount of about 1% to about 2% w/w. In other embodiments, the tapinarof is in an amount of about 2% to about 10% w/w. In other embodiments, the tapinarof is in an amount of about 2% to about 5% w/w. In other embodiments, the tapinarof is in an amount of about 5% to about 10% w/w. In other embodiments, the tapinarof is in an amount of 1.5% w/w. In other embodiments, the tapinarof is in an amount of 1 % w/w. In other embodiments the tapinarof is in an amount from about 1% w/w to about 2% w/w. In other embodiments, the tapinarof is in an amount of 0.75% w/w, 1% w/w, 2% w/w, 3% w/w, 4% w/w, 5% w/w, 6% w/w, 7% w/w, 8% w/w, 9% w/w, 10% w/w or any ranges thereof.
[061] In some embodiments, the composition comprises from about 0.01% to about 1% w/w an anti-oxidant. In some embodiments, the anti-oxidant is selected from the group consisting from butylated hydroxy toluene (BHT), parabens, propyl gallate, ascorbic acid, flavones, flavanones, flavonols, stilbenoids, gallic acid, cinnamic acid, ellagic acid, salicylic acid, curcumin, eugenol, citric acid, tocopherol, vitamin E, tocopherol polyethylene glycol succinate (TPGS), and any combination thereof. In other embodiments, the anti-oxidant is butylated hydroxy toluene (BHT). In other embodiments, the anti-oxidant is butylated hydroxy toluene (BHT), in an amount of 0.1% w/w.
[062] In some embodiments, the composition comprises from about 0.01% to about 1% w/w an anti-oxidant. In other embodiments, the anti-oxidant is in an amount of about 0.01% to about
0.02% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.01% to about 0.05% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.01% to about 0.1% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.01% to about 0.2% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.01% to about 0.5% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.02% to about 1% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.02% to about 0.05% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.02% to about 0.1% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.02% to about 0.2% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.02% to about 0.5% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.05% to about 1% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.05% to about 0.1% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.05% to about 0.2% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.05% to about 0.5% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.1% to about 1% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.1% to about 0.2% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.1% to about 0.5% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.2% to about 0.5% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.2% to about 1% w/w. In other embodiments, the anti-oxidant is in an amount of about 0.5% to about 1% w/w. In other embodiments, the anti-oxidant is in an amount of 0.5%. In another embodiment, the anti-oxidant is in an amount of 0.1%.
[063] Pharmaceutical carriers or vehicles suitable for preparation of the compositions provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.
[064] Pharmaceutical carriers or vehicles suitable for administration of the active agents provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration. In addition, the active agents may be formulated as the sole pharmaceutically active agent in the composition or may be combined with other active agents. The active agents are included in the carrier in an amount sufficient to exert a therapeutically useful effect. Generally, emollient or lubricating vehicles that help hydrate the skin are more preferred than volatile vehicles, such as ethanol, that dry the skin. Examples of suitable bases or vehicles for preparing compositions for use with human skin are petrolatum, petrolatum plus volatile silicones, lanolin, cold cream and hydrophilic ointment.
[065] Suitable pharmaceutically and dermatologically acceptable vehicles are organic in nature or an aqueous emulsion and capable of having the selected compound or compounds, which may be micronized, dispersed, suspended or dissolved therein. The vehicle may include pharmaceutically-acceptable emollients, moisturizers, including lactic acid, ammonium lactate and urea, skin penetration enhancers, coloring agents, fragrances, emulsifiers, thickening agents, vegetable oils, essential oils, zinc oxide and solvents.
[066] In one embodiment, the composition according to the invention is a cream. By addition of a fatty or oily phase, in an aqueous phase (O/W) or conversely (W/O), the composition can be in a form of suspensions or emulsions of soft, semi-liquid or solid consistency of a cream, or alternatively multiple emulsions (W/O/W or O/W/O), microemulsions, microcapsules, microparticles or vesicular dispersions of ionic and/or nonionic type, or wax/aqueous phase dispersions. In other embodiment, the composition according to the invention is a cream or an emulsion.
Medical treatment methods using compositions of this invention
[067] In some embodiments, this invention provides a method of treating a skin disorder in a patient in need thereof, said method comprises administering to said patient the topical cream composition as described herein, wherein said skin disorder is selected from psoriasis, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus (e.g. in the genitoanal region), alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and extensive pyodermas, acne, rosacea, atopic dermatitis, prurigo nodularis and hidradenitis suppurativa. In other embodiments, the acne is selected from acne vulgaris, papulopustular acne and nodular acne. In other embodiments, the rosacea is selected from erythematotelangiectatic rosacea, papulopustular rosacea, rhinophyma rosacea and ocular rosacea. [068] In some embodiments, this invention provides a method of treating a skin disorder in a patient in need thereof, said method comprises administering to said patient the topical cream composition comprising from about 1% w/w to about 2% w/w tapinarof or a pharmaceutically acceptable salt thereof and less than 1% w/w surfactant; wherein said skin disorder is selected from psoriasis, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus (e.g. in the genitoanal region), alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and extensive pyodermas, acne, rosacea, atopic dermatitis, prurigo nodularis and hidradenitis suppurativa. In another embodiment, the surfactant is ionic or non-ionic. In another embodiment, the surfactant is anionic. In another embodiment, the surfactant is cationic.
