EA040494B1 - ANTI-CANCER COMPOSITIONS - Google Patents

Description

The present invention relates to ARN-509 pharmaceutical compositions capable of being administered to a mammal, in particular a human, suffering from an androgen receptor (AR)-associated disease or condition, in particular cancer, more specifically prostate cancer, including, without limitation, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, previously chemotherapy-naive metastatic castration-resistant prostate cancer, biochemically recurrent hormone-sensitive prostate cancer, or high-risk non-metastatic castration-resistant prostate cancer. In one aspect, these compositions contain a solid dispersion of ARN-509, a copolymer of poly(meth)acrylate and HPMCAS. In one aspect, a solid dispersion of ARN-509, a poly(meth)acrylate/HPMCAS copolymer can be obtained, in particular obtained by melt extrusion of a mixture comprising ARN-509, a poly(meth)acrylate/HPMCAS copolymer, and optionally subsequent milling of said extruded melt mixture. In one aspect, a solid dispersion of ARN-509, poly(meth)acrylate/HPMCAS copolymer can be prepared, in particular, by spray drying a mixture comprising ARN-509, poly(meth)acrylate/HPMCAS copolymer in a suitable solvent.

The solid dispersion of ARN-509, poly(meth)acrylate-HPMCAS copolymer can be further mixed with a pharmaceutically acceptable carrier into a pharmaceutical formulation, such formulation providing improved stability or improved shelf life. The composition of the present invention provides a rapid release of the drug. With the composition of the present invention, it is possible to reduce the drug burden on a patient, in particular a patient having cancer, and thus, compliance with the treatment regimen and treatment efficacy can be improved.

figures

Fig. 1 is an X-ray diffraction pattern for form B of ARN-509.

Fig. 2 - IR spectrum for Form B ARN-509.

Fig. 3 is a DSC (Differential Scanning Calorimetry) curve for ARN-509 Form B.

Detailed description

ARN-509 is a potent and specific androgen receptor (AR) antagonist. The mechanism of action of ARN-509 is to antagonize androgen receptor signaling through inhibition of AR nuclear translocation and DNA binding to androgen response elements.

Androgen-androgen receptor interactions have been suggested in a number of diseases or conditions such as androgen-dependent cancers, virilization in women, and acne, among others. Compositions that reduce the effect of androgens on androgen receptors and/or reduce androgen receptor concentrations are useful in the treatment of diseases or conditions in which androgen receptors play a role.

AR-associated diseases or conditions include, without limitation, benign prostatic hyperplasia, hirsutism, acne, prostate adenomas and neoplasias, benign or malignant androgen receptor-containing tumor cells, hyperhairiness, seborrhea, endometriosis, polycystic ovarian syndrome, androgenetic alopecia, hypogonadism, osteoporosis, spermatogenesis suppression, libido, wasting, anorexia, androgen maintenance therapy for age-related testosterone decline, prostate cancer, breast cancer, endometrial cancer, uterine cancer, hot flashes, Kennedy's disease, muscle atrophy and weakness, skin atrophy, rarefaction bones, anemia, atherosclerosis, cardiovascular disease, loss of energy, loss of well-being, type 2 diabetes, and accumulation of abdominal fat. Given the central role of AR in the development and progression of prostate cancer, ARN-509 can be used to treat cancer, in particular prostate cancer, including, without limitation, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, previously chemo-naive metastatic castration -resistant prostate cancer, biochemically recurrent hormone-sensitive prostate cancer, or high-risk non-metastatic castration-resistant prostate cancer.

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 α-N-methylbenzamide is currently in clinical development as a non-aqueous lipid solution filled into softgels each containing 30mg of ARN-509. The daily dose currently being investigated is 240 mg/day orally (or 8 softgels). When used, gel capsules containing ARN-509 have been found to have a shelf life of only 6 months and require cold chain storage.

An aspect of the invention relates to pharmaceutical formulations, in particular solid pharmaceutical formulations, more specifically ARN-509 solid pharmaceutical formulations for oral administration, wherein such formulations have improved stability, longer shelf life, rapid drug release, or reduced drug burden on the patient, in particular a patient with cancer. The pharmaceutical compositions of the present invention provide a means to increase compliance and treatment efficacy.

An aspect of the invention is a solid dispersion comprising ARN-509, a copolymer of poly(meth)acrylate and HPMCAS.

Copolymers derived from esters of acrylic and methacrylic acids (poly(meth)acrylates) are known in the industry as Eudragit®. Eudragit® is the trade name for a wide range of poly(meth)acrylate based copolymers. Various brands are available. In an aspect of the invention, Eudragit® in dispersions with ARN-509 is Eudragit® L 100-55 which contains an anionic copolymer based on methacrylic acid and ethyl acrylate (CAS No. 25212-88-8; chemical name/IUPAC name: poly(methacrylic acid-co-ethyl acrylate) 1:1) (Evonik Industries)). In an aspect of the invention, Eudragit® in ARN-509 dispersions is Eudragit® E 100, which is a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate (CAS No. 24938-16-7; IUPAC chemical name/name: poly(butyl methacrylate -co-(2-dimethylaminoethyl)methacrylate-somethylmethacrylate) 1:2:1) (Evonik Industries)). HPMCAS, or hydroxypropyl methylcellulose acetate succinate, or hypromellose acetate succinate (CAS number 71138-97-1), is a mixture of esters of acetic acid and monosuccinic acid with hydroxypropyl methylcellulose (IUPAC name: cellulose, 2-hydroxypropyl methyl ether, acetate, hydrogen butanedioate ). Various grades are available, which are distinguished based on the degree/ratio of substitution (acetyl content, succinoyl content) and particle size (micronized and granular). In an aspect of the invention, the HPMCAS in dispersion with ARN-509 is HPMCAS LG (granular) or HPMCAS LF (micronized) (Shin-Etsu Chemical Co., Ltd), in particular HPMCAS LG.

An aspect of the invention is a solid dispersion comprising ARN-509, a poly(meth)acrylate copolymer selected from Eudragit® L 100-55 and Eudragit® E 100, and HPMCAS.

An aspect of the invention is a solid dispersion comprising ARN-509, a poly(meth)acrylate copolymer selected from Eudragit® L 100-55 and Eudragit® E 100, and HPMCAS selected from HPMCAS LG and HPMCAS LF.

An aspect of the invention is a solid dispersion comprising:

a) ARN-509, Eudragit® E 100 and HPMCAS LG;

b) ARN-509, Eudragit® E 100 and HPMCAS LF;

c) ARN-509, Eudragit® L 100-55 and HPMCAS LG or

d) ARN-509, Eudragit® L 100-55 and HPMCAS LF.

An aspect of the invention is a solid dispersion consisting of ARN-509, a copolymer of poly(meth)acrylate and HPMCAS.

An aspect of the invention is a solid dispersion consisting of ARN-509, a poly(meth)acrylate copolymer selected from Eudragit® L 100-55 and Eudragit® E 100, and HPMCAS.

An aspect of the invention is a solid dispersion consisting of ARN-509, a poly(meth)acrylate copolymer selected from Eudragit® L 100-55 and Eudragit® E 100, and HPMCAS selected from HPMCAS LG and HPMCAS LF.

An aspect of the invention is a solid dispersion consisting of:

a) ARN-509, Eudragit® E 100 and HPMCAS LG;

b) ARN-509, Eudragit® E 100 and HPMCAS LF;

c) ARN-509, Eudragit® L 100-55 and HPMCAS LG; or

d) ARN-509, Eudragit® L 100-55 and HPMCAS LF. The preferred grade of the poly(meth)acrylate copolymer in solid dispersions of the invention is Eudragit® L 100-55.

The preferred HPMCAS grade in the solid dispersions of the invention is HPMCAS LG due to better and safer handling properties.

