METHODS AND COMPOSITIONS FOR TREATING PROSTATE CANCER

Abstract

Methods and compositions for treating prostate cancer are described herein. More particularly, the methods for treating prostate cancer comprise administering abiraterone acetate in the form of a solid dosage form for oral administration wherein said solid dosage form for oral administration is capable of rapid reconstitution or disintegration in the oral cavity or an aliquot of liquid prior to ingestion, suitably administered in combination with a steroid.

Claims

1-40. (canceled)

41. A solid dosage form for oral administration comprising a stable, amorphous matrix comprising: (a) abiraterone acetate; (b) one or more water soluble polymers, and (c) one or more antioxidants, wherein said solid oral dosage form preferably further comprises a disintegrant and one or more pharmaceutically acceptable excipients, and wherein said solid dosage form for oral administration is capable of rapid reconstitution or disintegration in the oral cavity or an aliquot of liquid, prior to ingestion.

42. The solid dosage form for oral administration according to claim 41, wherein said stable, amorphous matrix exhibits one or more of the following: (i) X-ray amorphous character in the solid form; (ii) a glass transition when assessed via differential scanning calorimetry (DSC), and (iii) is stable for at least 3 months at 40° C., as demonstrated by a lack of significant decomposition and/or oxidation and/or crystallization of abiraterone acetate.

43. The solid dosage form for oral administration according to claim 41, wherein said stable, amorphous matrix comprises one or more water-soluble polymers selected from: polyvinylcaprolactam-polyvinyl acetate-polyethylene-glycol graft copolymers, poloxamers; polyvinylpyrrolidone, poly(acrylic acid), polyvinyl alcohol, ethylene glycol and vinyl alcohol graft copolymer, hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hypromellose acetate succinate, polyethylene oxide, polyethylene-glycol, poly(2-Ethyl-2-oxazoline), poly(methyl vinyl ether/maleic anhydride), poly(maleic acid-co-methyl vinyl ether, polyoxylglycerides, D-α-tocopherol polyethylene glycol 1000 succinate, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polylactic acid, poly(lactic-co-glycolic acid) and copolymers of vinylpyrrolidone and vinyl-acetate and poly(maleic acid-co-methyl-vinyl-ether), preferably polyvinylpyrrolidone, such as K12 or Kollidon 17PF, Kollidon 25, Kollidon 30 or Kollidon 90, most preferably a K12 grade.

44. The solid dosage form for oral administration according to claim 41, wherein said stable, amorphous matrix comprises one or more antioxidants selected from: ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHA), hypophosphorous acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate and tocopherols, preferably BHA and/or BHT.

45. The solid dosage form for oral administration according to claim 41, wherein said one or more pharmaceutically excipients are selected from group consisting of: diluents or fillers, binders, disintegrants and dispersing agents, lubricants, glidants, antiadherents, surfactants, sweeteners and flavourings.

