HK1234990A1 - Abiraterone acetate formulation and methods of use - Google Patents

Description

Abiraterone acetate formulations and methods of use

Background

Abiraterone ((3 β) -17- (pyridin-3-yl) androsta-5, 16-dien-3-ol; CAS #: 154229-19-3; molecular formula C₂₄H₃₁NO; molecular weight: 349.5g/mol) is an inhibitor of CYP17 and thus interferes with androgen synthesis in testicular, adrenal and prostate tumor tissues. Abiraterone acetate (17- (3-pyridyl) androstane-5, acetate; CAS #154229-18-2) (a prodrug of abiraterone) is approved in the United states for the treatment of castration-resistant prostate cancer (castration-resistant prostate cancer). Abiraterone acetate is considered to be poorly water soluble.

Tablets (250 mg; national drug code 57894-; NDA 202379) were approved in the United states for use in combination with prednisone in the treatment of patients with metastatic castration-resistant prostate cancer.Prescription information for tablets suggests once daily oral administration of 1,000mg (4 × 250mg tablets) in combination with twice daily oral administration of prednisone (5mg)For administration in combination with prednisone or prednisolone.

The prescription information of (a) indicates that it must be taken on an empty stomach and that food should not be taken at least 2 hours before and at least 1 hour after taking the drug. Prescription information indicates that in patients with metastatic, castration-resistant prostate cancer, at a dose of 1000mg per day, C_maxThe steady state value (mean. + -. SD) of (1) was 226. + -. 178ng/mL, and the steady state value of AUC was 1173. + -. 690 ng.hr/mL.Single dose (1000mg) crossover studies in healthy subjects found whenWhen administered with food, the systemic exposure to abiraterone was increased. In particular, whenAbiraterone C when administered with a low fat diet (7% fat, 300 calories) compared to administration in the fasted state_maxAnd AUC_0-∞About 7 times and 5 times higher, respectively. When in useAbiraterone C when administered with a high fat diet (57% fat, 825 calories) compared to administration in the fasted state_maxAnd AUC_0-∞About 17 and 10 times higher, respectively.

Disclosure of Invention

The present disclosure describes pharmaceutical compositions, including unit dosage forms, comprising abiraterone acetate therein, as well as methods for making and using such compositions.

Described herein are unit dosage forms of abiraterone acetate, wherein a 500mg dose of the unit dosage form is bioequivalent to a 1000mg dose in healthy male subjects in the fasted stateIt also describes: unit dosage form of abiraterone acetate, wherein a 500mg dose is administered to healthy male subjects in the fasted state and a 1000mg dose is administered to healthy male subjects in the fasted stateIn contrast, AUC_(0-∞)The ratio of the logarithms of the geometric means of (a) is selected from: 0.6 to 1.4, 0.7 to 1.3, 0.8 to 1.2, and 0.9 to 1.1; abiraterone acetate monoDosage form, wherein the dosage is 500mg for healthy male subjects in the fasted state and 1000mg for healthy male subjects in the fasted stateCompared with C_(max)The ratio of the logarithms of the geometric means of (a) is selected from: 0.6 to 1.4, 0.7 to 1.3, 0.8 to 1.2, and 0.9 to 1.1.

In some cases: [ D ] of Abiraterone acetate₉₀]Greater than 300nm and less than one of: 7500nm, 7000nm, 6000nm, 5000nm, 4500nm, 4000nm, 3000nm, 2000nm, 900nm, 800nm and 700 nm; [ D ] of Abiraterone acetate₅₀]Greater than 100nm and less than one of: 3500nm, 3000nm, 2500nm, 1600nm, 1400nm, 1200nm, 1000nm, 800nm, 500nm, 400nm and 300 nm; [ D ] of Abiraterone acetate_4,3]Greater than 300nm and less than one of: 7000nm, 6000nm, 5000nm, 4000nm, 3000nm, 2500nm, 2400nm, 2200nm, 2000nm, 1900nm, 1700nm, 1500nm, 1300nm, 1100nm, 900nm and 800 nm; the dissolution rate of abiraterone acetate in the unit dosage form is such that when a sample containing 100mg of abiraterone acetate is tested in 900ml of pH4.5 phosphate buffer containing 0.1% sodium lauryl sulfate using USP apparatus II at 75rpm, at least 70% of the abiraterone acetate dissolves in between 5 and 15 minutes or between 5 and 10 minutes; the dissolution rate of the abiraterone acetate in the unit dosage form is such that when a sample containing 125mg of fine particle abiraterone acetate is tested in 900ml of pH4.5 phosphate buffer containing 0.12% sodium lauryl sulfate using USP apparatus II at 75rpm, at least 70% of the abiraterone acetate dissolves in between 5 and 15 minutes or between 5 and 10 minutes; the unit dosage form contains 125mg of abiraterone acetate.

Also described are unit dosage forms of pharmaceutical compositions containing abiraterone acetate, wherein a 500mg dose, when administered orally to a population of healthy male subjects in the fasted state, provides a mean plasma Cmax of 50-120ng/ml_max. In some cases: when a 500mg dose is orally administered to a population of healthy male subjects in the fasted stateProvides a median plasma t of 1 to 2.5 hours_max. Described herein are unit dosage forms of pharmaceutical compositions comprising abiraterone acetate, wherein a mean plasma AUC of 240-_(0-∞). In some cases, the unit dosage form contains 125mg of abiraterone acetate.