In an aspect of the invention, the weight ratio of ARN-509: (poly(meth)acrylate-HPMCAS copolymer) in the solid dispersion described herein ranges from 1:1 to 1:10, preferably from 1:1 to 1:5, more preferably 1:1 to 1:3 or 1:2 to 1:3. In an aspect of the invention, the weight ratio of ARN-509: (copolymer of poly(meth)acrylate and HPMCAS) is 1:2. In an aspect of the invention, the weight ratio of ARN-509: (copolymer of poly(meth)acrylate and HPMCAS) is 1:3. In aspect

- 2 040494 of the invention, the weight ratio of ARN-509: (Eudragit® L 100-55 and HPMCAS LG) is 1:2. In an aspect of the invention, the weight ratio of ARN-509: (Eudragit® L 100-55 and HPMCAS LG) is 1:3. In an aspect of the invention, the weight ratio of ARN-509: (Eudragit® E 100 and HPMCAS LG) is 1:2. In an aspect of the invention, the weight ratio of ARN-509: (Eudragit® E 100 and HPMCAS LG) is 1:3. In an aspect of the invention, the weight ratio of ARN-509: (Eudragit® L 100-55 and HPMCAS LF) is 1:2. In an aspect of the invention, the weight ratio of ARN-509: (Eudragit® L 100-55 and HPMCAS LF) is 1:3. In an aspect of the invention, the weight ratio of ARN-509: (Eudragit® E 100 and HPMCAS LF) is 1:2. In an aspect of the invention, the weight ratio of ARN-509: (Eudragit® E 100 and HPMCAS LF) is 1:3.

In an aspect of the invention, the weight ratio of poly(meth)acrylate copolymer to HPMCAS in the solid dispersion described herein ranges from 5:95 to 95:5, in particular from 10:90 to 90:10, more specifically from 25: 75 to 75:25. Preferably, the weight ratio of poly(meth)acrylate copolymer to HPMCAS in the solid dispersion described herein is 50:50.

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, a copolymer of poly(meth)acrylate and HPMCAS, in particular in which the weight ratio of ARN-509: (copolymer of poly(meth)acrylate and HPMCAS) is 1:2 or 1:3, more specifically in which the weight ratio of poly(meth)acrylate copolymer to HPMCAS is in the range of 25:75 to 75:25, or is 25:75, 50:50 or 75:25, preferably 50:50.

An aspect of the invention is a particle consisting of a solid dispersion comprising:

a) ARN-509, Eudragit® E 100 and HPMCAS LG, in particular in which the weight ratio of ARN-509: (Eudragit® E 100 and HPMCAS LG) is 1:2 or 1:3, more specifically in which the weight ratio of Eudragit® E 100: HPMCAS LG is in the range of 25:75 to 75:25 or is 25:75, 50:50 or 75:25, preferably 50:50;

b) ARN-509, Eudragit® E 100 and HPMCAS LF, in particular in which the weight ratio of ARN-509: (Eudragit® E 100 and HPMCAS LF) is 1:2 or 1:3, more specifically in which the weight ratio of Eudragit® E 100: HPMCAS LF ranges from 25:75 to 75:25 or is 25:75, 50:50 or 75:25, preferably 50:50;

c) ARN-509, Eudragit® L 100-55 and HPMCAS LG, in particular in which the weight ratio of ARN509: (Eudragit® L 100-55 and HPMCAS LG) is 1:2 or 1:3, more specifically in which the weight ratio Eudragit® L 100-55: HPMCAS LG is in the range of 25:75 to 75:25 or 25:75, 50:50 or 75:25, preferably 50:50; or

d) ARN-509, Eudragit® L 100-55 and HPMCAS LF, in particular in which the weight ratio of ARN509: (Eudragit® L 100-55 and HPMCAS LF) is 1:2 or 1:3, more specifically in which the weight ratio Eudragit® L 100-55: HPMCAS LF ranges from 25:75 to 75:25 or is 25:75, 50:50 or 75:25, preferably 50:50.

An aspect of the invention is a particle consisting of a solid dispersion consisting of ARN-509, a copolymer of poly(meth)acrylate and HPMCAS, in particular in which the weight ratio of ARN509: (copolymer of poly(meth)acrylate and HPMCAS) is 1:2 or 1 :3, more specifically wherein the weight ratio of poly(meth)acrylate copolymer to HPMCAS is in the range of 25:75 to 75:25, or 25:75, 50:50 or 75:25, preferably 50:50.

An aspect of the invention is a particle consisting of a solid dispersion consisting of:

a) ARN-509, Eudragit® E 100 and HPMCAS LG, in particular in which the weight ratio of ARN-509: (Eudragit® E 100 and HPMCAS LG) is 1:2 or 1:3, more specifically in which the weight ratio of Eudragit® E 100: HPMCAS LG is in the range of 25:75 to 75:25 or is 25:75, 50:50 or 75:25, preferably 50:50;

b) ARN-509, Eudragit® E 100 and HPMCAS LF, in particular in which the weight ratio of ARN-509: (Eudragit® E 100 and HPMCAS LF) is 1:2 or 1:3, more specifically in which the weight ratio of Eudragit® E 100: HPMCAS LF ranges from 25:75 to 75:25 or is 25:75, 50:50 or 75:25, preferably 50:50;

c) ARN-509, Eudragit® L 100-55 and HPMCAS LG, in particular in which the weight ratio of ARN509: (Eudragit® L 100-55 and HPMCAS LG) is 1:2 or 1:3, more specifically in which the weight ratio Eudragit® L 100-55: HPMCAS LG is in the range of 25:75 to 75:25 or 25:75, 50:50 or 75:25, preferably 50:50; or

d) ARN-509, Eudragit® L 100-55 and HPMCAS LF, in particular in which the weight ratio of ARN509: (Eudragit® L 100-55 and HPMCAS LF) is 1:2 or 1:3, more specifically in which the weight ratio Eudragit® L 100-55: HPMCAS LF ranges from 25:75 to 75:25 or is 25:75, 50:50 or 75:25, preferably 50:50.

An aspect of the invention is a particle comprising a solid dispersion described in the previous parts of this document.

- 3 040494

An aspect of the invention is a particle comprising a solid dispersion comprising

ARN-509, a copolymer of poly(meth)acrylate and HPMCAS, in particular in which the weight ratio of ARN-509 is:

(copolymer of poly(meth)acrylate and HPMCAS) is 1:2 or 1:3, more specifically in which the weight ratio of the copolymer of poly(meth)acrylate to HPMCAS is in the range from 25:75 to 75:25 or is 25:75, 50:50 or 75:25, preferably 50:50.

An aspect of the invention is a particle comprising a solid dispersion comprising:

a) ARN-509, Eudragit® E 100 and HPMCAS LG, in particular in which the weight ratio of ARN-509: (Eudragit® E 100 and HPMCAS LG) is 1:2 or 1:3, more specifically in which the weight ratio of Eudragit® E 100: HPMCAS LG is in the range of 25:75 to 75:25 or is 25:75, 50:50 or 75:25, preferably 50:50;

b) ARN-509, Eudragit® E 100 and HPMCAS LF, in particular in which the weight ratio of ARN-509: (Eudragit® E 100 and HPMCAS LF) is 1:2 or 1:3, more specifically in which the weight ratio of Eudragit® E 100: HPMCAS LF ranges from 25:75 to 75:25 or is 25:75, 50:50 or 75:25, preferably 50:50;

c) ARN-509, Eudragit® L 100-55 and HPMCAS LG, in particular in which the weight ratio of ARN509: (Eudragit® L 100-55 and HPMCAS LG) is 1:2 or 1:3, more specifically in which the weight ratio Eudragit® L 100-55: HPMCAS LG is in the range of 25:75 to 75:25 or 25:75, 50:50 or 75:25, preferably 50:50; or

d) ARN-509, Eudragit® L 100-55 and HPMCAS LF, in particular in which the weight ratio of ARN509: (Eudragit® L 100-55 and HPMCAS LF) is 1:2 or 1:3, more specifically in which the weight ratio Eudragit® L 100-55: HPMCAS LF ranges from 25:75 to 75:25 or is 25:75, 50:50 or 75:25, preferably 50:50.

An aspect of the invention is a particle comprising a solid dispersion consisting of ARN-509, a copolymer of poly(meth)acrylate and HPMCAS, in particular in which the weight ratio of ARN509: (copolymer of poly(meth)acrylate and HPMCAS) is 1:2 or 1: 3, more specifically wherein the weight ratio of poly(meth)acrylate copolymer to HPMCAS is in the range of 25:75 to 75:25, or 25:75, 50:50 or 75:25, preferably 50:50.