46. The solid dosage form for oral administration according to claim 45, wherein said diluents or fillers are selected from: pullulan, lactose (anhydrous), lactose monohydrate, mannitol, sucrose, glucose, plant cellulose, calcium carbonate, magnesium carbonate, magnesium oxide, microcrystalline cellulose, silicified microcrystalline cellulose, sorbitol, starch, pregelatinized starch, isomalt, anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, calcium silicate, magnesium aluminium silicate, maltodextrin, dextrates; and/or said binders are selected from: pullulan, cellulose, methyl cellulose, microcrystalline cellulose, cellulose ethers such as hydroxypropyl cellulose, polyvinylpyrrolidone, polyethylene glycol, lactose, sucrose, mannitol, sorbitol and xylitol and their co-processed versions such as alpha-Lactose-monohydrate and cellulose or starch, urea crystals, sodium sulfate and calcium sulfate dehydrate; said disintegrants and dispersing agents are selected from: polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone (crospovidone), polyvinylcaprolactam-polyvinyl acetate-polyethylene-glycol graft copolymers, carboxymethyl cellulose, crosslinked cellulose and its sodium salt (crosscarmellose), crosslinked sodium carboxymethyl cellulose, modified starch, sodium starch glycolate, crosslinked starch, crosslinked alginic acid and sodium starch glycolate, colloidal silicon dioxide, soy polysaccharides and sodium deoxycholate; and/or said lubricants are selected from: polyethylene glycol, calcium stearate, silica, talc, stearic acid, sodium stearyl fumarate, sodium lauryl sulfate, sodium benzoate, stearic acid and magnesium stearate; and/or said glidants are selected from: silica gel, colloidal silicon dioxide, fumed silica, talc and magnesium carbonate; and/or said antiadherents are selected from: magnesium stearate, talc and starch; and/or said surfactants are selected from: polysorbates such as Tweens, polysorbates, Sodium dodecyl sulfate (sodium lauryl sulfate), lauryl dimethyl amine oxide, docusate sodium, cetyl trimethyl ammonium bromide (CTAB), polyethoxylated alcohols, polyoxyethylene sorbitan, octoxynol, N,N-dimethyldodecylamine-N-oxide, hexadecyltrimethylammonium bromide, polyoxyl 10 lauryl ether, Brij, bile salts (sodium deoxycholate, sodium cholate), polyoxyl castor oil, nonylphenol ethoxylate cyclodextrins, lecithin, methylbenzethonium chloride, petroleum sulphonates, alkylbenzenesulphonates, sulphated alkanolamides, polyoxyethylene surfactants, carboxylic esters, polyethylene glycol esters, glycol esters of fatty acids, carboxylic amides, quaternary ammonium salts, preferably docusate sodium and/or sodium lauryl sulfate; and/or said sweeteners are selected from: sodium saccharine, sucrose, saccharine, aspartame, acesulfame-K, sodium cyclamate and sorbitol.

47. The solid dosage form for oral administration according to claim 41, wherein said abiraterone acetate is present in said stable, amorphous matrix at an amount ranging from about 1.0% by weight to about 95.0% by weight, based on the total weight of the stable, amorphous matrix.

48. The solid dosage form for oral administration according to claim 41, wherein said stable, amorphous matrix is present at an amount ranging from about 1.0% by weight to about 95.0% by weight, based on the total weight of the solid dosage form, preferably wherein said stable, amorphous matrix is present in particulate form, preferably as a particulate or milled extrudate.

49. The solid dosage form for oral administration according to claim 41, wherein said solid dosage form is selected from: a tablet, coated tablet, effervescent tablet, tablet for oral suspension, fast melt tablet, lyophilized tablet, lyophilized wafer, disintegrating tablet, dispersible tablet, orodispersible tablet, mini-tablet, multilayer tablet, bi-layered tablet, tablet-in-tablet, pill, micro-pellet, small tablet unit, powder, powder for reconstitution, powder for oral suspension, pellets, beads, MUPS (multiple unit pellet system), granules, dry granules, roller compacted granules, effervescent granules, granules for oral suspension, slugs, microspheres, multiparticulates, sprinkles, preferably granules for oral suspension, wherein said solid dosage form is preferably packaged as a blister, bottle, capsule, stick or sachet.

50. The solid dosage form for oral administration according to claim 49, wherein said micro-pellet, small tablet unit, powder, powder for reconstitution, powder for oral suspension, pellets, beads, MUPS (multiple unit pellet system), granules, dry granules, roller compacted granules, effervescent granules, granules for oral suspension, slugs, microspheres, multiparticulates and sprinkles preferably have a D50 of greater than 300 micron and where less than about 10% by weight of the total mass of the solid dosage form is less than 63 microns, preferably wherein less than about 10% by weight of the total mass of the solid dosage form is less than 50 microns, as measured by laser diffraction or preferably sieve fractionation.

51. The solid dosage form for oral administration according to claim 41, wherein said solid dosage form is presented as one of the following: controlled release formulation, immediate release formulation, fast melt formulation, lyophilized formulations, delayed release formulation, extended release formulation, pulsatile release formulation, or mixed immediate release and controlled release formulation.

52. The solid dosage form for oral administration according to claim 41, which comprises a therapeutically effective amount of abiraterone acetate, ranging from about 10 mg to 2000 mg per dosage form, or about 50 mg to 1000 mg per dosage form, preferably about 62.5 mg to about 250 mg per dosage form.