It also describes: unit dosage form of a pharmaceutical composition comprising abiraterone acetate, wherein the mean plasma Cmax is the mean plasma Cmax when a 500mg dose is administered to healthy male subjects in the fasted state_maxA 90% confidence interval of between 50 and 120 ng/ml; and a unit dosage form of a pharmaceutical composition comprising abiraterone acetate, wherein the mean plasma AUC when a 500mg dose is administered to healthy male subjects in the fasted state_(0-∞)The 90% confidence interval of (c) is a value between 240 and 650h ng/ml.

The unit dosage forms described herein can contain an antioxidant (e.g., one or both of BHA and BHT).

Also described herein are methods for treating castration-resistant prostate cancer comprising administering to a patient in need thereof a therapeutically effective dose (e.g., 500mg) of an abiraterone acetate unit dosage form described herein and a glucocorticoid. In various embodiments: the glucocorticoid is selected from prednisone, prednisolone and methylprednisolone; the therapeutically effective dose is 500 mg/day; the therapeutically effective dose is administered using a dosage form containing: 100mg, 125mg or 150mg of abiraterone acetate; the 500mg dose is administered using 1, 2, 3, 4, 5 or 6 unit dosage forms.

Described herein is a method for producing a composition containing abiraterone acetate, the method comprising: dry milling a composition comprising abiraterone acetate, a millable grinding compound, an accelerating agent, and one or both of an antioxidant and a chelating agent in a mill for a time sufficient to produce a composition comprising milled abiraterone acetate, wherein the particle size of the abiraterone acetate is reduced by dry milling.

In some cases of the production method: [ D ] of Abiraterone acetate in milled compositions₉₀]Greater than 400nm and less than one of: 7500nm, 7000nm, 6000nm, 5000nm, 4500nm, 4000nm, 3000nm, 2000nm, 900nm, 800nm and 700 nm; [ D ] of Abiraterone acetate in milled compositions₅₀]Greater than 100nm and less than 3500nm, 3000nm, 2500nm, less than l600nm, less than 1400nm, less than 1200nm, less than 1000nm, less than 800nm, less than 500nm, less than 400nm, less than 300 nm; the dissolution rate of abiraterone acetate in the milled composition is such that when a sample containing 100mg of abiraterone acetate is tested in 900ml of pH4.5 phosphate buffer containing 0.1% sodium lauryl sulfate using USP apparatus II at 75rpm, at least 70% of the abiraterone acetate dissolves in between 5 and 15 minutes or between 5 and 10 minutes; the dissolution rate of abiraterone acetate in the milled composition is such that when a sample containing 125mg of abiraterone acetate is tested in 900ml of pH4.5 phosphate buffer containing 0.12% sodium lauryl sulfate using USP apparatus II at 75rpm, at least 70% of the abiraterone acetate dissolves in between 5 and 15 minutes or between 5 and 10 minutes; [ D ] of Abiraterone acetate in milled compositions₅₀]Greater than 200nm and less than 6500nm, 6000nm, 5500nm, less than 5000nm, less than 4000nm, less than 3000nm or less than 2000 nm; and the method further comprises: the composition containing abiraterone acetate fine particles is combined with one or more pharmaceutically acceptable diluents, disintegrants, lubricants, glidants or dispersants to prepare a unit dosage form.

In various embodiments, the particles of abiraterone acetate in the pharmaceutical composition (or for use in preparing a pharmaceutical composition) have a particle volume basis ([ D ])₅₀]Or D_[50]Or [ D50]]) A median particle diameter determined equal to or less than a size selected from the group consisting of: 5000nm, 4000nm, 3000nm, 2500nm, 2400nm, 2300nm, 2200nm, 2100nm, 2000nm, 1900nm, 1800nm, 1700nm, 1600nm, 1500nm, 1400nm, 1300nm, 1200nm, 1100nm, 1000nm, 900nm, 800nm, 700nm, 600nm, 500nm, 400nm, 300nm, and 200 nm. In some embodiments, [ D50]]Equal to or greater than 25nmOr 100nm or even 500 nm. In various embodiments, [ D50]]Between 5000nm and 100nm, between 3500nm and 100nm, between 2500nm and 100nm, between 1500nm and 100nm, between 1200nm and 100nm, between 1100nm and 100nm, between 1000nm and 100nm, between 800nm and 100nm, between 700nm and 100nm, between 600nm and 100nm, between 500nm and 100 nm. In various embodiments, D [4, 3]](volume average diameter) is: less than 7000nm, less than 5000nm, less than 3500nm, less than 3000nm, less than 2000nm, less than 1000 or less than 300 nm. In each case, e.g. those described above, D [4, 3]]Greater than 100nm or greater than 200 nm. In some cases, D [4, 3]](volume average diameter) is between: between 7000nm and 1000nm, between 6000nm and 200nm, between 5000nm and 1000nm, between 4000nm and 1000nm, between 3000nm and 1000nm, between 2000nm and 1000nm, between 1800nm and 1000nm, between 1600nm and 1000nm, between 1500nm and 500nm, between 4000nm and 2000nm, between 4000nm and 100nm, between 25000nm and 500nm, between 700nm and 100nm, between 600nm and 100nm, between 500nm and 100nm, between 1000nm and 200nm, between 900nm and 200nm, between 800nm and 200nm, between 700nm and 200 nm. In various embodiments, [ D90]]([D₉₀]Or D_[90]) Comprises the following steps: less than 8000nm, less than 7500nm, less than 7000nm, less than 6000nm, less than 4000nm, less than 2000nm, less than 1000nm, less than 500 nm. In some cases, D90 is between 5500nm and 300nm, 5000nm and 500nm, 4500nm and 500nm, 4000nm and 200nm, 4500nm and 750nm, and 3500nm and 500 nm. In various embodiments described herein, [ D90] of abiraterone acetate]Less than 5000nm or less than 4000 nm. In some embodiments, [ D ]₉₀]Comprises the following steps: 6000nm-500nm, 5500nm-500nm or 5000nm-500nm and 4000 nm-400 nm.

