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WO2025008784A1 - Solid dispersions of tapinarof and a process for the preparation thereof - Google Patents

Solid dispersions of tapinarof and a process for the preparation thereof Download PDF

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Publication number
WO2025008784A1
WO2025008784A1 PCT/IB2024/056540 IB2024056540W WO2025008784A1 WO 2025008784 A1 WO2025008784 A1 WO 2025008784A1 IB 2024056540 W IB2024056540 W IB 2024056540W WO 2025008784 A1 WO2025008784 A1 WO 2025008784A1
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Prior art keywords
solid dispersion
cellulose
tapinarof
pharmaceutically acceptable
acceptable excipient
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PCT/IB2024/056540
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French (fr)
Inventor
Venkata Raghavendra Acharyulu Palle
Suresh Kadam
Sachin GAVHANE
Avikumar DABE
Sagar KAWADE
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Alivus Life Sciences Ltd
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Glenmark Life Sciences Ltd
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Publication of WO2025008784A1 publication Critical patent/WO2025008784A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds

Definitions

  • the present invention relates to a solid dispersion comprising tapinarof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the present invention also relates to a process for the preparation of the solid dispersion, a pharmaceutical composition comprising the solid dispersion, and use of the solid dispersion or the pharmaceutical composition in the treatment of chronic inflammatory skin diseases.
  • Tapinarof is a therapeutic aryl hydrocarbon receptor (AhR)-modulating agent. It is also known as benvitimod, and was originally isolated from an insect-symbiotic bacteria Xenorhabdus species as reported in Journal of Chemical Ecology volume 7, pages 589-597 (1981). Tapinarof is known by its chemical name 5-[(E)-2- phenylethenyl]-2-[propan-2-yl] benzene-1, 3-diol. Tapinarof is a nonsteroidal, synthetic, hydroxylated stilbene compound, which is represented by a compound of formula I (the “compound I”),
  • Chinese Published Patent Application CN103172497A provides a process for the preparation of tapinarof wherein tapinarof is purified by crystallization in toluene to obtain white needle like crystals of tapinarof.
  • Chinese Published Patent Application CN105884581 A provides a process for the preparation of tapinarof wherein tapinarof is purified by crystallization in ethyl acetate- n-hexane mixed solvent to obtain tapinarof as the white solid.
  • PCT Publication No. WO 2019063002 refers to crystalline forms of tapinarof designated as Forms I, II, III and IV.
  • PCT Publication No. WO 2019094934 provides a method for the preparation of tapinarof, and also, refers to acetic acid solvate of tapinarof, and a crystalline form thereof, which is labelled as Form 1.
  • An aspect of the present invention is to provide a solid dispersion comprising tapinarof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient selected from a polymer, a non-polymeric material or a combination thereof.
  • Another aspect of the present invention is to provide a solid dispersion comprising tapinarof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient selected from a polymer, a non-polymeric material or a combination thereof, wherein the solid dispersion has crystallinity of 90 % or less.
  • Yet another aspect of the present invention is to provide a process for the preparation of a solid dispersion comprising tapinarof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient selected from a polymer, a non- polymeric material or a combination thereof; wherein the process comprises the steps of: a) dissolving tapinarof or a pharmaceutically acceptable salt thereof, in a solvent to obtain a solution or a suspension; b) adding a pharmaceutically acceptable excipient to the solution or suspension obtained in the step (a) to obtain a reaction mixture; and c) removing the solvent from the reaction mixture obtained in the step (b) to obtain the solid dispersion; and wherein the solid dispersion has crystallinity of 90 % or less.
  • a process for the preparation of a solid dispersion comprising tapinarof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient selected from a polymer, a non-polymeric material or a combination thereof; wherein the process comprises the steps of: i) combining tapinarof or a pharmaceutically acceptable salt thereof, with a solvent to obtain a slurry; ii) adding a pharmaceutically acceptable excipient to the slurry obtained in the step (i) to obtain a reaction mixture; and iii) removing the solvent from the reaction mixture obtained in the step (ii) to obtain the solid dispersion; and wherein the solid dispersion has crystallinity of 90 % or less.
  • a pharmaceutical composition comprising the solid dispersion of tapinarof as described herein, and a pharmaceutically acceptable excipient selected from the group consisting of a diluent, a disintegrant, a binder, a lubricant, a glidant, a surfactant or a mixture thereof.
  • a method for the treatment of chronic inflammatory skin diseases such as atopic dermatitis and plaque psoriasis comprising administering a therapeutically effective amount of the solid dispersion of the present invention, or a pharmaceutical composition comprising the solid dispersion of the present invention, to a patient in need thereof.
  • the solid dispersion of the present invention or the pharmaceutical composition comprising the solid dispersion in the treatment of chronic inflammatory skin diseases such as atopic dermatitis and plaque psoriasis.
  • Figure 1 illustrates characteristic XRPD (X-Ray Powder Diffraction) pattern of the solid dispersion of tapinarof as obtained in example 6.
  • Figure 2 illustrates characteristic XRPD (X-Ray Powder Diffraction) pattern of solid dispersion of tapinarof as obtained in example 7.
  • the present invention relates to a solid dispersion comprising tapinarof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient selected from a polymer, a non-polymeric material or a combination thereof.
  • solid dispersion refers to a system in a solid state comprising at least two components, and in the context of the present invention, one of the components is tapinarof or a pharmaceutically acceptable salt thereof, which is dispersed throughout the other component, and the other component is a pharmaceutically acceptable excipient. Alternately, the term “solid dispersion” may be interchangeably used with the term “premix”.
  • pharmaceutically acceptable refers to those compounds, materials, excipients, carrier, compositions or dosage forms which will be considered by a prudent medical practitioner, suitable for administration to humans and animals without excessive toxicity, irritation, allergic response or other complications commensurate with a reasonable benefit/risk ratio.
  • the term “pharmaceutically acceptable excipient” refers to both polymers and non-polymeric material, and combinations thereof, capable of dissolving or molecularly dispersing tapinarof or a pharmaceutically acceptable salt thereof.
  • the term “pharmaceutically acceptable salts” in reference to tapinarof encompasses the pharmaceutically acceptable salts of tapinarof selected from, but not limited to sodium and potassium salts.
  • a person of skill in the art would understand that these pharmaceutically acceptable salts of tapinarof can be prepared by reacting tapinarof with a suitable base such as sodium hydroxide and potassium hydroxide.
