WO2023067606A1 - Crystalline polymorph of tapinarof - Google Patents
Crystalline polymorph of tapinarof Download PDFInfo
- Publication number
- WO2023067606A1 WO2023067606A1 PCT/IL2022/051115 IL2022051115W WO2023067606A1 WO 2023067606 A1 WO2023067606 A1 WO 2023067606A1 IL 2022051115 W IL2022051115 W IL 2022051115W WO 2023067606 A1 WO2023067606 A1 WO 2023067606A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tapinarof
- tinea
- crystalline form
- dermatitis
- skin disorder
- Prior art date
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- ZISJNXNHJRQYJO-CMDGGOBGSA-N 5-[(e)-2-phenylethenyl]-2-propan-2-ylbenzene-1,3-diol Chemical compound C1=C(O)C(C(C)C)=C(O)C=C1\C=C\C1=CC=CC=C1 ZISJNXNHJRQYJO-CMDGGOBGSA-N 0.000 title claims abstract description 113
- 229940070118 tapinarof Drugs 0.000 title claims abstract description 109
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
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- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 claims description 14
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- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 6
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- 206010037575 Pustular psoriasis Diseases 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
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- RZOBLYBZQXQGFY-HSHFZTNMSA-N azanium;(2r)-2-hydroxypropanoate Chemical compound [NH4+].C[C@@H](O)C([O-])=O RZOBLYBZQXQGFY-HSHFZTNMSA-N 0.000 description 2
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- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 description 2
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- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
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- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 description 1
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
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- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
Definitions
- the present disclosure encompasses crystalline polymorphs of Tapinarof, processes for preparation thereof, and pharmaceutical compositions comprising thereof.
- 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- 17A, and enhance skin barrier function (J Invest Dermatol. 2017 Oct;137[10]:2110-9).
- Polymorphism the occurrence of different crystalline forms, is a property of some molecules and molecular complexes.
- a single molecule like Tapinarof, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviours (e.g., measured by thermogravimetric analysis - "TGA”, or differential scanning calorimetry - “DSC”), X-ray diffraction (XRD) pattern, infrared absorption fingerprint, and solid state ( 13 C) NMR spectrum.
- TGA thermogravimetric analysis -
- DSC differential scanning calorimetry -
- XRD X-ray diffraction
- 13 C solid state
- Different solid-state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different solid- state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different solid-state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different solid-state forms and solvate of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.
- the skin is a barrier that controls the body's moisture and prevents the penetration of microorganisms because the skin is composed of superficial layers of epidermis and stratum corneum that provide most of the skin barrier properties.
- the stratum corneum consists of layers of overlapping cell plates containing keratin.
- drug absorption via the skin is transcellular, that is, a passive diffusion process, which depends on the efficacy of the epidermal barrier and the nature of the drug itself.
- Drugs having low molecular weight of less than about 800 Daltons with high water and lipid solubility demonstrate the greatest skin penetration.
- Discovering new solid-state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms.
- New solid-state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelflife (chemical/physical stability).
- the present invention provides a novel Tapinarof polymorph referred to hereinafter as Tapinarof crystalline Form A.
- the present invention provides pharmaceutical compositions comprising Tapinarof crystalline Form A of the present invention and at least one pharmaceutically acceptable excipient.
- the Tapinarof crystalline Form A is characterized by an X-ray powder diffraction pattern exhibiting characteristic diffraction peaks at 6.9, 10.7, 16.3, 20.4 and 22.7 ⁇ 0.2 degrees 29.
- the present invention further provides methods of using a pharmaceutical composition comprising Tapinarof crystalline Form A of the present invention in the treatment of diseases or conditions including diseases or conditions for which Tapinarof provides therapeutic benefit to a mammal having the disease or condition, such as, treatment of psoriasis, dermatitis, acne, rosacea, ichthyosis, scaling skin, imbalance of skin barrier and tinea by topically or intralesionally administering to a subject in need thereof a therapeutically effective amount of Tapinarof crystalline Form A.
- diseases or conditions including diseases or conditions for which Tapinarof provides therapeutic benefit to a mammal having the disease or condition, such as, treatment of psoriasis, dermatitis, acne, rosacea, ichthyosis, scaling skin, imbalance of skin barrier and tinea by topically or intralesionally administering to a subject in need thereof a therapeutically effective amount of Tapinarof crystalline Form A.
- Figure 1 depicts the XRPD pattern of Tapinarof Form A.
- Figure 2 depicts the DSC curve of Tapinarof Form A.
- Figure 3 depicts the TGA curve of Tapinarof Form A.
- the present disclosure encompasses Tapinarof crystalline Form A, processes for preparation thereof, and pharmaceutical compositions comprising Tapinarof crystalline Form A and at least one pharmaceutically acceptable excipient.
- the pharmaceutical composition comprises Tapinarof crystalline Form A and an additional solid state form of Tapinarof, and at least one pharmaceutically acceptable excipient.
- the Tapinarof and solid-state forms thereof according to the present disclosure may have advantageous properties selected from at least one of the following: chemical or polymorphic purity, flowability, solubility, dissolution rate, bio-viability, morphology or crystal habit, stability- such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility, and bulk density.
- advantageous properties selected from at least one of the following: chemical or polymorphic purity, flowability, solubility, dissolution rate, bio-viability, morphology or crystal habit, stability- such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, low content of residual solvent, a lower degree of hy
- a solid-state form such as a crystal form
- graphical data include, for example, powder X-ray diffractograms.
- the graphical data potentially provides additional technical information to further define the respective solid- state form (a so-called "fingerprint") which cannot necessarily be described by reference to numerical values or peak positions alone.
- a crystal form of Tapinarof referred to herein as being characterized by graphical data "as depicted in” or “as substantially depicted in” a Figure will thus be understood to include any crystal forms of Tapinarof characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.
- the Tapinarof crystalline Form A described herein is anhydrous. In some embodiments, the Tapinarof crystalline Form A described herein is a non solvated Tapinarof crystalline Form A.
- anhydrous or “non solvated” in relation to crystalline forms of Tapinarof relates to a crystalline form of Tapinarof which does not include any crystalline water (“anhydrous”) or other solvents (non solvated) in a defined, stoichiometric amount within the crystal. Moreover, an “anhydrous” or “non solvated” form would typically, not contain more than 0.5% (w/w) of either water or organic solvents respectively as measured for example by TGA (Thermal Gravimetric Analysis).
- isolated in reference to crystalline polymorph of Tapinarof of the present disclosure corresponds to a crystalline polymorph of Tapinarof that is physically separated from the reaction mixture in which it is formed.
- reduced pressure refers to a pressure that is less than atmospheric pressure.
- reduced pressure is about 10 mbar to about 50 mbar.
- this present disclosure relates to Tapinarof crystalline Form A.
- the Tapinarof crystalline Form A is characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 1 and Table 1; an X-ray powder diffraction pattern having peaks at 6.9, 10.7, 16.3, 20.4 and 22.7 degrees 2-theta ⁇ 0.2 degrees 2-theta.
- the Tapinarof crystalline Form A is characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 1 and Table 1; an X-ray powder diffraction pattern having peaks at 6.9, 10.7, 16.3, 20.4 and 22.7 degrees 2-theta ⁇ 0.2 degrees 2-theta.
- the Tapinarof crystalline Form A is characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 1 and Table 1; an X-ray powder diffraction pattern having peaks at 6.9, 10.7, 16.3, 20.4 and
- Form A is anhydrous and non-solvated.
- the Tapinarof crystalline Form A is characterized by X-ray powder diffraction pattern having peaks at 6.9, 10.7, 12.2, 12.7, 14.6, 15.1, 16.3, 17.0, 20.4 and 22.7 degrees 2-theta ⁇ 0.2 degrees 2-theta.
- the Tapinarof crystalline Form A is characterized by X-ray powder diffraction pattern having peaks as presented in Table 1.
- the anhydrous/non-solvated character of Form A is demonstrated by TGA and DSC, showing negligible weight loss before decomposition, and single thermal endotherm (interpreted as melting) before decomposition.
- Tapinarof crystalline Form A described herein is characterized by the DSC melting peak at about 123°C, with Tonset of about 120°C.