In another embodiment, the abiraterone acetate crystallinity characteristics are selected from: at least 20% of the abiraterone acetate is crystalline, at least 30% of the abiraterone acetate is crystalline, at least 40% of the abiraterone acetate is crystalline, at least 50% of the abiraterone acetate is crystalline, at least 60% of the abiraterone acetate is crystalline, at least 70% of the abiraterone acetate is crystalline, at least 75% of the abiraterone acetate is crystalline, at least 85% of the abiraterone acetate is crystalline, at least 90% of the abiraterone acetate is crystalline, at least 95% of the abiraterone acetate is crystalline, and at least 98% of the abiraterone acetate is crystalline. In some embodiments, the crystallinity characteristic of abiraterone acetate is substantially equal to the crystallinity characteristic of abiraterone acetate prior to subjecting the material to the method as described herein.

In another embodiment, the amorphous content of abiraterone acetate is selected from: less than 80% of the abiraterone acetate is amorphous, less than 70% of the abiraterone acetate is amorphous, less than 60% of the abiraterone acetate is amorphous, less than 50% of the abiraterone acetate is amorphous, less than 40% of the abiraterone acetate is amorphous, less than 30% of the abiraterone acetate is amorphous, less than 25% of the abiraterone acetate is amorphous, less than 15% of the abiraterone acetate is amorphous, less than 10% of the abiraterone acetate is amorphous, less than 5% of the abiraterone acetate is amorphous, and less than 2% of the abiraterone acetate is amorphous. In some embodiments, the amorphous content of abiraterone acetate does not increase significantly after subjecting the material to the dry milling process described herein.

In some embodiments, the particles of abiraterone acetate are prepared by dry milling the abiraterone acetate with the millable grinding compound and the promoting agent in the presence of a milling body. Additional components may be present during milling, and the various components present during milling (in addition to abiraterone acetate and milling bodies) are collectively referred to as the milling matrix. In some cases, milling produces significantly reduced size abiraterone acetate particles dispersed in a milling matrix. Since all the components in the grinding matrix are pharmaceutically acceptable, a mixture of abiraterone acetate produced by grinding and the grinding matrix can be used to prepare the pharmaceutical composition. In some cases, some or all of the components of the grinding matrix decrease in size during grinding. In some cases, additional pharmaceutically acceptable components may be added to the mixture of abiraterone acetate and grinding matrix after grinding. In some embodiments, the dry milling is performed in the presence of milling bodies; in other cases, the particles are produced by milling in the absence of milling bodies, such as by milling in a jet mill or by other types of mills, such as mills that can reduce the particle size and/or increase the solubility of abiraterone acetate (when abiraterone acetate is milled in the presence of the millable milling compound, the particle size of the millable milling compound itself may or may not be reduced).

In some cases, abiraterone acetate is milled with one or more millable milling compounds selected from the group consisting of: lactose (e.g. lactose monohydrate or anhydrous lactose) and mannitol and one or more facilitator agents selected from sodium lauryl sulfate and povidone. In some cases, in addition to reducing the particle size of abiraterone acetate, milling also reduces the particle size of one or more components of the milling matrix. Thus, in some cases, milling reduces the particles of one or more materials (e.g., lactose) used as the millable milling compound. In some cases, abiraterone acetate is milled with lactose (e.g., lactose monohydrate) and sodium lauryl sulfate. In some cases, during dry milling, abiraterone acetate can be present from 20-60% (w/w), lactose up to 80% (w/w), mannitol up to 80% (w/w) and each (or both) of povidone and sodium lauryl sulfate from 1-10% (w/w).

