Anticancer composition

Abstract

The present invention relates to anticancer compositions, especially pharmaceutical preparations ARN 509, which can be applied to mammals suffering from androgen receptor (AR) related diseases or conditions, specifically cancer, more specifically prostate cancer. These preparations include solid dispersions of ARN 509 and poly (meth) acrylate copolymers. In one aspect, the solid dispersions of ARN 509 and poly (meth) acrylates can be obtained by melt extrusion comprising a mixture of ARN 509 and poly (meth) acrylate copolymers and optionally subsequently grinding the melt extruded mixture. In one aspect, the solid dispersions of ARN 509 and poly (meth) acrylate copolymers can be obtained by spray drying a mixture comprising ARN 509 and poly (meth) acrylate copolymers in a suitable solvent.

Description

[0001] This application is a divisional application of the invention patent application with application number 201580066192.9 and invention name “Anticancer Cancer Composition” filed on December 3, 2015.

[0002] The present invention relates to pharmaceutical preparation ARN-509, which can be applied to mammals with androgen receptor (AR) related diseases or conditions, specifically people, the AR related diseases or conditions are specifically cancer, more specifically prostate cancer, including but not limited to castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer without chemotherapy, biochemical recurrent hormone-sensitive prostate cancer, or high-risk non-metastatic castration-resistant prostate cancer. In one aspect, these preparations include solid dispersions of ARN-509 and poly (meth) acrylate copolymers. In one aspect, ARN-509 and a solid dispersion of poly (meth) acrylates can be obtained in the following manner, specifically by the following manner: melt extrusion comprising a mixture of ARN-509 and poly (meth) acrylate copolymers and optionally subsequently grinding the melt-extruded mixture. In one aspect, ARN-509 and a solid dispersion of poly (meth) acrylate copolymers can be obtained in the following manner, specifically by the following manner: spray drying a mixture comprising ARN-509 and poly (meth) acrylate copolymers in a suitable solvent.

[0003] The solid dispersion of ARN-509 and poly (meth) acrylate copolymer can also be formulated into a pharmaceutical preparation with a pharmaceutically acceptable carrier, which provides improved stability or improved shelf life. The preparation of the present invention provides rapid drug release. The use of the preparation of the present invention can reduce the medication burden of patients (particularly cancer patients), and therefore can improve treatment compliance and treatment efficiency.

[0004] Attached photos

[0005] Figure 1 : X-ray diffraction (XRD) pattern of ARN-509B.

[0006] Figure 2 : Infrared spectrum of ARN-509B.

[0007] Figure 3 : Differential scanning calorimetry (DSC) curve of ARN-509B. DETAILED DESCRIPTION

[0008] ARN-509 is a potent and specific antagonist of the androgen receptor (AR). The mechanism of action of ARN-509 is to antagonize androgen receptor signaling by inhibiting AR nuclear translocation and DNA binding to the androgen response element.

[0009] The action of androgens and androgen receptors is associated with many diseases or conditions, such as androgen-dependent cancers, female virilization, and acne, etc. Compounds that reduce the effects of androgens and androgen receptors and / or reduce androgen receptor concentrations can be used to treat diseases or conditions in which androgen receptors play a role.

[0010] AR-associated diseases or conditions include, but are not limited to, benign prostatic hyperplasia, hirsutism, acne, adenomas and tumors of the prostate, benign or malignant tumor cells containing androgen receptors, hyperhirsutism, seborrheic dermatitis, endometriosis, polycystic ovary syndrome, androgenic alopecia, hypogonadism, osteoporosis, suppression of spermatogenesis, libido, cachexia, anorexia, androgen supplementation for age-related decreases in testosterone levels, prostate cancer, breast cancer, endometrial cancer, uterine cancer, hot flashes, Kennedy's disease, muscle weakness and atrophy, skin atrophy, osteoporosis, anemia, atherosclerosis, cardiovascular disease, energy loss, loss of fitness, type 2 diabetes, and abdominal fat accumulation. Given the central role of AR in the development and progression of prostate cancer, ARN-509 can be used to treat cancer, specifically prostate cancer, including but not limited to castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, chemotherapy-naive metastatic castration-resistant prostate cancer, biochemically recurrent hormone-sensitive prostate cancer, or high-risk non-metastatic castration-resistant prostate cancer.

[0011] The chemical structure of ARN-509 is:

[0012]

[0013] ARN-509 or 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide is currently in clinical development and is used as a non-aqueous, lipid-based solution filled into soft capsules, each containing 30 mg of ARN-509. The oral daily dose under study is 240 mg / day (or 8 soft capsules). It has been found that in use, the storage life of soft capsules containing ARN-509 is only 6 months and cold chain storage is required.

[0014] One aspect of the present invention is a pharmaceutical formulation, specifically a solid pharmaceutical formulation, more specifically a solid pharmaceutical formulation for oral administration of ARN-509, wherein these formulations have improved stability, longer shelf life, provide rapid drug release or bring a reduced medication burden to patients (particularly cancer patients). The pharmaceutical formulation of the present invention provides a means to increase treatment compliance and treatment efficiency.

[0015] One aspect of the present invention is a solid dispersion comprising ARN-509 and a poly(meth)acrylate copolymer.

[0016] Copolymers derived from esters of acrylic acid and methacrylic acid (poly(meth)acrylates) are known in the industry as is a trade name for various copolymers based on poly(meth)acrylates. Different grades are available. In one aspect of the invention, ARN-509 is used in dispersions yes L 100-55, which contains an anionic copolymer based on methacrylic acid and ethyl acrylate (CAS No. 25212-88-8; Chemical / IUPAC name: poly(methacrylic acid-co-ethyl acrylate) 1:1) (Evonik Industries). In one aspect of the present invention, ARN-509 is used in the dispersion. yes E 100, a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate (CAS No. 24938-16-7; chemical / IUPAC name: poly(butyl methacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate) 1:2:1 (Evonik Industries).

[0017] One aspect of the present invention is a composition comprising ARN-509 and Solid dispersion of L 100-55.

[0018] One aspect of the present invention is a composition comprising ARN-509 and Solid dispersion of E 100.

[0019] One aspect of the present invention is a solid dispersion consisting of ARN-509 and a poly(meth)acrylate copolymer.

[0020] One aspect of the present invention is a combination of ARN-509 and A solid dispersion composed of L 100-55.

[0021] One aspect of the present invention is a combination of ARN-509 and Solid dispersion composed of E 100.

[0022] The preferred grade of poly(meth)acrylate copolymer in the solid dispersion of the present invention is L100-55.

[0023] In one aspect of the invention, the weight / weight ratio of ARN-509: poly(meth)acrylate copolymer in the solid dispersion as described herein is in the range of 1:1 to 1:10, preferably in the range of 1:1 to 1:5, more preferably in the range of 1:1 to 1:3 or 1:2 to 1:3. In one aspect of the invention, the weight / weight ratio of ARN-509: poly(meth)acrylate copolymer is 1:2. In one aspect of the invention, the weight / weight ratio of ARN-509: poly(meth)acrylate copolymer is 1:3. In one aspect of the invention, ARN-509: The weight / weight ratio of L 100-55 is 1:2. In one aspect of the present invention, ARN-509: The weight / weight ratio of L 100-55 is 1:3. In one aspect of the present invention, ARN-509: The weight / weight ratio of E 100 is 1:2. In one aspect of the present invention, ARN-509: The weight / weight ratio of E100 is 1:3.

[0024] One aspect of the invention is a particle consisting of a solid dispersion as described herein.

[0025] One aspect of the present invention is a particle consisting of a solid dispersion comprising ARN-509 and a poly(meth)acrylate copolymer, specifically wherein the weight / weight ratio of ARN-509:poly(meth)acrylate copolymer is 1:2 or 1:3.

[0026] One aspect of the present invention is a composition comprising ARN-509 and A solid dispersion of particles comprising L 100-55, specifically ARN-509: The weight / weight ratio of L 100-55 is 1:2 or 1:3.

[0027] One aspect of the present invention is a composition comprising ARN-509 and A solid dispersion of particles comprising E 100, specifically ARN-509: The weight / weight ratio of E 100 is 1:2 or 1:3.

[0028] One aspect of the present invention is a particle consisting of a solid dispersion consisting of ARN-509 and a poly(meth)acrylate copolymer, specifically wherein the weight / weight ratio of ARN-509:poly(meth)acrylate copolymer is 1:2 or 1:3.

[0029] One aspect of the present invention is a particle consisting of a solid dispersion consisting of ARN-509 and L 100-55, specifically ARN-509: The weight / weight ratio of L100-55 is 1:2 or 1:3.

[0030] One aspect of the present invention is a particle consisting of a solid dispersion consisting of ARN-509 and E 100 is composed of, specifically ARN-509: The weight / weight ratio of E 100 was 1:2 or 1:3.

[0031] One aspect of the invention is a particle comprising a solid dispersion as described above.

[0032] One aspect of the present invention is a particle comprising a solid dispersion comprising ARN-509 and a poly(meth)acrylate copolymer, specifically wherein the weight / weight ratio of ARN-509:poly(meth)acrylate copolymer is 1:2 or 1:3.

