US20170360707A1 - Anticancer compositions - Google Patents

Anticancer compositions Download PDF

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Publication number
US20170360707A1
US20170360707A1 US15/533,203 US201515533203A US2017360707A1 US 20170360707 A1 US20170360707 A1 US 20170360707A1 US 201515533203 A US201515533203 A US 201515533203A US 2017360707 A1 US2017360707 A1 US 2017360707A1
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arn
solid dispersion
poly
meth
acrylate copolymer
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Geert Verreck
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Aragon Pharmaceuticals Inc
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Aragon Pharmaceuticals Inc
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    • 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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/146—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 macromolecular compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention concerns pharmaceutical formulations of ARN-509, which can be administered to a mammal, in particular a human, suffering from an androgen receptor (AR)-related disease or condition, in particular cancer, more in particular prostate cancer, including but not limited to castration-resistant prostate cancer, metastatic castration resistant prostate cancer, chemotherapy-naive metastatic castration resistant prostate cancer, biochemically relapsed hormone sensitive prostate cancer, or high-risk, non-metastatic castration-resistant prostate cancer.
  • these formulations comprise a solid dispersion of ARN-509 and a poly(meth)acrylate copolymer.
  • the solid dispersion of ARN-509 and a poly(meth)acrylate copolymer is obtainable, in particular is obtained, by melt-extruding a mixture comprising ARN-509 and a poly(meth)acrylate copolymer and optionally subsequently milling said melt-extruded mixture.
  • the solid dispersion of ARN-509 and a poly(meth)acrylate copolymer is obtainable, in particular is obtained, by spray drying a mixture comprising ARN-509 and a poly(meth)acrylate copolymer in a suitable solvent.
  • the solid dispersion of ARN-509 and a poly(meth)acrylate copolymer may be further formulated with a pharmaceutically acceptable carrier into a pharmaceutical formulation, such formulation providing improved stability or improved shelf life.
  • a pharmaceutical formulation such formulation providing improved stability or improved shelf life.
  • the formulation of the present invention provides for a fast drug release. With the formulation of the present invention the pill burden for the patient, in particular the cancer patient, can be reduced, and hence therapy adherence and therapy efficiency can be improved.
  • FIG. 1 XRD pattern of ARN-509 Form B.
  • FIG. 2 IR spectrum of ARN-509 Form B.
  • FIG. 3 DSC curve of ARN-509 Form B.
  • ARN-509 is a potent and specific antagonist of the androgen receptor (AR). ARN-509's mechanism of action is antagonism of androgen receptor signaling through inhibition of AR nuclear translocation and DNA binding to androgen response elements.
  • AR-related diseases or conditions include, but are not limited to, benign prostate hyperplasia, hirsutism, acne, adenomas and neoplasias of the prostate, benign or malignant tumor cells containing the androgen receptor, hyperpilosity, seborrhea, endometriosis, polycystic ovary syndrome, androgenic alopecia, hypogonadism, osteoporosis, suppression of spermatogenesis, libido, cachexia, anorexia, androgen supplementation for age related decreased testosterone levels, prostate cancer, breast cancer, endometrial cancer, uterine cancer, hot flashes, Kennedy's disease muscle atrophy and weakness, skin atrophy, bone loss, anemia, arteriosclerosis, cardiovascular disease, loss of energy, loss of well-being, type 2 diabetes, and abdominal fat accumulation.
  • ARN-509 is useful for the treatment of cancer, in particular prostate cancer, including but not limited to castration-resistant prostate cancer, metastatic castration resistant prostate cancer, chemotherapy-naive metastatic castration resistant prostate cancer, biochemically relapsed hormone sensitive prostate cancer, or high-risk, non-metastatic castration-resistant prostate cancer.
  • ARN-509 The chemical structure of ARN-509 is:
  • ARN-509 or 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is currently in clinical development as a nonaqueous, lipid-based solution that is filled into softgel capsules, each containing 30 mg ARN-509.
  • the daily dose being studied is 240 mg/day by oral administration (or 8 softgel capsules). It has been found that in use, the softgel capsules containing ARN-509 have a shelf life of only 6 months and need cold chain storage.
  • An aspect of the invention are pharmaceutical formulations, in particular solid pharmaceutical formulations, more in particular solid pharmaceutical formulations for oral administration of ARN-509, where such formulations have an improved stability, a longer shelf life, provide for a fast drug release or provide for a reduced pill burden for the patient, in particular the cancer patient.
  • the pharmaceutical formulations of the present invention provide a means to increase therapy adherence and therapy efficiency.
  • An aspect of the invention is a solid dispersion comprising ARN-509 and a poly(meth)acrylate copolymer.
  • Copolymers derived from esters of acrylic and methacrylic acid are known in the industry as Eudragit®.
  • Eudragit® is the brand name for a diverse range of poly(meth)acrylate-based copolymers. Different grades are available.
  • the Eudragit® in the dispersions with ARN-509 is Eudragit® L 100-55 which contains an anionic copolymer based on methacrylic acid and ethyl acrylate (CAS number 25212-88-8; Chemical/IUPAC name: Poly(methacrylic acid-co-ethyl acrylate) 1:1) (Evonik Industries).
  • the Eudragit® in the dispersions with ARN-509 is Eudragit® E 100 which is a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (CAS number 24938-16-7; Chemical/IUPAC name: Poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1 (Evonik Industries).
  • An aspect of the invention is a solid dispersion comprising ARN-509 and Eudragit® L 100-55.
  • An aspect of the invention is a solid dispersion comprising ARN-509 and Eudragit® E 100.
  • An aspect of the invention is a solid dispersion consisting of ARN-509 and a poly(meth)acrylate copolymer.
  • An aspect of the invention is a solid dispersion consisting of ARN-509 and Eudragit® L 100-55.
  • An aspect of the invention is a solid dispersion consisting of ARN-509 and Eudragit® E 100.
  • a preferred grade of the poly(meth)acrylate copolymer in the solid dispersions of the invention is Eudragit® L 100-55.
  • the weight-by-weight ratio of ARN-509:poly(meth)acrylate copolymer in the solid dispersion as described herein is in the range from 1:1 to 1:10, preferably from 1:1 to 1:5, more preferably from 1:1 to 1:3 or from 1:2 to 1:3.
  • the weight-by-weight ratio of ARN-509:poly(meth)acrylate copolymer is 1:2.
  • the weight-by-weight ratio of ARN-509:poly(meth)acrylate copolymer is 1:3.
  • the weight-by-weight ratio of ARN-509:Eudragit® L 100-55 is 1:2.