  • the present invention relates to a solid dispersion comprising tapinarof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient selected from a polymer, a non-polymeric material or a combination thereof, wherein the solid dispersion has crystallinity of 90 % or less.
  • crystallinity refers to the degree of structural order in a sample of tapinarof. It will be known to a person skilled in the art that crystallinity is represented by a fraction or percentage as a measure of how likely atoms or molecules are to be arranged in a regular pattern such as a crystal. Crystallinity of a sample of tapinarof can be determined by any known method used for measuring crystallinity such as X-ray powder diffraction (XRPD) technique. A compound having higher crystallinity will have a powder X- ray diffraction pattern having defined peaks. As an example, a sample having a crystallinity of about 100% contains a solid that is highly crystalline. In a further example, a sample having a crystallinity of about 50% contains a solid that is a mixture of a crystalline and an amorphous form.
  • XRPD X-ray powder diffraction
  • the crystallinity of the solid dispersion of the present invention is in the range of 10% to 90%.
  • the polymer is a homopolymer or a copolymer of N-vinyl lactams selected from polyvinylpyrrolidone (PVP), polyvinylpolypyrrolidone (crospovidone), polyvinylcaprolactam or a mixture thereof.
  • PVP polyvinylpyrrolidone
  • crospovidone polyvinylpolypyrrolidone
  • polyvinylcaprolactam or a mixture thereof.
  • the polymer is a cellulose derivative selected from methyl cellulose, ethyl cellulose, propyl cellulose, carboxymethyl cellulose, methyl cellulose adipate, hydroxypropyl cellulose, 5-carboxypent-l-yl hydroxypropyl cellulose, methyl 5-carboxypentyl cellulose, ethyl 5 -carb oxypentyl cellulose, cellulose acetate propionate, cellulose acetate butyrate, carboxymethyl cellulose acetate butyrate, hydroxypropylmethyl cellulose, cellulose acetate adipate, cellulose acetate phthalate, cellulose acetate suberate, cellulose acetate adipate hydroxyethyl ester, cellulose acetate adipate propionate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose succinate, hydroxypropylmethyl cellulose acetate succinate, or a mixture thereof.
  • the polymer is a cellulose derivative selected from hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose succinate, hydroxypropylmethyl cellulose acetate succinate, or a mixture thereof.
  • the polymer is polyalkylene oxides selected from polyethylene oxide, polypropylene oxide, copolymers of poly(ethylene oxide) and polypropylene oxide), or a mixture thereof.
  • the polymer is an oligo- or polysaccharides selected from carrageenan’s, galactomannans, xanthan gum, cyclodextrin or hyaluronic acid.
  • the non-polymeric material is selected from stearic acid, cetostearyl alcohol, mineral oil, white wax, white petrolatum, glyceryl monooleate, glyceryl behenate, citric acid, glycerol triester of caprylic and capric acid, or a mixture thereof.
  • the pharmaceutically acceptable excipient used in the solid dispersion of the present invention is selected from hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose succinate, hydroxypropylmethyl cellulose acetate succinate, cetostearyl alcohol, stearic acid, white wax, or a mixture thereof.
  • the ratio of tapinarof to the pharmaceutically acceptable excipient used in the solid dispersion of the present invention ranges from about 1 : 0.2 to about 1 : 15 [w/w], [0040] In a further embodiment as may be combined with any of the preceding paragraphs, the ratio of tapinarof to the pharmaceutically acceptable excipient used in the solid dispersion of the present invention ranges from about 1 : 0.5 to about 1 : 10 [w/w], [0041] In a further embodiment as may be combined with any of the preceding paragraphs, the ratio of tapinarof to the pharmaceutically acceptable excipient used in the solid dispersion of the present invention ranges from about 1 : 1 to about 1 :5 [w/w], [0042] According to yet another aspect, the present invention provides, a process for the preparation of a solid dispersion comprising tapinarof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient
  • the solid dispersion obtained by the above process has crystallinity of 90 % or less.
  • the solvent used in the step (a) of the above process is selected from ethanol or methylene dichloride.
  • the reaction mixture obtained in the step (b) may be stirred for a suitable time.
  • the stirring time may range from about 10 minutes to about 5 hours, or longer at a temperature ranging from about 20°C to about 40°C.
  • the solvent is removed by methods selected from the group consisting of evaporation, distillation, filtration and spray drying.
  • the present invention provides, a process for the preparation of a solid dispersion comprising tapinarof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient selected from a polymer, a non- polymeric material or a combination thereof; wherein the process comprises the steps of: i) combining tapinarof or a pharmaceutically acceptable salt thereof, with a solvent to obtain a slurry; ii) adding a pharmaceutically acceptable excipient to the slurry obtained in the step (i) to obtain a reaction mixture; and iii) removing the solvent from the reaction mixture obtained in the step (ii) to obtain the solid dispersion.
  • the solid dispersion obtained by the above process has crystallinity of 90 % or less.
  • the solvent used in the step (i) of the above process may be selected from the solvents as described in the preceding embodiment in respect of the step (a).
  • the solvent used in the step (i) of the above process may be a hydrocarbon selected from hexane, heptane, toluene, xylene or a mixture thereof.
  • the pharmaceutically acceptable excipient is as discussed herein above.
  • the reaction mixture obtained in the step (ii) may be stirred for a suitable time.
  • the stirring time may range from about 10 minutes to about 5 hours, or longer at a temperature ranging from about 20°C to about 40°C.
  • the solvent is removed by methods selected from the group consisting of evaporation, distillation, filtration and spray drying.
  • the present invention provides a solid dispersion comprising tapinarof and hydroxypropyl cellulose, wherein the solid dispersion is characterised by the X-ray powder diffraction pattern substantially as shown in Figure 1.
  • the present invention provides a solid dispersion comprising tapinarof and hydroxypropyl cellulose, wherein the solid dispersion is characterised by the X-ray powder diffraction pattern substantially as shown in Figure 1 , and wherein the solid dispersion has crystallinity of 90 % or less.
  • the present invention provides a solid dispersion comprising tapinarof and hydroxypropyl cellulose, wherein the solid dispersion is characterised by the X-ray powder diffraction pattern substantially as shown in Figure 2.
  • the present invention provides a solid dispersion comprising tapinarof and hydroxypropyl cellulose, wherein the solid dispersion is characterised by the X-ray powder diffraction pattern substantially as shown in Figure 2, and wherein the solid dispersion has crystallinity of 90 % or less.
  • the present invention provides a solid dispersion comprising tapinarof and cetostearyl alcohol, wherein the solid dispersion has crystallinity of 90 % or less.