[069] In some embodiments, this invention provides a method of treating a skin disorder in a patient in need thereof, said method comprises administering to said patient the topical cream composition comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof and less than 1% w/w surfactant; wherein said skin disorder is selected from psoriasis, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus (e.g. in the genitoanal region), alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and extensive pyodermas, acne, rosacea, atopic dermatitis, prurigo nodularis and hidradenitis suppurativa. In another embodiment, the surfactant is ionic or non-ionic. In another embodiment, the surfactant is anionic. In another embodiment, the surfactant is cationic. [070] In some embodiments, this invention provides a method of treating a skin disorder in a patient in need thereof, said method comprises administering to said patient the topical cream composition comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, and optionally from about 0.01% to about 1% w/w an anti-oxidant, wherein the surfactant is ionic; wherein said skin disorder is selected from psoriasis, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus (e.g. in the genitoanal region), alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and extensive pyodermas, acne, rosacea, atopic dermatitis, prurigo nodularis and hidradenitis suppurativa. In another embodiment, the surfactant is anionic. In another embodiment, the surfactant is cationic. [071] In some embodiments, the methods and compositions provided herein are for use in the treatment of psoriasis. In some embodiments, the methods and compositions provided herein are for use in the treatment of toxic and allergic contact eczema. In some embodiments, the methods and compositions provided herein are for use in the treatment of atopic eczema. In some embodiments, the methods and compositions provided herein are for use in the treatment of seborrheic eczema. In some embodiments, the methods and compositions provided herein are for use in the treatment of lichen simplex. In some embodiments, the methods and compositions provided herein are for use in the treatment of sunburn, pruritus (e.g. in the genitoanal region). In some embodiments, the methods and compositions provided herein are for use in the treatment of alopecia areata. In some embodiments, the methods and compositions provided herein are for use in the treatment of hypertrophic scars. In some embodiments, the methods and compositions provided herein are for use in the treatment of discoid lupus erythematosus. In some embodiments, the methods and compositions provided herein are for use in the treatment of follicular and extensive pyodermas. In some embodiments, the methods and compositions provided herein are for use in the treatment of acne. In some embodiments, the methods and compositions provided herein are for use in the treatment of rosacea. In some embodiments, the methods and compositions provided herein are for use in the treatment of atopic dermatitis. In some embodiments, the methods and compositions provided herein are for use in the treatment of prurigo nodularis. In some embodiments, the methods and compositions provided herein are for use in the treatment of hidradenitis suppurativa.
[072] Dosage frequencies can be gradually attenuated over time and maintained at a steady dose suitable for long-term - six months, 1 year, 5 years, 10 years or more, up to lifelong administration to control the symptoms of the hidradenitis suppurativa. For example, dosage administration can begin at from twice a day, to once a day, to two times a week, to once a week, to once every two weeks or less frequent than once every two weeks.
[073] The frequency of administration can be determined empirically. Exemplary frequencies are once daily, twice daily, weekly, bi-weekly or monthly.
[074] Typical administration frequencies of the topical combination compositions of this invention are once daily and twice daily.
[075] Dosage frequencies can be gradually attenuated over time and maintained at a steady dose suitable for long-term - six months, 1 year, 5 years, 10 years or more, up to lifelong administration to control the symptoms of said skin disorders. For example, dosage administration can begin at from twice a day, to once a day, to two times a week, to once a week, to once every two weeks or less frequent than once every two weeks.
Kits
[076] There are provided kits containing the compositions of this invention, optionally including instructions for administration. The combinations include, for example, the compositions as provided herein. Additionally, provided herein are kits containing the above-described combinations and optionally instructions for administration by topical, transdermal, or other routes, depending on the composition to be delivered.
[077] The compositions provided herein can be packaged as articles of manufacture containing packaging material, a composition provided herein, and a label that indicates that the composition is for treating the skin disorders/diseases described hereinabove, and is formulated for topical delivery.
[078] The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products are well known to those of skill in the art. Examples of pharmaceutical packaging materials include, but are not limited to bottles, tubes, containers, application syringes and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
Embodiments
[079] In some embodiments provided herein a topical cream composition comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, and less than 1% w/w surfactant. In another embodiment, the surfactant is ionic or non-ionic. [080] In some embodiments provided herein a topical cream composition comprising from about from about 1% w/w to about 2% w/w tapinarof or a pharmaceutically acceptable salt thereof, and less than 1% w/w surfactant. In another embodiment, the surfactant is ionic or non-ionic.
[081] In some embodiments provided herein a topical cream composition comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, and optionally from about 0.01% to about 1% w/w an antioxidant, wherein the surfactant is ionic. In another embodiment, the surfactant is anionic. In another embodiment, the surfactant is cationic.
[082] In some embodiments provided herein a topical cream composition comprising from about 1% w/w to about 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, and optionally from about 0.01% to about 1% w/w an antioxidant, wherein the surfactant is ionic. In another embodiment, the surfactant is anionic. In another embodiment, the surfactant is cationic. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate or docusate sodium.
[083] In one embodiment, this invention provides a topical cream composition, comprising 1% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, and optionally from about 0.01% to about 1% w/w an anti-oxidant, wherein the surfactant is ionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is anionic. In another embodiment, the surfactant is cationic. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR- 1) sodium lauryl sulfate docusate sodium or combination thereof.
[084] In one embodiment, this invention provides a topical cream composition, comprising 1% w/w tapinarof or a pharmaceutically acceptable salt thereof, and less than 1% w/w surfactant. In another embodiment, the surfactant is ionic. In another embodiment, the surfactant is anionic. In another embodiment, the surfactant is non-ionic.
[085] In one embodiment, this invention provides a topical cream composition, comprising 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, and less than 1% w/w surfactant. In another embodiment, the surfactant is ionic. In another embodiment, the surfactant is anionic. In another embodiment, the surfactant is non-ionic.
[086] In one embodiment, this invention provides a topical cream composition, comprising from about 1% w/w to about 2% w/w tapinarof or a pharmaceutically acceptable salt thereof, less than 1% w/w surfactant and from about 0.1% to about 4% w/w gelling agent. In another embodiment, the surfactant is ionic or non-ionic. In another embodiment, the surfactant is ionic. In another embodiment, the surfactant is anionic.