  • the weight-by-weight ratio of ARN-509:Eudragit® L 100-55 is 1:3. In an aspect of the invention, the weight-by-weight ratio of ARN-509:Eudragit® E 100 is 1:2. In an aspect of the invention, the weight-by-weight ratio of ARN-509:Eudragit® E 100 is 1:3.
  • An aspect of the invention is a particle consisting of a solid dispersion as described herein.
  • An aspect of the invention is a particle consisting of a solid dispersion comprising ARN-509 and a poly(meth)acrylate copolymer, in particular wherein the weight-by-weight ratio of ARN-509:poly(meth)acrylate copolymer is 1:2 or 1:3.
  • An aspect of the invention is a particle consisting of a solid dispersion comprising ARN-509 and Eudragit® L 100-55, in particular wherein the weight-by-weight ratio of ARN-509:Eudragit® L 100-55 is 1:2 or 1:3.
  • An aspect of the invention is a particle consisting of a solid dispersion comprising ARN-509 and Eudragit® E 100, in particular wherein the weight-by-weight ratio of ARN-509:Eudragit® E 100 is 1:2 or 1:3.
  • An aspect of the invention is a particle consisting of a solid dispersion consisting of ARN-509 and a poly(meth)acrylate copolymer, in particular wherein the weight-by-weight ratio of ARN-509:poly(meth)acrylate copolymer is 1:2 or 1:3.
  • An aspect of the invention is a particle consisting of a solid dispersion consisting of ARN-509 and Eudragit® L 100-55, in particular wherein the weight-by-weight ratio of ARN-509:Eudragit® L 100-55 is 1:2 or 1:3.
  • An aspect of the invention is a particle consisting of a solid dispersion consisting of ARN-509 and Eudragit® E 100, in particular wherein the weight-by-weight ratio of ARN-509:Eudragit® E 100 is 1:2 or 1:3.
  • An aspect of the invention is a particle comprising a solid dispersion as described hereinabove.
  • An aspect of the invention is a particle comprising a solid dispersion comprising ARN-509 and a poly(meth)acrylate copolymer, in particular wherein the weight-by-weight ratio of ARN-509:poly(meth)acrylate copolymer is 1:2 or 1:3.
  • An aspect of the invention is a particle comprising a solid dispersion comprising ARN-509 and Eudragit® L 100-55, in particular wherein the weight-by-weight ratio of ARN-509:Eudragit® L 100-55 is 1:2 or 1:3.
  • An aspect of the invention is a particle comprising a solid dispersion comprising ARN-509 and Eudragit® E 100, in particular wherein the weight-by-weight ratio of ARN-509:Eudragit® E 100 is 1:2 or 1:3.
  • An aspect of the invention is a particle comprising a solid dispersion consisting of ARN-509 and a poly(meth)acrylate copolymer, in particular wherein the weight-by-weight ratio of ARN-509:poly(meth)acrylate copolymer is 1:2 or 1:3.
  • An aspect of the invention is a particle comprising a solid dispersion consisting of ARN-509 and Eudragit® L 100-55, in particular wherein the weight-by-weight ratio of ARN-509:Eudragit® L 100-55 is 1:2 or 1:3.
  • An aspect of the invention is a particle comprising a solid dispersion consisting of ARN-509 and Eudragit® E 100, in particular wherein the weight-by-weight ratio of ARN-509:Eudragit® E 100 is 1:2 or 1:3.
  • the particles as described herein are obtainable, in particular are obtained, by melt-extruding a mixture comprising ARN-509 and a poly(meth)acrylate copolymer and subsequently milling said melt-extruded mixture.
  • the particles as described herein are obtainable, in particular are obtained, by melt-extruding a mixture consisting of ARN-509 and a poly(meth)acrylate copolymer and subsequently milling said melt-extruded mixture.
  • the weight-by-weight ratio of ARN-509:poly(meth)acrylate copolymer is 1:2 or 1:3.
  • the particles as described herein are obtainable, in particular are obtained, by melt-extruding a mixture comprising ARN-509 and Eudragit® L 100-55 and subsequently milling said melt-extruded mixture.
  • the particles as described herein are obtainable, in particular are obtained, by melt-extruding a mixture consisting of ARN-509 and Eudragit® L 100-55 and subsequently milling said melt-extruded mixture.
  • the weight-by-weight ratio of ARN-509:Eudragit® L 100-55 is 1:2 or 1:3.
  • the particles as described herein are obtainable, in particular are obtained, by melt-extruding a mixture comprising ARN-509 and Eudragit® E 100 and subsequently milling said melt-extruded mixture.
  • the particles as described herein are obtainable, in particular are obtained, by melt-extruding a mixture consisting of ARN-509 and Eudragit® E 100 and subsequently milling said melt-extruded mixture.
  • the weight-by-weight ratio of ARN-509:Eudragit® E 100 is 1:2 or 1:3.
  • the particles as described herein are obtainable, in particular are obtained, by spray drying a mixture comprising ARN-509 and a poly(meth)acrylate copolymer in a suitable solvent.
  • the particles as described herein are obtainable, in particular are obtained, by spray drying a mixture consisting of ARN-509 and a poly(meth)acrylate copolymer in a suitable solvent.
  • the weight-by-weight ratio of ARN-509:poly(meth)acrylate copolymer is 1:2 or 1:3.
  • the particles as described herein are obtainable, in particular are obtained, by spray drying a mixture comprising ARN-509 and Eudragit® L 100-55 in a suitable solvent.
  • the particles as described herein are obtainable, in particular are obtained, by spray drying a mixture consisting of ARN-509 and Eudragit® L 100-55 in a suitable solvent.
  • the weight-by-weight ratio of ARN-509:Eudragit® L 100-55 is 1:2 or 1:3.
  • the particles as described herein are obtainable, in particular are obtained, by spray drying a mixture comprising ARN-509 and Eudragit® E 100 in a suitable solvent.
  • the particles as described herein are obtainable, in particular are obtained, by spray drying a mixture consisting of ARN-509 and Eudragit® E 100 in a suitable solvent.
  • the weight-by-weight ratio of ARN-509:Eudragit® E 100 is 1:2 or 1:3.
  • An aspect of the invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a solid dispersion as described herein.
  • An aspect of the invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and particles as described herein.
  • An aspect of the invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a solid dispersion, said solid dispersion comprising ARN-509 and a poly(meth)acrylate copolymer.
  • An aspect of the invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a solid dispersion, said solid dispersion consisting of ARN-509 and a poly(meth)acrylate copolymer.