53. The solid dosage form for oral administration according to claim 41, wherein said solid dosage form disintegrates and/or releases abiraterone acetate into an aliquot of liquid suitable for human consumption.

54. The solid dosage form for oral administration according to claim 53, wherein said aliquot of liquid suitable for human use is selected from: water, fruit juice such as orange juice, apple juice, pineapple juice or cranberry juice, coconut water, coconut milk, almond milk, oat milk, soya milk, rice milk, and dairy-derived milks such as cow's milk.

55. The solid dosage form for oral administration according to claim 53, wherein said solid dosage form disintegrates and/or releases at least 85% or more of said abiraterone acetate into said aliquot of liquid in less than about 10 minutes, preferably less than about 5 minutes, more preferably less than about 3 minutes, or less than about 1 minute or less, wherein said aliquot is 250 ml or less, such as about 50 or 60 ml.

56. The solid dosage form for oral administration according to claim 41, wherein said abiraterone acetate is present in said solid dosage form at about 1.0% by weight to about 20.0% by weight, or about 1.0% to about 10.0% by weight, preferably about 1.0% to about 5.0% by weight, based on the total weight of the solid dosage form.

57. A solid dosage form for oral administration comprising: (a) abiraterone acetate; (b) one or more water soluble polymers, and (c) one or more antioxidants, wherein said solid oral dosage form preferably further comprises a disintegrant and one or more pharmaceutically acceptable excipients, and wherein said solid dosage form for oral administration is capable of rapid reconstitution or disintegration in the oral cavity or an aliquot of liquid prior to ingestion, comprising: (a) 1-20% abiraterone acetate, (b) 5-60% water soluble polymer, (c) 35-90% fillers and/or diluents, (d) 5-20% binders, (e) 5-45% disintegrants, (f) 0.1-5% lubricants, (g) 0.1-5% antiadherents, (h) 0.1-5% glidants, (i) 0.01-2% antioxidants, and (j) 0.05-5% flavouring agents and/or sweeteners.

58. The solid dosage form for oral administration according to claim 41, for use in the treatment of prostate cancer.

59. Use of a solid dosage form for oral administration according to claim 41, in the manufacture of a medicament for the treatment of prostate cancer.

60. A method of producing a solid dosage form for oral administration comprising abiraterone acetate, wherein said solid dosage form for oral administration is capable of rapid reconstitution or disintegration in the oral cavity or an aliquot of liquid prior to ingestion, wherein said method comprising the steps of: (a) providing abiraterone acetate; (b) providing one or more water-soluble polymers, preferably polyvinylpyrrolidone, such as K12 or Kollidon 17PF, Kollidon 25, Kollidon 30 or Kollidon 90, most preferably a K12 grade; (c) providing one or more antioxidants; (d) processing (a), (b) and (c) by blending to produce powder blend comprising (a) to (c); (e) processing the product of step (d) by an extrusion process to produce an extruded composition; (f) processing the extruded composition of step (e) by size reduction such as milling, to produce a particulate or milled extrudate; (g) blending the particulate or milled extruded composition of step (f) with one or more pharmaceutically acceptable excipients such as fillers, diluents, binders, disintegrants, lubricants, antiadherents, glidants, flavoring agents and sweeteners to produce a composition blend; and (h) compressing the composition blend of step (g) into a solid dosage form such as via direct compression to form a tablet, or, preparing granules from the composition blend of step (g), via slugging and/or milling and/or roller compaction to produce such granules.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0274] FIG. 1 shows amorphous structure of HME milled granules (intragranular)

[0275] The following working Examples represent a preferred embodiment of the invention.

EXAMPLES

Example 1

[0276] Composition: Abiraterone acetate tablet for oral suspension—Prototype compositions of abiraterone acetate tablet for oral suspension formulations prepared are listed in Table 1 and Table 2.