An aspect of the invention is a particle comprising a solid dispersion consisting of:

a) ARN-509, Eudragit® E 100 and HPMCAS LG, in particular in which the weight ratio of ARN-509: (Eudragit® E 100 and HPMCAS LG) is 1:2 or 1:3, more specifically in which the weight ratio of Eudragit® E 100: HPMCAS LG is in the range of 25:75 to 75:25 or is 25:75, 50:50 or 75:25, preferably 50:50;

b) ARN-509, Eudragit® E 100 and HPMCAS LF, in particular in which the weight ratio of ARN-509: (Eudragit® E 100 and HPMCAS LF) is 1:2 or 1:3, more specifically in which the weight ratio of Eudragit® E 100: HPMCAS LF ranges from 25:75 to 75:25 or is 25:75, 50:50 or 75:25, preferably 50:50;

c) ARN-509, Eudragit® L 100-55 and HPMCAS LG, in particular in which the weight ratio of ARN509: (Eudragit® L 100-55 and HPMCAS LG) is 1:2 or 1:3, more specifically in which the weight ratio Eudragit® L 100-55: HPMCAS LG is in the range of 25:75 to 75:25 or 25:75, 50:50 or 75:25, preferably 50:50; or

d) ARN-509, Eudragit® L 100-55 and HPMCAS LF, in particular in which the weight ratio of ARN509: (Eudragit® L 100-55 and HPMCAS LF) is 1:2 or 1:3, more specifically in which the weight ratio Eudragit® L 100-55: HPMCAS LF ranges from 25:75 to 75:25 or is 25:75, 50:50 or 75:25, preferably 50:50.

In an aspect of the invention, the particles described herein can be obtained, in particular, obtained by melt extrusion of a mixture comprising ARN-509, a copolymer of poly(meth)acrylate and HPMCAS, and subsequent milling of said melt-extruded mixture. In an aspect, the particles described herein can be made, specifically made by melt extrusion of a mixture consisting of ARN-509, a poly(meth)acrylate copolymer and HPMCAS, and then milling said melt extruded mixture. In an aspect, the weight ratio of ARN509: (poly(meth)acrylate-HPMCAS copolymer) is 1:2 or 1:3. In an aspect, the weight ratio of poly(meth)acrylate copolymer: HPMCAS is in the range of 25:75 to 75:25, or 25:75, 50:50 or 75:25, preferably 50:50.

In an aspect of the invention, the particles described herein can be obtained, in particular obtained, by melt extrusion of a mixture comprising ARN-509, Eudragit® L 100-55 and HPMCAS LG, and subsequent milling of said melt-extruded mixture. In an aspect, the particles described herein can be obtained, in particular obtained, by melt extrusion of a mixture consisting of ARN-509, Eudragit® L 100-55 and HPMCAS LG, and subsequent milling of said melt-extruded mixture. In an aspect, the weight ratio of ARN-509: (Eudragit® L 100-55 and HPMCAS LG) is 1:2 or 1:3. In the aspect, the weight ratio of Eudragit® L 100- 4 040494

55: HPMCAS LG is in the range of 25:75 to 75:25, or is 25:75, 50:50 or 75:25, preferably 50:50.

In an aspect of the invention, the particles described herein can be obtained, in particular obtained, by melt extrusion of a mixture comprising ARN-509, Eudragit® E 100 and HPMCAS LG, and subsequent milling of said melt-extruded mixture. In an aspect, the particles described herein can be obtained, in particular obtained, by melt extrusion of a mixture consisting of ARN-509, Eudragit® E 100 and HPMCAS LG, and subsequent milling of said melt-extruded mixture. In an aspect, the weight ratio of ARN-509: (Eudragit® E 100 and HPMCAS LG) is 1:2 or 1:3. In an aspect, the weight ratio of Eudragit® E 100: HPMCAS LG is in the range of 25:75 to 75:25 or 25:75, 50:50 or 75:25, preferably 50:50.

In an aspect of the invention, the particles described herein can be obtained, in particular obtained, by melt extrusion of a mixture comprising ARN-509, Eudragit® L 100-55 and HPMCAS LF, and subsequent milling of said melt-extruded mixture. In an aspect, the particles described herein can be obtained, in particular obtained, by melt extrusion of a mixture consisting of ARN-509, Eudragit® L 100-55 and HPMCAS LF, and subsequent milling of said melt-extruded mixture. In an aspect, the weight ratio of ARN-509: (Eudragit® L 100-55 and HPMCAS LF) is 1:2 or 1:3. In an aspect, the weight ratio of Eudragit® L 10055: HPMCAS LF ranges from 25:75 to 75:25 or is 25:75, 50:50 or 75:25, preferably 50:50.

In an aspect of the invention, the particles described herein can be obtained, in particular obtained, by melt extrusion of a mixture comprising ARN-509, Eudragit® E 100 and HPMCAS LF, and subsequent milling of said melt-extruded mixture. In an aspect, the particles described herein can be obtained, in particular, obtained by melt extrusion of a mixture consisting of ARN-509, Eudragit® E 100 and HPMCAS LF, and subsequent milling of said melt-extruded mixture. In an aspect, the weight ratio of ARN-509: (Eudragit® E 100 and HPMCAS LF) is 1:2 or 1:3. In an aspect, the weight ratio of Eudragit® E 100: HPMCAS LF ranges from 25:75 to 75:25 or is 25:75, 50:50 or 75:25, preferably 50:50.

In an aspect of the invention, the particles described herein can be obtained, in particular, obtained by spray drying a mixture comprising ARN-509, a copolymer of poly(meth)acrylate and HPMCAS in a suitable solvent. In an aspect, the particles described herein can be obtained, in particular obtained, by spray drying a mixture consisting of ARN-509, a copolymer of poly(meth)acrylate and HPMCAS in a suitable solvent. In an aspect, the weight ratio of ARN-509: (copolymer of poly(meth)acrylate and HPMCAS) is 1:2 or 1:3. In an aspect, the weight ratio of poly(meth)acrylate copolymer: HPMCAS is in the range of 25:75 to 75:25, or 25:75, 50:50 or 75:25, preferably 50:50.

In an aspect of the invention, the particles described herein can be obtained, in particular obtained by spray drying a mixture comprising ARN-509, Eudragit® L 100-55 and HPMCAS LG in a suitable solvent. In an aspect, the particles described herein can be obtained, in particular obtained by spray drying a mixture consisting of ARN-509, Eudragit® L 100-55 and HPMCAS LG in a suitable solvent. In an aspect, the weight ratio of ARN-509: (Eudragit® L 100-55 and HPMCAS LG) is 1:2 or 1:3. In an aspect, the weight ratio of Eudragit® L 100-55: HPMCAS LG is in the range of 25:75 to 75:25 or 25:75, 50:50 or 75:25, preferably 50:50.

In an aspect of the invention, the particles described herein can be obtained, in particular obtained by spray drying a mixture comprising ARN-509, Eudragit® E 100 and HPMCAS LG in a suitable solvent. In an aspect, the particles described herein can be obtained, in particular obtained by spray drying a mixture consisting of ARN-509, Eudragit® E 100 and HPMCAS LG in a suitable solvent. In an aspect, the weight ratio of ARN-509: (Eudragit® E 100 and HPMCAS LG) is 1:2 or 1:3. In an aspect, the weight ratio of Eudragit® E 100: HPMCAS LG is in the range of 25:75 to 75:25 or 25:75, 50:50 or 75:25, preferably 50:50.

In an aspect of the invention, the particles described herein can be obtained, in particular obtained by spray drying a mixture comprising ARN-509, Eudragit® L 100-55 and HPMCAS LF in a suitable solvent. In an aspect, the particles described herein can be obtained, in particular obtained by spray drying a mixture consisting of ARN-509, Eudragit® L 100-55 and HPMCAS LF in a suitable solvent. In an aspect, the weight ratio of ARN-509: (Eudragit® L 100-55 and HPMCAS LF) is 1:2 or 1:3. In an aspect, the weight ratio of Eudragit® L 100-55: HPMCAS LF ranges from 25:75 to 75:25 or is 25:75, 50:50 or 75:25, preferably 50:50.

In an aspect of the invention, the particles described herein can be obtained, in particular

- 5 040494 is obtained by spray drying a mixture comprising ARN-509, Eudragit® E 100 and HPMCAS LF in a suitable solvent. In an aspect, the particles described herein can be obtained, in particular obtained by spray drying a mixture consisting of ARN-509, Eudragit® E 100 and HPMCAS LF in a suitable solvent. In an aspect, the weight ratio of ARN-509: (Eudragit® E 100 and HPMCAS LF) is 1:2 or 1:3. In an aspect, the weight ratio of Eudragit® E 100: HPMCAS LF ranges from 25:75 to 75:25 or is 25:75, 50:50 or 75:25, preferably 50:50.

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 a particle, in particular the particles 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, a poly(meth)acrylate copolymer and HPMCAS. 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, a poly(meth)acrylate copolymer and HPMCAS. In an aspect, the weight ratio of ARN-509: (copolymer of poly(meth)acrylate and HPMCAS) is 1:2 or 1:3. In an aspect, the weight ratio of poly(meth)acrylate copolymer: HPMCAS is in the range of 25:75 to 75:25, or 25:75, 50:50 or 75:25, preferably 50:50.