  • the weight-by-weight ratio of ARN-509:poly(meth)acrylate copolymer is 1:2 or 1:3.
  • An aspect of the invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a solid dispersion, said solid dispersion comprising ARN-509 and Eudragit® L 100-55.
  • An aspect of the invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a solid dispersion, said solid dispersion consisting of ARN-509 and Eudragit® L 100-55.
  • the weight-by-weight ratio of ARN-509:Eudragit® L 100-55 is 1:2 or 1:3.
  • An aspect of the invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a solid dispersion, said solid dispersion comprising ARN-509 and Eudragit® E 100.
  • An aspect of the invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a solid dispersion, said solid dispersion consisting of ARN-509 and Eudragit® E 100.
  • the weight-by-weight ratio of ARN-509:Eudragit® E 100 is 1:2 or 1:3.
  • An aspect of the invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and particles comprising a solid dispersion, said solid dispersion comprising ARN-509 and a poly(meth)acrylate copolymer.
  • An aspect of the invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and particles comprising a solid dispersion, said solid dispersion consisting of ARN-509 and a poly(meth)acrylate copolymer.
  • the weight-by-weight ratio of ARN-509:poly(meth)acrylate copolymer is 1:2 or 1:3.
  • the particles are obtainable, in particular are obtained, by spray drying as described herein.
  • the particles are obtainable, in particular are obtained, by melt extrusion as described herein.
  • An aspect of the invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and particles consisting of a solid dispersion, said solid dispersion comprising ARN-509 and a poly(meth)acrylate copolymer.
  • An aspect of the invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and particles consisting of a solid dispersion, said solid dispersion consisting of ARN-509 and a poly(meth)acrylate copolymer.
  • the particles are obtainable, in particular are obtained, by spray drying as described herein.
  • the particles are obtainable, in particular are obtained, by melt extrusion as described herein.
  • An aspect of the invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and particles comprising a solid dispersion, said solid dispersion comprising ARN-509 and Eudragit® L 100-55.
  • An aspect of the invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and particles comprising a solid dispersion, said solid dispersion consisting of ARN-509 and Eudragit® L 100-55.
  • the weight-by-weight ratio of ARN-509:Eudragit® L 100-55 is 1:2 or 1:3.
  • the particles are obtainable, in particular are obtained, by spray drying as described herein.
  • the particles are obtainable, in particular are obtained, by melt extrusion as described herein.
  • An aspect of the invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and particles comprising a solid dispersion, said solid dispersion comprising ARN-509 and Eudragit® E 100.
  • An aspect of the invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and particles comprising a solid dispersion, said solid dispersion consisting of ARN-509 and Eudragit® E 100.
  • the weight-by-weight ratio of ARN-509:Eudragit® E 100 is 1:2 or 1:3.
  • the particles are obtainable, in particular are obtained, by spray drying as described herein.
  • the particles are obtainable, in particular are obtained, by melt extrusion as described herein.
  • An aspect of the invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and particles consisting of a solid dispersion, said solid dispersion comprising ARN-509 and Eudragit® L 100-55.
  • An aspect of the invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and particles consisting of a solid dispersion, said solid dispersion consisting of ARN-509 and Eudragit® L 100-55.
  • the weight-by-weight ratio of ARN-509:Eudragit® L 100-55 is 1:2 or 1:3.
  • the particles are obtainable, in particular are obtained, by spray drying as described herein.
  • the particles are obtainable, in particular are obtained, by melt extrusion as described herein.
  • An aspect of the invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and particles consisting of a solid dispersion, said solid dispersion comprising ARN-509 and Eudragit® E 100.
  • An aspect of the invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and particles consisting of a solid dispersion, said solid dispersion consisting of ARN-509 and Eudragit® E 100.
  • the weight-by-weight ratio of ARN-509:Eudragit® E 100 is 1:2 or 1:3.
  • the particles are obtainable, in particular are obtained, by spray drying as described herein.
  • the particles are obtainable, in particular are obtained, by melt extrusion as described herein.
  • An aspect of the invention is a solid dispersion as described herein wherein no surfactant is present.
  • An aspect of the invention is a particle as described herein wherein no surfactant is present.
  • An aspect of the invention is a pharmaceutical formulation as described herein wherein no surfactant is present.
  • An aspect of the invention is a solid dispersion as described herein wherein ARN-509 is the only active pharmaceutical ingredient.
  • An aspect of the invention is a particle as described herein wherein ARN-509 is the only active pharmaceutical ingredient.
  • An aspect of the invention is a pharmaceutical formulation as described herein wherein ARN-509 is the only active pharmaceutical ingredient.
  • ARN-509 is present in base form or as a pharmaceutically acceptable addition salt, such as a pharmaceutically acceptable acid addition salt.
  • ARN-509 is present in base form.
  • the pharmaceutically acceptable addition salts are meant to comprise the therapeutically active non-toxic salt forms.
  • the acid addition salt forms can be obtained by treating the base form of ARN-509 with an appropriate acid, such as inorganic acids, including but not limited to, hydrohalic acids, e.g.
  • hydrochloric acid, hydrobromic acid and the like acids sulfuric acid; nitric acid; phosphoric acid; metaphosphoric acid and the like acids; or organic acids, including but not limited to, acetic acid, trifluoroacetic acid, trimethylacetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, glycolic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, mandelic acid, tartaric acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzoic acid, cinnamic acid, hydrocinnamic acid, benzenesulfonic acid, 4-methylbenzene-sulfonic acid, 2-naphthalenesulfonic acid,
  • salt forms can be converted by treatment with an appropriate base into the free base form.
  • hydrates also included are the hydrates, the solvent addition forms and mixtures thereof which ARN-509 or its salts are able to form.
  • examples of such forms are e.g. hydrates, alcoholates and the like, for instance an ethanolate.
  • doses employed for adult human treatment are typically in the range from 0.01 mg to 5000 mg per day. In one aspect, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day. In another aspect, doses employed for adult human treatment are from about 100 mg to about 500 mg per day. In another aspect, the dose employed for adult human treatment is 240 mg per day.
  • the exact dosage and frequency of administration of ARN-509 may depend on the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient as well as other medication the individual may be taking, as is known to those skilled in the art. Furthermore, it is evident that said daily amounts may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing ARN-509.
  • the daily dose is conveniently presented in a single dose or in divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the daily dose is administered in 4 divided doses.
  • the daily dose is administered in 4 divided doses administered simultaneously (or over a short period of time).
  • the daily dose is administered in 3 divided doses.
  • the daily dose is administered in 3 divided doses administered simultaneously (or over a short period of time).