TABLE-US-00001 TABLE 1 Compositions of abiraterone acetate tablet for oral suspension formulations prepared Theoretical quantity Sub lot Sub lot Sub lot Sub lot Sub lot Sub lot 1 to 6 7 8 9 10 11 Material % w/w % w/w % w/w % w/w % w/w % w/w 1 Hot melt extruded (HME) milled granules (Intra- granular) Abiraterone acetate 3.826 3.826 3.826 3.826 3.826 3.826 polyvinylpyrrolidone 19.133 19.133 19.133 19.133 19.133 19.133 (Plasdone K12), Butylated hydroxytoluene 0.025 0.025 0.025 0.025 0.025 0.025 (BHT) Butylated hydroxyanisole 0.025 0.025 0.025 0.025 0.025 0.025 (BHA) 2 Sodium deoxy cholate 2.3 2.3 2.3 2.3 2.3 2.3 3 Polyvinylcaprolactam- 15.31 15.31 15.31 15.31 15.31 15.31 polyvinyl acetate- polyethylene-glycol graft copolymers (Soluplus) 4 Lactose monohydrate 23.27 22.49 22.89 22.89 21.99 20.99 (Flowlac 100) 5 Microcrystalline cellulose 23.27 23.27 23.27 13.96 13.96 13.96 (Avicel PH101) 6 Microcrystalline cellulose — — — 9.31 9.31 9.31 (Vivapur 112) 7 Colloidal silicon dioxide — — — — 0.5 0.5 (Aerosil 200) 8 Crospovidone (Kollidon CL) 11.63 11.63 11.63 11.63 11.63 11.63 9 Polyethylene glycol 4000 1.23 2 1.6 1.6 2 3 Total 100 100 100 100 100 100

TABLE-US-00002 TABLE 2 Compositions of abiraterone acetate tablet for oral suspension formulations prepared Theoretical quantity Sub lot Sub lot Sub lot Sub lot 12 13 14 15 Material % w/w % w/w % w/w % w/w 1 HME milled granules (Intra- granular) Abiraterone acetate 3.826 3.826 3.826 3.826 polyvinylpyrrolidone 19.133 19.133 19.133 19.133 (Plasdone K12), Butylated hydroxytoluene 0.025 0.025 0.025 0.025 (BHT) Butylated hydroxy anisole 0.025 0.025 0.025 0.025 (BHA) 2 Sodium deoxy cholate 2.296 2.296 2.296 2.296 4 Polyvinylcaprolactam-polyvinyl 15.306 15.306 15.306 15.306 acetate-polyethylene-glycol graft copolymers (Soluplus) 5 Lactose monohydrate (Flowlac 100) 21.563 21.363 21.363 21.563 6 Microcrystalline cellulose (Avicel 13.959 13.959 13.959 13.959 PH101) 7 Microcrystalline cellulose (Vivapur 9.306 9.306 9.306 9.306 112) 8 Colloidal silicon dioxide (Aerosil 0.5 0.5 0.5 0.5 200) 9 Crospovidone (Kollidon CL) 11.633 11.633 11.633 11.633 10 Aspartame powder — — 0.2 — 11 Sodium saccharine — 0.2 — — 12 Polyethylene glycol 4000 2 2 2 2 13 Sodium sterayl fumarate 0.428 0.428 0.428 0.428 Total 100 100 100 100

[0277] Disintegration, assay and related substance, dissolution, processability and crystallinity of the prepared compositions were investigated right after the production and 1 and 3 months later. Results are seen in Table 3-6 and FIG. 1.

TABLE-US-00003 TABLE 3 Disintegration of abiraterone acetate tablet for oral suspension compositions prepared Mean Visual Disintegration- Sub Disintegration Apparatus LOD (%) lot (Sec) (Sec) Granules Final Blend  1A 180 110 ND 3.53  1B 150  87 ND 3.53  2 ND 117 2.5 2.78  3 175  97 2.31 2.69  4 NA NA 2.31 3.15  5 NA NA 2.45 2.93  6 180 145 2.38 2.97  7  78 NP NP 2.7  8  77 NP NP 3.67  9 148 138 NP 3.18 10 170 167 NP 2.59 11 NA NA NP 2.47 12 120 120 NP 2.41 13 170 165 NP 2.32 14 180 175 NP 1.98 15 124 125 NP 2.22 ND: Not detectable NP: Not performed NA: Not applicable