[087] In one embodiment, this invention provides a topical cream composition, comprising from about 1% w/w to about 2% w/w tapinarof or a pharmaceutically acceptable salt thereof, less than 1% w/w surfactant wherein the surfactant is selected from the group consisting of Carbomer Copolymer Type B, polysorbate 80, sorbitan monooleate, polysorbate 20, PEG 100 stearate, polysorbate 60, sodium dodecyl sulfate, sodium lauryl sulfate, cetearyl alcohol, dioctyl sodium sulfosuccinate (=docusate sodium), glyceryl oleate, glyceryl stearate, poloxamers and combination thereof.
[088] In one embodiment, this invention provides a topical cream composition, comprising from about 1% w/w to about 2% w/w tapinarof or a pharmaceutically acceptable salt thereof, less than 1% w/w surfactant wherein the surfactant is ionic.
[089] In one embodiment, this invention provides a topical cream composition, comprising from about 1% w/w to about 2% w/w tapinarof or a pharmaceutically acceptable salt thereof, less than 1% w/w surfactant wherein the surfactant is non-ionic.
[090] In one embodiment, this invention provides a topical cream composition, comprising from about 1% w/w to about 2% w/w tapinarof or a pharmaceutically acceptable salt thereof, less than 1% w/w surfactant and from about 0.1% to about 4% w/w gelling agent, wherein the surfactant is selected from the group consisting of Carbomer Copolymer Type B, polysorbate 80, sorbitan monooleate, polysorbate 20, PEG 100 stearate, polysorbate 60, sodium dodecyl sulfate, sodium lauryl sulfate, cetearyl alcohol, dioctyl sodium sulfosuccinate (=docusate sodium), glyceryl oleate, glyceryl stearate, poloxamers and combination thereof.
[091] In one embodiment, this invention provides a topical cream composition, comprising from about 1% w/w to about 2% w/w tapinarof or a pharmaceutically acceptable salt thereof, less than 1% w/w surfactant and from 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is selected from the group consisting of Carbomer Copolymer Type B, polysorbate 80, sorbitan monooleate, polysorbate 20, PEG 100 stearate, polysorbate 60, sodium dodecyl sulfate, sodium lauryl sulfate, cetearyl alcohol, dioctyl sodium sulfosuccinate (=docusate sodium), glyceryl oleate, glyceryl stearate, poloxamers and combination thereof.
[092] In one embodiment, this invention provides a topical cream composition, comprising from about 1% w/w to about 2% w/w tapinarof or a pharmaceutically acceptable salt thereof, less than 1% w/w surfactant and from 0.01% to about 1% w/w anti-oxidant, and from about 0.1% to about 4% w/w gelling agent, wherein the surfactant is selected from the group consisting of Carbomer Copolymer Type B, polysorbate 80, sorbitan monooleate, polysorbate 20, PEG 100 stearate, polysorbate 60, sodium dodecyl sulfate, sodium lauryl sulfate, cetearyl alcohol, dioctyl sodium sulfosuccinate (=docusate sodium), glyceryl oleate, glyceryl stearate, poloxamers and combination thereof.
[093] In one embodiment, this invention provides a topical cream composition, comprising a surfactant selected from the group consisting of Carbomer Copolymer Type B, polysorbate 80, sorbitan monooleate, polysorbate 20, PEG 100 stearate, polysorbate 60, sodium dodecyl sulfate, sodium lauryl sulfate, cetearyl alcohol, dioctyl sodium sulfosuccinate (=docusate sodium), glyceryl oleate, glyceryl stearate, poloxamers and combination thereof.
[094] In one embodiment, this invention provides a topical cream composition, comprising from about 1% w/w to about 2% w/w tapinarof or a pharmaceutically acceptable salt thereof, less than 1% w/w surfactant, from about 0.1% to about 4% w/w gelling agent and from about 0.01% to about 1% w/w antioxidant. In another embodiment, the surfactant is ionic or non-ionic. In another embodiment, the surfactant is ionic. In another embodiment, the surfactant is anionic.
[095] In one embodiment, this invention provides a topical cream composition, comprising from about 1% w/w to about 2% w/w tapinarof or a pharmaceutically acceptable salt thereof, less than 1% w/w surfactant and from about 0.01% to about 1% w/w anti-oxidant. In another embodiment, the surfactant is ionic or non-ionic. In another embodiment, the surfactant is ionic. In another embodiment, the surfactant is anionic.
[096] In one embodiment, this invention provides a topical cream composition, comprising 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, and optionally from about 0.01% to about 1% w/w an anti-oxidant, wherein the surfactant is ionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the surfactant is anionic. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[097] In one embodiment, this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, and optionally from about 0.01% to about 1% w/w an anti-oxidant, wherein the surfactant is ionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the surfactant is anionic. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof. [098] In one embodiment, this invention provides a topical cream composition, comprising 1% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, and optionally from about 0.01% to about 1% w/w an anti-oxidant, wherein the surfactant is ionic. . In another embodiment, the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the surfactant is anionic. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[099] In one embodiment, this invention provides a topical cream composition, comprising 1% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w gelling agent and optionally from about 0.01% to about 1% w/w an anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is Carbomer Copolymer Type B or docusate sodium, and the gelling agent is Carbomer Homopolymer Type C (Carbopol®980). In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w.
[100] In one embodiment, this invention provides a topical cream composition, comprising 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w gelling agent and optionally from about 0.01% to about 1% w/w an anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is Carbomer Copolymer Type B or docusate sodium, and the gelling agent is Carbomer Homopolymer Type C (Carbopol®980). In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w.
[101] In one embodiment, this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w gelling agent and optionally from about 0.01% to about 1% w/w an anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof, and the gelling agent is Carbomer Homopolymer Type C (Carbopol®980). In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w.