[0033] One aspect of the present invention is a particle comprising a solid dispersion comprising ARN-509 and L 100-55, specifically ARN-509: The weight / weight ratio of L 100-55 is 1:2 or 1:3.

[0034] One aspect of the present invention is a particle comprising a solid dispersion comprising ARN-509 and E 100, specifically ARN-509: The weight / weight ratio of E 100 was 1:2 or 1:3.

[0035] One aspect of the present invention is a particle comprising a solid dispersion consisting of ARN-509 and a poly(meth)acrylate copolymer, specifically wherein the weight / weight ratio of ARN-509:poly(meth)acrylate copolymer is 1:2 or 1:3.

[0036] One aspect of the present invention is a composition comprising ARN-509 and A solid dispersion of particles composed of L 100-55, specifically ARN-509: The weight / weight ratio of L 100-55 is 1:2 or 1:3.

[0037] One aspect of the present invention is a composition comprising ARN-509 and A solid dispersion of particles of the composition E 100, specifically wherein ARN-509: The weight / weight ratio of E 100 was 1:2 or 1:3.

[0038] In one aspect of the invention, the particles as described herein can be obtained by melt extruding a mixture comprising ARN-509 and a poly(meth)acrylate copolymer and subsequently grinding the melt extruded mixture. In one aspect, the particles as described herein can be obtained by melt extruding a mixture consisting of ARN-509 and a poly(meth)acrylate copolymer and subsequently grinding the melt extruded mixture. In one aspect, the weight / weight ratio of ARN-509: poly(meth)acrylate copolymer is 1:2 or 1:3.

[0039] In one aspect of the present invention, the particles as described herein can be obtained by the following method, specifically by the following method: melt extrusion comprising ARN-509 and In one aspect, the particles as described herein can be obtained by melt extruding ARN-509 and ARN-509-55 and then grinding the melt extruded mixture. ARN-509: The weight / weight ratio of L 100-55 is 1:2 or 1:3.

[0040] In one aspect of the present invention, the particles as described herein can be obtained by the following method, specifically by the following method: melt extrusion comprising ARN-509 and In one aspect, the particles as described herein can be obtained by melt extruding ARN-509 and E 100 and then grinding the melt extruded mixture. E 100 and subsequently grinding the melt-extruded mixture. In one aspect, ARN-509: The weight / weight ratio of E 100 was 1:2 or 1:3.

[0041] In one aspect of the invention, the particles as described herein can be obtained by spray drying a mixture comprising ARN-509 and a poly(meth)acrylate copolymer dissolved in a suitable solvent. In one aspect, the particles as described herein can be obtained by spray drying a mixture consisting of ARN-509 and a poly(meth)acrylate copolymer dissolved in a suitable solvent. In one aspect, the weight / weight ratio of ARN-509: poly(meth)acrylate copolymer is 1:2 or 1:3.

[0042] In one aspect of the present invention, the particles as described herein can be obtained by spray drying a mixture comprising ARN-509 and In one aspect, the particles as described herein can be obtained by the following method, specifically by the following method: spray drying ARN-509 and In one aspect, ARN-509: The weight / weight ratio of L 100-55 is 1:2 or 1:3.

[0043] In one aspect of the present invention, the particles as described herein can be obtained by spray drying a mixture comprising ARN-509 and In one aspect, the particles as described herein can be obtained by the following method, specifically by the following method: spray drying ARN-509 and In one aspect, ARN-509: The weight / weight ratio of E100 was 1:2 or 1:3.

[0044] One aspect of the present invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a solid dispersion as described herein.

[0045] One aspect of the invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and particles as described herein.

[0046] One aspect of the present invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a solid dispersion, the solid dispersion comprising ARN-509 and a poly(meth)acrylate copolymer. One aspect of the present invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a solid dispersion, the solid dispersion consisting of ARN-509 and a poly(meth)acrylate copolymer. In one aspect, the weight / weight ratio of ARN-509: poly(meth)acrylate copolymer is 1:2 or 1:3.

[0047] One aspect of the present invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a solid dispersion comprising ARN-509 and L 100-55. One aspect of the present invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a solid dispersion, wherein the solid dispersion is composed of ARN-509 and In one aspect, ARN-509: The weight / weight ratio of L 100-55 is 1:2 or 1:3.

[0048] One aspect of the present invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a solid dispersion comprising ARN-509 and E 100. One aspect of the present invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a solid dispersion, wherein the solid dispersion is composed of ARN-509 and E 100. In one aspect, ARN-509: The weight / weight ratio of E 100 was 1:2 or 1:3.

[0049] One aspect of the present invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and particles, the particles comprising a solid dispersion, the solid dispersion comprising ARN-509 and a poly(meth)acrylate copolymer. One aspect of the present invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and particles, the particles comprising a solid dispersion, the solid dispersion consisting of ARN-509 and a poly(meth)acrylate copolymer. In one aspect, the weight / weight ratio of ARN-509: poly(meth)acrylate copolymer is 1:2 or 1:3. In one aspect, the particles can be obtained by a spray drying method as described herein, specifically by a spray drying method as described herein. In one aspect, the particles can be obtained by a melt extrusion method as described herein, specifically by a melt extrusion method as described herein.

[0050] One aspect of the present invention is a pharmaceutical preparation comprising a pharmaceutically acceptable carrier and particles, the particles are composed of a solid dispersion, and the solid dispersion comprises ARN-509 and poly (meth) acrylate copolymer. One aspect of the present invention is a pharmaceutical preparation comprising a pharmaceutically acceptable carrier and particles, the particles are composed of a solid dispersion, and the solid dispersion is composed of ARN-509 and poly (meth) acrylate copolymer. In one aspect, the particles can be obtained by spray drying as described herein, specifically by spray drying as described herein. In one aspect, the particles can be obtained by melt extrusion as described herein, specifically by melt extrusion as described herein.

[0051] One aspect of the present invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and particles, wherein the particles comprise a solid dispersion, wherein the solid dispersion comprises ARN-509 and L 100-55. One aspect of the present invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and particles, wherein the particles comprise a solid dispersion, wherein the solid dispersion is composed of ARN-509 and In one aspect, ARN-509: The weight / weight ratio of L 100-55 is 1:2 or 1:3. In one aspect, the granules can be obtained by spray drying as described herein, in particular by spray drying as described herein. In one aspect, the granules can be obtained by melt extrusion as described herein, in particular by melt extrusion as described herein.

[0052] One aspect of the present invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and particles, wherein the particles comprise a solid dispersion, wherein the solid dispersion comprises ARN-509 and One aspect of the present invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and particles, wherein the particles comprise a solid dispersion, wherein the solid dispersion is composed of ARN-509 and E 100. In one aspect, ARN-509: The weight / weight ratio of E 100 is 1:2 or 1:3. In one aspect, the granules can be obtained by spray drying as described herein, in particular by spray drying as described herein. In one aspect, the granules can be obtained by melt extrusion as described herein, in particular by melt extrusion as described herein.

[0053] One aspect of the present invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and particles, wherein the particles consist of a solid dispersion comprising ARN-509 and L100-55. One aspect of the present invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and particles, wherein the particles are composed of a solid dispersion, wherein the solid dispersion is composed of ARN-509 and In one aspect, ARN-509: The weight / weight ratio of L 100-55 is 1:2 or 1:3. In one aspect, the granules can be obtained by spray drying as described herein, in particular by spray drying as described herein. In one aspect, the granules can be obtained by melt extrusion as described herein, in particular by melt extrusion as described herein.

[0054] One aspect of the present invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and particles, wherein the particles consist of a solid dispersion comprising ARN-509 and One aspect of the present invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and particles, wherein the particles are composed of a solid dispersion, wherein the solid dispersion is composed of ARN-509 and E 100. In one aspect, ARN-509: The weight / weight ratio of E100 is 1:2 or 1:3. In one aspect, the particles can be obtained by spray drying as described herein, specifically by spray drying as described herein. In one aspect, the particles can be obtained by melt extrusion as described herein, specifically by melt extrusion as described herein.

[0055] One aspect of the present invention is a solid dispersion as described herein, wherein a surfactant is absent from the solid dispersion.

[0056] One aspect of the present invention is a particle as described herein, wherein no surfactant is present in the particle.

[0057] One aspect of the present invention is a pharmaceutical formulation as described herein, wherein a surfactant is absent from the pharmaceutical formulation.

[0058] One aspect of the present invention is a solid dispersion as described herein, wherein ARN-509 is the sole active pharmaceutical ingredient.

[0059] One aspect of the invention is a granule as described herein, wherein ARN-509 is the sole active pharmaceutical ingredient.

[0060] One aspect of the present invention is a pharmaceutical formulation as described herein, wherein ARN-509 is the sole active pharmaceutical ingredient.

[0061] In the solid dispersion or particles or pharmaceutical formulation as described herein, ARN-509 is present in base form or as a pharmaceutically acceptable addition salt, such as a pharmaceutically acceptable acid addition salt. Preferably, ARN-509 is present in base form.