An aspect of the invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a solid dispersion, said solid dispersion comprising ARN-509, Eudragit® L 100-55 and HPMCAS LG. 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, Eudragit® L 100-55 and HPMCAS LG. In an aspect, the weight ratio of ARN509: (Eudragit® L 100-55 and HPMCAS LG) is 1:2 or 1:3. In an aspect, the weight ratio of Eudragit® L 100-55: HPMCAS LG ranges from 25:75 to 75:25 or is 25:75, 50:50 or 75:25, preferably 50:50.

An aspect of the invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a solid dispersion, said solid dispersion comprising ARN-509, Eudragit® E 100 and HPMCAS LG. 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, Eudragit® E 100 and HPMCAS LG. In an aspect, the weight ratio of ARN-509: (Eudragit® E 100 and HPMCAS LG) is 1:2 or 1:3. In an aspect, the weight ratio of Eudragit® E 100: HPMCAS LG is in the range of 25:75 to 75:25 or 25:75, 50:50 or 75:25, preferably 50:50.

An aspect of the invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a solid dispersion, said solid dispersion comprising ARN-509, Eudragit® L 100-55 and HPMCAS LF. 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, Eudragit® L 100-55 and HPMCAS LF. In an aspect, the weight ratio of ARN509: (Eudragit® L 100-55 and HPMCAS LF) is 1:2 or 1:3. In an aspect, the weight ratio of Eudragit® L 100-55: HPMCAS LF ranges from 25:75 to 75:25 or is 25:75, 50:50 or 75:25, preferably 50:50.

An aspect of the invention is a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a solid dispersion, said solid dispersion comprising ARN-509, Eudragit® E 100 and HPMCAS LF. 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, Eudragit® E 100 and HPMCAS LF. In an aspect, the weight ratio of ARN-509: (Eudragit® E 100 and HPMCAS LF) is 1:2 or 1:3. In an aspect, the weight ratio of Eudragit® E 100: HPMCAS LF ranges from 25:75 to 75:25 or is 25:75, 50:50 or 75:25, preferably 50:50.

An aspect of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a particle, in particular particles comprising a solid dispersion, said solid dispersion comprising ARN-509, a copolymer of poly(meth)acrylate and HPMCAS. An aspect of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a particle, in particular particles comprising a solid dispersion, said solid dispersion consisting of ARN-509, a copolymer of poly(meth)acrylate and HPMCAS. In an aspect, the weight ratio of ARN-509: (copolymer of poly(meth)acrylate and HPMCAS) is 1:2 or 1:3. In an aspect, the weight ratio of poly(meth)acrylate copolymer: HPMCAS is in the range of 25:75 to 75:25, or 25:75, 50:50 or 75:25, preferably 50:50. In an aspect, the particle can be obtained, in particular obtained, by spray drying, as described herein. In the aspect, this particle

- 6 040494 can be obtained, in particular obtained, by melt extrusion, as described in this document. In an aspect, the poly(meth)acrylate copolymer is selected from Eudragit® L 100-55 and Eudragit® E 100. In an aspect, HPMCAS is selected from HPMCAS LG and HPMCAS LF.

An aspect of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a particle, in particular particles, consisting of a solid dispersion, said solid dispersion comprising ARN-509, a copolymer of poly(meth)acrylate and HPMCAS. An aspect of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a particle, in particular particles, consisting of a solid dispersion, said solid dispersion consisting of ARN-509, a copolymer of poly(meth)acrylate and HPMCAS. In an aspect, the weight ratio of ARN-509: (copolymer of poly(meth)acrylate and HPMCAS) is 1:2 or 1:3. In an aspect, the weight ratio of poly(meth)acrylate copolymer: HPMCAS is in the range of 25:75 to 75:25, or 25:75, 50:50 or 75:25, preferably 50:50. In an aspect, the particle can be obtained, in particular obtained, by spray drying, as described herein. In an aspect, this particle can be obtained, in particular obtained, by melt extrusion, as described herein. In an aspect, the poly(meth)acrylate copolymer is selected from Eudragit® L 100-55 and Eudragit® E 100. In an aspect, HPMCAS is selected from HPMCAS LG and HPMCAS LF.

An aspect of the invention is the solid dispersion described herein, in which any surfactant is absent.

An aspect of the invention is the particle described herein in which any surfactant is absent.

An aspect of the invention is the pharmaceutical composition described herein, in which any surfactant is absent.

An aspect of the invention is the solid dispersion described herein in which ARN-509 is the only active pharmaceutical ingredient.

An aspect of the invention is the particle described herein, in which ARN-509 is the only active pharmaceutical ingredient.

An aspect of the invention is the pharmaceutical composition described herein, in which ARN-509 is the only active pharmaceutical ingredient.

In the solid dispersions or particles or pharmaceutical formulations described herein, ARN-509 is present in base form or as a pharmaceutically acceptable addition salt, in particular as a pharmaceutically acceptable acid addition salt. Preferably ARN-509 is present in base form.

The pharmaceutically acceptable addition salts are contemplated to contain 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 inorganic acids, including but not limited to hydrohalic acids such as hydrochloric acid, hydrobromic acid, and the like; sulfuric acid; nitric acid; phosphoric acid; metaphosphoric acid and the like; or organic acids, including, without limitation, 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 acid malic acid mandelic acid tartaric acid acid, 4-methylbenzenesulfonic acid, 2-naphthalenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, hexanoic acid, cyclopentanepropionic acid, 3-(4-hydroxybenzoyl)benzoic acid, 4-methylbicyclo-[ 2.2.2]oct-2-en-1-carboxylic acid, glucoheptonic acid, tertiary butylacetic acid acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid and the like.

Conversely, said salt forms can be converted by treatment with an acceptable base to the free base form.

Also included are the hydrates, solvent addition forms, and mixtures thereof that ARN-509 and its salts can form. Examples of such forms are, for example, hydrates, alcoholates, and the like, such as ethanolate.

In general, doses used to treat an adult will typically be in the range of 0.01 to 5000 mg per day. In one aspect, doses used to treat an adult human are from about 1 to about 1000 mg per day. In another aspect, doses used to treat an adult human are from about 100 to about 500 mg per day. In another aspect, the dose used to treat an adult is 240 mg per day. As is known to those skilled in the art, the precise dose 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 drugs, which the subject can accept. In addition, it is obvious that these daily amounts can be reduced or increased depending on the response of the subject under treatment, and/or on the judgment of the physician prescribing ARN-509. Thus, the doses given herein are only suggestions and do not limit the scope or application of the invention in any way. In an aspect of the invention, the daily dose is conveniently presented as a single dose or divided doses that are administered simultaneously (or over a short period of time) or at acceptable intervals, for example, as two, three, four or more dose portions per day. In an aspect of the invention, the daily dose is administered as 4 divided doses. In an aspect of the invention, the daily dose is administered as 4 divided doses administered simultaneously (or over a short period of time). In an aspect of the invention, the daily dose is administered as 3 divided doses. In an aspect of the invention, the daily dose is administered as 3 divided doses administered simultaneously (or over a short period of time). In an aspect of the invention, the daily dose is administered as 2 divided doses. In an aspect of the invention, the daily dose is administered as 2 divided doses administered simultaneously (or over a short period of time).

In an aspect of the invention, the pharmaceutical composition contains 240 mg of ARN-509.

In an aspect of the invention, the pharmaceutical composition contains 120 mg of ARN-509.

In an aspect of the invention, the pharmaceutical composition contains 60 mg of ARN-509.

In an aspect of the invention, the pharmaceutical composition contains 240 mg of ARN-509. The pharmaceutical composition is administered once a day.

In an aspect of the invention, the pharmaceutical composition contains 120 mg of ARN-509. Two of these formulations are administered daily, preferably simultaneously (or within a short period of time).

In an aspect of the invention, the pharmaceutical composition contains 60 mg of ARN-509. Four of these formulations are administered daily, preferably simultaneously (or within a short period of time).

The composition of the present invention can also be used in combination with another anti-cancer agent, in particular another agent for the treatment of prostate cancer, more specifically an inhibitor of androgen biosynthesis that inhibits 17a-hydroxylase/C17,20-lyase (CYP17), in particular abiraterone acetate. . The composition of the present invention can be further combined with prednisone.