In some embodiments, in addition to the at least one millable grinding compound and the at least one accelerating agent, abiraterone acetate is dry milled in the presence of one or more antioxidants and/or one or more chelating agents (i.e., agents that can chelate ions, such as metal ions). Thus, one or more of Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), ascorbic acid, fumaric acid, tartaric acid, and citric acid (e.g., anhydrous citric acid), or mixtures thereof, may be present during dry-milling. In some cases, at least one antioxidant and at least one chelating agent are present simultaneously during milling. During milling, ascorbic acid, fumaric acid, tartaric acid, and citric acid (e.g., anhydrous citric acid) may be present at 8% or less (e.g., 7% -0.1%, 1% -0.1%, or 0.2%, individually or in combination) on a w/w basis, and BHT and BHA may be present at 0.5% or less (e.g., 0.5% -0.01%, 0.2% -0.08%, 0.15% -0.05%, or 0.1%, individually or in combination). After milling is complete, one or more additional antioxidants and/or one or more additional chelating agents may be added to the milled material.

The pharmaceutical composition can be in unit dosage form, such as a capsule or tablet containing 50-500mg of abiraterone acetate (e.g., 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 115, 120, 125, 130, 135, 140, 145, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or 500mg) wherein the abiraterone acetate has a size distribution and/or dosage form having a dissolution profile as described herein.

Also described herein are methods for treating a patient comprising administering a daily dose of 1000mg to 50mg of abiraterone acetate (e.g., 900, 850, 800, 750, 700, 650, 600, 550, 525, 500, 475, 450, 425, 400, 375, 350, 325, 300, 275, 250, 225, 200, 150, 100, 90, 80, 70, 60, or 50mg) in the form of a pharmaceutical composition described herein (e.g., by administering one or more units of a unit dosage form described herein containing abiraterone acetate), wherein the abiraterone acetate has a size distribution described herein and/or the dosage form has a dissolution profile described herein. The patient may also be treated with a glucocorticoid such as prednisone, prednisolone, or dexamethasone. Alternatively, the patient may be treated with methylprednisolone, for example at 5-15 mg/day (e.g. 5, 6, 7, 8, 9, 10 mg/day, e.g. two 4mg doses/day). In some cases, patients, e.g., patients without liver damage, are treated at 500 mg/day by administering four 125mg abiraterone acetate unit dosage forms as described herein.

In some cases, for the dosage forms described herein, when administered with a low-fat diet (7% fat, 300 calories)In a single dose, the AUC of a unit dosage form described herein (or an effective dose thereof, e.g., 4 × 125mg)_0-∞Is 4-fold or less (3-fold or less, 2-fold or less, 1.5-fold or less) higher than when administered in the fasting state.

In some cases, for the dosage forms described herein, a single dose of a unit dosage form described herein (or an effective dose thereof, e.g., 4 × 125mg) has an AUC when administered with a high fat diet (57% fat, 825 calories)_0-∞(or AUC)_0-t) Is 8 times or less (7 times or less, 5 times or less, 3 times or less, 2 times or less, 1.5 times or less) higher than that when administered in the fasting state.

In some cases, for the dosage forms described herein, a single dose of a unit dosage form described herein (or an effective dose thereof, e.g., 4 × 125mg) of C when administered with a high fat diet (57% fat, 825 calories)_maxIs 15 times or less (13 times or less or 12 times or less, 11 times or less, 10 times or less, 9 times or less, 8 times or less, 7 times or less, 6 times or less, 5 times or less) higher than when administered in the fasting state.

In some cases, for the dosage forms described herein, a single dose of a unit dosage form described herein (or approved dose thereof, e.g., 4 × 125mg) of C when administered with a low fat diet (7% fat, 300 calories)_maxIs 6-fold or less (5-fold or less or 4-fold or less, 3-fold or less, 2-fold or less, 1.5-fold or less) higher than when administered in the fasting state.

Tablets containing 100mg or 125mg of abiraterone acetate have a dissolution rate such that at least 90% or at least 95% of the abiraterone acetate dissolves in 20 minutes or less (e.g., 19 minutes or less, 18 minutes or less, 17 minutes or less, 16 minutes or less, 15 minutes or less, 14 minutes or less, 13 minutes or less, 11 minutes or less, 9 minutes or less) when tested using USP apparatus II at 75rpm in 900ml of pH4.5 phosphate buffer containing 0.1% to 0.12% sodium lauryl sulfate (respectively). For example, 90% may dissolve in 9-19 minutes. In the case of tablets containing more than 125mg or less than 100mg of abiraterone acetate, the dissolution rates given are for a portion of the larger tablet (or tablets) providing 100-125mg of abiraterone acetate. In some cases, at least 80% or at least 85% of the abiraterone acetate dissolves in 15 minutes or less (e.g., 14 minutes or less, 13 minutes or less, 12 minutes or less, 11 minutes or less, 10 minutes or less, 9 minutes or less, 8 minutes or less, or 7 minutes or less). For example, 85% may dissolve in 7-14 minutes.

In some cases, at least 80% or at least 85% of the abiraterone acetate in a 125mg unit dosage form dissolves in 15 minutes or less (e.g., 14 minutes or less, 13 minutes or less, 12 minutes or less, 11 minutes or less, 10 minutes or less, 9 minutes or less, 8 minutes or less, or 7 minutes or less) after storage for 4 weeks or more (e.g., 8 weeks or 12 weeks) at 25 ℃, 60% RH. In some cases, at least 95% of the abiraterone acetate dissolves in 15 minutes or less (e.g., 14 minutes or less, 13 minutes or less, 11 minutes or less, 9 minutes or less) after storage at 40 ℃, 75% RH for 3 weeks or more (e.g., 6 weeks or 9 weeks). For example, 95% may dissolve in 8-14 minutes. In addition, where the tablets contain greater than 125mg or less than 100mg of abiraterone acetate, the dissolution rates given are for a portion of the larger tablet (or a plurality of smaller tablets) that provide 100-125mg of abiraterone acetate.