  • the daily dose is administered in 2 divided doses.
  • the daily dose is administered in 2 divided doses administered simultaneously (or over a short period of time).
  • the pharmaceutical formulation comprises 240 mg of ARN-509.
  • the pharmaceutical formulation comprises 120 mg of ARN-509.
  • the pharmaceutical formulation comprises 60 mg of ARN-509.
  • the pharmaceutical formulation comprises 240 mg of ARN-509.
  • the pharmaceutical formulation is administered once daily.
  • the pharmaceutical formulation comprises 120 mg of ARN-509. Two of said formulations are administered daily, preferably simultaneously (or over a short period of time).
  • the pharmaceutical formulation comprises 60 mg of ARN-509. Four of said formulations are administered daily, preferably simultaneously (or over a short period of time).
  • the formulation of the present invention can also be used in combination with another anticancer agent, in particular with another anti prostate cancer agent, more in particular with an androgen biosynthesis inhibitor, that inhibits 17 ⁇ -hydroxylase/C17,20-lyase (CYP17), in particular abiraterone acetate.
  • Another anticancer agent in particular with another anti prostate cancer agent, more in particular with an androgen biosynthesis inhibitor, that inhibits 17 ⁇ -hydroxylase/C17,20-lyase (CYP17), in particular abiraterone acetate.
  • CYP17 17 ⁇ -hydroxylase/C17,20-lyase
  • the formulation of the present invention can further be combined with prednisone.
  • the present invention also relates to a combination of a pharmaceutical formulation according to the invention and another anticancer agent, in particular another anti prostate cancer agent, more in particular an androgen biosynthesis inhibitor, that inhibits 17 ⁇ -hydroxylase/C17,20-lyase (CYP17), in particular abiraterone acetate.
  • another anticancer agent in particular another anti prostate cancer agent, more in particular an androgen biosynthesis inhibitor, that inhibits 17 ⁇ -hydroxylase/C17,20-lyase (CYP17), in particular abiraterone acetate.
  • another anticancer agent in particular another anti prostate cancer agent, more in particular an androgen biosynthesis inhibitor, that inhibits 17 ⁇ -hydroxylase/C17,20-lyase (CYP17), in particular abiraterone acetate.
  • CYP17 17 ⁇ -hydroxylase/C17,20-lyase
  • Said combination may further comprise prednisone.
  • a solid dispersion means a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, wherein one component is dispersed more or less evenly throughout the other component or components.
  • a solid solution When said dispersion of the components is such that the system is chemically and physically uniform or homogenous throughout or consists of one phase as defined in thermo-dynamics, such a solid dispersion will be called “a solid solution” herein.
  • Solid solutions are preferred physical systems because the components therein are usually readily bioavailable to the organisms to which they are administered. This advantage can probably be explained by the ease with which said solid solutions can form liquid solutions when contacted with a liquid medium such as gastric juice.
  • the ease of dissolution may be attributed at least in part to the fact that the energy required for dissolution of the components from a solid solution is less than that required for the dissolution of components from a crystalline or microcrystalline solid phase.
  • a solid dispersion also comprises dispersions which are less homogenous throughout than solid solutions. Such dispersions are not chemically and physically uniform throughout or comprise more than one phase.
  • the term “a solid dispersion” also relates to a system in a solid state comprising at least two components (a) and (b) and having domains or small regions wherein amorphous, microcrystalline or crystalline (a), or amorphous, microcrystalline or crystalline (b), or both, are dispersed more or less evenly in another phase comprising (b), or (a), or a solid solution comprising (a) and (b). Said domains are regions distinctively marked by some physical feature, small in size compared to the size of the system as a whole, and evenly and randomly distributed throughout the system.
  • the solid dispersions may be in the form of a dispersion wherein amorphous or microcrystalline ARN-509 or amorphous or microcrystalline poly(meth)acrylate copolymer is dispersed more or less evenly in a solid solution comprising ARN-509 and a poly(meth)acrylate copolymer.
  • ARN-509 is present in the solid dispersions as described herein in amorphous form.
  • the solid dispersion as described herein is a solid solution.
  • melt-extrusion e.g. hot melt extrusion
  • spray-drying e.g. spray-drying
  • solution-evaporation in particular hot melt-extrusion and spray-drying, spray-drying being preferred.
  • the particles according to the invention can be prepared by first preparing a solid dispersion of the components, and then optionally grinding or milling said dispersion.
  • the melt-extrusion process comprises the following steps:
  • melt and “melting” do not only mean the alteration from a solid state to a liquid state, but can also refer to a transition to a glassy state or a rubbery state, and in which it is possible for one component of the mixture to get embedded more or less homogeneously into the other. In particular cases, one component will melt and the other component(s) will dissolve in the melt thus forming a solution, which upon cooling may form a solid solution having advantageous dissolution properties.
  • the operating temperature preferably ranges between about 160° C. and about 190° C., more preferably ranges between about 160° C. and 175° C.
  • the lower temperature limit is defined by the point at which ARN-509 is still melting during extrusion with a given set of extrusion conditions.
  • ARN-509 is not completely molten, the extrudate may not provide the desired bioavailability.
  • the viscosity of the mixture is too high, the process of melt extrusion will be difficult. At higher temperatures the components may decompose to an unacceptable level.
  • a person skilled in the art will recognize the most appropriate temperature range to be used.
  • the throughput rate is also of importance because the components may start to decompose when they remain too long in contact with the heating element.
  • the working temperatures will also be determined by the kind of extruder or the kind of configuration within the extruder that is used. Most of the energy needed to melt, mix and dissolve the components in the extruder can be provided by the heating elements. However, the friction of the material within the extruder may also provide a substantial amount of energy to the mixture and aid in the formation of a homogenous melt of the components.
  • extruder such as, for example, a single screw, a twin screw extruder or a multi-screw extruder, for the preparation of the subject-matter of the present invention.
  • Spray-drying of a mixture of the components in a suitable solvent also yields a solid dispersion of said components or particles comprising or consisting of a solid dispersion of said components and may be a useful alternative to the melt-extrusion process, particularly in those cases where the poly(meth)acrylate copolymer is not sufficiently stable to withstand the extrusion conditions and where residual solvent can effectively be removed from the solid dispersion.
  • Yet another possible preparation consists of preparing a mixture of the components in a suitable solvent, pouring said mixture onto a large surface so as to form a thin film, and evaporating the solvent therefrom.
  • Solvents suitable for spray-drying can be any organic solvent in which ARN-509 and the poly(meth)acrylate copolymer, in particular Eudragit® L 100-55 or Eudragit® E 100, are miscable.