Thus, the present invention also relates to a combination of a pharmaceutical composition according to the present invention and another anticancer agent, in particular another agent for the treatment of prostate cancer, more specifically an androgen biosynthesis inhibitor that inhibits 17a-hydroxylase/C17,20-lyase (CYP17 ), in particular abiraterone acetate.

Said combination may additionally contain prednisone.

The term solid dispersion means a system in solid state (as opposed to liquid or gaseous state) comprising at least two components, in which one component is dispersed more or less uniformly in the other component or components. If said dispersion of the components is such that the entire system is chemically and physically uniform or homogeneous or consists of a single phase as defined by thermodynamics, such a solid dispersion is referred to herein as a solid solution. Solid solutions are preferred physical systems because the components in them are predominantly biologically readily available to the organisms to which they are administered. This advantage can probably be explained by the ease with which these solid solutions can form liquid solutions when in contact with a fluid such as gastric juice. The ease of dissolution can be explained at least in part by the fact that the energy required to dissolve the components in solid solution is less than the energy required to dissolve the components in the crystalline or microcrystalline solid phase.

The term solid dispersion also includes dispersions that are less homogeneous than solid solutions. Such dispersions are not chemically and physically homogeneous or contain more than one phase. For example, the term solid dispersion also refers to a solid state system comprising at least two components (a) (active ingredient) and (b) (polymer (copolymer of poly(meth)acrylate and HPMCAS)) and having domains or small regions, in which amorphous, microcrystalline or crystalline (a), or amorphous, microcrystalline or crystalline (b), or both are dispersed more or less uniformly in another phase comprising (b) or (a), or a solid solution comprising (a) and (b). These domains are areas that are clearly marked with some physical feature, are small in size compared to the system as a whole, and are uniformly and randomly distributed throughout the system.

The solid dispersions or particles described herein, in which ARN-509 is in the non-crystalline phase, are preferred because they have a higher velocity.

- 8 040494 dissolution than those in which ARN-509 is in microcrystalline or crystalline form.

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

In an aspect of the invention, ARN-509 is present in the solid dispersions described herein in amorphous form.

In an aspect of the invention, the solid dispersion described herein is a solid solution.

There are various techniques for preparing the solid dispersions of the invention, including melt extrusion (eg, hot melt extrusion), spray drying, and solution evaporation, in particular hot melt extrusion and spray drying, with spray drying being preferred.

Particles according to the invention can be obtained by, firstly, obtaining a solid dispersion of the components, and subsequently, optionally grinding or grinding said dispersion.

The melt extrusion process includes the following steps:

a) mixing ARN-509, poly(meth)acrylate copolymer and HPMCAS;

b) optionally mixing the additives with the mixture thus obtained;

c) heating the mixture thus obtained until a homogeneous melt is obtained;

d) passing the melt thus obtained through one or more orifices, and

e) cooling the melt until it solidifies.

The terms melt and melt not only mean a change 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 a more or less homogeneous incorporation of one component of the mixture into another is possible. In particular cases, one component melts and the other component(s) dissolve(s) in the melt, thus forming a solution which, upon cooling, can form a solid solution having advantageous dissolution properties.

One important melt extrusion parameter is the temperature at which the melt extruder operates. For the melt extrusion process of the present invention, the operating temperature is preferably between about 160 and about 190°C, more preferably between about 160 and 175°C. The lower temperature limit is determined by the point at which ARN-509 still melts during extrusion with a given set of extrusion conditions. If the ARN-509 is not completely melted, the extrudate may not provide the desired bioavailability. If the viscosity of the mixture is too high, the melt extrusion process will be difficult. At higher temperatures, the components may decompose to an unacceptable level. One skilled in the art will be able to recognize the most appropriate temperature range for the application.

Performance is also important because components can start to decompose if they remain in contact with the heating element for too long.

It should be understood that a person skilled in the art can optimize the parameters of the melt extrusion process within the above ranges. Operating temperatures will also be determined by the type of extruder or the type of configuration within the extruder being used. Most of the energy required 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 can also provide a significant amount of energy to the mixture and help form a homogeneous melt of the components.

The person skilled in the art will be able to recognize the most suitable extruder, such as, for example, a single screw extruder, a twin screw extruder, or a multiple screw extruder, to obtain the object of the present invention.

Spray drying a mixture of components in a suitable solvent also makes it possible to obtain a solid dispersion of said components or particles comprising or consisting of a solid dispersion of said components, and may be a suitable alternative to the melt extrusion process, in particular in cases where a poly(meth)acrylate copolymer or HPMCAS is not stable enough to withstand extrusion conditions, and when the solvent residue can be effectively removed from the solid dispersion. Another possibility is to prepare a mixture of the components in a suitable solvent, pour said mixture onto a large surface so as to form a thin film, and evaporate the solvent therefrom.

Solvents suitable for spray drying can be any organic solvent in which ARN-509 can be mixed, a poly(meth)acrylate copolymer, such as Eudragit® L 100-55 or Eudragit® E 100, and HPMCAS, such as HPMCAS LG or HPMCAS LF. In an aspect of the invention, the boiling point of the solvent is below the Tg (glass transition temperature) of the solid dispersion. In addition, the solvent must have relatively low toxicity and be removed from the dispersion to a level that is acceptable in accordance with International Committee for Harmonization (ICH) guidelines. To remove the solvent to this level, a post-drying step, such as tray drying after a spray drying process, may be required. 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 isobutyl ketone; esters such as ethyl acetate and propyl acetate; and various other solvents such as acetonitrile, dichloromethane, toluene and 1,1,1-trichloroethane. Less volatile solvents such as dimethylacetamide or dimethylsulfoxide can also be used. In an aspect of the invention, the solvent suitable for spray drying is a mixture of solvents. In an aspect of the invention, the spray drying solvent is a mixture of alcohol and acetone, in particular a mixture of methanol and acetone, more particularly a mixture of methanol and acetone 1:9 (wt:wt). In an aspect of the invention, the spray drying solvent is a mixture of alcohol and dichloromethane, in particular a mixture of methanol and dichloromethane, more specifically a mixture of methanol and dichloromethane 6:4 (wt:wt) or 5:5 (wt:wt), preferably 5:5 (wt:wt).

The particles described herein have a d ⁵⁰ 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. The particles obtained by spray drying preferably have a d ⁵⁰ value falling in the range of about 20 to about 100 microns, in particular a d ⁵⁰ value falling in the range of about 20 to about 70 microns, more specifically a d ⁵⁰ value of about 20 microns, 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.

As used herein, the term d ⁵⁰ has its common meaning known to the person skilled in the art and can be measured by particle size measurement techniques known in the art, such as, for example, sediment flow field fractionation, photon correlation spectroscopy, laser diffraction or disc centrifugation. The d ⁵⁰ value referred to herein may refer to particle volume distributions. In this case, the term d ⁵⁰ value of 50 microns means that at least 50% of the volume of the particles has a particle size of less than 50 microns. The same applies to other mentioned particle sizes. Similarly, the particle size d ⁵⁰ may refer to the mass distributions of the particles. In this case, the term d ⁵⁰ value of 50 microns means that at least 50% of the mass of the particles has a particle size of less than 50 microns. The same applies to other mentioned particle sizes. As a rule, the volume and mass distributions lead to the same or almost the same value for the average particle size.

Particle size can be an important factor in determining tableting speed, in particular the flowability and thus the large scale production processability of a particular dosage form or formulation, and the quality of the final product. For example, for capsules, the particle size may preferably range from about 100 to about 1500 microns (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 cause sticking on the tablet punch and processability problems.

The particles or solid dispersions described herein may further contain one or more pharmaceutically acceptable excipients such as, for example, plasticizers, flavoring agents, coloring agents, preservatives, and the like. Especially in the case of production by hot melt extrusion, said excipients should not be heat sensitive, in other words they should not show any significant degradation or decomposition at the operating temperature of the melt extruder.

Acceptable plasticizers are pharmaceutically acceptable and include low molecular weight polyhydric alcohols 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 of less than 1000 g/mol; polypropylene glycols having a molecular weight of less 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 glycolate; and amines such as monoethanolamine, diethanolamine, triethanolamine, monoisopropanolamine; triethylenetetramine, 2-amino-2-methyl-1,3-propanediol, and the like. Of these, low molecular weight polyethylene glycols, ethylene glycol, low molecular weight polypropylene glycols, and especially propylene glycol are preferred.

In an aspect of the invention, the particles or solid dispersions described herein do not contain a plasticizer.