In certain embodiments, the observed at C for the pharmaceutical compositions described herein when administered to healthy patients in the fasted state_max、AUC_(0-t)And AUC_(0-∞)Will be less than 60%, less than 50%, less than 40%, less than 30%, less than 25%, or less than 20%. in some embodiments, the pharmaceutical compositions described herein (125mg unit dosage form or 500mg unit dosage form, e.g., 4 × 125mg) are relative to, e.g., 250mg dosage form(or 1000 doses of 250mg dosage form)) In a comparable pharmacokinetic test at C_max、AUC_(0-t)And AUC_(0-∞)Exhibit minor variations in one or more of them.

In some cases, the abiraterone tablet has a hardness of between 100N and 190N (e.g., 110N to 180N).

The drug product intermediate may be prepared by dry milling: (A) 5-60% by weight abiraterone acetate, 30-95% by weight lactose (e.g. lactose monohydrate), 0.1-15% by weight sodium lauryl sulfate; 0.001-1 wt.% BHA and 0.001-1 wt.% BHT; (B) 10-50% by weight abiraterone acetate, 40-80% by weight lactose (e.g. lactose monohydrate), 0.5-10% by weight sodium lauryl sulfate; 0.01-0.8% by weight BHA and 0.01-0.8% by weight BHT; (C) 20-40% by weight abiraterone acetate, 50-70% by weight lactose (e.g. lactose monohydrate), 2-8% by weight sodium lauryl sulfate; 0.05-0.5% by weight BHA, and 0.05-0.5% by weight BHT; (D) 25-35% by weight abiraterone acetate, 60-70% by weight lactose (e.g. lactose monohydrate), 4-8% by weight sodium lauryl sulfate; 0.05-0.15 wt.% BHA, and 0.05-0.15 wt.% BHT; and (E) 30% by weight abiraterone acetate, 63.8% by weight lactose (e.g. lactose monohydrate), 6% by weight sodium lauryl sulfate; 0.1% by weight of BHA, 0.1% by weight of BHT.

The drug product intermediate described above can be processed into tablets with the following materials: (A) 5-50% by weight abiraterone acetate, 5-80% by weight lactose (e.g. lactose monohydrate), 0.1-10% by weight sodium lauryl sulfate, 0.001-1% by weight BHA, 0.001-1% by weight BHT, 5-80% by weight microcrystalline cellulose, 0.5-20% by weight croscarmellose sodium and 0.01-10% by weight sodium stearyl fumarate; (B) 8-40% by weight abiraterone acetate, 10-60% by weight lactose (e.g. lactose monohydrate), 0.5-8% by weight sodium lauryl sulfate, 0.01-0.05% by weight BHA, 0.01-0.5% by weight BHT, 10-70% by weight microcrystalline cellulose, 1-15% by weight croscarmellose sodium and 0.05-5% by weight sodium stearyl fumarate; (C) 10-30% by weight abiraterone acetate, 20-40% by weight lactose (e.g. lactose monohydrate), 1-5% by weight sodium lauryl sulfate; 0.01-0.2 wt.% BHA, 0.01-0.2 wt.% BHT, 20-60 wt.% microcrystalline cellulose, 2-10 wt.% croscarmellose sodium and 0.1-2 wt.% sodium stearyl fumarate; (D) 12-17% by weight abiraterone acetate, 25-35% by weight lactose (e.g. lactose monohydrate), 2-5% by weight sodium lauryl sulfate; 0.01-0.2 wt.% BHA, 0.01-0.2 wt.% BHT, 35-50 wt.% microcrystalline cellulose, 5-9 wt.% croscarmellose sodium and 0.2-0.8 wt.% sodium stearyl fumarate; and (E) 14.29% by weight abiraterone acetate, 30.38% by weight lactose (e.g. lactose monohydrate), 3.21% by weight sodium lauryl sulfate; 0.05% by weight of BHA, 0.05% by weight of BHT, 44-53% by weight of microcrystalline cellulose, 7% by weight of croscarmellose sodium and 0.5% by weight of sodium stearyl fumarate.

In some embodiments, the dry milling apparatus for dry milling abiraterone acetate is a mill selected from the group consisting of: attritor mill (horizontal or vertical), nutating mill, tower mill, bead mill (pearl mill), planetary mill, vibratory mill, eccentric vibratory mill, gravity-dependent ball mill, rod mill, roller mill, and crushing mill. In some embodiments, the dry milling apparatus for dry milling abiraterone acetate is a mill selected from the group consisting of: jet mills, screw jet mills, micro-mills or pulverizers. Preferably, the method is configured to produce abiraterone acetate in a rocking batch (swing batch) or continuous manner.