- Tapinarof crystalline Form A described herein is characterized by the DSC thermogram presented in the following Fig. 2.
- Tapinarof crystalline Form A described herein is characterized by the TGA weight loss of less than 0.5% up to 100°C. In other embodiments, the TGA weight loss is of about 0.1%, 0.2%, 0.3%, 0.4% or 0.5% up to 100°C. [0037] In some embodiments, Tapinarof crystalline Form A described herein is characterized by the TGA thermogram presented Fig. 3.
- this invention provides a process for the preparation of Tapinarof crystalline Form A .
- the starting material in these processes is produced by any suitable method, including synthesis methods known in the art.
- the Tapinarof starting material is obtained as described in Examples 1-5 of CN 101648851 which is incorporated herein by reference.
- the processes of the present invention produce high purity Tapinarof crystalline Form A.
- the chemical purity of the crystalline polymorph (Form A) of Tapinarof of the invention is from about 95% to about 100%.
- the chemical purity of the crystalline polymorph (Form A) of Tapinarof of the invention is from about 96% to about 100%.
- the chemical purity of the crystalline polymorph (Form A) of Tapinarof of the invention is from about 97% to about 100%. In another embodiments, the chemical purity of the crystalline polymorph (Form A) of Tapinarof of the invention is from about 98% to about 100%. In another embodiments, the chemical purity of the crystalline polymorph (Form A) of Tapinarof of the invention is from about 99% to about 100%. In another embodiments, the crystalline polymorph (Form A) of Tapinarof of the invention has a chemical purity of about 99%.
- this invention provides a crystalline polymorph (Form A) of Tapinarof, which is prepared by the process of this invention.
- step (ii) heating the solution of step (i) to obtain a clear solution
- step (iii) adding to the solution of step (ii) an anti-solvent
- the Tapinarof crystalline Form A obtained by the process described herein is an anhydrous or non-solvated Tapinarof crystalline Form A.
- the further cooling is done gradually for a period of about 1 hour. In another embodiment the further cooling is done gradually for a period of at least 1 hour.
- said aromatic hydrocarbon solvent is selected from substituted or unsubstituted toluene, benzene, or any combination thereof, etc.
- the said aromatic hydrocarbon solvent is toluene.
- the said aromatic hydrocarbon solvent is benzene.
- said anti-solvent is a saturated hydrocarbon.
- the saturated hydrocarbon is hexane, heptane, cyclohexane, methylcyclohexane or combination thereof, etc.
- step (iii) is done gradually. In a specific embodiment of the present invention, the addition of the antisolvent (step (iii)) is done for 10-15 min.
- heating is to a temperature of at least 75-85°C.
- the solution is stirred for at least 1 hour, and the first cooling (to start the crystallization) is carried out to a temperature of about 55- 60°C. In another embodiment, the first cooling is carried out to a temperature of about 55°C.
- the further cooling (to a temperature at which crystals of Tapinarof Form A begin to precipitate) is carried out to a temperature of about 25-30°C. In a specific embodiment of the present invention, the further cooling is done for at least 1 hour. In a specific embodiment of the present invention, the further cooling is done for about 1 hour.
- heating is to a temperature of at least 75°C and cooling is carried out to a temperature of 25-30°C or below.
- heating is to a temperature of at least 75°C and cooling is carried out to a temperature of 25-55°C or below.
- first cooling is carried out for at least 1 hour, 2hrs, 3hrs or for a period the crystallization starts, and the further cooling is carried out for at least 1 hour, for 2 hrs, 3 hrs, or until crystals of Tapinarof Form A precipitate.
- the crystals are washed with cyclohexane.
- the crystals are washed with methylcyclohexane.
- the crystals are washed with cyclohexane, methylcyclohexane or combination thereof.
- a process for preparing Tapinarof crystalline Form A comprises the steps of dissolving Tapinarof in toluene, preferably at a W/V ration of 1 g per about 4 mL, at a temperature of about 75-85°C and stirring for about 15- 20 minutes to afford a clear solution.
- the anti-solvent is added to the solution, preferably, cyclohexane or methylcyclohexane, preferably at a W/V ratio of 1 g per about 2 ml and stirring for about 1 hour at a temperature of about 55 °C about to start the crystallization. In another embodiment, temperature is between 55-60 °C to start the crystallization.
- isolating the crystals can be carried out by a method selected from drying, evaporation or removal of a solvent or solvents under reduced pressure and filtration.
- the crystals are isolated by filtration.
- the compound is at least 85% pure by weight, or at least 86% pure by weight, or at least 87% pure by weight, or at least 88% pure by weight, or at least 89% pure by weight, or at least 90% pure by weight, or at least 91% pure by weight, or at least 92% pure by weight, or at least 93% pure by weight, or at least 94% pure by weight, or at least 95% pure by weight, or at least 96% pure by weight, or at least 97% pure by weight, or at least 98% pure by weight, or at least 99% pure by weight. In some embodiments, the compound is at least 99% pure by weight.
- the compound is at least 85% Form A by weight, or at least 86% Form A by weight, or at least 87% Form A by weight, or at least 88% Form A by weight, or at least 89% Form B by weight, or at least 90% Form A by weight, or at least 91% Form A by weight, or at least 92% Form A by weight, or at least 93% Form A by weight, or at least 94% Form A by weight, or at least 95% Form A by weight, or at least 96% Form A by weight, or at least 97% Form A by weight, or at least 98% Form A by weight, or at least 99% Form A by weight.
- the Tapinarof compound has a cis isomer content of 0.1% or less, wherein the compound is at least 98% pure by weight, wherein the compound is at least 85% Form A, characterized by an x-ray powder diffraction pattern having peaks at 6.9, 10.7, 16.3, 20.4 and 22.7 ( ⁇ 0.2) °29.
- the Tapinarof compound has a cis isomer content of 0.1% or less and is at least 98% pure by weight, wherein the compound is at least 95% Form A.
- the Tapinarof compound has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% crystalline Form B.
- the present invention provides pharmaceutical compositions comprising the polymorph of the present invention, i.e., crystalline Form A of Tapinarof and at least one pharmaceutically acceptable excipient.
- this invention provides a Tapinarof having a chemical purity of at least 90% and a pharmaceutical composition comprising thereof. In other embodiments, this invention provides a Tapinarof having a chemical purity of at least 91%, 92%, 93%, 94%, 95% 99% and a pharmaceutical composition comprising thereof. In other embodiments, this invention provides a Tapinarof having at least 90% crystalline Form A and a pharmaceutical composition comprising thereof. In other embodiments, this invention provides a Tapinarof having at least 91%, 92%, 93%, 94%, 95% 99% crystalline Form A and a pharmaceutical composition comprising thereof.
- this invention provides a pharmaceutical composition comprising a combination of Tapinarof crystalline Form A and an amorphous or different solid form of Tapinarof or combination thereof.
- the weight ratio between the crystalline Form A and the amorphous or different solid form is in the range of between 10:1 to 1:10.
- the weight ratio between the crystalline polymorph and the amorphous or different solid form is 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3 or 1:2 or any ranges thereof.
- compositions of this invention are useful for the treatment, prevention or amelioration of skin disorders.
- the present invention provides methods for the treatment, prevention and/or amelioration of skin disorders comprising a composition comprising from about 0.25% w/w to about 10% w/w crystalline polymorph Form A of Tapinarof.
- the composition comprises from 0.25% w/w to 0.5% w/w crystalline polymorph Form A of Tapinarof. In another embodiment, the composition comprises from 0.5% w/w to 1% w/w crystalline polymorph Form A of Tapinarof. In another embodiment, the composition comprises from 1% w/w to 1.5% w/w crystalline polymorph Form A of Tapinarof. In another embodiment, the composition comprises from 1.5% w/w to 2% w/w crystalline polymorph Form A of Tapinarof. In another embodiment, the composition comprises from 2% w/w to 5% w/w crystalline polymorph Form A of Tapinarof.
- the composition comprises from 5% w/w to 10% w/w crystalline polymorph Form A of Tapinarof.
- the composition is a topical composition.
- the composition is an intralesional injection.