  • the present invention provides a solid dispersion comprising tapinarof and stearic acid, wherein the solid dispersion has crystallinity of 90 % or less.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the solid dispersion of tapinarof as described herein, and a pharmaceutically acceptable excipient selected from the group consisting of a diluent, a disintegrant, a binder, a lubricant, a glidant, a surfactant or a mixture thereof.
  • the present invention provides a pharmaceutical composition comprising the solid dispersion, wherein the solid dispersion is present in an amount ranging from about 50 % to about 80 % w/w.
  • the present invention provides a pharmaceutical composition comprising the solid dispersion, wherein the solid dispersion is obtained by the process for the preparation of the solid dispersion as described herein.
  • the pharmaceutical composition comprising the solid dispersion is in topical dosage form.
  • the pharmaceutical composition comprising the solid dispersion is in topical dosage form selected from cream, gel, ointment or lotion.
  • the topical dosage form containing the solid dispersion of the present invention is cream.
  • the present invention provides a method for the treatment of chronic inflammatory skin diseases selected from atopic dermatitis or plaque psoriasis comprising administering a therapeutically effective amount of the solid dispersion of the present invention, or a topical pharmaceutical composition comprising the solid dispersion of the present invention, to a patient in need thereof.
  • the present invention provides use of the solid dispersion of the present invention or the pharmaceutical composition comprising the solid dispersion in the treatment of chronic inflammatory skin diseases selected from atopic dermatitis or plaque psoriasis.
  • the present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
  • the measurements were performed on Philips X-Ray Diffractometer model XPERT- Empyrean (PANalytical) Detector: PIXcel 1D [1] using Cu lamp with type and wavelength of the X-ray radiation: K-ai 1.54060[A], K-co 1.5444[A]under the following conditions:
  • the measurements were carried out with a Fixed module programmable divergence slit and anti-scatter Slit (Offset 0.00°); Generator settings: 40 mA/45 kV, Time per step: 500s, Step size: , 0.013 and start angle (°) 2.0 and End angle: 50.0; Scan type: continuous; measurement performed at 25°C.
  • the XRPD instrument is calibrated using NIST SRM 6-40E silicon standard and NIST SRM 1976 Alumina.
  • Sample preparation Take an adequate amount of the sample to fill the sample holder using back-loading technique. Then load the sample holder between the X-ray optics-path and scan using the above described parameters. Integrate the obtained powder X-ray diffraction profiles using X’Pert HighScore Plus Software.
  • reaction mass was cooled to a temperature in the range of 25°C to 35°C and to it was added Vitride (70% in toluene) solution. Reaction mass was stirred for a period of 3-4 hours at a temperature in the range of 25°C to 35°C. Reaction mass was quenched with water (300 ml) & hydrochloric acid (300 ml), and the product was extracted in toluene layer.
  • stage (b) In a clean and dry autoclave the product obtained in stage (b) was dissolved in methylene chloride (400 ml), and to this were added cuprous iodide (7.99 gm), 4- dimethylaminopyridine and (2,2,6,6-Tetramethylpiperidin-l-yl)oxyl (TEMPO) (0.60 gm) to obtain a reaction mass.
  • the Reaction mass was stirred under air pressure of 4 to 5 kg at a temperature ranging from 45°C to 55°C for a period of 1 to 2 hours.
  • TEMPO was again added twice (each of 0.60 gm), and was further maintained under air pressure for a period of 1 to 3 hours each.
  • reaction mass was filtered and to this was added aqueous hydrochloric acid (12.60 gm in 350 mL water).
  • aqueous hydrochloric acid (12.60 gm in 350 mL water).
  • the product was extracted in methylene chloride layer and was subjected to distillation to obtain a residue.
  • methanol 400 ml was added and precipitated product was filtered and dried.
  • Example 4 Preparation of a solid dispersion of tapinarof with cetostearyl alcohol as the pharmaceutically acceptable excipient
  • Example 5 Preparation of a solid dispersion of tapinarof with hydroxypropyl cellulose as the pharmaceutically acceptable excipient
  • Example 6 Preparation of a solid dispersion of tapinarof with hydroxypropyl cellulose as the pharmaceutically acceptable excipient
  • Example 7 Preparation of a solid dispersion of tapinarof with hydroxypropyl cellulose as the pharmaceutically acceptable excipient
  • Example 8 Preparation of a solid dispersion of tapinarof with stearic acid as the pharmaceutically acceptable excipient
  • Example 9 Preparation of a solid dispersion of tapinarof with cetostearyl alcohol as the pharmaceutically acceptable excipient
  • reaction mass was then subjected to distillation under vacuum at a temperature ranging from 40°C to 45°C to obtain the solid dispersion.

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Abstract

The present invention relates to a solid dispersion comprising tapinarof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. The present invention also relates to a process for the preparation of the solid dispersion, a pharmaceutical composition comprising the solid dispersion, and use of the solid dispersion or the pharmaceutical composition in the treatment of chronic inflammatory skin diseases.

Description

SOLID DISPERSIONS OF TAPINAROF AND A PROCESS FOR THE PREPARATION THEREOF
PRIORITY
[0001] This application claims the benefit of Indian Provisional Application 202321044893 filed on July 04, 2023, entitled “SOLID DISPERSIONS OF TAPINAROF AND A PROCESS FOR THE PREPARATION THEREOF”, the contents of which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
Technical Field
[0002] The present invention relates to a solid dispersion comprising tapinarof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. The present invention also relates to a process for the preparation of the solid dispersion, a pharmaceutical composition comprising the solid dispersion, and use of the solid dispersion or the pharmaceutical composition in the treatment of chronic inflammatory skin diseases.
Description of the Related Art
[0003] Tapinarof is a therapeutic aryl hydrocarbon receptor (AhR)-modulating agent. It is also known as benvitimod, and was originally isolated from an insect-symbiotic bacteria Xenorhabdus species as reported in Journal of Chemical Ecology volume 7, pages 589-597 (1981). Tapinarof is known by its chemical name 5-[(E)-2- phenylethenyl]-2-[propan-2-yl] benzene-1, 3-diol. Tapinarof is a nonsteroidal, synthetic, hydroxylated stilbene compound, which is represented by a compound of formula I (the “compound I”),
Figure imgf000002_0001
I [0004] The US Food and Drug Administration (the USFDA) approved tapinarof for the treatment of plaque psoriasis in adults in May 2022, and this drug is marketed in the USA under the brand name VTAMA® as cream; a topical dosage form in strength 1%.