Solid dispersions or particles of the present invention can be used to prepare

- 10 040494 pharmaceutical formulations comprising a therapeutically effective amount of ARN-509. While pharmaceutical formulations for oral administration such as tablets and capsules are primarily contemplated, the solid dispersions or particles of the present invention can also be used to prepare pharmaceutical formulations, for example for rectal administration. Preferred formulations are formulations capable of being administered orally in the form of a tablet. They can be formed by conventional tableting techniques with commonly used ingredients or excipients (pharmaceutically acceptable carrier) and by conventional tableting equipment. To facilitate swallowing of such compositions by mammals, it is an advantage to give the compositions, in particular tablets, an acceptable form. The film coating on the tablet may further contribute to the ease with which it can be swallowed.

The compositions of the invention, in particular tablets, may include one or more commonly used excipients (pharmaceutically acceptable carrier) such as disintegrants, diluents, fillers, binders, buffering agents, lubricants, glidants, thickeners, sweeteners, flavors and colors. Some excipients can perform multiple functions. Preferably, the compositions of the present invention include a disintegrant, a diluent or filler, a lubricant and a glidant.

Acceptable disintegrators are those having a high coefficient of expansion. Examples of these are hydrophilic, insoluble or slightly water-soluble cross-linked polymers such as crospovidone (cross-linked polyvinylpyrrolidone) and croscarmellose sodium (cross-linked sodium carboxymethyl cellulose). The amount of disintegrant in tablets according to the present invention may conveniently range from about 3% to about 15% (w/w) and preferably range from about 3% to about 7%, in particular about 5% ( wt./wt.). Since disintegrants by their nature result in sustained release formulations when used in high volume, diluting them with an inert substance called a diluent or excipient is an advantage.

A variety of materials can be used as diluents or fillers. Examples are lactose monohydrate, lactose anhydrous, sucrose, dextrose, mannitol, sorbitol, starch, cellulose (e.g., microcrystalline cellulose (Avicel™), silicified microcrystalline cellulose), calcium phosphate dihydrate or anhydrous, and other substances known in the art and their mixtures (eg, spray-dried mixture of lactose monohydrate (75%) with microcrystalline cellulose (25%), which is commercially available as Microcelac™). Microcrystalline cellulose and silicified microcrystalline cellulose are preferred. The amount of diluent or excipient in tablets may conveniently range from about 20% to about 70% (w/w) and preferably range from about 55% to about 60% (w/w).

Lubricants and glidants can be used in the manufacture of certain dosage forms and are commonly used in the manufacture of 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 silica, colloidal anhydrous silica talc, mixtures thereof, and other substances known in the art. Lubricants of interest are magnesium stearate and mixtures of magnesium stearate with colloidal silicon dioxide. The preferred lubricant is magnesium stearate. The preferred glidant is colloidal anhydrous silica.

Glidants essentially constitute from 0.2 to 7.0% of the total weight of the tablet, in particular from 0.5 to 1.5%, more specifically from 1 to 1.5% (w/w).

Lubricants essentially constitute from 0.2 to 7.0% of the total weight of the tablet, in particular from 0.2 to 1%, more specifically from 0.5 to 1% (w/w).

Other excipients such as coloring agents and pigments can also be added to the compositions of the invention. Coloring agents and pigments include titanium dioxide and food acceptable colorants. The coloring agent is an optional ingredient in the composition of the invention, but when used, the coloring agent may be present in an amount of up to 3.5% based on the total weight of the tablet.

Flavorings are optional in the formulation and may be selected from synthetic fragrance oils and scented aromatics or natural oils, extracts from leaves, flowers, fruits, and the like. plants and their combinations. They may include cinnamon oil, wintergreen oil, peppermint oil, bay oil, anise oil, eucalyptus, thyme oil. Other flavors include vanillin, citrus oils including lemon, orange, grape, lime and grapefruit, and fruit essences including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot. etc. The amount of flavoring may depend on a number of factors, including the desired organoleptic effect. As such, the flavoring agent is present in an amount of from about 0 to about 3% (w/w).

As is known in the art, tablet blends may be dry granulated or wet granulated prior to tabletting. Otherwise, the tableting process as such is standard and is easily accomplished by forming a tablet from the desired composition or mixture of ingredients into a suitable form using a conventional tablet press.

Tablets of the present invention may optionally be film-coated, for example to improve taste, ease of swallowing and elegant appearance. Many suitable polymeric film coating materials are known in the art. The preferred film coating material is Opadry II 85F210036 green. Other suitable film-forming polymers may also be used in the present invention, including hydroxypropyl cellulose, hydroxypropyl methyl cellulose (HPMC), especially HPMC 2910 5 mPa-s, and acrylate-methacrylate copolymers. In addition to the film-forming polymer, the film coating may further comprise a plasticizer (eg propylene glycol) and optionally a pigment (eg titanium dioxide). The film coating slurry may also contain talc as a release agent. In tablets according to the invention, the film coating by weight is preferably about 3% (w/w) or less of the total weight of the tablet.

Preferred formulations are formulations in which the weight of the particles or solid dispersions described herein is in the range of 20 to 40%, in particular 30 to 40% of the total weight of the composition.

The present invention further relates to a process for preparing the solid dispersions described herein, comprising blending ARN-509, a poly(meth)acrylate copolymer, and HPMCAS and extruding said blend at a temperature in the range of about 160 to about 190°C.

The present invention further relates to a process for preparing the particles described herein, comprising mixing ARN-509, a poly(meth)acrylate copolymer and HPMCAS, extruding said mixture at a temperature in the range of about 160 to about 190°C, milling the extrudate, and optionally screening particles.

Acceptable extruders that can be used are the Haake mini extruder, the Leistritz 18 mm extruder, and the Leistritz 27 mm extruder.

The present invention further relates to a process for preparing the particles or solid dispersions described herein, comprising mixing ARN-509, a poly(meth)acrylate copolymer and HPMCAS in a suitable solvent and spray drying said mixture. In an aspect, a suitable solvent is a mixture of dichloromethane and methanol. In an aspect, a suitable solvent is a mixture of dichloromethane and methanol, in which the ratio of dichloromethane to methanol in the mixture is 4:6 (w/w) or 5:5 (w/w), preferably 5:5 (w/w). wt.).

The preferred crystalline form of ARN-509 for the preparation of the solid dispersions or particles described herein is Form B, which is an anhydrous crystalline form (see later in this document and also reference is made to WO 2013/184681 incorporated herein by reference).

Another object of the invention is to provide a process for the preparation of a pharmaceutical composition described herein, in particular in the form of a tablet or capsule, characterized by mixing a therapeutically effective amount of a solid dispersion or particles described herein with a pharmaceutically acceptable carrier and compressing said mixture into tablets or by filling said mixture into capsules.

Additionally, the invention relates to solid dispersions or particles described herein for use in the preparation of a pharmaceutical composition 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 specifically, prostate cancer, including, without limitation, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, previously chemotherapy-naive metastatic castration-resistant prostate cancer, biochemically recurrent hormone-sensitive prostate cancer, or high-risk non-metastatic castration -resistant prostate cancer.

The present invention also relates to the use of the solid dispersion or particles described herein for the preparation of a pharmaceutical composition 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 specifically, prostate cancer, including, without limitation, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, previously untreated metastatic castration-resistant prostate cancer, biochemically recurrent hormone-responsive prostate cancer, or characterized by high-risk non-metastatic castration-resistant prostate cancer.

The invention also relates to a method of treating an androgen receptor (AR)-associated disease or condition, in particular cancer, more specifically prostate cancer, including, without limitation, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, previously chemotherapy-naive metastatic castration-resistant prostate cancer, biochemically recurrent 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 a human, an effective anti-cancer amount of a pharmaceutical composition described in this document.

The invention further relates to the use of a pharmaceutical composition as set forth herein for the manufacture of a medicament for the treatment of an androgen receptor (AR) related disease or condition, in particular cancer, more specifically prostate cancer, including, without limitation, castration-resistant prostate cancer. metastatic castration-resistant prostate cancer, previously chemotherapy-naive metastatic castration-resistant prostate cancer, biochemically recurrent hormone-sensitive prostate cancer, or high-risk non-metastatic castration-resistant prostate cancer. Or alternatively, the invention relates to a pharmaceutical composition as defined herein for use in the treatment of an androgen receptor (AR) associated disease or condition, in particular cancer, more specifically prostate cancer, including, but not limited to, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer not previously treated with chemotherapy metastatic castration-resistant prostate cancer, biochemically recurrent hormone-sensitive prostate cancer, or high-risk non-metastatic castration-resistant prostate cancer.