- the skin disorders treated with the compositions of this disclosure are selected from psoriasis (selected from plaque psoriasis, scalp psoriasis, sebopsoriasis and genital psoriasis); dermatitis (also known as eczema) selected from atopic dermatitis, contact dermatitis, dyshidrotic dermatitis, nummular dermatitis and seborrheic dermatitis; acne selected from acne vulgaris, papulopustular acne and nodular acne; rosacea selected from erythematotelangiectatic rosacea, papulopustular rosacea, rhinophyma rosacea and ocular rosacea; ichthyosis; scaling skin; imbalance of skin barrier; and tinea selected from tinea pedis, tinea capitis, tinea barbae, tinea faciei, tinea corporis, tinea manum, tinea
- the present invention provides a process for preparing said pharmaceutical compositions by mixing Form A with at least one pharmaceutically acceptable excipient.
- compositions provided herein include any such excipients, carriers or vehicles known to those skilled in the art to be suitable for the particular mode of administration.
- compositions provided herein include any such excipients known to those skilled in the art to be suitable for topical administration or intralesional administration.
- compositions may be a solution, suspension, emulsion or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, sprays, patches, foams or any other formulation suitable for topical administration.
- 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 for topical application include those suited for use include lotions, creams, solutions, gels, tapes and the like.
- the vehicle is either 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 resulting composition may be a lotion, a solution, a suspension, an emulsion or the like and is formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, sprays, patches, foams, sebum control products or any other formulation suitable for topical administration.
- the preferred compositions are the cream, the lotion, the gel and the foam.
- compositions suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.
- Sebum control products may include ingredients selected from azelaic acid, salicylic acid, sulfur, nicotinamide, L-carnitine and combinations thereof.
- Suitable pharmaceutically and dermatologically acceptable excipients, vehicles for topical application include lotions, creams, foams, solutions, gels, patches and the like.
- the vehicle is either organic in nature or an aqueous emulsion and capable of accommodating the selected active agent(s), 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.
- a method of treatment, prevention or alleviation of a skin or mucosal disorder selected from palmoplantar psoriasis, hereditary palmoplantar keratoderma, acquired palmoplantar keratoderma, hydradenitis suppurativa, ichthyosis vulgaris, hereditary ichthyosis, acquired ichthyosis, actinic keratosis, a keratinization skin disorder, a keratinization mucosal disorder, Gorlin syndrome, nail psoriasis, flexural/inverse psoriasis, non-melanoma skin cancer and precancerous skin, mucosal and nail lesions, by topical administration to a subject in need thereof a therapeutically effective amount of the composition and combinations thereof and a carrier suitable for topical administration, wherein the composition is formulated in a dosage form selected from a cream, a gel
- a dosage form comprising the pharmaceutical composition of this invention wherein the composition is formulated in a dosage form selected from a cream, a gel, an ointment, an emulsion, a solution, a suspension, an elixir, a lotion, a tincture, a paste, a foam, an aerosol, a spray, a patch, a transdermal patch and an applicator syringe.
- the present invention further provides methods of using the anhydrous crystalline form A of Tapinarof of the present invention in the treatment of diseases or conditions including diseases or conditions for which Tapinarof provides therapeutic benefit to a mammal having the disease or condition, such as topical treatment of skin disorder, by administering to a subject in need thereof a therapeutically effective amount of said Tapinarof crystalline form.
- said skin disorder is selected from psoriasis (selected from plaque psoriasis, scalp psoriasis, sebopsoriasis and genital psoriasis); dermatitis (also known as eczema) selected from atopic dermatitis, contact dermatitis, dyshidrotic dermatitis, nummular dermatitis and seborrheic dermatitis; acne selected from acne vulgaris, papulopustular acne and nodular acne; rosacea selected from erythematotelangiectatic rosacea, papulopustular rosacea, rhinophyma rosacea and ocular rosacea; ichthyosis; scaling skin; imbalance of skin barrier; hidradenitis suppurativa; and tinea selected from tinea pedis, tinea capitis, tinea barbae, tinea faciei, tinea corporis, tinea manum, tine
- a method of treatment, prevention or alleviation of a skin disorder selected from plaque, guttate, flexural/inverse, pustular or erythrodermic psoriasis and atopic dermatitis by once daily or twice daily topical or intralesional administration to a subject in need thereof of the pharmaceutical composition of this invention, wherein the composition is formulated in a dosage form selected from a cream, a gel, an ointment, an emulsion, a solution, a suspension, an elixir, a lotion, a tincture, a paste, a foam, an aerosol, a spray, a patch, a transdermal patch and an applicator syringe.
- a dosage form selected from a cream, a gel, an ointment, an emulsion, a solution, a suspension, an elixir, a lotion, a tincture, a paste, a foam, an aerosol, a spray, a patch, a trans
- a topical composition comprising from about 0.25% w/w to about 10.0% w/w crystalline Form A of Tapinarof and at least one pharmaceutically acceptable excipient for topical or intralesional administration in the treatment, prevention or alleviation of a skin disorder selected from psoriasis, dermatitis, acne, rosacea, ichthyosis, scaling skin, imbalance of skin barrier and tinea.
- a method of treatment, prevention or alleviation of a skin disorder by topical administration to the affected area of a skin disorder subject in need thereof of a therapeutically effective amount of a composition, comprising from about 0.25% w/w to about 10.0% w/w crystalline Form A of Tapinarof.
- the skin disorder is selected from psoriasis, dermatitis, acne, rosacea, ichthyosis, scaling skin, imbalance of skin barrier, tinea, plaque psoriasis, scalp psoriasis, sebopsoriasis and genital psoriasis, acne (selected from acne vulgaris, papulopustular acne and nodular acne); rosacea, selected from erythematotelangiectatic rosacea, papulopustular rosacea, rhinophyma rosacea and ocular rosacea; dermatitis (eczema), selected from atopic dermatitis, contact dermatitis, dyshidrotic dermatitis, nummular dermatitis and seborrheic dermatitis; tinea, selected from tinea pedis, tinea capitis, tinea barbae, tinea faciei, tinea corporis, tinea manum
- the method for the treatment of skin disorder of this invention wherein the treatment comprises once daily or twice daily topical or intralesional administration to a skin disorder subject in need thereof of a therapeutically effective amount of said composition.
- a regimen of administration comprising the once daily or twice daily administration to a skin disorder subject in need thereof of a therapeutically effective dose of the composition of this invention until the skin disorder is cured, prevented or alleviated.
- a regimen of administration comprising the once daily or twice daily administration to a skin disorder subject in need thereof a therapeutically effective amount of the dosage form of this invention.
- kits comprising one or more dosage forms of this invention
- the present invention provides a method of treating a psoriasis and atopic dermatitis comprising administering to a subject in need thereof a composition comprising a crystalline polymorph (Form A) of Tapinarof of the invention.
- Therapeutical effective concentrations of a crystalline polymorph (Form A) of Tapinarof, for treatment, prevention or amelioration of the symptoms manifested by the skin disorder are determined by empirical methods known in the art.
- Exemplary dosages, strengths and concentrations of a crystalline polymorph (Form A) of Tapinarof composition administered topically can be in the range of between 0.25-10% w/w or between 0.25-5%, 0.25-3%, 0.25-2 %w/w or at 0.1%, 0.25%, 0.5%, 1%, 2% , 3%, 4% ,5%, 6%, 7%, 8%, 9%, 10%w/w.
- 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 the skin disorder.
- 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.
- compositions provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.
- the resulting composition may be a lotion, a solution, a suspension, an emulsion or the like and is formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, sprays, patches, foams, or any other formulation suitable for topical administration.
- the preferred compositions are the cream, the foam and the lotion.
- composition may be administered intralesional.
- composition is an intralesional injection or microneedles.
- compositions according to the invention are pharmaceutical compositions, and especially dermatological compositions, which may be in any form conventionally used for topical application and especially in the form of lotions, creams.
- a fatty or oily phase it may also be in the form of dispersions of the lotion or serum type, emulsions of liquid or semiliquid consistency of the milk type obtained by dispersing a fatty phase in an aqueous phase (O/W) or conversely (W/O), or suspensions or emulsions of soft, semi-liquid or solid consistency of the cream, gel or ointment type, 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 an intralesional composition.