[0005] Various processes for the preparation of tapinarof are reported in the art.
[0006] The publication “J. Org. Chem. 1992, 57, 14, 4040-4043” provides a process for the preparation of tapinarof wherein l,3-dimethoxy-5-[(E)-2-phenylethenyl]-2-(propan- 2-yl)benzene is demethylated using boron tribromide-methyl sulfide complex in 1,2- di chloroethane to obtain tapinarof which is further purified by flash column chromatography on silica gel using 3: 1 petroleum ether-ether to obtain crystalline tapinarof.
[0007] The publication “Advanced materials research, 2011, 2378-2382” provides a process for the preparation of tapinarof wherein l,3-dimethoxy-5-[(E)-2-phenylethenyl]- 2-(propan-2-yl)benzene is demethylated using pyridine chloride to obtain tapinarof, which is further purified by recrystallization in petroleum ether and ethyl acetate (V/V=6: l).
[0008] Chinese Published Patent Application CN103172497A provides a process for the preparation of tapinarof wherein tapinarof is purified by crystallization in toluene to obtain white needle like crystals of tapinarof.
[0009] Chinese Published Patent Application CN105884581 A provides a process for the preparation of tapinarof wherein tapinarof is purified by crystallization in ethyl acetate- n-hexane mixed solvent to obtain tapinarof as the white solid.
[0010] Also polymorphic forms of tapinarof are also known in the art, for instance, the PCT Publication No. WO 2019063002 refers to crystalline forms of tapinarof designated as Forms I, II, III and IV. PCT Publication No. WO 2019094934 provides a method for the preparation of tapinarof, and also, refers to acetic acid solvate of tapinarof, and a crystalline form thereof, which is labelled as Form 1.
[0011] As per the Product Quality Review for benvitimod published by the US FDA (https://www.accessdata.fda.gOv/drugsatfda_docs/nda/2022/215272Origls000ChemR.p df), tapinarof is practically insoluble in water. SUMMARY OF THE INVENTION
[0012] An aspect of the present invention is to provide a solid dispersion comprising tapinarof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient selected from a polymer, a non-polymeric material or a combination thereof.
[0013] Another aspect of the present invention is to provide a solid dispersion comprising tapinarof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient selected from a polymer, a non-polymeric material or a combination thereof, wherein the solid dispersion has crystallinity of 90 % or less.
[0014] Yet another aspect of the present invention is to provide a process for the preparation of a solid dispersion comprising tapinarof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient selected from a polymer, a non- polymeric material or a combination thereof; wherein the process comprises the steps of: a) dissolving tapinarof or a pharmaceutically acceptable salt thereof, in a solvent to obtain a solution or a suspension; b) adding a pharmaceutically acceptable excipient to the solution or suspension obtained in the step (a) to obtain a reaction mixture; and c) removing the solvent from the reaction mixture obtained in the step (b) to obtain the solid dispersion; and wherein the solid dispersion has crystallinity of 90 % or less.
[0015] According to another further aspect of the present invention, there is provided a process for the preparation of a solid dispersion comprising tapinarof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient selected from a polymer, a non-polymeric material or a combination thereof; wherein the process comprises the steps of: i) combining tapinarof or a pharmaceutically acceptable salt thereof, with a solvent to obtain a slurry; ii) adding a pharmaceutically acceptable excipient to the slurry obtained in the step (i) to obtain a reaction mixture; and iii) removing the solvent from the reaction mixture obtained in the step (ii) to obtain the solid dispersion; and wherein the solid dispersion has crystallinity of 90 % or less. [0016] According to another further aspect of the present invention, there is provided a pharmaceutical composition comprising the solid dispersion of tapinarof as described herein, and a pharmaceutically acceptable excipient selected from the group consisting of a diluent, a disintegrant, a binder, a lubricant, a glidant, a surfactant or a mixture thereof. [0017] According to another further aspect of the present invention, there is provided a method for the treatment of chronic inflammatory skin diseases such as atopic dermatitis and plaque psoriasis comprising administering a therapeutically effective amount of the solid dispersion of the present invention, or a pharmaceutical composition comprising the solid dispersion of the present invention, to a patient in need thereof.
[0018] According to another further aspect of the present invention, there is provided use of the solid dispersion of the present invention or the pharmaceutical composition comprising the solid dispersion in the treatment of chronic inflammatory skin diseases such as atopic dermatitis and plaque psoriasis.
[0019] These and other aspects of the present invention will be apparent from the following description, and reference to the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] Figure 1 illustrates characteristic XRPD (X-Ray Powder Diffraction) pattern of the solid dispersion of tapinarof as obtained in example 6.
[0021] Figure 2 illustrates characteristic XRPD (X-Ray Powder Diffraction) pattern of solid dispersion of tapinarof as obtained in example 7.
DETAILED DESCRIPTION OF THE INVENTION
[0022] In one aspect, the present invention relates to a solid dispersion comprising tapinarof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient selected from a polymer, a non-polymeric material or a combination thereof.
[0023] As used herein the term "solid dispersion" refers to a system in a solid state comprising at least two components, and in the context of the present invention, one of the components is tapinarof or a pharmaceutically acceptable salt thereof, which is dispersed throughout the other component, and the other component is a pharmaceutically acceptable excipient. Alternately, the term “solid dispersion” may be interchangeably used with the term “premix”. [0024] As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, excipients, carrier, compositions or dosage forms which will be considered by a prudent medical practitioner, suitable for administration to humans and animals without excessive toxicity, irritation, allergic response or other complications commensurate with a reasonable benefit/risk ratio.
[0025] As used herein, the term “pharmaceutically acceptable excipient” refers to both polymers and non-polymeric material, and combinations thereof, capable of dissolving or molecularly dispersing tapinarof or a pharmaceutically acceptable salt thereof.
[0026] As used herein, the term “pharmaceutically acceptable salts” in reference to tapinarof encompasses the pharmaceutically acceptable salts of tapinarof selected from, but not limited to sodium and potassium salts. A person of skill in the art would understand that these pharmaceutically acceptable salts of tapinarof can be prepared by reacting tapinarof with a suitable base such as sodium hydroxide and potassium hydroxide.
[0027] In another aspect, the present invention relates to a solid dispersion comprising tapinarof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient selected from a polymer, a non-polymeric material or a combination thereof, wherein the solid dispersion has crystallinity of 90 % or less.