[102] In one embodiment, this invention provides a topical cream composition, comprising 1% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w gelling agent, an additional gelling agent and optionally from about 0.01% to about 1% w/w an anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[103] In one embodiment, this invention provides a topical cream composition, comprising 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w gelling agent, an additional gelling agent and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[104] In one embodiment, this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w gelling agent, an additional gelling agent and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[105] In one embodiment, this invention provides a topical cream composition, comprising 1% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w gelling agent, an additional gelling agent and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic, and the gelling agent is Carbomer Homopolymer Type C (Carbopol®980). In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[106] In one embodiment, this invention provides a topical cream composition, comprising 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w gelling agent, an additional gelling agent and from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic, and the gelling agent is Carbomer Homopolymer Type C (Carbopol®980). In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[107] In one embodiment, this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w gelling agent, an additional gelling agent and from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic, and the gelling agent is Carbomer Homopolymer Type C (Carbopol®980). In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[108] In one embodiment, this invention provides a topical cream composition, comprising 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 4% w/w additional gelling agent and from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[109] In one embodiment, this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 4% w/w additional gelling agent and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[110] In one embodiment, this invention provides a topical cream composition, comprising 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 4% w/w additional gelling agent and optionally from about 0.01% to about 1% w/w antioxidant, wherein the surfactant is ionic, and the gelling agent is Carbomer Homopolymer Type C (Carbopol®980). In another embodiment the surfactant is anionic. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w.
[111] In one embodiment, this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 4% w/w additional gelling agent and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic, and the gelling agent is Carbomer Homopolymer Type C (Carbopol®980). In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[112] In one embodiment, this invention provides a topical cream composition, comprising 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, an additional surfactant, , and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[113] In one embodiment, this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, an additional surfactant, and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[114] In one embodiment, this invention provides a topical cream composition, comprising 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof from about 0.1% w/w to about 20% surfactant, an additional surfactant, from about 0.1% to about 4% w/w gelling agent, and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic, and the gelling agent is Carbomer Homopolymer Type C (Carbopol®980). In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[115] In one embodiment, this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, an additional surfactant, from about 0.1% to about 4% w/w gelling agent, and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic, and the gelling agent is Carbomer Homopolymer Type C (Carbopol®980). In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[116] In one embodiment, this invention provides a topical cream composition, comprising 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, an additional surfactant, from about 0.1% to about 4% w/w gelling agent, an additional gelling agent and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the gelling agent is Carbomer Homopolymer Type C (Carbopol®980). In another embodiment, the additional gelling agent is in amount of from about 0.1% to about 4% w/w. In another embodiment, the additional surfactant is in amount of from about 0.1% to about 4% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[117] In one embodiment, this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, an additional surfactant, from about 0.1% to about 4% w/w gelling agent, an additional gelling agent and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the gelling agent is Carbomer Homopolymer Type C (Carbopol®980). In another embodiment, the additional gelling agent is in amount of from about 0.1% to about 4% w/w. In another embodiment, the additional surfactant is in amount of from about 0.1% to about 4% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[118] In one embodiment, this invention provides a topical cream composition, comprising 1% w/w or 1.5 % w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w an additional surfactant, from about 0.1% to about 4% w/w gelling agent, and optionally from about 0.01% to about 1% w/w antioxidant, wherein the surfactant is ionic, and the gelling agent is Carbomer Homopolymer Type C (Carbopol®980). In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[119] In one embodiment, this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w an additional surfactant, from about 0.1% to about 4% w/w gelling agent, and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic, and the gelling agent is Carbomer Homopolymer Type C (Carbopol®980). In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[120] In one embodiment, this invention provides a topical cream composition, comprising 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w an additional surfactant, from about 0.1% to about 4% w/w gelling agent, an additional gelling agent and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the gelling agent is Carbomer Homopolymer Type C (Carbopol®980). In another embodiment, the additional gelling agent is in amount of from about 0.1% to about 4% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[121] In one embodiment, this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w additional surfactant, from about 0.1% to about 4% w/w gelling agent, an additional gelling agent and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the gelling agent is Carbomer Homopolymer Type C (Carbopol®980). In another embodiment, the additional gelling agent is in amount of from about 0.1% to about 4% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[122] In one embodiment, this invention provides a topical cream composition, comprising 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 1.5% w/w preservative, and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[123] In one embodiment, this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 1.5% w/w preservative, and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[124] In one embodiment, this invention provides a topical cream composition, comprising 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w gelling agent, an additional gelling agent, from about 0.1% to about 1.5% w/w preservative, and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the additional gelling agent is in amount of from about 0.1% to about 4% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[125] In one embodiment, this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w gelling agent, an additional gelling agent, from about 0.1% to about 1.5% w/w preservative, and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the additional gelling agent is in amount of from about 0.1% to about 4% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[126] In one embodiment, this invention provides a topical cream composition, comprising 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, an additional surfactant, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 1.5% w/w preservative, and from about 0.01% to about 1% w/w antioxidant, wherein the surfactant is ionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment the surfactant is anionic. In another embodiment, the additional surfactant is in amount of from about 0.1% to about 4% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[127] In one embodiment, this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, an additional surfactant, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 1.5% w/w preservative, and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the additional surfactant is in amount of from about 0.1% to about 4% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[128] In one embodiment, this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w additional surfactant, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 4% w/w additional gelling agent, from about 0.1% to about 1.5% w/w preservative, and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the composition comprises 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[129] In one embodiment, this invention provides a topical cream composition, comprising 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 1.5% w/w preservative, a penetration enhancer and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the composition further comprises an additional gelling agent. In another embodiment, the composition further comprises an additional surfactant. In another embodiment, the additional gelling agent is in amount of from about 0.1% to about 4% w/w. In another embodiment, the additional surfactant is in amount of from about 0.1% to about 4% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[130] In one embodiment, this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 1.5% w/w preservative, a penetration enhancer and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the composition further comprises an additional gelling agent. In another embodiment, the composition further comprises an additional surfactant. In another embodiment, the additional gelling agent is in amount of from about 0.1% to about 4% w/w. In another embodiment, the additional surfactant is in amount of from about 0.1% to about 4% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) sodium lauryl sulfate docusate sodium or combination thereof.