- intralesional administration is done by regular injections or with microneedles.
- the pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution.
- This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents.
- Such sterile formulations may be prepared using a non-toxic parenterally-acceptable diluent or solvent, such as water or 1,3- butane diol, for example.
- compositions that are useful in the methods of the invention may be administered, prepared, packaged, and/or sold in formulations suitable for intralesional delivery.
- the compositions may contain pharmaceutically-acceptable excipients/carriers and other ingredients known to enhance and facilitate drug administration.
- Other possible formulations, such as nanoparticles, liposomes may also be used.
- said composition further comprises at least one fatty alcohol. In yet other embodiments, said composition further comprises a polyacrylic acid homopolymer or copolymer.
- said water in said oil in water emulsion further comprises at least one water soluble humectant.
- said at least one water soluble humectant is selected from the group consisting of propylene glycol, glycerin, and polyethylene glycol-X, where X is in the range of 200 to 10,000.
- X is in the range of 200 to 10,000.
- the crystalline Form A of Tapinarof encapsulated in a microcapsule where “microcapsule” refers to a microparticle having a core shell structure, wherein said core comprises a crystalline Form A of Tapinarof defined herein, being coated by a shell forming the microcapsule entrapping the core.
- compositions of this invention for treating skin disorder are controlled or slowed release drug delivery system, wherein the active agent is encapsulated, coated, adsorbed, embedded, impregnated, dispersed, entrapped, or encased in a polymeric material and providing a sustained release formulation.
- a delivery system (which in the present invention is a topical delivery system) that enables the release of the Tapinarof in predetermined amounts over a specified period.
- said system is a core-shell system of a microcapsule or a porous matrix structure, such as for example a microsponge.
- embedded should be understood to encompass an inert system that provides a barrier between the Tapinarof, and its surrounding environment in the composition.
- said agent is entrapped and/or encapsulated in said controlled release system.
- the XRPD measurements are taken using Bruker D8 Advance powder X-ray diffractometer equipped with LYNXEYE XE-T detector, utilizing CuKa radiation, with step size of 0.02°29 and count time of 0.30 seconds per step.
- DSC Differential scanning calorimetry
- DSC data was collected using Mettler-Toledo make and model is TGA/DSC1 STAR System. DSC performed on 3.7442 mg of Solid sample in crucible. Heating range: 40-400°C, heating rate: 10°/minute.
- TGA Thermal gravimetric analysis
- TGA data was collected using Mettler-Toledo make and model is TGA/DSC1 STAR System. TGA performed on 4.1753 mg of solid sample in crucible. Heating range: 30-400°C, heating rate: 20°/minute.
- Example 1- Preparation of Tapinarof crystalline Form A by crystallization from Toluene cyclohexane.
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Abstract
The present disclosure encompasses crystalline polymorph of Tapinarof, e.g., Tapinarof crystalline Form A, processes for preparation thereof, and pharmaceutical compositions comprising thereof.
Description
CRYSTALLINE POLYMORPH OF TAPINAROF
FIELD OF THE INVENTION
[0001] The present disclosure encompasses crystalline polymorphs of Tapinarof, processes for preparation thereof, and pharmaceutical compositions comprising thereof.
BACKGROUND OF THE INVENTION
[0002] The chemical name of Tapinarof, also known as benvitimod, is 3,5-dihydroxy-4- isopropyl-trans- stilbene, and it has the following chemical structure:
[0003] Tapinarof is a first-in-class drug, whose mechanism is not yet fully understood.
[0004] 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- 17A, and enhance skin barrier function (J Invest Dermatol. 2017 Oct;137[10]:2110-9).
[0005] Processes for its preparation are described in CN101648851, as well as by Kronenwerth et al. (Eur J. Org. Chem. 2014, 8026-8028). PCT applications WO 2019/094934 (US Pat. No. 10,647,649) and WO 2019/063002 described crystalline forms of Tapinarof.
[0006] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule, like Tapinarof, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviours (e.g., measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), X-ray diffraction (XRD) pattern, infrared absorption fingerprint, and solid
state (13C) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.
[0007] Different solid-state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different solid- state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different solid-state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different solid-state forms and solvate of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.
[0008] The skin is a barrier that controls the body's moisture and prevents the penetration of microorganisms because the skin is composed of superficial layers of epidermis and stratum corneum that provide most of the skin barrier properties. The stratum corneum consists of layers of overlapping cell plates containing keratin.
[0009] Usually, drug absorption via the skin is transcellular, that is, a passive diffusion process, which depends on the efficacy of the epidermal barrier and the nature of the drug itself. Drugs having low molecular weight of less than about 800 Daltons with high water and lipid solubility demonstrate the greatest skin penetration.
[0010] Different crystalline forms or polymorphs of the same pharmaceutical compounds have different aqueous solubility hence different absorption profile.
[0011] Discovering new solid-state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New solid-state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelflife (chemical/physical stability). For at least these reasons, there is a need for additional solid- state forms of Tapinarof having relatively higher water solubility. Moreover, the processes for
preparing such forms should be suitable for industrial production and not cumbersome. The present invention provides such novel crystalline form and processes for its preparation.
SUMMARY OF THE INVENTION
[0012] The present invention provides a novel Tapinarof polymorph referred to hereinafter as Tapinarof crystalline Form A.
[0013] In an aspect of the present invention, a process for preparing the Tapinarof crystalline Form A is provided.
[0014] The present invention provides pharmaceutical compositions comprising Tapinarof crystalline Form A of the present invention and at least one pharmaceutically acceptable excipient. [0015] The Tapinarof crystalline Form A is characterized by an X-ray powder diffraction pattern exhibiting characteristic diffraction peaks at 6.9, 10.7, 16.3, 20.4 and 22.7 ±0.2 degrees 29.
[0016] The present invention further provides methods of using a pharmaceutical composition comprising Tapinarof crystalline Form A of the present invention in the treatment of diseases or conditions including diseases or conditions for which Tapinarof provides therapeutic benefit to a mammal having the disease or condition, such as, treatment of psoriasis, dermatitis, acne, rosacea, ichthyosis, scaling skin, imbalance of skin barrier and tinea by topically or intralesionally administering to a subject in need thereof a therapeutically effective amount of Tapinarof crystalline Form A.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] Figure 1 depicts the XRPD pattern of Tapinarof Form A.
[0018] Figure 2 depicts the DSC curve of Tapinarof Form A.
[0019] Figure 3 depicts the TGA curve of Tapinarof Form A.
DETAILED DESCRIPTION OF THE INVENTION
[0020] The present disclosure encompasses Tapinarof crystalline Form A, processes for preparation thereof, and pharmaceutical compositions comprising Tapinarof crystalline Form A and at least one pharmaceutically acceptable excipient.
[0021] In another embodiment, the pharmaceutical composition comprises Tapinarof crystalline Form A and an additional solid state form of Tapinarof, and at least one pharmaceutically acceptable excipient.
[0022] The Tapinarof and solid-state forms thereof according to the present disclosure may have advantageous properties selected from at least one of the following: chemical or polymorphic purity, flowability, solubility, dissolution rate, bio-viability, morphology or crystal habit, stability- such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility, and bulk density. Each represent a separate embodiment of this invention.
[0023] A solid-state form, such as a crystal form, may be referred to herein as being characterized by graphical data "as depicted in" or "as substantially depicted in" a Figure. Such data include, for example, powder X-ray diffractograms. As is well-known in the art, the graphical data potentially provides additional technical information to further define the respective solid- state form (a so-called "fingerprint") which cannot necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to certain factors such as, but not limited to, variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms. A crystal form of Tapinarof referred to herein as being characterized by graphical data "as depicted in" or "as substantially depicted in" a Figure will thus be understood to include any crystal forms of Tapinarof characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.
[0024] In some embodiments, the Tapinarof crystalline Form A described herein is anhydrous. In some embodiments, the Tapinarof crystalline Form A described herein is a non solvated Tapinarof crystalline Form A.