  • the boiling point of the solvent is lower than the Tg (glass transition temperature) of the solid dispersion.
  • the solvent should have relatively low toxicity and be removed from the dispersion to a level that is acceptable according to The International Committee on Harmonization (ICH) guidelines. Removal of solvent to this level may require a post drying step such as for instance tray-drying, subsequent to the spray-drying process.
  • Solvents include alcohols such as methanol, ethanol, n-propanol, iso-propanol, and butanol, in particular methanol; ketones such as acetone, methyl ethyl ketone and methyl iso-butyl ketone; esters such as ethyl acetate and propylacetate; and various other solvents such as acetonitrile, dichloromethane, toluene, and 1,1,1-trichloroethane. Lower volatility solvents such as dimethyl acetamide or dimethylsulfoxide can also be used.
  • the solvent suitable for spray drying is a mixture of solvents.
  • the solvent for spray drying is a mixture of an alcohol and acetone, in particular a mixture of methanol and acetone, more in particular a mixture of methanol and acetone 1:9 (w:w).
  • the solvent for spray drying is a mixture of an alcohol and dichloromethane, in particular a mixture of methanol and dichloromethane, more in particular a mixture of methanol and dichloromethane 5:5 (w:w) or 6:4 (w:w), preferably 5:5 (w:w).
  • the particles as described herein have a d 50 of about 1500 ⁇ m, of about 1000 ⁇ m, of about 500 ⁇ m, of about 400 ⁇ m, of about 250 ⁇ m, of about 200 ⁇ m, of about 150 ⁇ m, of about 125 ⁇ m, of about 100 ⁇ m, of about 70 ⁇ m, of about 65 ⁇ m, of about 60 ⁇ m, of about 55 ⁇ m, of about 50 ⁇ m, of about 45 ⁇ m, of about 40 ⁇ m, of about 35 ⁇ m, of about 30 ⁇ m, of about 25 ⁇ m, or of about 20 ⁇ m.
  • Particles obtained by spray drying have preferably a d 50 -value falling in the range from about 20 ⁇ m to about 100 ⁇ m, in particular a d 50 -value falling in the range from about 20 ⁇ m to about 70 ⁇ m, more in particular a d 50 -value of about 20 ⁇ m, of about 25 ⁇ m, of about 30 ⁇ m, of about 35 ⁇ m, of about 40 ⁇ m, of about 45 ⁇ m, of about 50 ⁇ m, of about 55 ⁇ m, of about 60 ⁇ m, of about 65 ⁇ m, or of about 70 ⁇ m.
  • the term d 50 has its conventional meaning as known to the person skilled in the art and can be measured by art-known particle size measuring techniques such as, for example, sedimentation field flow fractionation, photon correlation spectroscopy, laser diffraction or disk centrifugation.
  • the d 50 mentioned herein may be related to volume distributions of the particles. In that instance, by “a d 50 of 50 ⁇ m” it is meant that at least 50% of the volume of the particles has a particle size of less than 50 ⁇ m. The same applies to the other particle sizes mentioned.
  • the d 50 particle size may be related to weight distributions of the particles.
  • d 50 of 50 ⁇ m it is meant that at least 50% of the weight of the particles has a particle size of less than 50 ⁇ m.
  • volume and weight distribution result in the same or about the same value for the average particle size.
  • the particle size can be an important factor determining the tabletting speed, in particular the flowability and therefore the manufacturability on a large scale of a particular dosage form or formulation, and the quality of the final product.
  • the particle size may range preferably from about 100 to about 1500 ⁇ m (d 50 ); for tablets the particle size is preferably less than 250 ⁇ m, more preferably less than 100 ⁇ m (d 50 ). Too small particles ( ⁇ 10-20 ⁇ m) often cause sticking on the tablet punches and manufacturability issues.
  • the particles or solid dispersions as described herein may further comprise one or more pharmaceutically acceptable excipients such as, for example, plasticizers, flavors, colorants, preservatives and the like.
  • excipients such as, for example, plasticizers, flavors, colorants, preservatives and the like.
  • said excipients should not be heat-sensitive, in other words, they should not show any appreciable degradation or decomposition at the working temperature of the melt-extruder.
  • Suitable plasticizers are pharmaceutically acceptable and include low molecular weight polyalcohols such as ethylene glycol, propylene glycol, 1,2 butylene glycol, 2,3-butylene glycol, styrene glycol; polyethylene glycols such as diethylene glycol, triethylene glycol, tetraethylene glycol; other polyethylene glycols having a molecular weight lower than 1,000 g/mol; polypropylene glycols having a molecular weight lower than 200 g/mol; glycol ethers such as monopropylene glycol monoisopropyl ether; propylene glycol monoethyl ether; diethylene glycol monoethyl ether; ester type plasticizers such as triethyl citrate, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, allyl glycollate; and amines such as monoethanolamine, diethanolamine, triethanolamine, monoisopropanolamine
  • the particles or solid dispersions as described herein do not contain a plasticizer.
  • the solid dispersions or the particles of the present invention can be formulated into pharmaceutical formulations comprising a therapeutically effective amount of ARN-509.
  • pharmaceutical formulations for oral administration such as tablets and capsules
  • the solid dispersions or the particles of the present invention can also be used to prepare pharmaceutical formulations e.g. for rectal administration.
  • Preferred formulations are those adapted for oral administration shaped as a tablet. They can be produced by conventional tabletting techniques with conventional ingredients or excipients (pharmaceutically acceptable carrier) and with conventional tabletting machines.
  • the formulations of the invention may include one or more conventional excipients (pharmaceutically acceptable carrier) such as disintegrants, diluents, fillers, binders, buffering agents, lubricants, glidants, thickening agents, sweetening agents, flavors, and colors.
  • excipients can serve multiple purposes.
  • the formulations of the present invention include a disintegrant, a diluent or filler, a lubricant and glidant.
  • Suitable disintegrants are those that have a large coefficient of expansion. Examples thereof are hydrophilic, insoluble or poorly water-soluble crosslinked polymers such as crospovidone (crosslinked polyvinylpyrrolidone) and croscarmellose sodium (crosslinked sodium carboxymethylcellulose).
  • the amount of disintegrant in the tablets according to the present invention may conveniently range from about 3 to about 15% (w/w) and preferably range from about 3 to 7%, in particular is about 5% (w/w). Because disintegrants by their nature yield sustained release formulations when employed in bulk, it is advantageous to dilute them with an inert substance called a diluent or filler.