In some embodiments, when the mill uses milling bodies, the milling bodies within the milling apparatus are mechanically agitated by 1, 2, or 3 axes of rotation. The abrasive body may be formed from a material selected from the group consisting of: ceramics, glass, steel, polymers, ferromagnetic materials, and metals, among other suitable materials. In some embodiments, the abrasive body is a steel ball having a diameter selected from the group consisting of: 1 to 20mm, 2 to 15mm and 3 to 10 mm. In various embodiments of the dry milling method, the abrasive bodies are zirconia balls having a diameter selected from the group consisting of: 1 to 20mm, 2 to 15mm and 3 to 10 mm.

In another embodiment, the milling time is selected from the following ranges: 10 minutes to 6 hours, 10 minutes to 2 hours, 10 minutes to 90 minutes, 10 minutes to 1 hour, 10 minutes to 45 minutes, 10 minutes to 30 minutes, 5 minutes to 20 minutes, 2 minutes to 10 minutes, 2 minutes to 5 minutes, 1 minute to 2 minutes.

Additional abrasive matrix and promoting agent

In embodiments, the abrasive matrix is a single material or a mixture of two or more materials in any ratio. In some embodiments, the single material or the mixture of two or more materials is selected from: mannitol, sorbitol, isomalt, xylitol, maltitol, lactitol, erythritol, arabitol, ribitol, glucose, fructose, mannose, galactose, anhydrous lactose, lactose monohydrate, sucrose, maltose, trehalose, and maltodextrin. In some embodiments, the single material or the mixture of two or more materials is selected from: dextrin, inulin, dextrates, polydextrose, starch, wheat flour, corn flour, rice starch, tapioca flour, tapioca starch, potato flour, potato starch, other flours and starches, milk powder, skim milk powder, other milk solids and derivatives, soybean flour, soybean meal or other soybean products, cellulose, microcrystalline cellulose-based blend materials, pregelatinized (or partially gelatinized) starch, hypromellose, carboxymethylcellulose, hydroxypropylcellulose, citric acid, tartaric acid, malic acid, maleic acid, fumaric acid, ascorbic acid, succinic acid, sodium citrate, sodium tartrate, sodium malate, sodium ascorbate, potassium citrate, potassium tartrate, potassium malate, sodium acetate, potassium ascorbate, sodium carbonate, potassium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium carbonate, calcium hydrogen phosphate, calcium bicarbonate, calcium carbonate, and the like, Calcium phosphate, sodium sulfate, sodium chloride, sodium metabisulfite, sodium thiosulfate, ammonium chloride, mirabilite, ammonium carbonate, sodium bisulfate, magnesium sulfate, potassium alum, potassium chloride, sodium bisulfate, sodium hydroxide, crystalline hydroxides, bicarbonates, ammonium chloride, methylamine hydrochloride, ammonium bromide, silica, thermal silica, alumina, titanium dioxide, talc, chalk, mica, kaolin, bentonite, hectorite, magnesium trisilicate, clay-based or aluminum silicates, sodium lauryl sulfate, sodium stearyl sulfate, sodium cetyl sulfate, sodium cetostearyl sulfate, docusate sodium, deoxycholate sodium, N-lauroylsarcosine sodium salt, glyceryl monostearate, glyceryl distearate, glyceryl palmitostearate, glyceryl behenate, glyceryl caprylate, glyceryl oleate, benzalkonium chloride, cetrimide, ammonium chloride, sodium chloride, ammonium carbonate, sodium laurylsarcosine, sodium stearate, magnesium sulfate, potassium sulfate, cetrimide, cetylpyridinium chloride, cetylpyridinium bromide, benzethonium chloride, polyoxyl 40 stearate, polyoxyl 100 stearate, poloxamer 188, poloxamer 338, poloxamer 407, polyoxyethylene 2 stearyl ether, polyoxyethylene 100 stearyl ether, polyoxyethylene 20 stearyl ether, polyoxyethylene 10 stearyl ether, polyoxyethylene 20 cetyl ether, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polyoxyethylene 35 castor oil, polyoxyethylene 40 castor oil, polyoxyethylene 60 castor oil, polyoxyethylene 100 castor oil, polyoxyethylene 200 castor oil, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 60 hydrogenated castor oil, polyoxyethylene 100 hydrogenated castor oil, polyoxyethylene 200 hydrogenated castor oil, cetearyl alcohol, polyoxyl 15-hydroxystearate (macrogol 15hydroxystearate), Sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate, sucrose palmitate, sucrose stearate, sucrose distearate, sucrose laurate, glycocholic acid, sodium glycocholate, cholic acid, sodium cholate, sodium deoxycholate, deoxycholic acid, sodium taurocholate, taurocholic acid, sodium taurodeoxycholate, taurodeoxycholic acid, soybean lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkylnaphthalenesulfonate condensate/lignosulfonate blend, calcium dodecylbenzenesulfonate, sodium dodecylbenzenesulfonate, diisopropylnaphthalenesulfonate, erythritol distearate, naphthalenesulfonate formaldehyde condensate, nonylphenol ethoxylate (poe-30), tristyrylphenol ethoxylate (tristyrylphenol ethyoxyl), Polyoxyethylene (15) tallow alkylamine, sodium alkylnaphthalene sulfonate condensate, sodium alkylbenzenesulfonate, sodium isopropylnaphthalene sulfonate, sodium methylnaphthalene formaldehyde sulfonate, sodium n-butylnaphthalene sulfonate, tridecyl alcohol ethoxylate (poe-18), triethanolamine isodecanol phosphate, triethanolamine tristyryl phosphate, tristyrylphenol ethoxylate sulfate, bis (2-hydroxyethyl) tallow alkylamine.