[0025] As used herein, and unless stated otherwise, the term "anhydrous" or “non solvated” in relation to crystalline forms of Tapinarof, relates to a crystalline form of Tapinarof which does not include any crystalline water (“anhydrous”) or other solvents (non solvated) in a defined, stoichiometric amount within the crystal. Moreover, an "anhydrous" or “non solvated” form would typically, not contain more than 0.5% (w/w) of either water or organic solvents respectively as measured for example by TGA (Thermal Gravimetric Analysis).
[0026] As used herein, the term "isolated" in reference to crystalline polymorph of Tapinarof of the present disclosure corresponds to a crystalline polymorph of Tapinarof that is physically separated from the reaction mixture in which it is formed.
[0027] As used herein, the term "reduced pressure" refers to a pressure that is less than atmospheric pressure. For example, reduced pressure is about 10 mbar to about 50 mbar.
[0028] In one aspect, this present disclosure relates to Tapinarof crystalline Form A.
[0029] In some embodiments, the Tapinarof crystalline Form A is characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 1 and Table 1; an X-ray powder diffraction pattern having peaks at 6.9, 10.7, 16.3, 20.4 and 22.7 degrees 2-theta ± 0.2 degrees 2-theta. In another embodiment, the Tapinarof crystalline
Form A is anhydrous and non-solvated.
[0030] In another embodiment, the Tapinarof crystalline Form A is characterized by X-ray powder diffraction pattern having peaks at 6.9, 10.7, 12.2, 12.7, 14.6, 15.1, 16.3, 17.0, 20.4 and 22.7 degrees 2-theta ± 0.2 degrees 2-theta. [0031] In another embodiment, the Tapinarof crystalline Form A is characterized by X-ray powder diffraction pattern having peaks as presented in Table 1.
[0033] In some embodiments, the anhydrous/non-solvated character of Form A is demonstrated by TGA and DSC, showing negligible weight loss before decomposition, and single thermal endotherm (interpreted as melting) before decomposition. [0034] In some embodiments, Tapinarof crystalline Form A described herein is characterized by the DSC melting peak at about 123°C, with Tonset of about 120°C.
[0035] In some embodiments, Tapinarof crystalline Form A described herein is characterized by the DSC thermogram presented in the following Fig. 2.
[0036] In some embodiments, Tapinarof crystalline Form A described herein is characterized by the TGA weight loss of less than 0.5% up to 100°C. In other embodiments, the TGA weight loss is of about 0.1%, 0.2%, 0.3%, 0.4% or 0.5% up to 100°C.
[0037] In some embodiments, Tapinarof crystalline Form A described herein is characterized by the TGA thermogram presented Fig. 3.
[0038] In one embodiment, this invention provides a process for the preparation of Tapinarof crystalline Form A . The starting material in these processes is produced by any suitable method, including synthesis methods known in the art. For example, the Tapinarof starting material is obtained as described in Examples 1-5 of CN 101648851 which is incorporated herein by reference. [0039] In some embodiments, the processes of the present invention produce high purity Tapinarof crystalline Form A. In another embodiments, the chemical purity of the crystalline polymorph (Form A) of Tapinarof of the invention is from about 95% to about 100%. In another embodiments, the chemical purity of the crystalline polymorph (Form A) of Tapinarof of the invention is from about 96% to about 100%. In another embodiments, the chemical purity of the crystalline polymorph (Form A) of Tapinarof of the invention is from about 97% to about 100%. In another embodiments, the chemical purity of the crystalline polymorph (Form A) of Tapinarof of the invention is from about 98% to about 100%. In another embodiments, the chemical purity of the crystalline polymorph (Form A) of Tapinarof of the invention is from about 99% to about 100%. In another embodiments, the crystalline polymorph (Form A) of Tapinarof of the invention has a chemical purity of about 99%.
[0040] In one embodiment, this invention provides a crystalline polymorph (Form A) of Tapinarof, which is prepared by the process of this invention.
[0041] According to a specific embodiment of the present invention, there is provided a process for preparing Tapinarof crystalline Form A, said process comprising:
(i) dissolving Tapinarof in an aromatic hydrocarbon solvent;
(ii) heating the solution of step (i) to obtain a clear solution;
(iii) adding to the solution of step (ii) an anti-solvent;
(iv) first cooling the mixture to start the crystallization to 55-60 °C, and further cooling it to a temperature at which crystals of Tapinarof Form A begin to precipitate; and
(v) isolating the crystals, optionally washing the crystals and, optionally, drying.
[0042] In other embodiments, the Tapinarof crystalline Form A obtained by the process described herein is an anhydrous or non-solvated Tapinarof crystalline Form A.
[0043] In another embodiment the further cooling is done gradually for a period of about 1 hour. In another embodiment the further cooling is done gradually for a period of at least 1 hour.
[0044] In a specific embodiment of the present invention, said aromatic hydrocarbon solvent is selected from substituted or unsubstituted toluene, benzene, or any combination thereof, etc. In
another embodiment, the said aromatic hydrocarbon solvent is toluene. In another embodiment, the said aromatic hydrocarbon solvent is benzene.
[0045] In a specific embodiment of the present invention, said anti-solvent is a saturated hydrocarbon. In another embodiment, the saturated hydrocarbon is hexane, heptane, cyclohexane, methylcyclohexane or combination thereof, etc.
[0046] In a specific embodiment of the present invention, the addition of the anti-solvent (step (iii)) is done gradually. In a specific embodiment of the present invention, the addition of the antisolvent (step (iii)) is done for 10-15 min.
[0047] In a specific embodiment of the present invention, heating is to a temperature of at least 75-85°C.
[0048] In another specific embodiment of the present invention, the solution is stirred for at least 1 hour, and the first cooling (to start the crystallization) is carried out to a temperature of about 55- 60°C. In another embodiment, the first cooling is carried out to a temperature of about 55°C.
[0049] In a specific embodiment of the present invention, the further cooling (to a temperature at which crystals of Tapinarof Form A begin to precipitate) is carried out to a temperature of about 25-30°C. In a specific embodiment of the present invention, the further cooling is done for at least 1 hour. In a specific embodiment of the present invention, the further cooling is done for about 1 hour.
[0050] In another specific embodiment of the present invention, heating is to a temperature of at least 75°C and cooling is carried out to a temperature of 25-30°C or below.
[0051] In another specific embodiment of the present invention, heating is to a temperature of at least 75°C and cooling is carried out to a temperature of 25-55°C or below.
[0052] In another specific embodiment of the present invention, first cooling is carried out for at least 1 hour, 2hrs, 3hrs or for a period the crystallization starts, and the further cooling is carried out for at least 1 hour, for 2 hrs, 3 hrs, or until crystals of Tapinarof Form A precipitate.
[0053] According to a specific embodiment of the present invention, the crystals are washed with cyclohexane. According to a specific embodiment of the present invention, the crystals are washed with methylcyclohexane. According to a specific embodiment of the present invention, the crystals are washed with cyclohexane, methylcyclohexane or combination thereof.
[0054] According to a specific embodiment of the present invention, a process for preparing Tapinarof crystalline Form A comprises the steps of dissolving Tapinarof in toluene, preferably at a W/V ration of 1 g per about 4 mL, at a temperature of about 75-85°C and stirring for about 15- 20 minutes to afford a clear solution.
[0055] According to the present invention, the anti-solvent is added to the solution, preferably, cyclohexane or methylcyclohexane, preferably at a W/V ratio of 1 g per about 2 ml and stirring for about 1 hour at a temperature of about 55 °C about to start the crystallization. In another embodiment, temperature is between 55-60 °C to start the crystallization.
[0056] According to the present invention, isolating the crystals can be carried out by a method selected from drying, evaporation or removal of a solvent or solvents under reduced pressure and filtration.
[0057] According to a specific embodiment of the present invention, the crystals are isolated by filtration.