[0028] As used herein, the term “crystallinity” refers to the degree of structural order in a sample of tapinarof. It will be known to a person skilled in the art that crystallinity is represented by a fraction or percentage as a measure of how likely atoms or molecules are to be arranged in a regular pattern such as a crystal. Crystallinity of a sample of tapinarof can be determined by any known method used for measuring crystallinity such as X-ray powder diffraction (XRPD) technique. A compound having higher crystallinity will have a powder X- ray diffraction pattern having defined peaks. As an example, a sample having a crystallinity of about 100% contains a solid that is highly crystalline. In a further example, a sample having a crystallinity of about 50% contains a solid that is a mixture of a crystalline and an amorphous form.
[0029] In an embodiment, the crystallinity of the solid dispersion of the present invention is in the range of 10% to 90%.
[0030] In an embodiment, the crystallinity of the solid dispersion of the present invention is in the range of 20% to 80%. [0031] In an embodiment, the polymer is selected from the group consisting of homopolymers or copolymers of N-vinyl lactams, cellulose derivatives, polyalkylene oxides, polyacrylates, polymethacrylates (Eudragit polymers), vinyl acetate polymers, polyacrylamides, polyvinyl alcohol, oligo- or polysaccharides, polyhydroxyalkylacrylates, polyhydroxyalkyl-methacrylates, copolymers of methyl methacrylate and acrylic acid, polyethylene glycols (PEGs), propylene glycol monocaprylate, or mixture thereof.
[0032] In another embodiment, the polymer is a homopolymer or a copolymer of N-vinyl lactams selected from polyvinylpyrrolidone (PVP), polyvinylpolypyrrolidone (crospovidone), polyvinylcaprolactam or a mixture thereof.
[0033] In yet another embodiment, the polymer is a cellulose derivative selected from methyl cellulose, ethyl cellulose, propyl cellulose, carboxymethyl cellulose, methyl cellulose adipate, hydroxypropyl cellulose, 5-carboxypent-l-yl hydroxypropyl cellulose, methyl 5-carboxypentyl cellulose, ethyl 5 -carb oxypentyl cellulose, cellulose acetate propionate, cellulose acetate butyrate, carboxymethyl cellulose acetate butyrate, hydroxypropylmethyl cellulose, cellulose acetate adipate, cellulose acetate phthalate, cellulose acetate suberate, cellulose acetate adipate hydroxyethyl ester, cellulose acetate adipate propionate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose succinate, hydroxypropylmethyl cellulose acetate succinate, or a mixture thereof.
[0034] In yet another embodiment, the polymer is a cellulose derivative selected from hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose succinate, hydroxypropylmethyl cellulose acetate succinate, or a mixture thereof.
[0035] In another further embodiment, the polymer is polyalkylene oxides selected from polyethylene oxide, polypropylene oxide, copolymers of poly(ethylene oxide) and polypropylene oxide), or a mixture thereof.
[0036] In yet another further embodiment, the polymer is an oligo- or polysaccharides selected from carrageenan’s, galactomannans, xanthan gum, cyclodextrin or hyaluronic acid.
[0037] In yet another further embodiment, the non-polymeric material is selected from stearic acid, cetostearyl alcohol, mineral oil, white wax, white petrolatum, glyceryl monooleate, glyceryl behenate, citric acid, glycerol triester of caprylic and capric acid, or a mixture thereof.
[0038] In yet another further embodiment, the pharmaceutically acceptable excipient used in the solid dispersion of the present invention is selected from hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose succinate, hydroxypropylmethyl cellulose acetate succinate, cetostearyl alcohol, stearic acid, white wax, or a mixture thereof.
[0039] In a further embodiment as may be combined with any of the preceding paragraphs, the ratio of tapinarof to the pharmaceutically acceptable excipient used in the solid dispersion of the present invention ranges from about 1 : 0.2 to about 1 : 15 [w/w], [0040] In a further embodiment as may be combined with any of the preceding paragraphs, the ratio of tapinarof to the pharmaceutically acceptable excipient used in the solid dispersion of the present invention ranges from about 1 : 0.5 to about 1 : 10 [w/w], [0041] In a further embodiment as may be combined with any of the preceding paragraphs, the ratio of tapinarof to the pharmaceutically acceptable excipient used in the solid dispersion of the present invention ranges from about 1 : 1 to about 1 :5 [w/w], [0042] According to yet another aspect, the present invention provides, a process for the preparation of a solid dispersion comprising tapinarof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient selected from a polymer, a non- polymeric material or a combination thereof; wherein the process comprises the steps of: a) dissolving tapinarof or a pharmaceutically acceptable salt thereof, in a solvent to obtain a solution or a suspension; b) adding a pharmaceutically acceptable excipient to the solution or suspension obtained in the step (a) to obtain a reaction mixture; and c) removing the solvent from the reaction mixture obtained in the step b) to obtain the solid dispersion.
[0043] In an embodiment, the solid dispersion obtained by the above process has crystallinity of 90 % or less.
[0044] In one embodiment, the solvent used in the step (a) of the above process, may be selected from the group consisting of (Ci-Ce) alcohols such as methanol, ethanol, n- propanol, isopropanol, n-butanol and the like; halogenated hydrocarbons such as methylene dichloride, ethylene dichloride, chloroform and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1-4-di oxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, tert-butyl acetate and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone; dimethyl sulfoxide (DMSO); hydrocarbons such as hexane, heptane, toluene, xylene and the like; N-methyl pyrrolidinone (NMP) water or a mixture thereof.
[0045] In one embodiment, the solvent used in the step (a) of the above process is a (Cl - C6) alcohol selected from methanol, ethanol, n-propanol, isopropanol, n-butanol or a mixture thereof.
[0046] In one embodiment, the solvent used in the step (a) of the above process is a halogenated hydrocarbon selected from methylene dichloride, ethylene dichloride, chloroform or a mixture thereof.
[0047] In one embodiment, the solvent used in the step (a) of the above process is selected from ethanol or methylene dichloride.
[0048] In one embodiment, the step (a) involving dissolving tapinarof in a solvent is carried out at a temperature ranging from about 20°C to about 40°C.
[0049] In one embodiment, the pharmaceutically acceptable excipient is as discussed herein above.
[0050] In an embodiment, the reaction mixture obtained in the step (b) may be stirred for a suitable time. The stirring time may range from about 10 minutes to about 5 hours, or longer at a temperature ranging from about 20°C to about 40°C.
[0051] In an embodiment, in the step (c) of the above process, the solvent is removed by methods selected from the group consisting of evaporation, distillation, filtration and spray drying.