In some embodiments, the concentration of the single (or first) component of the abrasive matrix is selected from: 5-99% w/w, 10-95% w/w, 15-85% w/w, 20-80% w/w, 25-75% w/w, 30-60% w/w, 40-50% w/w. In some embodiments, the concentration of the second or subsequent component of the abrasive matrix is selected from: 5-50% w/w, 5-40% w/w, 5-30% w/w, 5-20% w/w, 10-40% w/w, 10-30% w/w, 10-20% w/w, 20-40% w/w or 20-30% w/w, or if the second or subsequent material is a surfactant or a water-soluble polymer, said concentration is selected from 0.1-10% w/w, 0.1-5% w/w, 0.1-2.5% w/w, 0.1-2% w/w, 0.1-1%, 0.5-5% w/w, 0.5-3% w/w, 0.5-2% w/w, 0.5-1.5%, 0.5-1% w/w, 0.75-1.25% w/w, 0.75-1% and 1% w/w.

In some embodiments, abiraterone acetate is milled in the presence of:

(a) lactose monohydrate or lactose monohydrate in combination with at least one substance selected from the group consisting of: xylitol; anhydrous lactose; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; trisodium citrate dihydrate; d, L-malic acid; sodium pentane sulfate; sodium stearyl sulfate; polyoxyethylene 100 stearyl ether; polyoxyethylene 10 stearyl ether; n-lauroyl sarcosine sodium; lecithin; docusate sodium; polyoxyethylene-40-stearic acid; hydrophobic colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants having chain lengths between C5 and C18; polyvinylpyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG6000, sodium lauryl sulfate and PEG8000, sodium lauryl sulfate and PEG10000, sodium lauryl sulfate and polyoxyethylene 100 stearyl ether, sodium lauryl sulfate and poloxamer 407, sodium lauryl sulfate and poloxamer 338, sodium lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer 338, poloxamer 188, an alkylnaphthalene sulfonate condensate/lignosulfonate blend; calcium dodecylbenzenesulfonate (branched); diisopropyl naphthalene sulfonic acid; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; a naphthalenesulfonic acid-formaldehyde condensate; nonylphenol ethoxylate, POE-30; phosphate esters, tristyrylphenol ethoxylate, free acids; polyoxyethylene (15) tallow alkylamine; sodium alkylnaphthalene sulfonate; sodium alkylnaphthalenesulfonate condensates; sodium alkyl benzene sulfonate; sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; a formaldehyde sulfonate; n-butylnaphthalene sulfonic acid sodium salt; tridecyl alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate; triethanolamine tristyryl phosphate; tristyrylphenol ethoxylate sulfate; bis (2-hydroxyethyl) tallow alkylamine.

(b) Anhydrous lactose or anhydrous lactose in combination with at least one substance selected from the group consisting of: lactose monohydrate; xylitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; trisodium citrate dihydrate; d, L-malic acid; sodium pentane sulfate; sodium stearyl sulfate; polyoxyethylene 100 stearyl ether; polyoxyethylene 10 stearyl ether; n-lauroyl sarcosine sodium; lecithin; docusate sodium; polyoxyethylene-40-stearic acid; hydrophobic colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants having chain lengths between C5 and C18; polyvinylpyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG6000, sodium lauryl sulfate and PEG8000, sodium lauryl sulfate and PEG10000, sodium lauryl sulfate and polyoxyethylene 100 stearyl ether, sodium lauryl sulfate and poloxamer 407, sodium lauryl sulfate and poloxamer 338, sodium lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer 338, poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate blend; calcium dodecylbenzenesulfonate (branched); diisopropyl naphthalene sulfonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; a naphthalenesulfonic acid-formaldehyde condensate; nonylphenol ethoxylate, POE-30; phosphate esters, tristyrylphenol ethoxylate, free acids; polyoxyethylene (15) tallow alkylamine; sodium alkylnaphthalene sulfonate; sodium alkylnaphthalenesulfonate condensates; sodium alkyl benzene sulfonate; sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; a formaldehyde sulfonate; n-butylnaphthalene sulfonic acid sodium salt; tridecyl alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate; triethanolamine tristyryl phosphate; tristyrylphenol ethoxylate sulfate; bis (2-hydroxyethyl) tallow alkylamine.