TABLE-US-00004 TABLE 4 Processability of tablet for oral suspension formulations prepared Tablets Mean Machine parameter (Yes/No) Friability (N) Sub lot Weight Thickness compressed Comments (%) Hardness  1A 8 3 Yes No issues 1.13 88.27  1B 8 3 Yes Sticking 2.55 67.34  2 8 3 Yes Rat hole effect, 0.84 ND Sticking  3 8 3 Yes Sticking 1.21 79.9  4 8 3 No Rat hole effect NA NA  5 8 3 No Bridging effect NA NA  6 8 3 Yes No issues 0.81 95.3  7 8 3 Yes No issues 1.52 67.5  8 8 3 Yes Sticking 1.17 77.7  9 8 3 Yes Intense 0.92 89.2 Sticking 10 8 3 Yes Minor sticking 0.87 89.7 11 8 3 No Rat hole effect, NA NA Sticking 12 8 3 Yes No issues 1.56 79.4 13 8 3 Yes No issues 0.83 81.4 14 8 3 Yes No issues 0.88 85.4 15 8 3 Yes No issues 1.28 75.6 NA: Not applicable

[0278] The process was scaled-up and 36 Kg batch of sublot 13 was prepared.

[0279] 9 Kg of intra-granular extrudate was prepared triturating BHT and BHA with a small portion of polyvinylpyrrolidone (Plasdone K12) and then screened and blended. More polyvinylpyrrolidone (Plasdone K12) was added to the mixture then blended again. The blend transferred to a 30 L Pharmatech blender and the residual amount of polyvinylpyrrolidone (Plasdone K12) as well as the abiraterone acetate was added into the blender shell then the material was blended again. A hot-melt extruder was set up according to the following parameters. Extrusion melt pressure was less than 300 PSI, Feed rate was 30 g/min (volumetric feeding), the temperature of all zones was 150° C. and the temperature of feed zone was 10° C. The Screw speed was set to 100 rpm and the die dimension was 1.0 mm. The extrudate was collected to an appropriate click lock container. The extrudated filament was milled with using a Quadro Comil having a 1143 μm screen at approximately 5,000 rpm speed. The appropriate amount of intragranular HME milled granules were dispensed for further process. Approximately 1 kg HME granules and the right amount of sodium deoxycholate, sodium saccharine and colloidal silicon dioxide were mixed manually then dispensed to a 30 L blender shell and blended together with the residual HE milled granules. The blend was transferred to a 100 L Pharmatech blender shell together with the appropriate amount of Soluplus, lactose monohydrate, microcrystalline cellulose (Avicel PH101), microcrystalline cellulose (Vivapur 112) and crospovidone then blended.

[0280] The polyethylene glycol 4000 and sodium stearyl fumarate and a small portion of the blend from the previous step were co-screened and transferred into the above 100 L blender shell then the 36 kg final tableting blend was lubricated.

[0281] The lubricated tableting blend was then compressed to tablets in a rotary press. The tablets were packed into an aluminum (PET/PE/Al/PE) pouch and heat sealed.

TABLE-US-00005 TABLE 5 Assay and related substance results of abiraterone acetate tablet for oral suspension formulations prepared at different timepoints Storage time at 40° C./75% RH Assay (%) Total related substances (%) T = 0  98% 0.1% T = 1 month  95% 0.2% T = 3 months  98% 0.5% T = 6 months 101% 0.8% T = 12 months  96% 0.9% Storage time at 25° C./60% RH Assay (%) Total related substances (%) T = 0  98% 0.1% T = 1 month  98% 0.1% T = 3 months 100% 0.2% T = 6 months 100% 0.2% T = 9 months 102% 0.3% T = 12 months  97% 0.3% T = 18 months 100% 0.7%