[0052] According to yet another aspect, the present invention provides, a process for the preparation of a solid dispersion comprising tapinarof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient selected from a polymer, a non- polymeric material or a combination thereof; wherein the process comprises the steps of: i) combining tapinarof or a pharmaceutically acceptable salt thereof, with a solvent to obtain a slurry; ii) adding a pharmaceutically acceptable excipient to the slurry obtained in the step (i) to obtain a reaction mixture; and iii) removing the solvent from the reaction mixture obtained in the step (ii) to obtain the solid dispersion.
[0053] In an embodiment, the solid dispersion obtained by the above process has crystallinity of 90 % or less.
[0054] In one embodiment, the solvent used in the step (i) of the above process, may be selected from the solvents as described in the preceding embodiment in respect of the step (a).
[0055] In another embodiment, the solvent used in the step (i) of the above process, may be a hydrocarbon selected from hexane, heptane, toluene, xylene or a mixture thereof.
[0056] In one embodiment, the step (i) involving combining tapinarof with a solvent is carried out at a temperature ranging from about 20°C to about 40°C.
[0057] In one embodiment, the pharmaceutically acceptable excipient is as discussed herein above.
[0058] In an embodiment, the reaction mixture obtained in the step (ii) may be stirred for a suitable time. The stirring time may range from about 10 minutes to about 5 hours, or longer at a temperature ranging from about 20°C to about 40°C.
[0059] In an embodiment, in the step (iii) of the above process the solvent is removed by methods selected from the group consisting of evaporation, distillation, filtration and spray drying.
[0060] In an embodiment, the present invention provides a solid dispersion comprising tapinarof and hydroxypropyl cellulose, wherein the solid dispersion is characterised by the X-ray powder diffraction pattern substantially as shown in Figure 1.
[0061] In further embodiment, the present invention provides a solid dispersion comprising tapinarof and hydroxypropyl cellulose, wherein the solid dispersion is characterised by the X-ray powder diffraction pattern substantially as shown in Figure 1 , and wherein the solid dispersion has crystallinity of 90 % or less.
[0062] In an embodiment, the present invention provides a solid dispersion comprising tapinarof and hydroxypropyl cellulose, wherein the solid dispersion is characterised by the X-ray powder diffraction pattern substantially as shown in Figure 2.
[0063] In further embodiment, the present invention provides a solid dispersion comprising tapinarof and hydroxypropyl cellulose, wherein the solid dispersion is characterised by the X-ray powder diffraction pattern substantially as shown in Figure 2, and wherein the solid dispersion has crystallinity of 90 % or less.
[0064] In an embodiment, the present invention provides a solid dispersion comprising tapinarof and cetostearyl alcohol, wherein the solid dispersion has crystallinity of 90 % or less.
[0065] In an embodiment, the present invention provides a solid dispersion comprising tapinarof and stearic acid, wherein the solid dispersion has crystallinity of 90 % or less.
[0066] In another aspect, the present invention provides a pharmaceutical composition comprising the solid dispersion of tapinarof as described herein, and a pharmaceutically acceptable excipient selected from the group consisting of a diluent, a disintegrant, a binder, a lubricant, a glidant, a surfactant or a mixture thereof.
[0067] In an embodiment, the present invention provides a pharmaceutical composition comprising the solid dispersion, wherein the solid dispersion is present in an amount ranging from about 50 % to about 80 % w/w.
[0068] In another embodiment, the present invention provides a pharmaceutical composition comprising the solid dispersion, wherein the solid dispersion is obtained by the process for the preparation of the solid dispersion as described herein.
[0069] In further embodiment, the pharmaceutical composition comprising the solid dispersion is in topical dosage form.
[0070] In an embodiment, the pharmaceutical composition comprising the solid dispersion is in topical dosage form selected from cream, gel, ointment or lotion.
[0071] In an embodiment, the topical dosage form containing the solid dispersion of the present invention is cream.
[0072] According to yet another aspect, the present invention provides a method for the treatment of chronic inflammatory skin diseases selected from atopic dermatitis or plaque psoriasis comprising administering a therapeutically effective amount of the solid dispersion of the present invention, or a topical pharmaceutical composition comprising the solid dispersion of the present invention, to a patient in need thereof.
[0073] According to yet another aspect, the present invention provides use of the solid dispersion of the present invention or the pharmaceutical composition comprising the solid dispersion in the treatment of chronic inflammatory skin diseases selected from atopic dermatitis or plaque psoriasis. [0074] The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Examples:
General methods:
X-Ray Powder Diffraction (XRPD) (Instrumental settings):
The measurements were performed on Philips X-Ray Diffractometer model XPERT- Empyrean (PANalytical) Detector: PIXcel1D [1] using Cu lamp with type and wavelength of the X-ray radiation: K-ai 1.54060[A], K-co 1.5444[A]under the following conditions: The measurements were carried out with a Fixed module programmable divergence slit and anti-scatter Slit (Offset 0.00°); Generator settings: 40 mA/45 kV, Time per step: 500s, Step size: , 0.013 and start angle (°) 2.0 and End angle: 50.0; Scan type: continuous; measurement performed at 25°C. The XRPD instrument is calibrated using NIST SRM 6-40E silicon standard and NIST SRM 1976 Alumina.
Sample preparation: Take an adequate amount of the sample to fill the sample holder using back-loading technique. Then load the sample holder between the X-ray optics-path and scan using the above described parameters. Integrate the obtained powder X-ray diffraction profiles using X’Pert HighScore Plus Software.