[0062] Pharmaceutically acceptable addition salts are intended to include therapeutically active non-toxic salt forms. Acid addition salt forms can be obtained by treating the base form of ARN-509 with a suitable acid, such as an inorganic acid or an organic acid, wherein the inorganic acid includes but is not limited to: hydrohalic acid, such as hydrochloric acid, hydrobromic acid and the like; sulfuric acid; nitric acid; phosphoric acid; metaphosphoric acid and the like; organic acids include but are not limited to: acetic acid, trifluoroacetic acid, trimethylacetic acid, propionic acid, glycolic acid, 2-hydroxypropionic acid, 2-oxopropionic acid, glycolic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, mandelic acid, tartaric acid, 2-hydroxy-1,2,3-propanetriol, methanesulfonic acid, acetic acid, trifluoroacetic acid, trimethylacetic acid, prop ... hydroxyacetic acid, 2-hydroxypropionic acid, 2-oxopropionic acid, glycolic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, mandelic acid, tartaric acid, 2-hydroxy-1,2,3-propanetriol, methanesulfonic acid Acids such as ethylsulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethylsulfonic acid, benzoic acid, cinnamic acid, hydrocinnamic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, 2-naphthalenesulfonic acid, cyclohexylaminosulfonic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, hexanoic acid, cyclopentylpropionic acid, 3-(4-hydroxybenzoyl)benzoic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, and valproic acid.

[0063] Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.

[0064] Also included are hydrates, solvent addition forms, and mixtures thereof that ARN-509 or its salts are able to form. Examples of such forms are, for example, hydrates, alcoholates, and the like, such as ethanolates.

[0065] Generally speaking, the dosage for adult treatment is usually within the range of 0.01mg to 5000mg per day. In one aspect, the dosage for adult treatment is about 1mg to about 1000mg per day. In another aspect, the dosage for adult treatment is about 100mg to about 500mg per day. In another aspect, the dosage for adult treatment is 240mg per day. As known to those skilled in the art, the exact dosage and frequency of ARN-509 administration may depend on the specific condition being treated, the severity of the condition being treated, the age, weight and overall physical condition of a specific patient, and other agents that an individual may be taking. In addition, it is clear that the daily amount may be reduced or increased according to the response of the subject receiving treatment and / or according to the evaluation of the physician prescribing ARN-509. Therefore, the dosage mentioned herein is only for guidance and is not intended to limit the scope or use of the present invention to any extent. In one aspect of the present invention, the daily dose is suitably provided in a single dose or in divided doses administered at the same time (or in a short period of time) or at appropriate intervals, such as two, three, four or more sub-doses / day. In one aspect of the present invention, the daily dose is administered in 4 divided doses. In one aspect of the invention, the daily dose is administered in 4 divided doses administered simultaneously (or in a short period of time). In one aspect of the invention, the daily dose is administered in 3 divided doses. In one aspect of the invention, the daily dose is administered in 3 divided doses administered simultaneously (or in a short period of time). In one aspect of the invention, the daily dose is administered in 2 divided doses. In one aspect of the invention, the daily dose is administered in 2 divided doses administered simultaneously (or in a short period of time).

[0066] In one aspect of the invention, the pharmaceutical formulation comprises 240 mg ARN-509.

[0067] In one aspect of the invention, the pharmaceutical formulation comprises 120 mg ARN-509.

[0068] In one aspect of the invention, the pharmaceutical formulation comprises 60 mg ARN-509.

[0069] In one aspect of the invention, the pharmaceutical formulation comprises 240 mg ARN-509. The pharmaceutical formulation is administered once a day.

[0070] In one aspect of the invention, the pharmaceutical formulation comprises 120 mg ARN-509. Two of the formulations are administered daily, preferably simultaneously (or within a short period of time).

[0071] In one aspect of the invention, the pharmaceutical formulation comprises 60 mg ARN-509. Four of the formulations are administered daily, preferably simultaneously (or within a short period of time).

[0072] The formulation of the present invention can also be used in combination with another anticancer agent, specifically another antiprostate cancer agent, more specifically an androgen biosynthesis inhibitor (specifically abiraterone acetate) that inhibits 17α-hydroxylase / C17,20-lyase (CYP17). The formulation of the present invention can also be combined with prednisone.

[0073] Therefore, the present invention also relates to a combination of a pharmaceutical formulation according to the present invention and another anticancer agent, in particular a combination with another antiprostate cancer agent, more particularly a combination with an androgen biosynthesis inhibitor that inhibits 17α-hydroxylase / C17,20-lyase (CYP17), in particular abiraterone acetate.

[0074] The combination may also include prednisone.

[0075] The term "solid dispersion" refers to a solid (as opposed to a liquid or gaseous) system comprising at least two components, wherein one component is more or less evenly dispersed throughout the other one or more components. When the dispersion of each component makes the entire system chemically and physically uniform or homogeneous, or is composed of a phase as defined in thermodynamics, this solid dispersion will be referred to as a "solid solution" in this article. Solid solutions are preferred physical systems because the components therein are usually easily bioavailable for the organism to which the components are applied. This advantage can be explained by the fact that when contacted with a liquid medium such as gastric juice, the solid solution can easily form a liquid solution. Being easy to dissolve can be at least partially attributed to the fact that the energy required to dissolve the components from the solid solution is less than the energy required to dissolve the components from the crystalline or microcrystalline solid phase.

[0076] The term "solid dispersion" also includes dispersions whose overall homogeneity is poorer than that of a solid solution. Such dispersions are chemically and physically uniform as a whole, or contain more than one phase. For example, the term "solid dispersion" also refers to a solid-state system that comprises at least two components (a) and (b) and has a plurality of domains or small regions in which (a) is amorphous, microcrystalline or crystalline, or (b) is amorphous, microcrystalline or crystalline, or both are more or less uniformly dispersed in another phase comprising (b) or (a) or in a solid solution comprising (a) and (b). The domain refers to a region that has some significantly different physical characteristics, is smaller in size, and is uniformly and randomly distributed throughout the system compared to the overall size of the system.

[0077] Preferred are solid dispersions or particles as described herein in which ARN-509 is in a non-crystalline phase because they have an inherently faster dissolution rate than those solid dispersions or particles in which some or all of the ARN-509 is in microcrystalline or crystalline form.

[0078] Alternatively, the solid dispersion may be in the form of a dispersion in which amorphous or microcrystalline ARN-509 or amorphous or microcrystalline poly(meth)acrylate copolymer is more or less uniformly dispersed in a solid solution comprising ARN-509 and poly(meth)acrylate copolymer.

[0079] In one aspect of the invention, ARN-509 is present in an amorphous form in a solid dispersion as described herein.

[0080] In one aspect of the invention, the solid dispersion as described herein is a solid solution.

[0081] Various techniques for preparing the solid dispersion of the present invention include melt extrusion (eg, hot melt extrusion), spray drying, and solution evaporation, and specifically among hot melt extrusion and spray drying, spray drying is preferred.

[0082] The particles according to the invention can be prepared by first preparing a solid dispersion of the components and then optionally comminuting or grinding the dispersion.

[0083] The melt extrusion method comprises the following steps:

[0084] a) mixing ARN-509 and poly(meth)acrylate copolymer,

[0085] b) optionally blending additives with the mixture thus obtained,

[0086] c) heating the blend thus obtained until a homogeneous melt is obtained,

[0087] d) forcing the melt thus obtained through one or more nozzles; and

[0088] e) Cooling the melt until solidified.

[0089] The term "melt" or "melting" not only means a change from a solid to a liquid state, but can also refer to a transition to a glassy or rubbery state, in which one component of the mixture may be more or less embedded in another component. In certain cases, one component will melt, and the other component will dissolve in the melt to form a solution, which, when cooled, can form a solid solution with favorable dissolution properties.

[0090] An important parameter of melt extrusion is the temperature at which the melt extruder operates. For the melt extrusion method of the present invention, the operating temperature is preferably in the range of about 160°C and about 190°C, more preferably in the range of about 160°C and 175°C. The lower temperature limit is defined by the temperature point at which ARN-509 is still melted during the extrusion process using a given set of extrusion conditions. When ARN-509 is not completely melted, the extrudate may not provide the desired bioavailability. When the viscosity of the mixture is too high, the process of melt extrusion will be difficult. At higher temperatures, the components may decompose to unacceptable levels. Those skilled in the art will recognize the most suitable temperature range to be used.

[0091] Throughput rate is also important because components may begin to decompose when they remain in contact with the heating element for too long.

[0092] It should be understood that those skilled in the art will be able to optimize the parameters of the melt extrusion process within the above given ranges. The operating temperature can also be determined by the type of extruder or the type of construction in the extruder used. Most of the energy required for melting, mixing and dissolving the components in the extruder can be provided by the heating element. However, the friction of the material in the extruder can also provide a large amount of energy for the mixture and help to form a homogeneous melt of the components.

[0093] One skilled in the art will recognize the most suitable extruder for preparing the subject matter of the present invention, such as, for example, a single screw, twin screw extruder, or a multi-screw extruder.