[131] In one embodiment, this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w additional surfactant, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 4% w/w additional gelling agent, from about 0.1% to about 1.5% w/w preservative, a penetration enhancer and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the composition comprises 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) or docusate sodium.
[132] In one embodiment, this invention provides a topical cream composition, comprising 1% w/w or 1.5 % w/w tapinarof or a pharmaceutically acceptable salt thereof from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 1.5% w/w preservative, about 0.1% to about 20% w/w penetration enhancer and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the composition further comprises an additional gelling agent. In another embodiment, the composition further comprises an additional surfactant. In another embodiment, the additional gelling agent is in amount of from about 0.1% to about 4% w/w. In another embodiment, the additional surfactant is in amount of from about 0.1% to about 4% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) or docusate sodium.
[133] In one embodiment, this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 1.5% w/w preservative, about 0.1% to about 20% w/w penetration enhancer and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the composition further comprises an additional gelling agent. In another embodiment, the composition further comprises an additional surfactant. In another embodiment, the additional gelling agent is in amount of from about 0.1% to about 4% w/w. In another embodiment, the additional surfactant is in amount of from about 0.1% to about 4% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) or docusate sodium.
[134] In one embodiment, this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w additional surfactant, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 4% w/w additional gelling agent, from about 0.1% to about 1.5% w/w preservative, about 0.1% to about 20% w/w penetration enhancer and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the composition comprises 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) or docusate sodium.
[135] In one embodiment, this invention provides a topical cream composition, comprising 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w gelling agent, a penetration enhancer and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the composition further comprises an additional gelling agent. In another embodiment, the composition further comprises an additional surfactant. In another embodiment, the additional gelling agent is in amount of from about 0.1% to about 4% w/w. In another embodiment, the additional surfactant is in amount of from about 0.1% to about 4% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) or docusate sodium.
[136] In one embodiment, this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant,, from about 0.1% to about 4% w/w gelling agent, a penetration enhancer and optionally from about 0.01% to about 1% w/w anti-oxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the composition further comprises an additional gelling agent. In another embodiment, the composition further comprises an additional surfactant. In another embodiment, the additional gelling agent is in amount of from about 0.1% to about 4% w/w. In another embodiment, the additional surfactant is in amount of from about 0.1% to about 4% w/w. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) or docusate sodium. [137] In one embodiment, this invention provides a topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, from about 0.1% to about 4% w/w additional surfactant, from about 0.1% to about 4% w/w gelling agent, from about 0.1% to about 4% w/w additional gelling agent, a penetration enhancer and optionally from about 0.01% to about 1% w/w antioxidant, wherein the surfactant is ionic. In another embodiment the surfactant is anionic. In another embodiment, the surfactant is in amount of from about 0.1% to about 1.5% w/w. In another embodiment, the surfactant is less than 1% w/w. In another embodiment, the composition comprises 1% w/w or 1.5% w/w tapinarof or a pharmaceutically acceptable salt thereof. In another embodiment, the surfactant is Carbomer Copolymer Type B (Pemulen®TR-1) or docusate sodium.
[138] In some embodiments, provided herein a method of treating a skin disorder in a patient in need thereof, said method comprises administering to said patient the topical cream composition provided herein, wherein said skin disorder is selected from psoriasis, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and extensive pyodermas, acne, rosacea, atopic dermatitis, prurigo nodularis and hidradenitis suppurativa.
[139] In some embodiments, the composition provided herein is for use in treating a skin disorder in a patient in need thereof, said method comprises administering to said patient the topical cream composition provided herein, wherein said skin disorder is selected from psoriasis, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and extensive pyodermas, acne, rosacea, atopic dermatitis, prurigo nodularis and hidradenitis suppurativa.
Definitions
[140] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the invention pertains. In case of conflict, the specification, including definitions, takes precedence. All patents, patent applications, published applications, articles, publications and other published materials referred to throughout the entire disclosure herein, unless noted otherwise, are incorporated by reference in their entirety.
[141] As used herein, the indefinite articles "a" and "an" mean "at least one" or "one or more" unless the context clearly dictates otherwise. [142] As used herein, the term "treating" or” treatment" includes curing a condition, treating a condition, preventing a condition, treating symptoms of a condition, curing symptoms of a condition, ameliorating symptoms of a condition, treating effects of a condition, ameliorating effects of a condition, and preventing results of a condition.
[143] As used herein, the terms “pharmaceutically active agent” or “active agent” or “active pharmaceutical ingredient” or “API” are interchangeable and mean the ingredient is a pharmaceutical drug which is biological active and is regulatory approved or approvable as such.
[144] The term “ingredient” refers to a pharmaceutically acceptable ingredient which is included or is amenable to be included in FDA’s Inactive Ingredient database (IIG). Inactive ingredients sometimes exhibit some therapeutic effects, although they are not drugs.
[145] As used herein, a "pharmaceutical composition" refers to a composition comprising one or more active ingredients with other components such as pharmaceutically acceptable ingredients or excipients. The purpose of a pharmaceutical composition is to facilitate administration of an active ingredient to a subject.
[146] Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases “ranging/ranges between” a first indicate number and a second indicate number and “ranging/ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.
[147] The dimensions and values disclosed herein are not to be understood as being strictly limited to the exact numerical values recited. Instead, unless otherwise specified, each such dimension is intended to mean both the recited value and a functionally equivalent range surrounding that value. For example, a dimension disclosed as “10 pm” is intended to mean “about 10 pm”.