The invention also relates to pharmaceutical packaging acceptable for commercial sale, including a container, a pharmaceutical composition described in this document, and written materials related to said packaging.

The term about, as used herein in relation to a numeric value, is intended to have its usual meaning in the context of a numeric value. Where necessary, the word about can be replaced by a numerical value of ± 10%, or ± 5%, or ± 2%, or ± 1%.

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

The following examples are intended to illustrate the present invention.

Example 1: Forms ARN-509

For various (crystalline) forms of ARN-509, reference is made to WO 2013/184681, which is incorporated herein by reference. Various (crystalline or amorphous) forms of ARN-509 can be used to prepare solid dispersions, particles or compositions in accordance with the present invention.

The preferred form of ARN-509 for use in the preparation of a solid dispersion, particle, or composition according to the present invention is Form B of ARN-509, which is an anhydrous crystal. It was prepared by suspending Form A of ARN-509 (reference is made to WO 2013/184681 including diffraction data) in water according to USP standards and heating this liquid mass to 55 ± 5°C while holding at the indicated temperature. for at least 24 hours, followed by cooling the liquid mass to 25 ± 5°C. The resulting slurry was filtered and the wet cake was washed once with USP water. The wet cake was removed from the filter and dried under vacuum to give ARN-509 Form B. Also below is a link to example 2.

Solubility Form A: 0.01 mg/ml in water.

Solubility of form B: 0.004 mg/ml in water.

Example 2 Characterization of Form B ARN-509

Powder X-ray diffraction

X-ray powder diffraction (XRPD) was performed on a PANalytical X'PertPRO MPD diffractometer (Philips). The device is equipped with a Cu LFF X-ray tube. The composition was applied to a sample holder with zero diffraction background.

Instrument parameters Generator voltage: 45 kV Generator current: 40 mA Geometry: BreggBrentano Base: Rotating base

- 13 040494

Measurement conditions Scanning mode: Continuous scanning range: 3 to 50° 2Θ Step size: 0.02°/step Counting time: 30 s/step Rotator rotation time: 1 s Radiation type: CuKa

Incident beam path Path of the diffracted beam programs, gap divergence: 15 mm LONG anti-scatter screen: + Soller gap: 0.04 rad Soller gap: 0.04 rad beam mask: 15 mm Ni filter: + anti-scatter gap: 1° detector: X'Celerator wedge-shaped obstacle for the beam: +

The X-ray powder diffraction pattern of ARN-509 Form B shows diffraction peaks without the presence of a halo, indicating that this composition is present as a crystalline product. In FIG. 1 shows an X-ray diffraction pattern for Form B of ARN-509.

Infrared spectroscopy (micro ATR IR)

Samples were analyzed using a suitable micro-ATR attachment (attenuated total internal reflection IR spectroscopy).

Device: 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 Beam splitter: Ge per KBr Micro ATR attachment: Harrick Split Pea with crystal Si

In FIG. 2 shows the spectrum for form B of ARN-509.

Differential Scanning Calorimetry (DSC)

The composition was transferred to a standard TA-Instrument aluminum sample pan. The sample vial was closed with a suitable lid and a DSC curve was recorded on a TA-Instruments Q1000 MTDSC instrument equipped with an RCS cooling module using the following parameters: initial temperature: 25°C, heating rate: 10°C/min, final temperature: 250°C .

The DSC curve for form B of ARN-509 shows the melting of the product at 194.9° C. with a heat of fusion of 73 J/g (See Fig. 3).

Example 3.1. Solid dispersion preparation ARN-509: Eudraqit® L-100-55: HPMCAS LG 1:1.5: .5

ARN-509 250.0 mg

Eudragit® L-100-55 375.0 mg

HPMCAS LG 375.0 mg

Dichloromethane, ^a 9500.0 mg

Methanol ^a 9500.0 mg ^a Removed during processing (quantities given are based on 1 g SDP (spray dried product))

The dichloromethane and methanol were transferred to a suitable container and mixing started. Form B of ARN509 was added to the solvent mixture with continuous stirring and stirred until dissolved. Eudragit® L 100-55 was added to the mixture and mixed. HPMCAS LG was added to the mixture and the resulting mixture was stirred overnight. After mixing of the ingredients was completed, the mixture was spray dried using a suitable spray dryer, such as a Buchi mini spray dryer, with the following parameters: spray rate in the range of 7.3-7.5 g/min, outlet temperature in the range of 40 to 42° C and condenser temperature in the range from -19 to -20°C. The spray dried product (SDP) was dried in a suitable dryer, such as a tray dryer, using vacuum, nitrogen flow and a drying temperature of 40°C.

In a manner analogous to that described in Example 3.1, the following products were obtained after spray drying:

SDP with ratio ARN-509: Eudragit® L 100-55: HPMCAS LG: 1:0.75:2.25 (after spray drying the mixture in dichloromethane/methanol 40/60)

SDP with ratio ARN-509: Eudragit® L 100-55: HPMCAS LG: 1: 2.25: 0.75 (after spray drying the mixture in dichloromethane/methanol 50/50)

Example 3.2. Preparation of tablets comprising a solid dispersion ARN-509: Eudragit® L 100-55: HPMCAS LG: 1: 1.5: 1.5

Spray dried powder from 3.1 (SDP) 240.0 mg

Colloidal anhydrous silica 9.1 mg

Croscarmellose sodium 35.0 mg

Silicified microcrystalline cellulose 412.4 mg

Magnesium stearate 3.5 mg (amounts per tablet)

Spray dried product, part (2955/4124) silicified microcrystalline cellulose, part (10/13) colloidal anhydrous silica and part (1/2) croscarmellose

- 14 040494 sodium was sieved (950 μm) and mixed into a homogeneous mixture using a suitable blender. A dry granulate was prepared using an acceptable compaction technique. The remainder of silicified microcrystalline cellulose (1169/4124), 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 screened and added to the mixture and further mixed using a suitable blender. The mixture was compressed into tablets using an eccentric tablet press.

In a manner analogous to that described in example 3.2, the following tablets 3.3 and 3.4 were obtained. Tablet 3.3.

Ratio SDP ARN-509: Eudragit® L 100-55: HPMCAS LG: 1:0.75:2.25 240.0 mg Colloidal anhydrous silica 9.1 mg Croscarmellose sodium 35.0 mg

Silicified microcrystalline cellulose 412.4 mg

Magnesium stearate 3.5 mg (amounts per tablet)

Tablet 3.4.

SDP with ratio ARN-509: Eudragit® L 100-55: HPMCAS LG:

1:2.25:0.75 240.0 mg

Colloidal anhydrous silica 9.1 mg

Croscarmellose sodium 35.0 mg

Silicified microcrystalline cellulose 412.4 mg

Magnesium stearate 3.5 mg (amounts per tablet)

Example 4.1. Obtaining a solid dispersion ARN-509: Eudragit® L 100-55: HPMCAS LG: 1: 1.5: 1.5 by hot melt extrusion (HME)

ARN-509 250.0 mg

Eudragit® L-100-55 375.0 mg

HPMCAS LG 37 5.0mg (Amounts shown are based on 1g of HME product)

HPMCAS LG, Eudragit® L 100-55 and Form B ARN-509 were mixed in an acceptable receiver using an acceptable blender. Hot melt extrusion was carried out in a suitable extruder, maximum temperature 165° C., screw speed 80 rpm. The hot melt extrudate was collected and ground in a suitable mill. The milled hot melt extrudate was screened using a suitable sieve.

Example 4.2. Preparation of tablets comprising a solid dispersion ARN-509: Eudragit® L 100-55: HPMCAS LG: 1: 1.5: 1.5

NME powder from 4.1 240.0 mg

Colloidal anhydrous silica 9.1 mg

Croscarmellose sodium 35.0 mg

Silicified microcrystalline cellulose 412.4 mg

Magnesium stearate 3.5 mg (amounts per tablet)

Silicified microcrystalline cellulose, croscarmellose sodium, colloidal anhydrous silica and hot melt extrudate were sieved (950 µm) and mixed into a homogeneous mixture using a suitable blender. Magnesium stearate was screened and added to the mixture and further mixed using a suitable blender. The mixture was compressed into tablets using an eccentric tablet press.