[0094] Spray drying of a mixture of the components dissolved in a suitable solvent also produces solid dispersions of the components, or particles comprising or consisting of solid dispersions of the components, and may be a useful alternative to the melt extrusion process, particularly in those cases where the poly(meth)acrylate copolymer is not stable enough to withstand the extrusion conditions and where residual solvent can be effectively removed from the solid dispersion. Another possible preparation consists of preparing a mixture of the components in a suitable solvent, pouring the mixture onto a large surface to form a film, and evaporating the solvent from the film.

[0095] A suitable solvent for spray drying may be ARN-509 and poly (meth) acrylate copolymer (specifically L 100-55 or E 100) can be mixed with any organic solvent. In one aspect of the invention, the boiling point of the solvent is lower than the Tg (glass transition temperature) of the solid dispersion. In addition, the solvent should have relatively low toxicity and be removed from the dispersion to an acceptable level according to the International (Drug Registration) Harmonization Conference (ICH) guidelines. Removing the solvent to this level may require a subsequent drying step, such as tray drying after the spray drying process. Solvents include: alcohols, such as methanol, ethanol, n-propanol, isopropanol and butanol, especially methanol; ketones, such as acetone, methyl ethyl ketone and methyl isobutyl ketone; esters, such as ethyl acetate and propyl acetate; and various other solvents, such as acetonitrile, dichloromethane, toluene and 1,1,1-trichloroethane. Solvents with lower volatility, such as dimethylacetamide or dimethyl sulfoxide, can also be used. In one aspect of the invention, the solvent suitable for spray drying is a mixture of multiple solvents. In one aspect of the present invention, the solvent for spray drying is a mixture of alcohol and acetone, specifically a mixture of methanol and acetone, more specifically a 1:9 (w:w) mixture of methanol and acetone. In one aspect of the present invention, the solvent for spray drying is a mixture of alcohol and dichloromethane, specifically a mixture of methanol and dichloromethane, more specifically a 5:5 (w:w) or 6:4 (w:w), preferably a 5:5 (w:w) mixture of methanol and dichloromethane.

[0096] The particles as described herein have a d of about 1500 μm, about 1000 μm, about 500 μm, about 400 μm, about 250 μm, about 200 μm, about 150 μm, about 125 μm, about 100 μm, about 70 μm, about 65 μm, about 60 μm, about 55 μm, about 50 μm, about 45 μm, about 40 μm, about 35 μm, about 30 μm, about 25 μm, or about 20 μm. 50 The particles obtained by spray drying preferably have a d falling within the range of about 20 μm to about 100 μm. 50 values, specifically falling within the range of about 20 μm to about 70 μm 50 values, more specifically about 20 μm, about 25 μm, about 30 μm, about 35 μm, about 40 μm, about 45 μm, about 50 μm, about 55 μm, about 60 μm, about 65 μm, or about 70 μm. 50 value.

[0097] As used herein, the term d 50 has the conventional meaning known to those skilled in the art and can be measured by particle size measurement techniques known in the art, such as, for example, sedimentation field flow fractionation, photon correlation spectroscopy, laser diffraction or disk centrifugation. 50 can be related to the volume distribution of the particles. In this case, “50 μm d 50" means that at least 50% by volume of the particles have a particle size of less than 50 μm. The same applies to the other particle sizes mentioned. In a similar manner, d 50 Particle size may be related to the weight distribution of the particles. In this case, “50 μm d 50 " means that at least 50% by weight of the particles have a particle size of less than 50 μm. The same applies to the other particle sizes mentioned. Usually, the volume and weight distributions result in the same or approximately the same average particle size values.

[0098] Particle size can be an important factor in determining tableting speed, in particular flowability and therefore manufacturability of a particular dosage form or formulation on a large scale and quality of the final product. For example, for capsules, the particle size may preferably be in the range of about 100 to about 1500 μm (d 50 ); for tablets, the particle size is preferably less than 250 μm, more preferably less than 100 μm (d 50 Particles that are too small (<10-20 μm) often lead to sticking on tablet punches and manufacturability problems.

[0099] The particles or solid dispersions as described herein may further comprise one or more pharmaceutically acceptable excipients, such as, for example, plasticizers, flavoring agents, coloring agents, preservatives, etc. In particular in the case of preparation by hot melt extrusion, the excipients should not be heat sensitive, in other words, they should not show any appreciable degradation or decomposition at the operating temperature of the melt extruder.

[0100] Suitable plasticizers are pharmaceutically acceptable and include low molecular weight polyols such as ethylene glycol, propylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, phenylene glycol; polyethylene glycols such as diethylene glycol, triethylene glycol, tetraethylene glycol; other polyethylene glycols with a molecular weight below 1,000 g / mol; polypropylene glycols with a molecular weight below 200 g / mol; glycol ethers such as monopropylene glycol monoisopropyl ether; propylene glycol monoethyl ether; diethylene glycol monoethyl ether; ester plasticizers such as triethyl citrate, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, allyl glycolate; and amines such as monoethanolamine, diethanolamine, triethanolamine, monoisopropanolamine; triethylenetetramine, 2-amino-2-methyl-1,3-propanediol, etc. Preferred among them are low molecular weight polyethylene glycols, ethylene glycol, low molecular weight polypropylene glycols, particularly propylene glycol.

[0101] In one aspect of the invention, the particles or solid dispersion as described herein are free of plasticizers.

[0102] The solid dispersion or particles of the present invention can be formulated into a pharmaceutical preparation containing a therapeutically effective amount of ARN-509. Although it is first envisioned that pharmaceutical preparations such as tablets and capsules are used for oral administration, the solid dispersion or particles of the present invention can also be used to prepare pharmaceutical preparations such as for rectal administration. Preferred preparations are those suitable for being formed into tablets and taken orally. They can be prepared by conventional tableting techniques, using conventional ingredients or excipients (pharmaceutically acceptable carriers) and using conventional tablet presses. In order to facilitate mammals to swallow this preparation, it is advantageous to give the preparation, especially the tablet, a suitable shape. The film coating on the tablet can further contribute to the easy swallowability of the tablet.

[0103] The preparation of the present invention, specifically tablets, may contain one or more conventional excipients (pharmaceutically acceptable carriers), such as disintegrants, diluents, fillers, binders, buffers, lubricants, glidants, thickeners, sweeteners, flavors and colorants. Some excipients can be used for various purposes. Preferably, the preparation of the present invention contains disintegrants, diluents or fillers, lubricants and glidants.

[0104] Suitable disintegrants are those with a large coefficient of expansion. Examples thereof are hydrophilic, insoluble or poorly soluble cross-linked polymers such as polyvinylpyrrolidone (cross-linked polyvinyl pyrrolidone) and cross-linked sodium carboxymethylcellulose (cross-linked sodium carboxymethylcellulose). The amount of disintegrant in the tablet according to the invention may conveniently be in the range of about 3% to about 15% (w / w), and preferably in the range of about 3% to 7%, in particular about 5% (w / w). Since disintegrants, by their nature, produce sustained-release formulations when used in bulk, it is advantageous to dilute them with an inert substance known as a diluent or filler.

[0105] Various materials can be used as diluents or fillers. Examples of diluents or fillers are lactose monohydrate, anhydrous lactose, sucrose, glucose, mannitol, sorbitol, starch, cellulose (e.g., microcrystalline cellulose (Avicel TM ), silicified microcrystalline cellulose), dibasic calcium phosphate dihydrate or anhydrous, and other substances known in the art, and mixtures thereof (e.g., a spray-dried mixture of lactose monohydrate (75%) and microcrystalline cellulose (25%), which can be used as Microcelac TM ) are commercially available. Preferred are microcrystalline cellulose and silicified microcrystalline cellulose. The amount of diluent or filler in the tablet may conveniently be in the range of about 20% to about 70% (w / w), and preferably in the range of about 55% to about 60% (w / w).

[0106] Lubricants and glidants can be used to make certain dosage forms, and will generally be used when making tablets. Examples of lubricants and glidants are hydrogenated vegetable oils, such as hydrogenated cottonseed oil, magnesium stearate, stearic acid, sodium lauryl sulfate, magnesium lauryl sulfate, colloidal silicon dioxide, colloidal anhydrous silicon dioxide talc, mixtures thereof, and other substances known in the art. Lubricants of interest are magnesium stearate, and mixtures of magnesium stearate and colloidal silicon dioxide. A preferred lubricant is magnesium stearate. A preferred glidant is colloidal anhydrous silicon dioxide.

[0107] Glidants generally comprise 0.2% to 7.0%, specifically 0.5% to 1.5%, more specifically 1% to 1.5% (w / w) of the total tablet weight.

[0108] Lubricants generally comprise 0.2% to 7.0%, specifically 0.2% to 1%, more specifically 0.5% to 1% (w / w) of the total tablet weight.

[0109] Other excipients such as colorants and pigments may also be added to the formulations of the present invention. Colorants and pigments include titanium dioxide and food-compatible dyes. Colorants are optional ingredients in the formulations of the present invention, and when used, colorants may be present in an amount up to 3.5% based on the total tablet weight.