  • diluents or fillers A variety of materials may be used as diluents or fillers. Examples are lactose monohydrate, anhydrous lactose, sucrose, dextrose, mannitol, sorbitol, starch, cellulose (e.g. micro-crystalline cellulose (AvicelTM), silicified microcrystalline cellulose), dihydrated or anhydrous dibasic calcium phosphate, and others known in the art, and mixtures thereof (e.g. spray-dried mixture of lactose monohydrate (75%) with microcrystalline cellulose (25%) which is commercially available as MicrocelacTM) Preferred is microcrystalline cellulose and silicified microcrystalline cellulose.
  • the amount of diluent or filler in the tablets may conveniently range from about 20% to about 70% (w/w) and preferably ranges from about 55% to about 60% (w/w).
  • Lubricants and glidants can be employed in the manufacture of certain dosage forms, and will usually be employed when producing tablets.
  • examples of lubricants and glidants are hydrogenated vegetable oils, e.g hydrogenated Cottonseed oil, magnesium stearate, stearic acid, sodium lauryl sulfate, magnesium lauryl sulfate, colloidal silica, colloidal anhydrous silica talc, mixtures thereof, and others known in the art.
  • interesting lubricants are magnesium stearate, and mixtures of magnesium stearate with colloidal silica.
  • a preferred lubricant is magnesium stearate.
  • a preferred glidant is colloidal anhydrous silica.
  • Glidants generally comprise 0.2 to 7.0% of the total tablet weight, in particular 0.5 to 1.5%, more in particular 1 to 1.5% (w/w).
  • Lubricants generally comprise 0.2 to 7.0% of the total tablet weight, in particular 0.2 to 1%, more in particular 0.5 to 1% (w/w).
  • Coloring agents and pigments include titanium dioxide and dyes suitable for food.
  • a coloring agent is an optional ingredient in the formulation of the invention, but when used the coloring agent can be present in an amount up to 3.5% based on the total tablet weight.
  • Flavors are optional in the formulation and may be chosen from synthetic flavor oils and flavoring aromatics or natural oils, extracts from plants leaves, flowers, fruits and so forth and combinations thereof. These may include cinnamon oil, oil of wintergreen, peppermint oils, bay oil, anise oil, eucalyptus, thyme oil. Also useful as flavors are vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth, The amount of flavor may depend on a number of factors including the organoleptic effect desired. Generally the flavor will be present in an amount from about 0% to about 3% (w/w).
  • tablet blends may be dry-granulated or wet-granulated before tabletting.
  • the tabletting process itself is otherwise standard and readily practised by forming a tablet from desired blend or mixture of ingredients into the appropriate shape using a conventional tablet press.
  • Tablets of the present invention may further be film-coated e.g. to improve taste, to provide ease of swallowing and an elegant appearance.
  • suitable polymeric film-coating materials are known in the art.
  • a preferred film-coating material is Opadry II 85F210036 Green.
  • Other suitable film-forming polymers also may be used herein, including, hydroxypropylcellulose, hydroxypropyl methylcellulose (HPMC), especially HPMC 2910 5 mPa ⁇ s, and acrylate-methacrylate copolymers.
  • the film coat may further comprise a plasticizer (e.g. propylene glycol) and optionally a pigment (e.g. titanium dioxide).
  • the film-coating suspension also may contain talc as an anti-adhesive.
  • the film coat in terms of weight preferably accounts for about 3% (w/w) or less of the total tablet weight.
  • Preferred formulations are those wherein the weight of the particles or solid dispersions as described herein ranges from 20 to 40%, in particular from 30 to 40% of the total weight of the formulation.
  • the present invention further concerns a process of preparing solid dispersions as described herein, comprising blending ARN-509 and a poly(meth)acrylate copolymer and extruding said blend at a temperature in the range from about 160° C. to about 190° C.
  • the present invention further concerns a process of preparing particles as described herein, comprising blending ARN-509 and a poly(meth)acrylate copolymer, extruding said blend at a temperature in the range from about 160° C. to about 190° C., grinding the extrudate, and optionally sieving the particles.
  • Suitable extruders that may be used are the Haake mini-extruder, Leistritz 18 mm extruder, and the Leistritz 27 mm extruder.
  • the present invention further concerns a process of preparing particles or solid dispersions as described herein comprising mixing ARN-509 and a poly(meth)acrylate copolymer in a suitable solvent and spray drying said mixture.
  • the suitable solvent is a mixture of dichloromethane and methanol.
  • the suitable solvent is a mixture of dichloromethane and methanol wherein the w:w ratio of dichloromethane to methanol in the mixture is 4:6 or 5:5, preferably 5:5.
  • a preferred crystalline form of ARN-509 for preparing the solid dispersions or particles as described herein is Form B, which is an anhydrous crystalline form (see hereinafter and reference is also made to WO2013/184681, which is incorporated herein by reference).
  • this invention concerns a solid dispersion or particles as described herein, for use in preparing a pharmaceutical formulation for administration, in particular oral administration, to a mammal, in particular a human, suffering from an androgen receptor (AR)-related disease or condition, in particular cancer, more in particular prostate cancer, including but not limited to castration-resistant prostate cancer, metastatic castration resistant prostate cancer, chemotherapy-naive metastatic castration resistant prostate cancer, biochemically relapsed hormone sensitive prostate cancer, or high-risk, non-metastatic castration-resistant prostate cancer.
  • AR androgen receptor
  • the present invention also concerns the use of a solid dispersion or particles as described herein, for the preparation of a pharmaceutical formulation for administration, in particular oral administration, to a mammal, in particular a human, suffering from an androgen receptor (AR)-related disease or condition, in particular cancer, more in particular prostate cancer, including but not limited to castration-resistant prostate cancer, metastatic castration resistant prostate cancer, chemotherapy-naive metastatic castration resistant prostate cancer, biochemically relapsed hormone sensitive prostate cancer, or high-risk, non-metastatic castration-resistant prostate cancer.
  • AR androgen receptor
  • the invention also relates to a method of treating an androgen receptor (AR)-related disease or condition, in particular cancer, more in particular prostate cancer, including but not limited to castration-resistant prostate cancer, metastatic castration resistant prostate cancer, chemotherapy-naive metastatic castration resistant prostate cancer, biochemically relapsed hormone sensitive prostate cancer, or high-risk, non-metastatic castration-resistant prostate cancer, in a mammal, in particular a human, which comprises administering, in particular orally, to said mammal, in particular human, an effective anticancer amount of a pharmaceutical formulation as described herein.