[148] As used herein, numerical ranges preceded by the term “about” should not be considered to be limited to the recited range. Rather, numerical ranges preceded by the term “about” should be understood to include a range accepted by those skilled in the art for any given element in formulations according to this invention.
[149] As used herein, when a numerical value is preceded by the term "about", the term "about" is intended to indicate +/-10%.
[150] The terms "comprise", "comprising", "includes", "including", “having” and their conjugates mean "including but not limited to".
[151] The term “consisting of’ means “including and limited to”. [152] The term "consisting essentially of' means that the composition, method formulation may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.
[153] As used herein the term "method" refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
[154] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.
[155] Various embodiments and aspects of this invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples.
EXAMPLES
[156] Reference is now made to the following examples, which together with the above descriptions illustrate some embodiments of the invention in a non-limiting fashion.
[157] Generally, the nomenclature used herein and the laboratory procedures utilized in this invention include chemical, molecular and biochemical, techniques. Such techniques are thoroughly explained in the literature. General references are provided throughout this document. The procedures therein are believed to be well known in the art and are provided for the convenience of the reader. All the information contained therein is incorporated herein by reference.
Example 1
Preparation of a Tapinarof Cream Composition [158] The topical tapinarof cream consisted of:
Figure imgf000038_0001
Figure imgf000038_0003
Figure imgf000038_0002
Figure imgf000039_0001
Example 2
Psoriasis treatment using tapinarof compositions
Goal
[159] The objective of this study was to determine the efficacy of tapinarof composition as described in Example 1 compared to the vehicle and Dexamethasone as shown below. The evaluation was based on histology analysis following application of the respective test formulations.
[160] This study is focused on the effect of tapinarof on experimentally induced psoriasis. In this model, a psoriasis phenotype is induced in normal skin grafted onto beige-severe combined immunodeficient mice by intradermal injection of natural killer/T-cells derived from psoriatic patients (Gilhar et al., Psoriasis is mediated by a cutaneous defect triggered by activated immunocytes: induction of psoriasis by cells with natural killer receptors, J. Invest. Dermatol. 2002 Aug; 119(2):384-9I).
Experimental details
[161] In order to address the aim of the experiment, the psoriatic humanized mice were established Additionally, 10 psoriatic patients were recruited (six males and four females), ranging from 21 to 66 years (mean age 45 years). All patients had classic plaque psoriasis. Normal skin from one healthy volunteer was obtained for grafting.
[162] The efficacy study has been conducted on female mice. The total duration of the experiment was 8 weeks, upon receiving of the human skin. Normal skin from healthy volunteers were obtained for grafting. Healthy human abdominal skin pieces with a width of 0.4 mm and surface area of 1.5 x 1.5 cm were provided. The skin sample was preserved in isotonic saline solution and transplanted within 6-12 hours after skin donation. In addition, blood samples were collected from psoriatic patients having classic plaque psoriasis and not undergoing any treatment. 20 mL blood samples were taken from both males and females psoriatic patients (from psoriatic patients having classic plaque psoriasis and not undergoing any treatment), and peripheral blood mononuclear cells (PBMC) were separated immediately after blood withdrawal. [163] Mice: Beige-severe combined immunodeficient mice C.B-17/IcrHsdscid- bg (beige-SCID) mice (weight ~25 g) were included in this study. Mice were monitored twice a week for vital signs such as weight, food intake, coat, eyes, anal genital areas, discharge/soiling, behavior and criteria related to skin transplantation. Normal healthy human donor skin were transplanted onto the beige- SCID mice as previously described (See Keren A. et al., Novel nanosome delivery system combined with siRNA targeting the antimicrobial gene DFB4: a new approach for psoriasis management? ExpDermatol. 2014; 23:464-465; Bracke S. et al., Targeted silencing of DEFB4 in a bioengineered skin-humanized mouse model for psoriasis: development of siRNA SECosome- based novel therapies. ExpDermatol. 2014; 23: 199-201; Zaretsky M. et al., Directed evolution of a soluble human IL-17A receptor for the inhibition of psoriasis plaque formation in a mouse model. Chem Biol. 2013 21; 20:202-2; Gilhar A. et al., The beneficial effect of blocking Kvl.3 in the psoriasiform SCID mouse model. J Invest Dermatol. 2011; 131 : 118 124; Keren A. et al., Innate lymphoid cells 3 induce psoriasis in xenotransplanted healthy human skin. J Allergy Clin Immunol. 2018;142:305-308. e6.).
[164] PBMC's from the psoriatic patient's blood were isolated and cultured in the presence of a high dose of IL-2; Prospec ,100 U/mL of media- RPMI 1640,10% human AB serum (Sigma, St.Louis,MO), 1% glutamine, 1% antibiotics (media components; Biologicallndustries, Kibbutz Beit Haemeck, Israel) , as previously described (Gilhar A. et al., The beneficial effect of blocking Kvl.3 in the psoriasiform SCID mouse model. J Invest Dermatol. 2011;131 : 118-124; Nousbeck J. et al., IGFBP7 as a potential therapeutic target in Psoriasis. J Invest Dermatol. 2011; 131 : 1767- 1770; Schafer PH. et al., Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates antiinflammatory activity in vitro and in a model of psoriasis. British Journal of Pharmacology 2010; 159:842-855).
[165] Four weeks following the engraftment, each mouse was injected (intradermally) with 1 x 107 IL-2 enriched allogeneic PBMC's from psoriatic patients (1 x 107 cells injected/mouse). Cells from different psoriasis patients were equally distributed between treatment groups. Each patient was represented in each treatment group.
[166] Fourteen days following cells injections, the mice were divided into treatment groups (Table 1, see below ) and treated according to the timeline indicated below (see Scheme 1). Each transplant was equally topically treated (50 pg) by using a sterile spatula.