[0110] Flavoring agent is optional in preparation, and can be selected from synthetic flavor oil and flavoring aromatic or natural oil, extract from plant leaf, flower, fruit etc., and their combination.These flavoring agents can comprise cinnamon oil, wintergreen oil, peppermint oil, bay oil, anise oil, eucalyptus, thyme oil.Also can be used as flavoring agent is vanilla, citrus oil (comprising lemon, orange, grape, lime and grapefruit), and fruit essence (comprising apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot etc.).The amount of flavoring agent can depend on many factors, including required organoleptic effect.Usually, flavoring agent will be present with the amount of about 0% to about 3% (w / w).

[0111] As is known in the art, the tablet blend may be dry granulated or wet granulated prior to tableting. The tableting process itself is standard and easily practiced by forming tablets from the desired blend or mixture of ingredients into appropriate shapes using a conventional tablet press.

[0112] The tablets of the present invention can be further film-coated, for example to improve taste, thereby providing easy swallowing and an aesthetically pleasing appearance. Many suitable polymer film coating materials are known in the art. A preferred film coating material is Opadry II 85F210036Green. Other suitable film-forming polymers can also be used herein, including hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), especially HPMC 2910 5mPa.s and acrylate-methacrylate copolymers. In addition to the film-forming polymer, the film coating may also include a plasticizer (e.g., propylene glycol) and optionally a pigment (e.g., titanium dioxide). The film coating suspension may also include talc as an anti-adhesive. In tablets according to the present invention, the film coating preferably accounts for about 3% (w / w) or less of the total tablet weight by weight.

[0113] Preferred formulations are those wherein the weight of particles or solid dispersion as described herein ranges from 20% to 40%, specifically 30% to 40%, of the total weight of the formulation.

[0114] The present invention also relates to a method of preparing a solid dispersion as described herein, comprising blending ARN-509 and a poly(meth)acrylate copolymer, and extruding the blend at a temperature in the range of about 160°C to about 190°C.

[0115] The present invention also relates to a method of preparing the particles as described herein, comprising blending ARN-509 and a poly(meth)acrylate copolymer, extruding the blend at a temperature in the range of about 160°C to about 190°C, grinding the extrudate, and optionally sieving the particles.

[0116] Suitable extruders that may be used are the Haake mini-extruder, the Leistritz 18 mm extruder and the Leistritz 27 mm extruder.

[0117] The present invention also relates to a method for preparing particles or solid dispersions as described herein, comprising mixing ARN-509 and poly(meth)acrylate copolymer in a suitable solvent, and spray drying the mixture. In one aspect, the suitable solvent is a mixture of dichloromethane and methanol. In one aspect, the suitable solvent is a mixture of dichloromethane and methanol, wherein the weight:weight ratio of dichloromethane to methanol in the mixture is 4:6 or 5:5, preferably 5:5.

[0118] The preferred crystalline form of ARN-509 for use in preparing solid dispersions or particles as described herein is Form B, which is an anhydrous crystalline form (see below, and with reference to WO 2013 / 184681, which is incorporated herein by reference).

[0119] Another object of the present invention is to provide a method for preparing a pharmaceutical preparation as described herein, specifically a pharmaceutical preparation in the form of a tablet or capsule, characterized in that a therapeutically effective amount of the solid dispersion or granules as described herein is blended with a pharmaceutically acceptable carrier, and the blend is compressed into a tablet or the blend is filled in a capsule.

[0120] In addition, the present invention relates to a solid dispersion or particle as described herein, for preparing a pharmaceutical preparation for administration (particularly oral administration) to a mammal (particularly a human) suffering from an androgen receptor (AR)-related disease or condition, wherein the AR-related disease or condition is specifically cancer, more specifically prostate cancer, including but not limited to castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, chemotherapy-naive metastatic castration-resistant prostate cancer, biochemically recurrent hormone-sensitive prostate cancer, or high-risk non-metastatic castration-resistant prostate cancer.

[0121] The present invention also relates to the use of the solid dispersion or particles as described herein for preparing a pharmaceutical preparation for administration (particularly oral administration) to a mammal (particularly a human) suffering from an androgen receptor (AR)-related disease or condition, wherein the AR-related disease or condition is specifically cancer, more specifically prostate cancer, including but not limited to castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, chemotherapy-naive metastatic castration-resistant prostate cancer, biochemically recurrent hormone-sensitive prostate cancer, or high-risk non-metastatic castration-resistant prostate cancer.

[0122] The present invention also relates to a method for treating an androgen receptor (AR)-related disease or condition in a mammal (particularly a human), wherein the AR-related disease or condition is specifically cancer, more specifically prostate cancer, including but not limited to castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, chemotherapy-naive metastatic castration-resistant prostate cancer, biochemically recurrent hormone-sensitive prostate cancer or high-risk non-metastatic castration-resistant prostate cancer, the method comprising administering (particularly orally administering) an effective anticancer amount of a pharmaceutical formulation as described herein to the mammal (particularly a human).

[0123] The present invention also relates to 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, wherein the AR-related disease or condition is specifically cancer, more specifically prostate cancer, including but not limited to castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer without chemotherapy, biochemical recurrent hormone-sensitive prostate cancer, or high-risk non-metastatic castration-resistant prostate cancer. Alternatively, the present invention relates to a pharmaceutical formulation as specified herein, which is used to treat an androgen receptor (AR)-related disease or condition, wherein the AR-related disease or condition is specifically cancer, more specifically prostate cancer, including but not limited to castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer without chemotherapy, biochemical recurrent hormone-sensitive prostate cancer, or high-risk non-metastatic castration-resistant prostate cancer.

[0124] The present invention also relates to a pharmaceutical package suitable for commercial sale, comprising a container, a pharmaceutical formulation as described herein, and associated with said packaging writing.

[0125] The term "about" used herein in conjunction with a numerical value is intended to have its usual meaning in the context of the numerical value. If necessary, the word "about" can be replaced by a numerical value ±10% or ±5% or ±2% or ±1%.

[0126] All documents cited herein are incorporated by reference in their entirety.

[0127] The following examples are intended to illustrate the present invention.

[0128] Example 1: ARN-509 Forms

[0129] Regarding 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 may be used to prepare solid dispersions, particles or formulations according to the invention.

[0130] The preferred form of ARN-509 for preparing a solid dispersion, particle or formulation according to the present invention is ARN-509B type, which is anhydrous crystal. It is prepared by the following steps: ARN-509A type (reference WO2013 / 184681, including diffraction data) is suspended in USP water and the slurry is heated to 55 ± 5 ° C, kept at the temperature for at least 24 hours, and then the slurry is cooled to 25 ± 5 ° C. The resulting slurry is filtered, and the wet cake is washed once with USP water. The wet cake is unloaded from the filter and vacuum dried to obtain ARN-509B type. Also refer to Example 2 below.

[0131] Solubility of type A: 0.01 mg / ml in water.

[0132] Solubility of type B: 0.004 mg / ml in water.

[0133] Example 2

[0134] Characterization of ARN-509B

[0135] Powder XRD

[0136] X-ray powder diffraction (XRPD) analysis was performed on a PANalytical (Philips) X'PertPRO MPD diffractometer. The instrument was equipped with a Cu LFF X-ray tube.

[0137] Apply the compound to the zero-background sample holder.

[0138] Instrument parameters

[0139]

[0140] Measurement conditions

[0141]

[0142]

[0143] The X-ray powder diffraction pattern of ARN-509B shows diffraction peaks without diffraction halos, indicating that the compound exists as a crystalline product. Figure 1 middle.

[0144] Infrared spectroscopy analysis (micro ATR-IR)

[0145] Analyze samples using a suitable micro-ATR accessory.

[0146]

[0147] The spectrum of ARN-509B is shown in Figure 2 middle.

[0148] Differential Scanning Calorimetry (DSC)

[0149] The compounds were transferred to standard aluminum TA-Instrument sample pans. The sample pans were closed with appropriate lids and DSC curves were recorded on a TA-Instruments Q1000MTDSC equipped with an RCS cooling unit using the following parameters:

[0150] Initial temperature: 25℃

[0151] Heating rate: 10℃ / min

[0152] Final temperature: 250℃

[0153] The DSC curve of ARN-509B shows that the product melts at 194.9°C with a melting heat of 73 J / g. Figure 3 .

[0154] Example 3.1: Preparation of ARN-509: L100-55 is a 1:2 solid dispersion

[0155]

[0156] a Remove during processing

[0157] (The reported amount is for 1 g of SDP (spray dried product))

[0158] Transfer the acetone and methanol to a suitable container and add L 100-55 and ARN-509B. After mixing the ingredients using a suitable mixer, the mixture is spray dried using a suitable spray dryer (e.g., Buchi micro spray dryer) with the following parameters: spray rate in the range of 6.4 g / min to 6.7 g / min, outlet temperature in the range of 49° C. to 50° C., and condenser temperature in the range of -18° C. to -22° C. The spray dried product (SDP) is dried in a suitable dryer (e.g., tray dryer) using vacuum, nitrogen flow, and a drying temperature of 25° C.