Example 1: Preparation of 3, 5-dimethoxy-4-(propan-2-yl)benzaldehyde a) Preparation of methyl 3, 5-dimethoxy-4-(propan-2-yl) benzoate
In a clean and dry flask, a solution of methyl-3, 5-dimethoxybenzoate (100 gm) in methylene chloride (500 ml) was added with 2-chloropropane (60.04 gm) and aluminium chloride (135.88 gm) to obtain a reaction mass. The reaction mass was stirred for a period of 9-10 hours at a temperature in the range of 25°C to 35°C. Reaction mass was quenched in water (500 ml), and the product was extracted in methylene chloride layer. Reaction mass was then subjected to distillation and product was isolated using methanol (700 ml) as a wet cake. b) Preparation of [3, 5-dimethoxy-4-(propan-2-yl)phenyl] methanol
In a clean and dry flask, a solution of wet cake obtained in stage (a) in toluene (700 ml) was subjected to distillation under vacuum to remove some quantity of toluene (200 ml to 250 ml) to obtain a reaction mass. The reaction mass was cooled to a temperature in the range of 25°C to 35°C and to it was added Vitride (70% in toluene) solution. Reaction mass was stirred for a period of 3-4 hours at a temperature in the range of 25°C to 35°C. Reaction mass was quenched with water (300 ml) & hydrochloric acid (300 ml), and the product was extracted in toluene layer. Reaction mass was then subjected to distillation and product was isolated using heptane (500 ml) by steps of filtration and drying. c) Preparation of 3, 5-dimethoxy-4-(propan-2-yl)benzaldehyde
In a clean and dry autoclave the product obtained in stage (b) was dissolved in methylene chloride (400 ml), and to this were added cuprous iodide (7.99 gm), 4- dimethylaminopyridine and (2,2,6,6-Tetramethylpiperidin-l-yl)oxyl (TEMPO) (0.60 gm) to obtain a reaction mass. The Reaction mass was stirred under air pressure of 4 to 5 kg at a temperature ranging from 45°C to 55°C for a period of 1 to 2 hours. To the reaction mass TEMPO was again added twice (each of 0.60 gm), and was further maintained under air pressure for a period of 1 to 3 hours each. The reaction mass was filtered and to this was added aqueous hydrochloric acid (12.60 gm in 350 mL water). The product was extracted in methylene chloride layer and was subjected to distillation to obtain a residue. To the residue methanol (400 ml) was added and precipitated product was filtered and dried.
Yield: 64 gm
Example 2: Preparation of l,3-dimethoxy-5-[(E)-2-phenyl ethenyl] -2-(propan-2- yl)benzene
In a clean and dry flask a solution of 3, 5-dimethoxy-4-(propan-2-yl)benzaldehyde (100 gm) and diethyl benzylphosphonate (120.55 gm) in toluene (300 ml) was added to solution of potassium tertiary butoxide (107.22 gm) in toluene (500 ml) at a temperature in the range of 0°C to 10°C to obtain a reaction mass. The reaction mass was warmed to 25°C to 35°C. Reaction mass was stirred for 3-4 hours at a temperature in the range of 25°C to 35°C. Water (400 ml) was added to the reaction mass and product was extracted in toluene layer, which was subjected to distillation. Product was isolated using methanol (320 ml), filtered and dried.
Yield: 108.4 gm.
Example 3: Preparation of Tapinarof
In a clean and dry flask a solution of l,3-dimethoxy-5-[(E)-2-phenylethenyl]-2-(propan- 2-yl)benzene (100 gm) in toluene was added with diethyl aniline and aluminium chloride to obtain a reaction mass. The reaction mass heated to 50°C to 60°C. The reaction mass was stirred for 2-3 hours at a temperature in the range of 50°C to 60°C. The reaction mass was quenched to a solution of water (700 ml), concentrated hydrochloric acid (240 gm) and ethyl acetate (400 ml) at a temperature in the range of 0°C to 10°C. The product was extracted with ethyl acetate. The reaction mass was then subjected to distillation and product was isolated using toluene (400 ml) and heptane (300 ml) by steps of filtration and drying.
Yield: 76 gm
Example 4: Preparation of a solid dispersion of tapinarof with cetostearyl alcohol as the pharmaceutically acceptable excipient
In a clean and dry flask a solution of tapinarof in methylene chloride was added followed by addition of cetostearyl alcohol to obtain a reaction mass. The reaction mass was stirred for 15 minutes at a temperature in the range of 25°C to 35°C. To this was added methylene chloride and stirred to obtain a solution. The obtained solution was stirred for 15 minutes at a temperature in the range of 25°C to 35°C. The solution was distilled under vacuum at a temperature in the range of 40°C to 45°C to obtain the solid dispersion.
Crystallinity: Less than 90 %
Example 5: Preparation of a solid dispersion of tapinarof with hydroxypropyl cellulose as the pharmaceutically acceptable excipient
In a clean and dry flask, a solution of tapinarof in ethanol was added followed by addition of hydroxypropyl cellulose to obtain a reaction mass. The reaction mass was stirred for 15 minutes at a temperature ranging from 25°C to 35°C. The reaction mass was then subjected to distillation under vacuum at a temperature ranging from 40°C to 45°C to obtain the solid dispersion.
Crystallinity: Less than 90 %
Example 6: Preparation of a solid dispersion of tapinarof with hydroxypropyl cellulose as the pharmaceutically acceptable excipient
In a clean and dry flask, a solution of tapinarof (1.6 gm) in methylene chloride (30 ml) was added followed by addition of hydroxypropyl cellulose (0.4 gm) to obtain a reaction mass. The reaction mass was stirred for 15 minutes at a temperature ranging from 25°C to 35°C. The reaction mass was then subjected to distillation under vacuum at a temperature ranging from 40°C to 45°C to obtain the solid dispersion.
Yield: 1.85 gm.
Crystallinity: 88.77 %
Example 7: Preparation of a solid dispersion of tapinarof with hydroxypropyl cellulose as the pharmaceutically acceptable excipient
In a clean and dry flask a solution of tapinarof (1.0 gm) in methylene chloride (30 ml) was added followed by addition of hydroxypropyl cellulose (1.0 gm) to obtain a reaction mass. The reaction mass was stirred for 15 minutes at a temperature ranging from 25°C to 35°C. The reaction mass was then subjected to distillation under vacuum at a temperature in the range of 40°C to 45°C to obtain the solid dispersion.
Yield: 1.85 gm.
Crystallinity: 58.49 %
Example 8: Preparation of a solid dispersion of tapinarof with stearic acid as the pharmaceutically acceptable excipient
In a clean and dry flask a solution of tapinarof in methylene chloride was added followed by addition of stearic acid to obtain a reaction mass. The reaction mass was stirred for 15 minutes at a temperature 25°C to 35°C. The reaction mass was then subjected to distillation under vacuum at a temperature in the range of 40°C to 45°C to obtain the solid dispersion.
Crystallinity: Less than 90 %
Example 9: Preparation of a solid dispersion of tapinarof with cetostearyl alcohol as the pharmaceutically acceptable excipient
In a clean and dry flask a solution of tapinarof (1.6 gm) in methylene chloride (30 ml) was added followed by addition of cetostearyl alcohol (0.4 gm) to obtain a reaction mass. The reaction mass was stirred for 15 minutes at a temperature in the range of 25°C to 35°C. The reaction mass was then subjected to distillation under vacuum at a temperature ranging from 40°C to 45°C to obtain the solid dispersion.
Yield: 1.85 gm.