TABLE-US-00006 TABLE 6 Dissolution of tablet for abiraterone acetate oral suspension formulations prepared at different timepoints. Dissolution (% Release) Storage time at 40° C./ 1 min 5 min 10 min 15 min 75% RH Mean Range Mean Range Mean Range Mean Range T = 0 48 29-93 90 90-91 94 91-95 94 94-95 T = 1 month 50 46-58 96 94-98 97 95-98 96 95-99 T = 3 months 55 48-59 95 93-93 95 93-96 95 94-96 T = 6 months 67 57-75 93 92-94 93 92-94 93 91-95 T = 12 months 70 64-78 95 94-97 95 94-97 96 95-97 Storage time at 25° C./ 60% RH Mean Range Mean Range Mean Range Mean Range T = 0 48 29-93 90 90-91 94 91-95 94 94-95 T = 1 month 47 43-52 94 93-96 96 94-98 95 93-97 T = 3 months 52 48-60 96 95-96 96 95-97 96 94-97 T = 6 months 46 41-60 94 92-96 95 93-97 95 93-97 T = 9 months 49 42-59 94 92-97 94 92-95 95 93-98 T = 12 months 57 48-72 94  91-100 93 92-93 94 92-95 T = 18 months 40 32-47 93 91-95 94 92-95 94 92-96

Composition: Abiraterone Acetate Granules for Oral Suspension

[0282] For the development of granules for reconstitution the same formulation composition as Sublot 13, presented in Table 2 was used for sachet product development.

[0283] 9 Kg of intra-granular extrudate was prepared triturating BHT and BHA with a small portion of polyvinylpyrrolidone (Plasdone K12) and then screened and blended. More polyvinylpyrrolidone (Plasdone K12) was added to the mixture then blended again. The blend transferred to a 30 L Pharmatech blender and the residual amount of polyvinylpyrrolidone (Plasdone K12) as well as the abiraterone acetate was added into the blender shell then the material was blended again. A hot-melt extruder was set up according to the following parameters. Extrusion melt pressure was less than 300 PSI, Feed rate was 30 g/min (volumetric feeding), the temperature of all zones was 150° C. and the temperature of feed zone was 10° C. The Screw speed was set to 100 rpm and the die dimension was 1.0 mm. The extrudate was collected to an appropriate click lock container. The extrudated filament was milled with using a Quadro comil having a 1143 m screen at approximately 5,000 rpm speed. The appropriate amount of intragranular HME milled granules were dispensed for further process.

[0284] Approximately 1 kg HME granules and the right amount of sodium deoxycholate, sodium saccharine and colloidal silicon dioxide were mixed manually then dispensed to a 30 L blender shell and blended together with the residual HME milled granules. The blend was transferred to a 100 L Pharmatech blender shell together with the appropriate amount of Soluplus, lactose monohydrate, microcrystalline cellulose (Avicel PH101), microcrystalline cellulose (Vivapur 112) and crospovidone then blended.

[0285] The polyethylene glycol 4000 and half of the sodium stearyl fumarate and a small portion of the blend from the previous step were co-screened and transferred into the above 100 L blender shell then the 36 kg final tableting blend was lubricated.

[0286] The lubricated blend was then roller compacted using suitable process parameters in order to prepare granules.

[0287] The granules were transferred packed into the above 100 L blender shell.

[0288] The second half of the sodium stearyl fumarate was screened and transferred the above 100 L blender shell then the 36 kg final granules were lubricated.

[0289] The granules were then packed into an aluminum (PET/PE/Al/PE) pouch and heat sealed.

[0290] Lead granule composition was selected based on the process visual observations, physical and chemical assessment. During manufacturing smooth compaction and grinding, and no building up of the ribbons were observed.

[0291] Based on physical assessment optimum granules particle size with the least amount of fines generated was selected. The granules could be described as having [0292] Mean particle size=641 μm [0293] Particles <125 μm=22.04% [0294] Fine particles <90 μm=15.35%

[0295] Based on analytical assessment assay, filter assay, reconstitution time and dissolution profile results were within the specifications.