  • AR androgen receptor
  • the invention further concerns the use of a pharmaceutical formulation as specified herein, for the manufacture of a medicament for treating an androgen receptor (AR)-related disease or condition, in particular cancer, more in particular prostate cancer, including but not limited to castration-resistant prostate cancer, metastatic castration resistant prostate cancer, chemotherapy-naive metastatic castration resistant prostate cancer, biochemically relapsed hormone sensitive prostate cancer, or high-risk, non-metastatic castration-resistant prostate cancer.
  • AR androgen receptor
  • the invention concerns a pharmaceutical formulation as specified herein for use in the treatment of an androgen receptor (AR)-related disease or condition, in particular cancer, more in particular prostate cancer, including but not limited to castration-resistant prostate cancer, metastatic castration resistant prostate cancer, chemotherapy-naive metastatic castration resistant prostate cancer, biochemically relapsed hormone sensitive prostate cancer, or high-risk, non-metastatic castration-resistant prostate cancer.
  • AR androgen receptor
  • the invention also relates to a pharmaceutical package suitable for commercial sale comprising a container, a pharmaceutical formulation as described herein, and associated with said package written matter.
  • ARN-509 For the preparation of different (crystalline) forms of ARN-509, reference is made to WO2013/184681, which is incorporated herein by reference. Different (crystalline or amorphous) forms of ARN-509 can be used to prepare the solid dispersions, particles or formulations according to the present invention.
  • ARN-509 for use in the preparation of the solid dispersions, particles or formulations according to the present invention is ARN-509 Form B, which is an anhydrous crystal. It was prepared by suspending ARN-509 Form A (reference is made to WO2013/184681, including for the diffraction data) in USP water and heating the slurry to 55 ⁇ 5° C., holding at said temperature for at least 24 hours, followed by cooling the slurry to 25 ⁇ 5° C. The resulting slurry was filtered, and the wet cake washed once with USP water. The wet cake was unloaded from the filter and dried under vacuum to afford ARN-509 Form B. Reference is also made to Example 2 below.
  • Solubility of Form A 0.01 mg/ml in water.
  • Solubility of Form B 0.004 mg/ml in water.
  • X-ray powder diffraction (XRPD) analyses were carried out on a PANalytical (Philips) X'PertPRO MPD diffractometer. The instrument is equipped with a Cu LFF X-ray tube.
  • the compound was spread on a zero background sample holder.
  • generator voltage 45 kV generator amperage: 40 mA geometry: Bragg-Brentano stage: spinner stage
  • Incident beam path Diffracted beam path program divergence slit: 15 mm long anti scatter shield: + Soller slit: 0.04 rad Soller slit: 0.04 rad beam mask: 15 mm Ni filter: + anti scatter slit: 1° detector: X'Celerator beam knife: +
  • the X-ray powder diffraction pattern of ARN-509 Form B shows diffraction peaks without the presence of a halo, indicating that this compound is present as a crystalline product.
  • the XRD pattern of ARN-509 Form B is shown in FIG. 1 .
  • the samples were analyzed using a suitable microATR accessory.
  • Thermo Nexus 670 FTIR spectrometer number of scans 32 resolution: 1 cm ⁇ 1 wavelength range: 4000 to 400 cm ⁇ 1 detector: DTGS with KBr windows beamsplitter: Ge on KBr micro ATR accessory: Harrick Split Pea with Si crystal
  • the compound was transferred into a standard aluminum TA-Instrument sample pan.
  • the sample pan was closed with the appropriate cover and the DSC curve was recorded on a TA-Instruments Q1000 MTDSC equipped with a RCS cooling unit, using the following parameters:
  • the DSC curve of ARN-509 Form B shows the melting of the product at 194.9° C. with a heat of fusion of 73 J/g. See FIG. 3 .
  • the acetone and methanol were transferred into a suitable container, and Eudragit® L 100-55 and ARN-509 Form B, were added.
  • the mixture was spray dried using a suitable spray dryer e.g. Buchi mini spray dryer with the following parameters: spray rate in the range from 6.4-6.7 gram/minutes, outlet temperature in the range from 49° C.-50° C. and condenser temperature in the range from ⁇ 18° C. to ⁇ 22° C.
  • the spray dried product (SDP) was dried in a suitable dryer, e.g. tray dryer using vacuum, nitrogen flow and a drying temperature of 25° C.
  • Example 3.2 Preparation of Tablets Comprising a Solid Dispersion of ARN-509:Eudragit® L 100-55 1:2
  • the SDP, part (3555/4724) of the silicified microcrystalline cellulose, part (10/13) of the colloidal anhydrous silica and part (1/2) of the croscarmellose sodium were sieved and mixed to a homogenous blend using a suitable blender.
  • a dry granulate was made by using a suitable compaction technique.
  • the remainder of the silicified microcrystalline cellulose (1169/4724), colloidal anhydrous silica (3/13) and croscarmellose sodium (1/2) were sieved and added to the dry granulate and further mixed using a suitable blender.
  • Magnesium stearate was sieved and added to the blend and mixed further using a suitable blender.
  • the blend was compressed into tablets using an eccentric tabletting press.
  • Example 4.1 Preparation of a Solid Dispersion of ARN-509:Eudragit® L 100-55 1:2 by Hot Melt Extrusion (HME)
  • the Eudragit® L 100-55 and ARN-509 Form B were blended in a suitable recipient using a suitable blender.
  • Hot melt extrusion was performed in a Haake extruder, flush mode, maximum temperature 190° C., screw speed 30 rpm.
  • the hot melt extrudate was collected and milled in a suitable mill.
  • the milled hot melt extrudate was sieved using a suitable sieve (250 ⁇ m).
  • Example 4.2 Preparation of Tablets Comprising a Solid Dispersion of ARN-509: Eudragit® L 100-55 1:2 (HME)
  • silicified microcrystalline cellulose, croscarmellose sodium and colloidal anhydrous silica were sieved and mixed with the hot melt extrudate to a homogenous blend using a suitable blender.
  • Magnesium stearate was sieved and added to the blend and mixed further using a suitable blender.
  • the blend was compressed into tablets using an eccentric tableting press.
  • Formulation 1 60 mg tablet containing ARN-509-Eudragit® L 100-55 ratio 1/2
  • SDP Formulation 2 60 mg tablet containing ARN-509-Eudragit® L 100-55 ratio 1/2
  • HME Formulation 3 a nonaqueous, lipid-based solution filled into softgel capsules, each containing 30 mg ARN-509
  • Blood samples (2 ml on EDTA) were taken from a jugular vein. Within 1 hour of sampling, the blood samples were centrifuged and within 2 hours after the start of centrifugation, plasma was stored in the freezer.