[0058] In some embodiments provided herein a Tapinarof compound having a cis isomer content of Tapinarof of 0.1% or less and the Tapinarrof compound is at least 85% pure by weight, wherein the compound is at least 85% Form A by weight, characterized by an x-ray powder diffraction pattern having peaks at 6.9, 10.7, 16.3, 20.4 and 22.7 degrees 2-theta ± 0.2 degrees 2-theta. In some embodiments, the compound is at least 85% pure by weight, or at least 86% pure by weight, or at least 87% pure by weight, or at least 88% pure by weight, or at least 89% pure by weight, or at least 90% pure by weight, or at least 91% pure by weight, or at least 92% pure by weight, or at least 93% pure by weight, or at least 94% pure by weight, or at least 95% pure by weight, or at least 96% pure by weight, or at least 97% pure by weight, or at least 98% pure by weight, or at least 99% pure by weight. In some embodiments, the compound is at least 99% pure by weight. In some embodiments, the compound is at least 85% Form A by weight, or at least 86% Form A by weight, or at least 87% Form A by weight, or at least 88% Form A by weight, or at least 89% Form B by weight, or at least 90% Form A by weight, or at least 91% Form A by weight, or at least 92% Form A by weight, or at least 93% Form A by weight, or at least 94% Form A by weight, or at least 95% Form A by weight, or at least 96% Form A by weight, or at least 97% Form A by weight, or at least 98% Form A by weight, or at least 99% Form A by weight.
[0059] In some embodiments, the Tapinarof compound has a cis isomer content of 0.1% or less, wherein the compound is at least 98% pure by weight, wherein the compound is at least 85% Form A, characterized by an x-ray powder diffraction pattern having peaks at 6.9, 10.7, 16.3, 20.4 and 22.7 (±0.2) °29. In some embodiments, the Tapinarof compound has a cis isomer content of 0.1% or less and is at least 98% pure by weight, wherein the compound is at least 95% Form A. In other embodiments, the Tapinarof compound has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% crystalline Form B.
[0060] In some embodiments, the present invention provides pharmaceutical compositions comprising the polymorph of the present invention, i.e., crystalline Form A of Tapinarof and at least one pharmaceutically acceptable excipient.
[0061] In some embodiment, this invention provides a Tapinarof having a chemical purity of at least 90% and a pharmaceutical composition comprising thereof. In other embodiments, this invention provides a Tapinarof having a chemical purity of at least 91%, 92%, 93%, 94%, 95% 99% and a pharmaceutical composition comprising thereof. In other embodiments, this invention provides a Tapinarof having at least 90% crystalline Form A and a pharmaceutical composition comprising thereof. In other embodiments, this invention provides a Tapinarof having at least 91%, 92%, 93%, 94%, 95% 99% crystalline Form A and a pharmaceutical composition comprising thereof.
[0062] It will be understood by one of skill in the art that the percentage of a particular form of Tapinarof compound is expressed in relation to all forms of Tapinarof present in a sample. For example, the phrase “Tapinarof having at least 90% crystalline Form A” is meant to convey that at least 90% of all forms of the Tapinarof present is in form A. The “additional solid state form” of Tapinarof refers to any solid state form of Tapinarof or any solid state form of Tapinarof known in the art. For Example, US 10,647,649, and WO 2019/063002-incorporated herein by reference, disclosing a solid state form 1, 1, II, III or IV of Tapinarof.
[0063] In some embodiment, this invention provides a pharmaceutical composition comprising a combination of Tapinarof crystalline Form A and an amorphous or different solid form of Tapinarof or combination thereof. In other embodiments, the weight ratio between the crystalline Form A and the amorphous or different solid form is in the range of between 10:1 to 1:10. In another embodiment the weight ratio between the crystalline polymorph and the amorphous or different solid form is 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3 or 1:2 or any ranges thereof.
[0064] In some embodiment, the compositions of this invention are useful for the treatment, prevention or amelioration of skin disorders.
[0065] In one embodiment, the present invention provides methods for the treatment, prevention and/or amelioration of skin disorders comprising a composition comprising from about 0.25% w/w to about 10% w/w crystalline polymorph Form A of Tapinarof.
[0066] In another embodiment, the composition comprises from 0.25% w/w to 0.5% w/w crystalline polymorph Form A of Tapinarof. In another embodiment, the composition comprises from 0.5% w/w to 1% w/w crystalline polymorph Form A of Tapinarof. In another embodiment,
the composition comprises from 1% w/w to 1.5% w/w crystalline polymorph Form A of Tapinarof. In another embodiment, the composition comprises from 1.5% w/w to 2% w/w crystalline polymorph Form A of Tapinarof. In another embodiment, the composition comprises from 2% w/w to 5% w/w crystalline polymorph Form A of Tapinarof. In another embodiment, the composition comprises from 5% w/w to 10% w/w crystalline polymorph Form A of Tapinarof. Each possibility represents a separate embodiment of the present invention. In another embodiment, the composition is a topical composition. In another embodiment, the composition is an intralesional injection.
[0067] In another embodiment, the skin disorders treated with the compositions of this disclosure are selected from psoriasis (selected from plaque psoriasis, scalp psoriasis, sebopsoriasis and genital psoriasis); dermatitis (also known as eczema) selected from atopic dermatitis, contact dermatitis, dyshidrotic dermatitis, nummular dermatitis and seborrheic dermatitis; acne selected from acne vulgaris, papulopustular acne and nodular acne; rosacea selected from erythematotelangiectatic rosacea, papulopustular rosacea, rhinophyma rosacea and ocular rosacea; ichthyosis; scaling skin; imbalance of skin barrier; and tinea selected from tinea pedis, tinea capitis, tinea barbae, tinea faciei, tinea corporis, tinea manum, tinea cruris and tinea interdigital
[0068] Therapeutically effective amounts of crystalline Form A of Tapinarof with a suitable pharmaceutically acceptable excipient suitable for topical use, for the treatment, prevention or alleviation of the symptoms manifested by a skin disorder.
[0069] The present invention provides a process for preparing said pharmaceutical compositions by mixing Form A with at least one pharmaceutically acceptable excipient.
[0070] Pharmaceutical acceptable excipients suitable for preparation of the compositions provided herein include any such excipients, carriers or vehicles known to those skilled in the art to be suitable for the particular mode of administration.
[0071] Pharmaceutical acceptable excipients, carriers or vehicles suitable for preparation of the compositions provided herein include any such excipients known to those skilled in the art to be suitable for topical administration or intralesional administration.
[0072] The resulting compositions may be a solution, suspension, emulsion or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, sprays, patches, foams or any other formulation suitable for topical administration.
[0073] 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.
[0074] Suitable pharmaceutically and dermatologically acceptable vehicles for topical application include those suited for use include lotions, creams, solutions, gels, tapes and the like. Generally, the vehicle is either 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.
[0075] The resulting composition may be a lotion, a solution, a suspension, an emulsion or the like and is formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, sprays, patches, foams, sebum control products or any other formulation suitable for topical administration. The preferred compositions are the cream, the lotion, the gel and the foam.
[0076] Pharmaceutical carriers or vehicles suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.
[0077] Sebum control products may include ingredients selected from azelaic acid, salicylic acid, sulfur, nicotinamide, L-carnitine and combinations thereof.
[0078] Suitable pharmaceutically and dermatologically acceptable excipients, vehicles for topical application include lotions, creams, foams, solutions, gels, patches and the like. Generally, the vehicle is either organic in nature or an aqueous emulsion and capable of accommodating the selected active agent(s), 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.
[0079] According to an aspect of the invention, there is provided a method of treatment, prevention or alleviation of a skin or mucosal disorder selected from palmoplantar psoriasis, hereditary palmoplantar keratoderma, acquired palmoplantar keratoderma, hydradenitis suppurativa, ichthyosis vulgaris, hereditary ichthyosis, acquired ichthyosis, actinic keratosis, a keratinization skin disorder, a keratinization mucosal disorder, Gorlin syndrome, nail psoriasis,
flexural/inverse psoriasis, non-melanoma skin cancer and precancerous skin, mucosal and nail lesions, by topical administration to a subject in need thereof a therapeutically effective amount of the composition and combinations thereof and a carrier suitable for topical administration, wherein the composition is formulated in a dosage form selected from a cream, a gel, an ointment, an emulsion, a solution, a suspension, an elixir, a lotion, a tincture, a paste, a foam, an aerosol, a spray, a patch, a transdermal patch and a pre-filled applicator syringe.