TABLE-US-00007 TABLE 7 Assay and related substance results of granule for abiraterone acetate granules for oral suspension formulations prepared at different timepoints Storage time at 40° C./75% RH Assay (%) Total related substances (%) T = 0  99% 0.1% T = 1 month 101% 0.2% T = 3 months  98% 0.3% Storage time at 25° C./60% RH Assay (%) Total related substances (%) T = 0  99% 0.1% T = 1 month 102% 0.1% T = 3 months 100% 0.1%

Example 2

[0296] An experiment was undertaken to investigate the effect of antioxidants on the stability of abiraterone acetate when produced as a milled HME (hot melt extrusion) matrix. Abiraterone acetate (API) and PVP were present at a ratio of 1:4 in the extrudate.

[0297] The melt extruded samples were ground using an IKA A11 basic analytical mill (IKA-Werke GmbH & CO. KG, Staufen, Germany).

TABLE-US-00008 TABLE 8 Abiraterone acetate (%) Amount of Right 2 1 2 3 antioxidants / after weeks, month, months, months, 300 mg API Initial extrusion 40° C. 40° C. 40° C. 40° C. — 99.93 99.44 n./a. 98.96 98.62 98.20  10 mg TPGS 99.83 99.69 99.76 99.59 99.53 0.4 mg BHT 99.71 99.72 99.76 99.65 99.60 0.8 mg BHT 99.76 99.67 99.82 99.61 99.69 1.6 mg BHT 99.78 99.73 99.82 99.66 99.72 2.5 mg BHA 99.76 99.74 99.81 99.69 99.72 1.6 mg BHT, 99.80 n./a. 99.74 99.81 99.77 1.6 mg BHA 1.6 mg BHT, 99.75 n./a. 99.74 99.81 99.78 2.5 mg BHA 1.6 mg BHT, 99.64 n./a. 99.79 99.66 99.57 10 mg BHA

[0298] As can be seen, the absence of any antioxidant in the extruded composition results in a loss (degradation) of abiraterone acetate. However, when an optimal blend of BHA and BHT are present, the loss/degradation is negligible i.e. <0.3% after storage for 3 months at 40° C.

Example 3

Pharmacokinetics in Healthy Man

[0299] FDA considers an abiraterone acetate formulation equivalent to Zytiga® in case the main pharmacokinetic parameters (AUC, C.sub.max) fall between the lower and upper limits defined as parameters determined for Zytiga® in the fasted and modified fasting state, respectively. Two clinical pharmacokinetic studies were designed to characterize the pharmacokinetic properties of the novel formulation in order to determine the dose regimen equivalent to 1000 mg daily Zytiga® and to investigate the effect of food on absorption characteristics.

[0300] Healthy subjects were selected by the investigators based on their medical history, physical examination, electrocardiograms and routine clinical laboratory test results. Twelve (C01) and twenty (C02) male subjects aged 21-65 years were enrolled. All subjects gave written informed consent and received an inconvenience allowance for their participation.

[0301] Study C01 (dose proportionality) and Study C02 (comparative food effect) were both single-dose, randomized, open-label, four-period, four-treatment crossover studies conducted at a single center at Quotient Clinical (Nottingham, UK) in accordance with the Clinical Protocol, with the Declaration of Helsinki and its amendments, with the International Conference on Harmonisation Good Clinical Practice (ICH GCP) Guidelines, and in accordance with all applicable regulatory requirements. The abiraterone acetate tablet for oral suspension was manufactured by hot melt extrusion and formulated as 62.5 mg unit dose tablets for oral suspension (as per sublot 13 above). The administered doses were prepared prior to dosing by the reconstitution of the tablet(s) in 240 ml of water. Zytiga® tablets were obtained commercially and were administered orally as four 250 mg tablets swallowed with 240 ml of water. In both studies venous blood samples of approximately 4 ml were collected for the determination of plasma concentrations of abiraterone immediately prior to dosing and at 0.25, 0.5, 0.75, 1, 1.5 2, 3, 4, 6, 8, 12, 16, 24, 48 and 72 hours post dose and pharmacokinetic parameters were calculated. The minimum washout period between the consecutive doses was at least 7 days.