Crystallinity: 88.72 % Example 10: Preparation of a solid dispersion of tapinarof with cetostearyl alcohol as the pharmaceutically acceptable excipient
In a clean and dry flask a solution of tapinarof (1 gm) in methylene chloride (20 ml) was added followed by addition of cetostearyl alcohol (1 gm) to obtain a reaction mass. The reaction mass was stirred for 15 minutes at a temperature in the range of 25°C to 35°C.
The reaction mass was then subjected to distillation under vacuum at a temperature ranging from 40°C to 45°C to obtain the solid dispersion.
Yield: 1.88 gm.
Crystallinity: 87.06 %

Claims

1. A solid dispersion comprising tapinarof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient selected from a polymer, a non- polymeric material or a combination thereof.
2. A solid dispersion as claimed in claim 1, wherein the solid dispersion has crystallinity of 90 % or less.
3. The solid dispersion as claimed in claim 1 or claim 2, wherein the pharmaceutically acceptable excipient is a polymer selected from homopolymers or copolymers of N- vinyl lactams, cellulose derivatives, polyalkylene oxides, polyacrylates, polymethacrylates (Eudragit polymers), vinyl acetate polymers, polyacrylamides, polyvinyl alcohol, oligo- or polysaccharides, polyhydroxyalkylacrylates, polyhydroxyalkyl-methacrylates, copolymers of methyl methacrylate and acrylic acid, polyethylene glycols (PEGs), propylene glycol monocaprylate, or a mixture thereof.
4. The solid dispersion as claimed in any one of claims 1, 2 and 3, wherein the polymer is a cellulose derivative selected from methyl cellulose, ethyl cellulose, propyl cellulose, carboxymethyl cellulose, methyl cellulose adipate, hydroxypropyl cellulose, 5-carboxypent-l-yl hydroxypropyl cellulose, methyl 5 -carb oxypentyl cellulose, ethyl 5-carboxypentyl cellulose, cellulose acetate propionate, cellulose acetate butyrate, carboxymethyl cellulose acetate butyrate, hydroxypropylmethyl cellulose, cellulose acetate adipate, cellulose acetate phthalate, cellulose acetate suberate, cellulose acetate adipate hydroxyethyl ester, cellulose acetate adipate propionate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose succinate, hydroxypropylmethyl cellulose acetate succinate, or a mixture thereof.
5. The solid dispersion as claimed in any one of claims 1, 2, 3 and 4, wherein the polymer is a cellulose derivative selected from hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose succinate, hydroxypropylmethyl cellulose acetate succinate, or a mixture thereof.
6. The solid dispersion as claimed in claim 1 or claim 2, wherein the pharmaceutically acceptable excipient is a non-polymeric material selected from stearic acid, cetostearyl alcohol, mineral oil, white wax, white petrolatum, glyceryl monooleate, glyceryl behenate, citric acid, glycerol triester of caprylic & capric acid, or a mixture thereof.
7. The solid dispersion as claimed in any one of the preceding claims 1 to 6, wherein the ratio of tapinarof to the pharmaceutically acceptable excipient ranges from about 1 : 0.2 to about 1 : 15 [w/w],
8. A process for the preparation of a solid dispersion as claimed in any one of the claims 1 to 7; wherein the process comprises the steps of: a) dissolving tapinarof or a pharmaceutically acceptable salt thereof, in a solvent to obtain a solution or a suspension; b) adding a pharmaceutically acceptable excipient to the solution or suspension obtained in the step (a) to obtain a reaction mixture; and c) removing the solvent from the reaction mixture obtained in the step b) to obtain the solid dispersion.
9. The process as claimed in claim 8, wherein the solvent used in the step (a) is selected from the group consisting of (C1-C6) alcohols, ethers, esters, ketones, hydrocarbons, halogenated hydrocarbons, dimethyl sulfoxide, and N-methyl pyrrolidinone.
10. The process as claimed in claim 8 or claim 9, wherein the solvent is (C1-C6) alcohol selected from methanol, ethanol, n-propanol, isopropanol, n-butanol or a mixture thereof.
11. The process as claimed in claim 8 or claim 9, wherein the solvent is halogenated hydrocarbons selected from methylene dichloride, ethylene dichloride, or chloroform.
12. The process as claimed in claim 8, wherein in the step (b), the reaction mixture is stirred at a temperature ranging from about 20°C to about 40°C.
13. The process as claimed in claim 8, wherein in the step (c), the solvent is removed by a method selected from the group consisting of evaporation, distillation, filtration and spray drying.
14. The process as claimed in any of the claims 8 to 13, wherein the solid dispersion obtained has crystallinity of 90 % or less
15. A pharmaceutical composition comprising the solid dispersion as claimed in any one of the claims 1 to 7, and optionally a pharmaceutical acceptable excipient selected from a diluent, a disintegrant, a binder, a lubricant, a glidant, a surfactant or a mixture thereof.
16. A method for the treatment of a chronic inflammatory skin disease selected from atopic dermatitis or plaque psoriasis comprising administering a therapeutically effective amount of the solid dispersion as claimed in any one of the claims 1 to 7, or a pharmaceutical composition as claimed in claim 15, to a patient in need thereof.
17. Use of the solid dispersion as claimed in any one of the claims 1 to 7, or the pharmaceutical composition as claimed in claim 15, in the treatment of chronic inflammatory skin diseases selected from atopic dermatitis or plaque psoriasis.
PCT/IB2024/056540 2023-07-04 2024-07-04 Solid dispersions of tapinarof and a process for the preparation thereof Pending WO2025008784A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200147000A1 (en) * 2018-11-13 2020-05-14 Dermavant Sciences GmbH Use of tapinarof for the treatment of chronic plaque psoriasis
WO2020227151A1 (en) * 2019-05-03 2020-11-12 Azora Therapeutics, Inc. Compositions comprising indigo and/or an indigo derivative and methods of use thereof
WO2021059281A1 (en) * 2019-09-26 2021-04-01 Sol-Gel Technologies Ltd. Treatment of skin disorders with topical combination compositions comprising tapinarof and an additional ahr activator

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200147000A1 (en) * 2018-11-13 2020-05-14 Dermavant Sciences GmbH Use of tapinarof for the treatment of chronic plaque psoriasis
WO2020227151A1 (en) * 2019-05-03 2020-11-12 Azora Therapeutics, Inc. Compositions comprising indigo and/or an indigo derivative and methods of use thereof
WO2021059281A1 (en) * 2019-09-26 2021-04-01 Sol-Gel Technologies Ltd. Treatment of skin disorders with topical combination compositions comprising tapinarof and an additional ahr activator

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