  • the dichloromethane and methanol were transferred into a suitable container and stirring was started. Under continuous stirring ARN-509 Form B was added to the solvent mixture and stirred until dissolved. Eudragit® L 100-55 was added to the solution and stirred overnight. A clear solution was obtained.
  • the solution was filtered inline through a GRID filter.
  • the solution was spray dried using a suitable spray dryer, e.g. Niro A/S PSD3 with a high pressure nozzle with the following parameters: feed flow of 75 kg/hour, outlet temperature of 40° C. and a condenser temperature of ⁇ 8° C.
  • the spray dried product (SDP) was dried in a suitable dryer, e.g. tray dryer using vacuum, nitrogen flow and a drying temperature of 50° C.
  • the water content was determined by means of a vaporized coulometric Karl Fischer determination in accordance with USP/Ph. Eur.
  • the powder was stored as indicated in table a below.
  • Generator electrode Electrode with diapraghm Metrohm 6.0344.100 Indicator electrode: Double Pt-wire electrode Metrohm 6.0341.100
  • Anode solution Hydranal Coulomat AG Oven (Fluka 34739)
  • Cathode solution Hydranal Coulomat CG (Fluka 34840)
  • Water standard Hydranal Water Standard 1.00 (Fluka 34828)
  • the physical stability of the powder stored under different storage conditions was followed up using powder X-Ray diffraction.
  • the XRD pattern of the powder was compared to the XRD pattern of the corresponding powder measured at time zero (amorphous product).
  • the powder was brought on to the zero background sample holder. A X-ray measurement of the sample was performed.
  • Sample stage spinner
  • Sample holder zero background sample holder
  • Step size 0.02° Scan range: from 3° 2 ⁇ to 50° 2 ⁇ Counting time per step: 60 sec
  • the concentration of ARN-509 and its degradation products in the powder stored under different storage conditions were determined by gradient Reversed-Phase UHPLC with UV Detection.
  • Powders were stored as indicated in table b below.
  • the sample solution is stable for 4 days, if stored in refrigerator, protected from light (closed cabinet).
  • the water activity was determined with a Novasina a w -meter.
  • Example 6 The following tablets were prepared from the powder of Example 6 analogous to Example 3.2.
  • Spray dried powder 180 mg Colloidal Anhydrous Silica 7 mg Croscarmellose sodium 17.5 mg Microcrystalline Cellulose 355.5 mg Colloidal Anhydrous Silica 2.1 mg Croscarmellose sodium 17.5 mg Silicified Microcrystalline Cellulose 116.9 mg Magnesium stearate 3.5 mg (amounts for 1 tablet)
  • the tablets were coated with green OPADRY II 85F210036.
  • the purified water was transferred into a suitable container.
  • the coating powder was added and mixed with a suitable mixer.
  • the core tablets were film coated with the coating suspension using a suitable coater.
  • the water content was determined by means of a vaporized coulometric Karl Fischer determination in accordance with USP/Ph. Eur.
  • Tablets were grinded using a Retsch Mixer Mill. Immediately after grinding, about 50.00 mg ( ⁇ 5.00 mg) of the sample was weighted accurately into a vial and the vial was crimped securely.
  • Generator electrode Electrode with diapraghm Metrohm 6.0344.100 Indicator electrode: Double Pt-wire electrode Metrohm 6.0341.100
  • Anode solution Hydranal Coulomat AG Oven (Fluka 34739)
  • Cathode solution Hydranal Coulomat CG (Fluka 34840)
  • Water standard Hydranal Water Standard 1.00 (Fluka 34828)
  • the physical stability of different tablets stored under different storage conditions was followed up using powder X-Ray diffraction.
  • the XRD pattern of the tablets was compared to the XRD pattern of the corresponding tablets at time zero (amorphous product).
  • One tablet was gently grinded to a fine powder using a mortar and pestle.
  • the powder was loaded into the 16 mm sample holder using the back loading technique.
  • a X-ray measurement of the sample was performed.
  • Sample stage spinner Sample holder: cavity diameter 16 mm, cavity depth 2.5 mm
  • Programmable divergence slit irradiated length 10 mm Soller slit: 0.04 rad Beam mask: 10 mm Anti-scatter slit: 1° Beam knife +
  • Step size 0.02° Scan range: from 3° 2 ⁇ to 50° 2 ⁇ Counting time per step: 100 sec
  • Amorphous drug substance in drug product 3 Amorphous drug substance in drug product
  • Light ICH Amorphous drug substance in drug product
  • the concentration of ARN-509 and its degradation products in tablets stored under different storage conditions were determined by gradient Reversed-Phase UHPLC with UV Detection.
  • the sample solution is stable for 4 days, if stored in refrigerator, protected from light (closed cabinet).
  • the dissolution test was performed using Paddle Apparatus (USP type 2, Ph. Eur., JP.) at 75 rpm in 900 mL of 0.5% (w/v) cetyltrimethylammonium bromide (CTAB) in 0.05 M sodium phosphate buffer pH 4.5.
  • PCB cetyltrimethylammonium bromide
  • Samples were taken by Distek® sample needles with solid housing and samples were filtered with Whatman®Spartan® 0.45 ⁇ m RC (regenerated cellulose) membrane 30 mm diameter filters.
  • the determination of the quantity of ARN-509 present in the dissolution samples was based upon an isocratic ultra high performance liquid chromatographic (UHPLC) method with UV detection.
  • Dissolution Instrument Paddle apparatus (USP type 2, Ph. Eur., JP).
  • UHPLC Instrument Waters Acquity H-Class with UV detector.
  • pH Meter Sensitive to 0.01 pH units.
  • Thermometer Sensitive to 0.1° C.
  • Acetonitrile HPLC Grade.
  • Apparatus Paddle Apparatus (USP type 2, Ph. Eur, JP.). Vessels: 1-L glass.
  • Dissolution Medium 0.5% (w/v) CTAB in 0.05 M Phosphate Buffer pH 4.5.
  • Sinker Use no sinker.
  • Sample Introduction Transfer 1 tablet into each dissolution vessel.
  • the water activity was determined with a Novasina a w -meter.
  • microbiological purity of the tablets was tested according to USP ⁇ 61> and ⁇ 62>, and Ph. Eur. 2.6.12 and 2.6.13.
US15/533,203 2014-12-05 2015-12-03 Anticancer compositions Abandoned US20170360707A1 (en)

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WO2020144650A1 (en) 2019-01-10 2020-07-16 Aragon Pharmaceuticals, Inc. Anti-androgens for the treatment of prostate cancer
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