[0302] In Study C01 subjects (n=12) were administered 1-4 abiraterone acetate tablets for oral suspension (corresponding to 62.5 mg, 125 mg, 187.5 mg and 250 mg of abiraterone acetate) in the fasted state. Study C02 (n=20) was a comparative study between 1000 mg Zytiga® and 250 mg abiraterone acetate tablet for oral suspension (four tablets) including the investigation of the effect of food on the pharmacokinetics of the tablet for oral suspension. Subjects were administered Zytiga® in the fasted state and in the modified fasting state (meal 2 hours before administration, as described in the Zytiga® label), while the tablet for oral suspension was administered in the fasted state and after an FDA standard high-fat breakfast which was consumed within 30 minutes prior to dosing.

[0303] Following the administration of increasing doses of abiraterone acetate tablet for oral suspension in the fasted state (C01 study) mean abiraterone plasma concentrations increased rapidly to peak and declined in a biphasic manner. Mean t.sub.max occurred within 1 hour regardless of dose. Dose proportional increases of C.sub.max, and more, than dose proportional increases of AUC were observed. AUC and C.sub.max values indicated that in the fasted state the pharmacokinetic parameters for the 250 mg abiraterone acetate tablet for oral suspension will fall between the lower and upper limits (Table 8).

[0304] Comparative investigations with Zytiga® (C02 study) were in agreement with this prediction. In the fasted state 1000 mg Zytiga® exhibited very low plasma concentrations, while in the modified fasting state AUC and C.sub.max increased 6.5-times and 5.3-times, respectively. AUC and C.sub.max for abiraterone acetate tablet for oral suspension fell between this range in the fasted state. A high-fat breakfast reduced AUC and C.sub.max by 25% and 65%, respectively. As a result, while C.sub.max was still in the range defined by the Zytiga® arms, AUC was slightly (˜10%) below the minimal AUC defined by 1000 mg Zytiga® when taken in the fasted state. (Table 9).

[0305] In conclusion, a single daily 250 mg dose of the abiraterone acetate tablet for oral suspension satisfies the FDA defined conditions for Zytiga® equivalent formulations when administered in the fasted state, while AUC falls ˜10% below the lower limit in the fed state. Repeat dose simulations indicate that trough concentrations are below 8.2 ng/ml, which was shown to be an important threshold for the pharmacological response to therapy. 250 mg BID dosing satisfies the equivalence criteria for both C.sub.max and AUC in both the fasted and the fed states, while simulation of repeat BID dosing indicates that trough plasma levels will be 13-14 ng/ml. In summary, 250 mg BID is expected to deliver adequate and safe abiraterone plasma levels with more reliable abiraterone plasma concentrations when compared to Zytiga® without the need to take the drug on an empty stomach. Furthermore, the novel dosage form (water dispersible tablet) allows more convenient drug administration in patients with dysphagia or with problems with the large pill burden of taking four large Zytiga® tablets.

TABLE-US-00009 TABLE 8 Pharmacokinetic parameters (mean +/− SD) of abiraterone following the oral administration of increasing doses of abiraterone tablet for oral suspension in the fasted state. Dose (mg) t.sub.max (h) C.sub.max (ng/ml) AUC.sub.last (h*ng/ml) T1/2 (h) 62.5 0.73 ± 0.33 47.6 ± 26.9 97.4 ± 41.7 15.6 ± 2.0 125 0.70 ± 0.31 147.0 ± 101.1 261.6 ± 105.6 17.3 ± 5.7 187.5 0.68 ± 0.16 296.5 ± 166.4 544.5 ± 202.0 15.8 ± 5.8 250 0.86 ± 0.13 451.7 ± 190.1 913.1 ± 350.2 14.6 ± 7.6

TABLE-US-00010 TABLE 9 Pharmacokinetic parameters (mean +/− SD) of abiraterone following the oral administration of 250 mg abiraterone acetate tablet for oral suspension or 1000 mg Zytiga ® at different prandial states. Abiraterone Abiraterone acetate tablet acetate tablet for oral for oral Zytiga suspension suspension Zytiga Modified Fasted Fed Fasted Fasted AUC(ng*h/ml) 715 534 606 3926 2*AUC(ng*h/ml) 1431 1070 N.A. N.A. Cmax(ng/ml) 381 140 119 632 tmax(h) 0.7 0.9 1.9 2.7