[0080] In some embodiments provided herein a dosage form comprising the pharmaceutical composition of this invention wherein the composition is formulated in a dosage form selected from a cream, a gel, an ointment, an emulsion, a solution, a suspension, an elixir, a lotion, a tincture, a paste, a foam, an aerosol, a spray, a patch, a transdermal patch and an applicator syringe. [0081] The present invention further provides methods of using the anhydrous crystalline form A of Tapinarof of the present invention in the treatment of diseases or conditions including diseases or conditions for which Tapinarof provides therapeutic benefit to a mammal having the disease or condition, such as topical treatment of skin disorder, by administering to a subject in need thereof a therapeutically effective amount of said Tapinarof crystalline form. In another embodiment, said skin disorder is selected from psoriasis (selected from plaque psoriasis, scalp psoriasis, sebopsoriasis and genital psoriasis); dermatitis (also known as eczema) selected from atopic dermatitis, contact dermatitis, dyshidrotic dermatitis, nummular dermatitis and seborrheic dermatitis; acne selected from acne vulgaris, papulopustular acne and nodular acne; rosacea selected from erythematotelangiectatic rosacea, papulopustular rosacea, rhinophyma rosacea and ocular rosacea; ichthyosis; scaling skin; imbalance of skin barrier; hidradenitis suppurativa; and tinea selected from tinea pedis, tinea capitis, tinea barbae, tinea faciei, tinea corporis, tinea manum, tinea cruris and tinea interdigital.
[0082] A method of treatment, prevention or alleviation of a skin disorder selected from plaque, guttate, flexural/inverse, pustular or erythrodermic psoriasis and atopic dermatitis, by once daily or twice daily topical or intralesional administration to a subject in need thereof of the pharmaceutical composition of this invention, wherein the composition is formulated in a dosage form selected from a cream, a gel, an ointment, an emulsion, a solution, a suspension, an elixir, a lotion, a tincture, a paste, a foam, an aerosol, a spray, a patch, a transdermal patch and an applicator syringe.
[0083] In some embodiments, a topical composition comprising from about 0.25% w/w to about 10.0% w/w crystalline Form A of Tapinarof and at least one pharmaceutically acceptable excipient for topical or intralesional administration in the treatment, prevention or alleviation of a skin
disorder selected from psoriasis, dermatitis, acne, rosacea, ichthyosis, scaling skin, imbalance of skin barrier and tinea. In some embodiment, provided herein, a method of treatment, prevention or alleviation of a skin disorder, by topical administration to the affected area of a skin disorder subject in need thereof of a therapeutically effective amount of a composition, comprising from about 0.25% w/w to about 10.0% w/w crystalline Form A of Tapinarof.
[0084] In another embodiment, the skin disorder is selected from psoriasis, dermatitis, acne, rosacea, ichthyosis, scaling skin, imbalance of skin barrier, tinea, plaque psoriasis, scalp psoriasis, sebopsoriasis and genital psoriasis, acne (selected from acne vulgaris, papulopustular acne and nodular acne); rosacea, selected from erythematotelangiectatic rosacea, papulopustular rosacea, rhinophyma rosacea and ocular rosacea; dermatitis (eczema), selected from atopic dermatitis, contact dermatitis, dyshidrotic dermatitis, nummular dermatitis and seborrheic dermatitis; tinea, selected from tinea pedis, tinea capitis, tinea barbae, tinea faciei, tinea corporis, tinea manum, tinea cruris and tinea interdigital. Each represent a separate embodiment of this invention. In another embodiment, said skin disorder is selected from plaque, guttate, flexural/inverse, pustular or erythrodermic psoriasis and combinations thereof. Each represent a separate embodiment of this invention.
[0085] In some embodiments, the method for the treatment of skin disorder of this invention, wherein the treatment comprises once daily or twice daily topical or intralesional administration to a skin disorder subject in need thereof of a therapeutically effective amount of said composition. [0086] In some embodiments, provided herein, a regimen of administration comprising the once daily or twice daily administration to a skin disorder subject in need thereof of a therapeutically effective dose of the composition of this invention until the skin disorder is cured, prevented or alleviated.
[0087] In some embodiments, provided herein, a regimen of administration comprising the once daily or twice daily administration to a skin disorder subject in need thereof a therapeutically effective amount of the dosage form of this invention.
[0088] In some embodiments, provided herein, a kit comprising one or more dosage forms of this invention
[0089] In another aspect, the present invention provides a method of treating a psoriasis and atopic dermatitis comprising administering to a subject in need thereof a composition comprising a crystalline polymorph (Form A) of Tapinarof of the invention. Therapeutical effective concentrations of a crystalline polymorph (Form A) of Tapinarof, for treatment, prevention or amelioration of the symptoms manifested by the skin disorder are determined by
empirical methods known in the art. Exemplary dosages, strengths and concentrations of a crystalline polymorph (Form A) of Tapinarof composition administered topically, can be in the range of between 0.25-10% w/w or between 0.25-5%, 0.25-3%, 0.25-2 %w/w or at 0.1%, 0.25%, 0.5%, 1%, 2% , 3%, 4% ,5%, 6%, 7%, 8%, 9%, 10%w/w.
[0090] 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.
[0091] 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 skin disorder. 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.
[0092] Pharmaceutical excipients, 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.
[0093] The resulting composition may be a lotion, a solution, a suspension, an emulsion or the like and is formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, sprays, patches, foams, or any other formulation suitable for topical administration. The preferred compositions are the cream, the foam and the lotion.
[0094] The resulting composition may be administered intralesional. In another embodiments the composition is an intralesional injection or microneedles.
[0095] The compositions according to the invention are pharmaceutical compositions, and especially dermatological compositions, which may be in any form conventionally used for topical application and especially in the form of lotions, creams. By addition of a fatty or oily phase, it may also be in the form of dispersions of the lotion or serum type, emulsions of liquid or semiliquid consistency of the milk type obtained by dispersing a fatty phase in an aqueous phase (O/W) or conversely (W/O), or suspensions or emulsions of soft, semi-liquid or solid consistency of the cream, gel or ointment type, 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.
[0096] The composition according to the invention is an intralesional composition. In another embodiment, intralesional administration is done by regular injections or with microneedles. The
pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents. Such sterile formulations may be prepared using a non-toxic parenterally-acceptable diluent or solvent, such as water or 1,3- butane diol, for example. Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or diglycerides. Pharmaceutical compositions that are useful in the methods of the invention may be administered, prepared, packaged, and/or sold in formulations suitable for intralesional delivery. The compositions may contain pharmaceutically-acceptable excipients/carriers and other ingredients known to enhance and facilitate drug administration. Other possible formulations, such as nanoparticles, liposomes may also be used.
[0097] In other embodiments, said composition further comprises at least one fatty alcohol. In yet other embodiments, said composition further comprises a polyacrylic acid homopolymer or copolymer.
[0098] In some embodiments, said water in said oil in water emulsion further comprises at least one water soluble humectant.
[0099] In other embodiments, said at least one water soluble humectant is selected from the group consisting of propylene glycol, glycerin, and polyethylene glycol-X, where X is in the range of 200 to 10,000. Each possibility represents a separate embodiment of the present invention.
[00100] In some embodiments, the crystalline Form A of Tapinarof encapsulated in a microcapsule, where “microcapsule” refers to a microparticle having a core shell structure, wherein said core comprises a crystalline Form A of Tapinarof defined herein, being coated by a shell forming the microcapsule entrapping the core.
[00101] In further embodiments, the compositions of this invention for treating skin disorder are controlled or slowed release drug delivery system, wherein the active agent is encapsulated, coated, adsorbed, embedded, impregnated, dispersed, entrapped, or encased in a polymeric material and providing a sustained release formulation.
[00102] When referring to a "controlled or slowed release drug delivery system" it should be understood to relate to a delivery system (which in the present invention is a topical delivery system) that enables the release of the Tapinarof in predetermined amounts over a specified period. In some embodiments said system is a core-shell system of a microcapsule or a porous matrix structure, such as for example a microsponge.
[00103] The term "embedded" should be understood to encompass an inert system that provides a barrier between the Tapinarof, and its surrounding environment in the composition. In some embodiments said agent is entrapped and/or encapsulated in said controlled release system.
[00104] The term “about” in reference to a numerical value stated herein is to be understood as the stated value +/- 10%.