[167] Dexamethasone (D2915, Sigma): was freshly prepared for each administration by dilution in saline to final concentration (50 mg/ml). Dexamethasone serves as a positive control and was administered topically twice daily for 14 days following cells injections (at Day 42 following human skin transplantation) until the end of the study (Day 56).
[168] The vehicle was administered topically (50 pg) once daily for 14 days.
Scheme 1:
Figure imgf000041_0001
[169] On Day 56, the entire skin graft was excised and placed in 10% formaldehyde in saline overnight. Then, the specimens were placed in 70% ethanol and embedded and stained according to the standard HematoxylinZEosin protocol.
[170] Skin graft histological assessment was performed (according to the psoriatic criteria including epidermal thickness) using light microscopy, and two observers blindly performed the evaluations. Epidermal thickness was determined using an ocular micrometer at a minimum of 50 points along the epidermis selected to represent points of maximal and minimal thickness. Thickness of the suprapapillary plate was measured similarly at 50 points for each sample. Three slices were examined for each sample.
[171] The experiment (study 1) comprised 30 mice divided into 3 groups (Table 1; with results found in Tables 2-4) as follows: Group 1: Vehicle; Group 2: Dexamethasone; Group 3: Tapinarof 1%, cream A (cream of Example 1).
[172] Another experiment (study 2) comprised 30 mice divided into 3 groups (Table 5; with results found in Tables 6-9) as follows: Group 1 : dexamethasone; Group 2: Tapinarof 1%', cream D (Table 10); Group 3: Tapinarof 1% , cream A (cream of Example 1);
Results
Evaluation of normal human skin grafts from psoriatic T-cell-injected beige-SCID mice Study 1-Results
[173] Normal human skin xenotransplanted onto beige-SCID mice treated with psoriatic T-cells expressing NK receptors, expressed psoriatic features that included epidermal thickening (acanthosis), enhanced epidermal proliferation, hyperkeratosis, parakeratosis, along with a dermal lymphocytic infiltrate, some areas with retention, others lacking the granular layer. Elongation of rete ridges was also observed in most psoriatic skin grafts, and vascular dilatation associated with a perivascular lymphocytic infiltrate was noted in the papillary dermis. Conversely, normal skin grafts from mice treated with dexamethasone showed complete (9/10) recovery from the psoriatic features. Specifically, these dexamethasone-treated grafts underwent a complete normalization of the skin, including a significant decrease in epidermal thickness compared to the Vehicle cream group (254±59 pm versus 713±293 pm, P<0.002) (Tables 2-4, Figure 1).
Table 1: Study groups
Figure imgf000042_0001
Table 2: Histological evaluation of human skin grafts following treatment
Figure imgf000043_0001
Table 3: Histology of treated psoriasis grafts (mean epidermal thickness, scoring, complete recovery/total No grafts)
Figure imgf000043_0002
Table 4: Pathological scores based on Baker's scoring system (A[IQRJ) (Average, SD).*
* Many of the psoriatic pathohistological components are missing in the Dexa and the tested treated transplants, therefore the results are spread out and the SD is large. In contrast, all the psoriatic parameters are present in the vehicle group, therefore the SD is small and thus the results are close to the mean.
** Appearance of neutrophils in the upper spinous layer or in the corneal cell layer.
Parameters of pathological/inflammatory angiogenesis, edema and vascular enlargement, increased tortuosity and elongation in the dermal papilla. Vehicle versus all treated groups (p<0.004, Kruskal-Wallis test, followed by the Mann-Whitney U test).
Figure imgf000044_0001
all treated groups (p<0.004, Kruskal-Wallis test, followed by the Mann-Whitney U test).
Study 2-Results [174] Normal human skin xenotransplanted onto beige-SCID mice treated with psoriatic T-cells expressing NK receptors, expressed psoriatic features that included epidermal thickening (acanthosis), enhanced epidermal proliferation, hyperkeratosis, parakeratosis, along with a dermal lymphocytic infiltrate, some areas with retention, others lacking the granular layer. Elongation of rete ridges was also observed in most psoriatic skin grafts, and vascular dilatation associated with a perivascular lymphocytic infiltrate was noted in the papillary dermis.
[175] The results demonstrated (Error! Reference source not found, and Figures 2-3) a therapeutic effect of Tapinarof 1% of Cream A demonstrating similar histological score (including epidermal thickness, proliferation index, Baker’s scoring, immunological markers) as Cream D. The creams demonstrated a complete normalization of the psoriatic phenotype in 8/10 grafts, including decreased epidermal thickness in both groups.
[176] In conclusion, the study confirmed a therapeutic effect of Tapinarof 1% in cream A, demonstrating a similar histological score as cream D, in the humanized mouse model for psoriasis. However, the surfactant of cream A, i.e. pemulen TRI, is found at much lower concentration (0.4% w/w) compared to the surfactants of cream D (sum of concentrations of polysorbate 80, stearate 2 and stearate 20 is 4.4% w/w).
Table 5: Study groups
Figure imgf000045_0001
20
Table 6: Histological evaluation of human skin grafts following treatment
Figure imgf000045_0002
Table 7: Histology of treated psoriasis grafts (mean epidermal thickness, scoring, complete recovery/total No grafts)
Figure imgf000046_0001
Table 8: Pathological scores based on Baker's scoring system (A[IQR]) (Average, SD).*
Figure imgf000046_0002
* Many of the psoriatic pathohistological components are missing in the Dexamethasone and the tested treated transplants, therefore the results are spread out and the SD is large. ** Appearance of neutrophils in the upper spinous layer or in the corneal cell layer.