Example 5.1. Preparation of a solid dispersion ARN-509: Eudragit® L 100-55: HPMCAS LG: 1: 0.75: 2.25 by hot melt extrusion (HME)

ARN-509 250.0 mg

Eudragit® L-100-55 187.5 mg

HPMCAS LG 562.5mg (Amounts shown are based on 1g of HME product)

HPMCAS LG, Eudragit® L 100-55 and Form B ARN-509 were mixed in an acceptable receiver using an acceptable blender. Hot melt extrusion was carried out in a suitable extruder, maximum temperature 170° C., screw speed 80 rpm. The hot melt extrudate was collected and ground in a suitable mill. The milled hot melt extrudate was screened using a suitable sieve.

Example 5.2. Preparation of tablets comprising a solid dispersion ARN-509: Eudragit® L 100-55: HPMCAS LG: 1: 0.75: 2.25

NME powder from 5.1 240.0 mg

Colloidal anhydrous silica 9.1 mg

Croscarmellose sodium 35.0 mg

Silicified microcrystalline cellulose 412.4 mg

Magnesium stearate 3.5 mg (amounts per tablet)

Silicified microcrystalline cellulose, croscarmellose sodium, colloidal

Claims (34)

the aqueous silica and the hot melt extrudate were sieved (950 µm) and mixed into a homogeneous mixture using a suitable blender. Magnesium stearate was sieved and added to the mixture and further mixed using a suitable blender. The mixture was compressed into tablets using an eccentric tablet press. Example 6.1. Preparation of solid dispersion ARN-509: Eudragit® L 100-55: HPMCAS LG: 1:2.25:0.75 via hot melt extrusion (HME) ARN-509 250.0 mg Eudragit® L-100-55 562.5 mg HPMCAS LG 187.5mg (Amounts shown are based on 1g of HME product) HPMCAS LG, Eudragit® L 100-55 and Form B ARN-509 were mixed in an acceptable receiver using an acceptable blender. Hot melt extrusion was carried out in a suitable extruder, maximum temperature 165° C., screw speed 80 rpm. The hot melt extrudate was collected and ground in a suitable mill. The milled hot melt extrudate was screened using a suitable sieve. Example 6.2. Preparation of tablets comprising a solid dispersion ARN-509: Eudragit® L 100-55: HPMCAS LG: 1: 2.25: 0.75 NME powder from 6.1 240.0 mg Colloidal anhydrous silica 9.1 mg Croscarmellose sodium 35.0 mg Silicified microcrystalline cellulose 412.4 mg Magnesium stearate 3.5 mg (amounts per tablet) Silicified microcrystalline cellulose, croscarmellose sodium, colloidal anhydrous silica and hot melt extrudate were sieved (950 µm) and mixed into a homogeneous mixture using a suitable blender. Magnesium stearate was sieved, added to the mixture and further mixed using a suitable blender. The mixture was compressed into tablets using an eccentric tablet press. Example 7 In Vitro Dissolution Study Dissolution method The tablets were placed in 300 ml SGFsp (simulated gastric juice without pepsin) for 15 min, mixed in a paddle mixer (100 rpm), then placed in 900 ml FaSSIF (simulated intestinal juice on an empty stomach), mixed in a paddle mixer (100 rpm). /min). The % dissolved ARN-509 was measured by UHPLC with UV detection at 242 nm. The dose per vessel was 120 mg. 60 mg tablets were used. Two tablets per container. Results (% solute versus time (min)). Time (minutes) 5 14 20 25 35 45 60 75 105 135 285 Pills example 4.3 6, 9 67.3 73.5 73.6 73.0 71.4 71.7 68.4 66.5 63.7 3.2 4.4 6, 9 65.6 69.8 70.5 69.4 68.4 66.9 65.0 63.4 56.9 Pills 3.3 4.3 6.2 54.1 64.4 66.6 66.9 66.4 66.9 62.4 64.0 61.7 4.1 6.4 54.9 62.0 59.8 64.5 59.7 63.3 63.2 61.9 58.8 Pills 4.6 7.1 77.1 77.5 75.9 72.5 69.1 64.2 65.2 61.0 57.1 4.6 7.2 75.5 77.4 75.3 72.7 66.7 66.4 64.2 59.9 44.2 Example tablets 3.1 4.7 78.4 88.7 86.8 85.7 84.5 73.7 37.6 24.3 19.5 4.2 3.2 4.8 78.3 88.0 83.8 85.9 84.2 62.2 29.0 22.7 18.9 Pills example 3.5 5.3 61.7 77.9 80.3 80.4 79.0 76.4 75.5 75.0 59.2 5.2 3.3 5.4 66.7 79.0 81.3 79.8 77.5 78.0 74.3 71.8 57.4 Pills example 6.2 2.2 3.4 76.7 85.2 85.1 78.5 49.8 21.4 17.7 17.1 15, 7 CLAIM 1. Solid dispersion comprising (ARN-509), poly(meth)acrylate copolymer and hydroxypropyl methylcellulose acetate succinate (HPM-16 040494 CAS). 2. Solid dispersion according to claim 1, wherein the dispersion consists of ARN-509, a copolymer of poly(meth)acrylate and HPMCAS. 3. A solid dispersion according to claim 1 or 2, wherein the weight ratio of ARN-509: (poly(meth)acrylate-HPMCAS copolymer) in the solid dispersion is in the range of 1:1 to 1:5. 4. The solid dispersion according to claim 3, wherein the weight ratio of ARN-509: (poly(meth)acrylate-HPMCAS copolymer) in the solid dispersion is 1:3. 5. Solid dispersion according to claim 3, wherein the weight ratio of ARN-509: (poly(meth)acrylate-HPMCAS copolymer) in the solid dispersion is 1:2. 6. A solid dispersion according to claim 3, wherein the weight ratio of ARN-509: (poly(meth)acrylate-HPMCAS copolymer) in the solid dispersion is 1:1. 7. A solid dispersion according to any one of the preceding claims, wherein the weight ratio of poly(meth)acrylate copolymer to HPMCAS in the solid dispersion is in the range of 5:95 to 95:5. 8. Solid dispersion according to claim 7, wherein the weight ratio of poly(meth)acrylate copolymer to HPMCAS in the solid dispersion is in the range of 25:75 to 75:25. 9. The solid dispersion of claim 8, wherein the weight ratio of poly(meth)acrylate copolymer to HPMCAS in the solid dispersion is 50:50. 10. Solid dispersion according to any one of the preceding claims, wherein ARN-509 is present in amorphous form. 11. A solid dispersion according to any one of the preceding claims, wherein the solid dispersion is a solid solution. 12. A solid dispersion according to any one of the preceding claims, wherein the poly(meth)acrylate copolymer is a 1:1 copolymer of methacrylic acid and ethyl acrylate. 13. A solid dispersion according to any one of the preceding claims, wherein the HPMCAS is HPMCAS granular grade. 14. Solid dispersion according to any one of the preceding claims, which is obtained by spray drying. 15. Solid dispersion according to any one of claims 1 to 13, which is obtained by hot melt extrusion. 16. A particle consisting of a solid dispersion as defined in any one of the preceding claims. 17. A particle comprising a solid dispersion as defined in any one of claims 1-15. 18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a solid dispersion according to any one of claims 1-15. 19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a particle according to claim 16 or 17. 20. Composition according to claim 18 or 19 containing 60 mg of ARN-509. 21. Composition according to claim 18 or 19 containing 120 mg of ARN-509. 22. Composition according to claim 18 or 19 containing 240 mg of ARN-509. 23. A composition according to any one of claims 18 to 22, wherein the solid dispersion is between 20% and 40% by weight of the total composition. 24. Composition according to any one of claims 18-23, wherein the composition is a tablet. 25. The composition according to claim 24, which is acceptable for oral administration. 26. A method for preparing a solid dispersion according to claim 14, comprising the steps of mixing ARN-509, a poly(meth)acrylate copolymer and HPMCAS in a suitable solvent and spray drying said mixture. 27. The method of claim 26 wherein the suitable solvent is a mixture of dichloromethane and methanol. 28. The method according to claim 27, wherein the weight ratio of dichloromethane and methanol in the mixture is 50:50. 29. The use of a pharmaceutical composition according to any one of claims 18 to 25 for the preparation of a medicament for the treatment of prostate cancer. 30. Use according to claim 29, wherein the drug is for oral administration. 31. A combination of a pharmaceutical composition according to any one of claims 18-25 and another anticancer agent. 32. The combination of claim 31 wherein the other anti-cancer agent is an androgen biosynthesis inhibitor. 33. The combination of claim 31 wherein the other anticancer agent is abiraterone acetate. 34. Combination according to any one of claims 31-33, additionally containing prednisone. -