[0159] Example 3.2: Preparation of ARN-509 containing: L 100-55 is a 1:2 solid dispersion tablet

[0160]

[0161] (Amount of 1 tablet)

[0162]

[0163] (Amount of 1 tablet)

[0164] A portion of SDP, silicified microcrystalline cellulose (3555 / 4724), a portion of colloidal anhydrous silicon dioxide (10 / 13), and a portion of cross-linked sodium carboxymethyl cellulose (1 / 2) were sieved and mixed into a uniform blend using a suitable blender. Dry granules were prepared using a suitable compaction technique. The remaining silicified microcrystalline cellulose (1169 / 4724), colloidal anhydrous silicon dioxide (3 / 13), and cross-linked sodium carboxymethyl cellulose (1 / 2) were sieved, then added to the dry granules and further mixed using a suitable blender. Magnesium stearate was sieved, added to the blend, and further mixed using a suitable agitator. The blend was compressed into tablets using an eccentric tablet press.

[0165] Example 4.1: Preparation of ARN-509 by hot melt extrusion (HME): L 100-55 is 1:2 solid Dispersion

[0166] ARN-509 333.33mg

[0167] L 100-55 666.67mg

[0168] (Amounts reported are for 1 g of HME product)

[0169] Use a suitable mixer L 100-55 and ARN-509B are blended in a suitable container. Hot melt extrusion is performed in a Haake extruder in flush mode, a maximum temperature of 190°C, and a screw speed of 30 rpm. The hot melt extrudate is collected and ground in a suitable grinder. The ground hot melt extrudate is sieved using a suitable sieve (250 μm).

[0170] Example 4.2: Preparation of ARN-509 containing: L100-55 is a 1:2 solid dispersion (HME) tablet Agent

[0171]

[0172] (Amount of 1 tablet)

[0173] Silicified microcrystalline cellulose, croscarmellose sodium and colloidal anhydrous silicon dioxide are sieved and mixed with the hot melt extrudate into a uniform blend using a suitable blender. Magnesium stearate is sieved, added to the blend, and further mixed using a suitable blender. The blend is compressed into tablets using an eccentric tablet press.

[0174] Example 5

[0175] Bioavailability studies

[0176] Test system

[0177] Species: Marshall beagle dog

[0178] Supplier: Marshall Farms, Italy / USA

[0179] Gender and age: Male (n=12), approximately 1-7 years old

[0180] Body weight: 8 to 13 kg at the beginning of the experimental period

[0181] Food and water:

[0182] Continuous water supply

[0183] Dosing: Dogs were fasted for approximately 21 hours before dosing and until ±2 hours after dosing. Thereafter, dogs were free to eat until late afternoon.

[0184] Test compounds and formulations

[0185] Preparation 1: Contains L 100-55 Weight ratio 1 / 2 SDP 60mg tablet

[0186] Preparation 2: Contains L 100-55 Weight ratio 1 / 2 HME 60mg tablet

[0187] Formulation 3: Non-aqueous, lipid-based solution filled into softgel capsules, each containing 30 mg ARN-509

[0188] Blood collection and plasma preparation

[0189] Blood samples (2 ml in EDTA) were collected from the jugular vein. Blood samples were centrifuged within 1 hour of sampling and plasma was stored in a freezer within 2 hours of the start of centrifugation.

[0190] Dosage

[0191]

[0192] Biological analysis

[0193] All study samples were analyzed using a qualified LC-MS / MS method. Samples were subjected to selective sample cleanup prior to HPLC-MS / MS.

[0194] HPLC separations were performed using achiral reversed-phase liquid chromatography. Subsequent MS / MS analysis was performed using triple quadrupole mass spectrometry in multiple reaction monitoring (MRM) mode, with the analytical method optimized for the compound. Samples were quantified based on a calibration curve constructed to cover the concentration range of each study sample. The curve was constructed in the same matrix as the study samples. For each analytical batch, an independent quality control sample prepared in the same matrix as the samples was analyzed together with the study samples and the calibration curve. All analytical batches were accepted based on calibration curves and QC acceptance criteria that met current FDA guidelines.

[0195] Data analysis

[0196] Pharmacokinetic analysis of individual plasma concentration-time profiles was performed using validated Phoenix software. Noncompartmental analysis using the linear ascent / logarithmic decline trapezoidal rule was used for all data.

[0197] result

[0198] The average C of ARN-509 in male beagle dogs after a single oral dose of the three formulations max 、T max , AUC and F rel The values ​​are as follows:

[0199]

[0200] 1) T in most animals 1ast 168h; 2) n = 2

[0201] Preparation 1: L 100-55 ratio is 1 / 2 (SDP)

[0202] Preparation 2: L 100-55 ratio is 1 / 2 (HME)

[0203] Formulation 3: Control soft capsule

[0204] Example 6: Preparation of ARN-509: L100-55 is a 1:2 solid dispersion (SDP)

[0205]

[0206] a Remove during processing

[0207] (The reported amounts are for 1 g SDP (spray dried product))

[0208] Transfer the dichloromethane and methanol to a suitable container and begin stirring. Add ARN-509B to the solvent mixture with continued stirring and stir until dissolved. 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. A suitable spray dryer (e.g. Niro A / S PSD3 with a high pressure nozzle) was used and the solution was spray dried using the following parameters: feed flow rate of 75 kg / h, outlet temperature of 40°C, and condenser temperature of -8°C.

[0209] The spray dried product (SDP) is dried in a suitable dryer (eg, tray dryer) using vacuum, nitrogen flow, and a drying temperature of 50°C.

[0210] Stability testing of spray-dried powders

[0211] The following stability test was performed on the powder of Example 6 packaged in LDPE / Alu bags.

[0212] 1. Appearance test

[0213] Visual inspection was performed on powders stored under different storage conditions as shown in Table a below.

[0214] The results are recorded in Table a below.

[0215] 2. Water content

[0216] The water content was determined using vaporized coulometric Karl Fischer determination according to USP / Ph. Eur.

[0217] The powders were stored as shown in Table a below.

[0218] Approximately 50.00 mg (± 5.00 mg) of sample was accurately weighed into the vial, and the vial was securely crimped capped.

[0219] The results are recorded in Table a below.

[0220] The following instruments, reagents and solutions and parameters were used.

[0221] instrument

[0222] Coulometer: 831KF Coulometer Metrohm

[0223] Oven: Metrohm 774 Sample Oven Processor

[0224] Generator electrode: Electrode with diapraghm Metrohm 6.0344.100

[0225] Indicator electrode: Metrohm double platinum wire electrode 6.0341.100 (Double Pt-wire electrode Metrohm6.0341.100)

[0226] Reagents and solutions

[0227] Anolyte: Hydranal Coulomat AG Oven (Fluka 34739)

[0228] Cathodic liquid: Hydranal Coulomat CG (Fluka 34840)

[0229] Water standard: Hydranal Water Standard 1.00 (Fluka34828)

[0230] Oven parameters

[0231] Carrier gas: N2

[0232] Flow rate: set to 60mL / min

[0233] The minimum reading is 20mL / min

[0234] Oven temperature: 120℃

[0235] Coulometer parameters

[0236] Titration parameters

[0237] Extraction time: 60s

[0238] Drift correction: Automatic

[0239] Starting conditions

[0240] Pause: 60s

[0241] Initial drift: Maximum 12μg / min

[0242] Conductivity time OK: 10s

[0243] Stop Parameters

[0244] Relative drift: 5μg / min

[0245] Alternative coulomb counter parameters may be used provided system suitability requirements are met

[0246] 3. pXRD test for detecting crystalline ARN-509

[0247] The physical stability of the powders stored under different storage conditions was followed using powder X-ray diffraction. The XRD pattern of the powders was compared with the XRD pattern of the corresponding powder (amorphous product) measured at the start of the time.

[0248] Place the powder on the zero background sample holder. Perform X-ray measurement on the sample.

[0249] The results are recorded in Table a below.

[0250] The following instruments and parameters were used.

[0251] instrument

[0252] Pananalytical X'Pert PRO MPD Diffractometer PW3050 / 60

[0253] X-ray tube Cu LFF PW3373 / 10

[0254] Detector: X'Celerator

[0255] Sample stage: Rotating stage

[0256] Sample holder: Zero background sample holder

[0257] Instrument Setup

[0258] Rotation time: 1rps

[0259] Generator voltage: 45kV

[0260] Generator current: 40mA

[0261] Optics in the X-ray beam path

[0262] Incident beam path:

[0263] Programmable divergence slit: radiation length 15mm

[0264] Soller slit: 0.04 rad

[0265] Beam mask: 15mm

[0266] Anti-scatter slit: 1°

[0267] Beam Knife+

[0268] Diffraction beam path:

[0269] Programmable anti-scatter slit: 1°

[0270] Soller slit: 0.04 rad

[0271] Filter: Ni

[0272] Instrument parameters

[0273] Geometry: Bragg-Brentano

[0274] Radiation: CuKα

[0275] Step size: 0.02°

[0276] Scan range: 3°2θ to 50°2θ

[0277] Counting time per step: 60 seconds

[0278] Table a: Test conditions and results for powders stored in LDPE / Alu bags - appearance and water content and crystallinity fruit

[0279]

[0280] a Qualified: White to light yellow, fine granular powder

[0281] Regarding appearance, no significant stability-related changes were observed during storage of the drug product intermediate powder under different storage conditions.