ANALYTICAL METHODS
Powder X-Rav Diffraction XRD Method
[00105] As used herein, unless stated otherwise, the XRPD measurements are taken using Bruker D8 Advance powder X-ray diffractometer equipped with LYNXEYE XE-T detector, utilizing CuKa radiation, with step size of 0.02°29 and count time of 0.30 seconds per step.
Differential scanning calorimetry (DSC) method
[00106] DSC data was collected using Mettler-Toledo make and model is TGA/DSC1 STAR System. DSC performed on 3.7442 mg of Solid sample in crucible. Heating range: 40-400°C, heating rate: 10°/minute.
Thermal gravimetric analysis (TGA) method
[00107] TGA data was collected using Mettler-Toledo make and model is TGA/DSC1 STAR System. TGA performed on 4.1753 mg of solid sample in crucible. Heating range: 30-400°C, heating rate: 20°/minute.
EXAMPLES
[00108] The following examples further illustrate the invention but should not be construed as in any way limiting its scope.
Example 1- Preparation of Tapinarof crystalline Form A by crystallization from Toluene cyclohexane.
[00109] Toluene (8 mL) was added to Tapinarof (2 g) and the mixture was heated to 75-85°C and stirred for 15-20 min until a clear solution was obtained. Cyclohexane (4.0 ml) was added in 10- 15 min to the formed clear solution and crystallization started at 55°C. the mixture was gradually cooled for an hour from a temperature of 55°C to 25-30°C, and after reaching 25-30°C, the mixture
was stirred for an hour at this temperature. The precipitated crystals were collected by filtration, washed twice with 2 mL of cyclohexane and dried at 50-55°C under reduced pressure to afford anhydrous tapinarof crystalline Form A (1.3 g, 65% yield). Example 2- Preparation of Tapinarof crystalline Form A by crystallization from Toluene and methylcyclohexane
[00110] Toluene (8 mL) was added to Tapinarof (2 g) and the mixture was heated to 75-85°C and stirred for 15-20 min until a clear solution was obtained. Methlcyclohexane (4.0 ml) was added in 10-15 min to the formed clear solution and crystallization started at 55°C. The mixture was gradually cooled for an hour from a temperature of 55oC to 25-30°C, and after reaching 25-30°C, the mixture was stirred for an hour at this temperature. The precipitated crystals were collected by filtration, washed twice with 2 mL of methylcyclohexane and dried at 50-55°C under reduced pressure to afford anhydrous tapinarof crystalline Form A (1.2 g, 60% yield).
Claims
1. Tapinarof crystalline Form A characterized by an X-ray powder diffraction pattern exhibiting characteristic diffraction peaks at 6.9, 10.7, 16.3, 20.4 and 22.7 ±0.2 degrees 29.
2. The crystalline Form A of claim 1, further characterized by one or more peaks of the following peaks: 12.2, 12.7, 14.6, 15.1 and 17.0 ±0.2 degrees 29.
3. The crystalline Form A of claim 1, having the X-ray powder diffraction peak positions and intensities as depicted in Fig. 1 or in Table 1.
4. The crystalline Form A of claim 1, further characterized by DSC curve as depicted in Fig. 3 exhibiting peak maximum at about 123°C, with Tonset of about 120°C.
5. A process for preparing the Tapinarof crystalline Form A of claim 1, comprising:
(i) dissolving Tapinarof in an aromatic hydrocarbon solvent to obtain a solution;
(ii) heating the solution of step (i) to obtain a clear solution;
(iii) adding to the solution of step (ii) an anti-solvent;
(iv) first cooling the mixture 55-60° C to start the crystallization, and further cooling it to a temperature at which crystals of Tapinarof Form A begin to precipitate; and
(v) isolating the crystals, optionally washing the crystals and, optionally, drying.
6. The process of claim 5, wherein said aromatic hydrocarbon solvent is toluene.
7. The process of claim 5, wherein said anti-solvent solvent is cyclohexane or methylcyclohexane .
8. The process of claim 5, wherein said heating is heating to a temperature of at least 75-85°C.
9. The process of claim 5, wherein said further cooling is cooling to a temperature between 25-30°C.
The process of claim 5, wherein said isolating the crystals is carried out by a method selected from drying, evaporation or removal of a solvent or solvents under reduced pressure, freeze drying or spray drying and filtration. The process of claim 10, wherein the crystals are isolated by filtration. A pharmaceutical composition comprising Tapinarof crystalline Form A according to any one of claims 1-4 and at least one pharmaceutically acceptable excipient. A dosage form comprising the composition of claims 12, wherein said composition is formulated in a dosage form selected from a cream, a lotion, a gel, an ointment, an emulsion, a solution, a suspension, an elixir, a tincture, a paste, a foam, an aerosol, a spray, a patch, a transdermal patch and an applicator syringe. A method of treatment, prevention or alleviation of a skin disorder, by topical or intralesional administration to the affected area of a skin disorder subject in need thereof of a therapeutically effective amount of a composition of claim 12, comprising from about 0.25% w/w to about 10.0% w/w crystalline Form A of Tapinarof. The method of claim 14, wherein the skin disorder is selected from psoriasis, dermatitis, acne, rosacea, ichthyosis, scaling skin, imbalance of skin barrier and tinea. The method of claim 14, wherein the skin disorder is psoriasis, selected from plaque psoriasis, scalp psoriasis, sebopsoriasis and genital psoriasis. The method of claim 14, wherein the skin disorder is acne, selected from acne vulgaris, papulopustular acne and nodular acne. The method of claim 14, wherein the skin disorder is rosacea, selected from erythematotelangiectatic rosacea, papulopustular rosacea, rhinophyma rosacea and ocular rosacea. The method of claim 14, wherein the skin disorder is dermatitis (eczema), selected from atopic dermatitis, contact dermatitis, dyshidrotic dermatitis, nummular dermatitis and seborrheic dermatitis.
The method of claim 14, wherein the skin disorder is tinea, selected from tinea pedis, tinea capitis, tinea barbae, tinea faciei, tinea corporis, tinea manum, tinea cruris and tinea interdigital. The method of any one of claims 14-20, wherein the treatment comprises once daily or twice daily topical or intralesional administration to a skin disorder subject in need thereof of a therapeutically effective amount of said composition. A kit comprising one or more dosage forms of claim 13 and instructions for use.
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Citations (4)
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WO2019063002A1 (en) * | 2017-09-30 | 2019-04-04 | 北京文丰天济医药科技有限公司 | Crystal form of benvitimod, and use thereof and preparation method therefor |
WO2019094934A1 (en) * | 2017-11-10 | 2019-05-16 | Dermavant Sciences GmbH | Process for preparing tapinarof |
WO2021100051A1 (en) * | 2019-11-24 | 2021-05-27 | Sol-Gel Technologies Ltd. | Treatment of skin disorders with topical compositions comprising tapinarof and a pde4 inhibitor |
WO2021236709A1 (en) * | 2020-05-19 | 2021-11-25 | Teva Pharmaceuticals International Gmbh | Solid state forms of tapinarof |
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2022
- 2022-10-21 WO PCT/IL2022/051115 patent/WO2023067606A1/en unknown
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WO2019063002A1 (en) * | 2017-09-30 | 2019-04-04 | 北京文丰天济医药科技有限公司 | Crystal form of benvitimod, and use thereof and preparation method therefor |
WO2019094934A1 (en) * | 2017-11-10 | 2019-05-16 | Dermavant Sciences GmbH | Process for preparing tapinarof |
WO2021100051A1 (en) * | 2019-11-24 | 2021-05-27 | Sol-Gel Technologies Ltd. | Treatment of skin disorders with topical compositions comprising tapinarof and a pde4 inhibitor |
WO2021236709A1 (en) * | 2020-05-19 | 2021-11-25 | Teva Pharmaceuticals International Gmbh | Solid state forms of tapinarof |
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HARRY G. BRITTAIN (ED.): "Polymorphism in Pharmaceutical solids ED. 2", 1 January 1999, M. DEKKER , USA , ISBN: 978-0-8247-0237-3, article DAVID J.W. GRANT, J. KEITH GUILLORY: "Chapter 5", pages: 1 - 10, 183-226, XP055517836 * |
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