*** Parameters of pathological/inflammatory angiogenesis, edema and vascular enlargement, increased tortuosity and elongation in the dermal papilla. Table 9: Immunohistochemical markers for psoriasis in human xenotransplants
Figure imgf000047_0001
Table 10: - cream D, which is formulation 21 of Tapinarof (1% w/w) in Table 8 of US
10,195,160:
Figure imgf000047_0002
Example 3
Tapinarof Cream, 1% with docusate sodium (=dioctyl sodium sulfosuccinate) as surfactant Table 11: Tapinarof composition with docusate sodium
Figure imgf000048_0001
Figure imgf000048_0002
Figure imgf000049_0003
Table 12: Stability results of the tapinarof composition with docusate:
Figure imgf000049_0001
Example 4
Tapinarof Cream, 1% with sodium lauryl sulfate as surfactant Table 13: Tapinarof composition with sodium lauryl sulfate
Figure imgf000049_0002
Oil phase preparation
Figure imgf000050_0001
Example 5
Tapinarof Cream, 1% with PEG 100 stearate (non-ionic) as surfactant
Table 14: Tapinarof composition with PEG 100 stearate (non-ionic)
Figure imgf000051_0001
Figure imgf000051_0002

Claims

CLAIMS A topical cream composition, comprising from about 1% w/w to about 2% w/w tapinarof or a pharmaceutically acceptable salt thereof and less than 1% w/w surfactant. The composition of claim 1, wherein the surfactant is selected from the group consisting of Carbomer Copolymer Type B, polysorbate 80, sorbitan monooleate, polysorbate 20, PEG 100 stearate, polysorbate 60, sodium dodecyl sulfate, sodium lauryl sulfate, cetearyl alcohol, dioctyl sodium sulfosuccinate (=docusate sodium), glyceryl oleate, glyceryl stearate, poloxamers and combination thereof. The composition of claim 1 or claim 2, wherein the surfactant is ionic or non-ionic. The composition of any one of claims 1-3, further comprising from about 0.1% to about 4% w/w gelling agent. The composition according to any one of claims 1-4, further comprising from about 0.01% to about 1% w/w anti-oxidant. A topical cream composition, comprising from about 0.25% w/w to about 10.0% w/w tapinarof or a pharmaceutically acceptable salt thereof, from about 0.1% w/w to about 20% surfactant, and optionally from about 0.01% to about 1% w/w an anti-oxidant, wherein the surfactant is ionic. The composition of claim 6, wherein the composition comprises 1% or 1.5% w/w tapinarof. The composition of claim 6 or claim 7, wherein the surfactant is anionic. The composition of claim 8, wherein the surfactant is selected from the group consisting from Carbomer Copolymer Type B, sodium lauryl sulfate, sodium dodecyl sulfate and dioctyl sodium sulfosuccinate (docusate sodium). The composition of any one of claims 6-9, wherein the surfactant is Carbomer Copolymer Type B or docusate. The composition of any one of claims 6-10, wherein the concentration of the surfactant is 5% w/w or less than 5% w/w. The composition of claim 11, wherein the concentration of the surfactant is from 0.2 % to 0.8% w/w. The composition of any one of claims 6-12, wherein the composition further comprises from about 0.1% w/w to about 4% w/w gelling agent. The composition according to any one of claims 4-5 and 13, further comprising an additional gelling agent. The composition of claim 14, wherein said gelling agent and said additional gelling agent are each selected independently from a carbomer, Natrosol hydroxyethylcellulose, starch, pectin, gelatin, agar, alginic acid and salts thereof, carboxymethylcellulose, hydroxypropylmethylcellulose and any combination thereof. The composition of claim 15, wherein said gelling agent is Carbomer Homopolymer Type C in an amount of about 0.1% to about 4% w/w. The composition according to any one of claims 1-16, further comprising an additional surfactant. The composition of claim 17, wherein said additional surfactant is selected from the group consisting of Carbomer Copolymer Type B, polysorbate 80, sorbitan monooleate, polysorbate 20, PEG 100 stearate, polysorbate 60, sodium dodecyl sulfate, sodium lauryl sulfate, cetearyl alcohol, dioctyl sodium sulfosuccinate, glyceryl oleate, glyceryl stearate, poloxamers and combination thereof. The composition according to any one of claims 5-13, wherein said composition comprises from about 0.01% to about 0.2 % w/w anti-oxidant. The composition according to any one of claims 5-13, wherein said anti-oxidant is selected from butylated hydroxy toluene, parabens, propyl gallate, ascorbic acid, flavones, flavanones, flavonols, stilbenoids, gallic acid, cinnamic acid, ellagic acid, salicylic acid, curcumin, eugenol, citric acid, tocopherol, vitamin E, tocopherol polyethylene glycol succinate and any combination thereof. The composition according to any one of claims 1-20, wherein the composition further comprises from about 0.1% to about 1.5% w/w preservative. The composition of claim 21, wherein the preservative is selected from benzoic acid, methylparaben, phenoxyethanol, imidurea, chlorocresol, propyl paraben, benzalkonium chloride, benzyl alcohol, imidazolidinyl urea, sodium benzoate, sorbic acid, thimerosal sorbic acid, sodium sorbate, sodium sulfite, ethanol, tocopherols and any combination thereof. The composition according to any one of claims 1-22, wherein the composition further comprises a penetration enhancer. The composition of claim 23, wherein the penetration enhancer is selected from dimethylsulfoxide, diethylene glycol monoethyl ether, methyl sulfonylmethane, propylene glycol, dimethyl isosorbide, oleic acid, oleyl alcohol, ethanol, isopropyl alcohol, a polyethylene glycol, hexylene glycol, glycofurol, isopropyl myristate, glycerin, mono- and di- carboxylic acid esters and any combination thereof. The composition according to any one of claims 1-24, wherein the purity of said tapinarof is greater than 97%. A method of treating a skin disorder in a patient in need thereof, said method comprises administering to said patient the topical cream composition according to any one of claims 1-25, wherein said skin disorder is selected from psoriasis, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and extensive pyodermas, acne, rosacea, atopic dermatitis, prurigo nodularis and hidradenitis suppurativa.
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