[0282] Regarding water content, no significant stability-related changes were observed during storage of the drug product intermediate powders under different storage conditions.

[0283] Regarding crystallinity, no significant stability-related changes were observed during storage of the drug product under different storage conditions.

[0284] 4. Determination of ARN-509 chromatographic purity

[0285] The concentrations of ARN-509 and its degradation products in powders stored under different storage conditions were determined by gradient reverse phase UHPLC with UV detection.

[0286] The powder was stored as shown in Table b below.

[0287] Accurately weigh 180.00 mg of powder into a 250 mL volumetric flask. Add about 125 mL of acetonitrile using a graduated cylinder and mechanically shake the whole for 30 minutes, then dilute to volume with water until it is about 1 cm below the mark. Shake the whole vigorously by hand. Allow the sample solution to equilibrate to ambient temperature, then dilute to volume with water. Shake the volumetric flask manually just before filtering. Filter the sample solution through a chemically resistant 0.2 μm filter. Discard the first 3 mL of filtrate into a waste container and do not return it to the volumetric flask.

[0288] If the sample solution is stored in a refrigerator, the sample solution is stable for 4 days protected from light (placed in a closed cupboard).

[0289] The results are recorded in Table b below.

[0290] The following solutions and instruments and parameters were used.

[0291] Mobile phase

[0292] Mobile phase A

[0293] 10 mM NH4Ac + 0.1% TFA / acetonitrile (90 / 10, v / v).

[0294] Mobile phase B

[0295] Acetonitrile

[0296] UHPLC identification conditions, assays, and chromatographic purity

[0297] Column: Acquity BEH C18, 150 mm length × 2.1 mm inner diameter, 1.7 μm particle size

[0298] Column temperature: 45°C

[0299] Autosampler temperature: 5°C

[0300] Flow rate: 0.40mL / min

[0301] Detection: UV = UV

[0302] Wavelength: 268nm

[0303] Injection volume: 3 μL

[0304] Data collection time: 35 minutes

[0305] Analysis run time: 40 minutes

[0306] Program the linear gradient as shown in the table below.

[0307] Linear Gradient Program

[0308]

[0309]

[0310] Table b: Test conditions and results for powders stored in LDPE / Alu bags - assays and degradation product results

[0311]

[0312] No significant stability-related changes were observed during storage of the drug product intermediate powder under different storage conditions.

[0313] 5. Water activity

[0314] The water activity was measured using a Novasina aw water activity meter.

[0315] The results are recorded in Table c below.

[0316] Table c: Test conditions and results of powders - water activity results

[0317]

[0318] Stability testing of coated tablets prepared from spray-dried powders

[0319] The powder of the following Tablet Example 6 was prepared in a manner similar to Example 3.2.

[0320]

[0321] (Amount of 1 tablet)

[0322] The tablets were coated with green OPADRY II 85F210036.

[0323] ARN-509 (60 mg) tablets 600.18 g

[0324] Opadry II 85F210036Green 22.53g

[0325] Purified water a 89.97g

[0326] a Remove during processing

[0327] 857 tablets per batch

[0328] Transfer the purified water to a suitable container. Add the coating powder and mix using a suitable mixer. Film coat the core tablets with the coating suspension using a suitable coater.

[0329] The stability test was performed on the above tablets stored in HDPE bottles containing a desiccant (silica gel).

[0330] 1. Appearance test

[0331] Tablets stored under different storage conditions as shown in Table 1 below were visually inspected.

[0332] The results are recorded in Table 1 below.

[0333] 2. Water content

[0334] The water content was determined using vaporized coulometric Karl Fischer determination according to USP / Ph. Eur.

[0335] Tablets were stored as shown in Table 1 below.

[0336] The tablets were ground using a Retsch Mixer Mill. Immediately after grinding, approximately 50.00 mg (± 5.00 mg) of sample was accurately weighed into a vial and the vial was securely crimped capped.

[0337] The results are recorded in Table 1 below.

[0338] The following instruments, reagents and solutions, and parameters were used.

[0339] instrument

[0340] Coulometer: 831KF Coulometer Metrohm

[0341] Oven: Metrohm 774 Sample Oven Processor

[0342] Generator electrode: Electrode with diapraghm Metrohm 6.0344.100

[0343] Indicator electrode: Metrohm double platinum wire electrode 6.0341.100 (Double Pt-wire electrode Metrohm6.0341.100)

[0344] Reagents and solutions

[0345] Anolyte: Hydranal Coulomat AG Oven (Fluka 34739)

[0346] Cathodic liquid: Hydranal Coulomat CG (Fluka 34840)

[0347] Water standard: Hydranal Water Standard 1.00 (Fluka34828)

[0348] Oven parameters

[0349] Carrier gas: N2

[0350] Flow rate: set to 60mL / min

[0351] The minimum reading is 20mL / min

[0352] Oven temperature: 120℃

[0353] Coulometer parameters

[0354] Titration parameters

[0355] Extraction time: 60s

[0356] Drift correction: Automatic

[0357] Starting conditions

[0358] Pause: 60s

[0359] Initial drift: Maximum 12μg / min

[0360] Conductivity time OK: 10s

[0361] Stop Parameters

[0362] Relative drift: 5μg / min

[0363] Alternative coulomb counter parameters may be used provided system suitability requirements are met

[0364] Table 1: Test conditions and results for tablets stored in HDPE bottles with desiccant (silica gel) - appearance and water content Quantity Results

[0365]

[0366]

[0367] a Qualified: Green rectangular tablet

[0368] Light ICH: Overall near-ultraviolet energy is not less than 200W.h / m 2 , the overall illumination is not less than 1200klux.h

[0369] Regarding appearance, no significant stability-related changes were observed during storage of the drug product under different storage conditions.

[0370] 3. pXRD test for detecting crystalline ARN-509

[0371] Powder X-ray diffraction was used to follow the physical stability of different tablets stored under different storage conditions. The XRD pattern of the tablets was compared with the XRD pattern of the corresponding tablet at the start of the time (amorphous product).

[0372] One tablet was lightly ground into a fine powder using a mortar and pestle. The powder was loaded into a 16 mm sample holder using a back loading technique. The sample was subjected to X-ray measurement.

[0373] The results are reported in Table 2 below.

[0374] The following instruments and parameters were used.

[0375] instrument

[0376] Philips X'Pert PRO MPD Diffractometer PW3050 / 60

[0377] X-ray tube Cu LFF PW3373 / 10

[0378] Detector: X'Celerator

[0379] Sample stage: Rotating stage

[0380] Sample holder: cavity diameter 16mm, cavity depth 2.5mm

[0381] Instrument Setup

[0382] Rotation time: 1rps

[0383] Generator voltage: 45kV

[0384] Generator current: 40mA

[0385] Optics in the X-ray beam path

[0386] Incident beam path:

[0387] Programmable divergence slit: radiation length 10mm

[0388] Soller slit: 0.04 rad

[0389] Beam mask: 10mm

[0390] Anti-scatter slit: 1°

[0391] Beam Knife+

[0392] Diffraction beam path:

[0393] Programmable anti-scatter slit: 1°

[0394] Soller slit: 0.04 rad

[0395] Filter: Ni

[0396] Instrument parameters

[0397] Geometry: Bragg-Brentano

[0398] Radiation: CuKα

[0399] Step size: 0.02°

[0400] Scan range: 3°2θ to 50°2θ

[0401] Counting time per step: 100 seconds

[0402] Table 2: Test conditions and results for tablets stored in HDPE bottles with desiccant (silica gel) - Crystallinity results

[0403]

[0404]

[0405] Light ICH: Overall near-ultraviolet energy is not less than 200W.h / m2, and overall illumination is not less than 1200klux.h

[0406] No significant stability-related changes were observed during storage of the drug product under different storage conditions.

[0407] 4. Determination of ARN-509 chromatographic purity

[0408] The concentrations of ARN-509 and its degradation products in tablets stored under different storage conditions were determined by gradient reversed-phase UHPLC with UV detection.

[0409] Tablets were stored as shown in Table 3 below.

[0410] Accurately weigh five tablets. Determine the average tablet weight. Grind the tablets into a fine powder. Accurately weigh an amount of uniform powder equivalent to the average tablet weight into a 250 mL volumetric flask. Add approximately 125 mL of acetonitrile using a graduated cylinder and mechanically shake the whole for 30 minutes and then dilute to volume with water until it is approximately 1 cm below the mark. Vigorously shake the whole manually. Allow the sample solution to equilibrate to ambient temperature and then dilute to volume with water. Manually shake the volumetric flask immediately before filtering. Filter the sample solution through a chemically resistant 0.2 μm filter. Discard the first 3 mL of filtrate into a waste container and do not return it to the volumetric flask.

[0411] If the sample solution is stored in a refrigerator, the sample solution is stable for 4 days protected from light (placed in a closed cupboard).

[0412] The results are recorded in Table 3 below.

[0413] The following solutions, instruments, and parameters were used.

[0414] Mobile phase

[0415] Mobile phase A

[0416] 10 mM NH4Ac (ammonium acetate aqueous solution) + 0.1% TFA (trifluoroacetic acid) / acetonitrile (90 / 10, v / v).

[0417] Mobile phase B

[0418] Acetonitrile

[0419] UHPLC identification conditions, assays, and chromatographic purity

[0420] Column: Acquity BEH C18, 150 mm length × 2.1 mm inner diameter, 1.7 μm particle size

[0421] Column temperature: 45°C

[0422] Autosampler temperature: 5°C

[0423] Flow rate: 0.40mL / min

[0424] Detection: UV = UV

[0425] Wavelength: 268nm

[0426] Injection volume: 3 μL

[0427] Data collection time: 35 minutes

[0428] Analysis run time: 40 minutes

[0429] Program the linear gradient as shown in the table below.

[0430] Linear Gradient Program

[0431] Time (min) A (volume %) B (volume %) 0 100 0 35 30 70 36 100 0 40 100 0

[0432] Table 3: Test conditions and results for tablets stored in HDPE bottles containing desiccant (silica gel) - determination and degradation Solution product results

[0433]

[0434]

[0435] Light ICH: Overall near-ultraviolet energy is not less than 200W·h / m 2 , the overall illumination is not less than 1200klux·h

[0436] No significant stability-related changes were observed during storage of the drug product under different storage conditions.

[0437] 5. Dissolution

[0438] Dissolution testing was performed using a Paddle Apparatus (USP Type 2, European Pharmacopoeia, Japanese Pharmacopoeia) at a speed of 75 rpm in 900 mL of a solution of 0.5% (w / v) cetyltrimethylammonium bromide (CTAB) in 0.05 M sodium phosphate buffer at pH 4.5.

[0439] Use a solid shell The sampling needle takes samples and uses a 30mm diameter The samples were filtered through a 0.45 μm RC (regenerated cellulose) membrane filter.

[0440] Determination of the amount of ARN-509 present in the dissolution samples was based on an isocratic ultra-high performance liquid chromatography (UHPLC) method with UV detection.

[0441] Tablets stored under different storage conditions as shown in Table 4 below were tested.

[0442] The following instruments, reagents and solutions and parameters were used.

[0443] instrument

[0444] Dissolution Apparatus: Paddle Apparatus (USP Type 2, European Pharmacopoeia, Japanese Pharmacopoeia).

[0445] UHPLC instrument: Waters Acquity H-Class with UV detector.

[0446] Data acquisition system: Waters Empower.

[0447] Analytical balance: sensitive to 0.01g.

[0448] Analytical balance: sensitive to 0.01 mg.

[0449] pH meter: sensitive to 0.01 pH unit.

[0450] Thermometer: sensitive to 0.1°C.

[0451] Reagents and solutions

[0452] Reagents

[0453] Cetyltrimethylammonium bromide, cetyltrimethylammonium bromide, (CTAB): for analysis, 99.0% purity.

[0454] Sodium dihydrogen phosphate monohydrate (NaH2PO4.H2O): ACS grade.

[0455] Ammonium Acetate: HPLC grade, 99% purity.

[0456] Acetonitrile: HPLC grade.

[0457] Mobile phase

[0458] Mobile phase A: 10 mM ammonium acetate

[0459] Mobile phase B: acetonitrile

[0460] step

[0461] Dissolution parameters

[0462] Apparatus: Paddle apparatus (USP Type 2, European Pharmacopoeia, Japanese Pharmacopoeia).

[0463] Vessel: Class 1-L.

[0464] Rotation speed: 75rpm.

[0465] Dissolution medium: 0.5% (w / v) CTAB in 0.05 M phosphate buffer at pH 4.5.

[0466] Volume of medium: 900 mL.

[0467] Degassing of media: Not required.

[0468] Media Replacement: Not required.

[0469] Temperature: 37.0±0.5℃.

[0470] Sinkers: Sinkers are not used.

[0471] Sample Introduction: Transfer 1 tablet into each dissolution vessel.

[0472] Analysis and collation - UHPLC parameters

[0473] condition

[0474] Column: Acquity BEH C18, particle size 1.7 μm, 50×2.1 mm inner diameter

[0475] Column temperature: 45±5℃.

[0476] Sample temperature: room temperature.

[0477] Flow rate: 0.6mL / min.

[0478] Detection: UV at 242 nm.

[0479] Injection volume: 2 μL.

[0480] Elution mode: isocratic.

[0481] Mobile phase: 50 / 50 (v:v) 10 mM ammonium acetate:acetonitrile.

[0482] Degas using appropriate means.

[0483] Running time (guided): 1.5 minutes.

[0484] Retention time (guide): about 0.7 minutes for ARN-509

[0485] Washing solvent: methanol.

[0486] Purge solvent: 75 / 25 (v:v) water / methanol.

[0487] Sampling rate: 20 points / second, filter constant normal.

[0488] Table 4: Test conditions and results of tablets stored in HDPE bottles containing desiccant (silica gel) - dissolution results

[0489]

[0490] Light ICH: Overall near-ultraviolet energy not less than 200W·h / m 2 , the overall illumination is not less than 1200kluxh

[0491] No significant stability-related changes were observed during storage of the drug product under different storage conditions.

[0492] 6. Water activity

[0493] Water activity was measured using Novasina a w Determined by water activity meter.

[0494] The results are recorded in Table 5 below.

[0495] Table 5: Tablet test conditions and results - water activity results

[0496]

[0497] 7. Microbiological purity

[0498] According to the United States Pharmacopeia <61> and <62> The tablets were tested for microbiological purity according to Pharmacopoeia Europe 2.6.12 and 2.6.13.

[0499] The results are recorded in Table 6 below.

[0500] Table 6: Test conditions and results of the tablets of Example 3.3 stored in HDPE bottles containing desiccant (silica gel) Results - Microbiological Purity

[0501]

[0502] No significant stability-related changes were observed during storage of the drug product under different storage conditions.

[0503] It is within the technician's knowledge to identify the same conditions, solutions, reagents, parameters and apparatus as above. It is within the technician's knowledge to identify appropriate reference solutions, calculation methods, suitability tests.

Claims

1. A solid dispersion comprising (hereinafter referred to as ARN-509) and a poly(meth)acrylate copolymer, wherein the weight / weight ratio of ARN-509:poly(meth)acrylate copolymer in the solid dispersion is in the range of 1:1 to 1:

5.

2. The solid dispersion according to claim 1, wherein the dispersion consists of ARN-509 and a poly(meth)acrylate copolymer.

3. The solid dispersion according to claim 1, wherein the weight / weight ratio of ARN-509:poly(meth)acrylate copolymer in the solid dispersion is 1:

2. 4 . The solid dispersion according to claim 1 , wherein the weight / weight ratio of ARN-509:poly(meth)acrylate copolymer in the solid dispersion is 1:

1.

5. The solid dispersion according to any one of the preceding claims, wherein ARN-509 is present in an amorphous form.

6. A solid dispersion according to any one of the preceding claims, wherein the dispersion is a solid solution.

7. The solid dispersion according to any one of the preceding claims, wherein the poly(meth)acrylate copolymer is poly(methacrylic acid-co-ethyl acrylate) 1:

1.

8. A solid dispersion according to any one of the preceding claims, obtainable by spray drying.

9. The solid dispersion according to any one of claims 1 to 7, obtainable by hot melt extrusion.

10. A particle consisting of a solid dispersion as defined in any one of the preceding claims.

11. A particle comprising a solid dispersion as defined in any one of claims 1 to 9.

12. A pharmaceutical preparation comprising a pharmaceutically acceptable carrier and the solid dispersion according to any one of claims 1 to 9.

13. A pharmaceutical preparation comprising a pharmaceutically acceptable carrier and the particles according to claim 10 or 11.

14. The formulation according to claim 12 or 13, wherein the formulation comprises 60 mg of ARN-509.

15. The formulation according to claim 12 or 13, wherein the formulation comprises 120 mg of ARN-509.

16. The formulation according to claim 12 or 13, wherein the formulation comprises 240 mg of ARN-509.

17. The formulation according to any one of claims 12 to 16, wherein the weight of the solid dispersion is 20 to 40% of the total weight of the formulation.

18. The formulation according to any one of claims 12-17, wherein the formulation is a tablet.

19. The formulation of claim 18, which is suitable for oral administration.

20. A method for preparing the solid dispersion according to claim 8, comprising the following steps: ARN-509 and poly(meth)acrylate copolymer are mixed in a suitable solvent, and the mixture is spray dried.

21. The process of claim 20, wherein the suitable solvent is a mixture of dichloromethane and methanol.

22. The method of claim 21, wherein the weight:weight ratio of dichloromethane to methanol in the mixture is 5:

5.

23. Use of the pharmaceutical preparation according to any one of claims 12 to 19 for preparing a medicament for treating prostate cancer.

24. The use according to claim 23, wherein the medicament is for oral administration.

25. A combination of a pharmaceutical formulation according to any one of claims 12 to 19 and another anticancer agent.

26. The combination according to claim 25, wherein the other anticancer agent is an androgen biosynthesis inhibitor.

27. The combination according to claim 25, wherein the other anticancer agent is abiraterone acetate.

28. The combination according to any one of claims 25 to 27, further comprising prednisone.

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