(c) Mannitol or mannitol in combination with at least one substance selected from the group consisting of: lactose monohydrate; xylitol; anhydrous lactose; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; trisodium citrate dihydrate; d, L-malic acid; sodium pentane sulfate; sodium stearyl sulfate; polyoxyethylene 100 stearyl ether; polyoxyethylene 10 stearyl ether; n-lauroyl sarcosine sodium; lecithin; docusate sodium; polyoxyethylene-40-stearic acid; hydrophobic colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants having chain lengths between C5 and C18; polyvinylpyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG6000, sodium lauryl sulfate and PEG8000, sodium lauryl sulfate and PEG10000, sodium lauryl sulfate and polyoxyethylene 100 stearyl ether, sodium lauryl sulfate and poloxamer 407, sodium lauryl sulfate and poloxamer 338, sodium lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer 338, poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate blend; calcium dodecylbenzenesulfonate (branched); diisopropyl naphthalene sulfonic acid; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; a naphthalenesulfonic acid-formaldehyde condensate; nonylphenol ethoxylate, POE-30; phosphate esters, tristyrylphenol ethoxylate, free acids; polyoxyethylene (15) tallow alkylamine; sodium alkylnaphthalene sulfonate; sodium alkylnaphthalenesulfonate condensates; sodium alkyl benzene sulfonate; sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; a formaldehyde sulfonate; n-butylnaphthalene sulfonic acid sodium salt; tridecyl alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate; triethanolamine tristyryl phosphate; tristyrylphenol ethoxylate sulfate; bis (2-hydroxyethyl) tallow alkylamine.

(d) Sucrose or sucrose in combination with at least one substance selected from the group consisting of: lactose monohydrate; anhydrous lactose; mannitol; microcrystalline cellulose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; d, L-malic acid; sodium pentane sulfate; sodium stearyl sulfate; polyoxyethylene 100 stearyl ether; polyoxyethylene 10 stearyl ether; n-lauroyl sarcosine sodium; lecithin; docusate sodium; polyoxyethylene-40-stearic acid; hydrophobic colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants having chain lengths between C5 and C18; polyvinylpyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG6000, sodium lauryl sulfate and PEG8000, sodium lauryl sulfate and PEG10000, sodium lauryl sulfate and polyoxyethylene 100 stearyl ether, sodium lauryl sulfate and poloxamer 407, sodium lauryl sulfate and poloxamer 338, sodium lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer 338, poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate blend; calcium dodecylbenzenesulfonate (branched); diisopropyl naphthalene sulfonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; a naphthalenesulfonic acid-formaldehyde condensate; nonylphenol ethoxylate, POE-30; phosphate esters, tristyrylphenol ethoxylate, free acids; polyoxyethylene (15) tallow alkylamine; sodium alkylnaphthalene sulfonate; sodium alkylnaphthalenesulfonate condensates; sodium alkyl benzene sulfonate; sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; a formaldehyde sulfonate; n-butylnaphthalene sulfonic acid sodium salt; tridecyl alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate; triethanolamine tristyryl phosphate; tristyrylphenol ethoxylate sulfate; bis (2-hydroxyethyl) tallow alkylamine.

(e) Glucose or glucose in combination with at least one member selected from the group consisting of: lactose monohydrate; anhydrous lactose; mannitol; microcrystalline cellulose; sucrose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; d, L-malic acid; sodium pentane sulfate; sodium stearyl sulfate; polyoxyethylene 100 stearyl ether; polyoxyethylene 10 stearyl ether; n-lauroyl sarcosine sodium; lecithin; docusate sodium; polyoxyethylene-40-stearic acid; hydrophobic colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants having chain lengths between C5 and C18; polyvinylpyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG6000, sodium lauryl sulfate and PEG8000, sodium lauryl sulfate and PEG10000, sodium lauryl sulfate and polyoxyethylene 100 stearyl ether, sodium lauryl sulfate and poloxamer 407, sodium lauryl sulfate and poloxamer 338, sodium lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer 338, poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate blend; calcium dodecylbenzenesulfonate (branched); diisopropyl naphthalene sulfonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; a naphthalenesulfonic acid-formaldehyde condensate; nonylphenol ethoxylate, POE-30; phosphate esters, tristyrylphenol ethoxylate, free acids; polyoxyethylene (15) tallow alkylamine; sodium alkylnaphthalene sulfonate; sodium alkylnaphthalenesulfonate condensates; sodium alkyl benzene sulfonate; sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; a formaldehyde sulfonate; n-butylnaphthalene sulfonic acid sodium salt; tridecyl alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate; triethanolamine tristyryl phosphate; tristyrylphenol ethoxylate sulfate; bis (2-hydroxyethyl) tallow alkylamine.

(f) Sodium chloride or sodium chloride in combination with at least one member selected from the group consisting of: lactose monohydrate; anhydrous lactose; mannitol; microcrystalline cellulose; sucrose; glucose; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; d, L-malic acid; sodium pentane sulfate; sodium stearyl sulfate; polyoxyethylene 100 stearyl ether; polyoxyethylene 10 stearyl ether; n-lauroyl sarcosine sodium; lecithin; docusate sodium; polyoxyethylene-40-stearic acid; hydrophobic colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants having chain lengths between C5 and C18; polyvinylpyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG6000, sodium lauryl sulfate and PEG8000, sodium lauryl sulfate and PEG10000, sodium lauryl sulfate and polyoxyethylene 100 stearyl ether, sodium lauryl sulfate and poloxamer 407, sodium lauryl sulfate and poloxamer 338, sodium lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer 338, poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate blend; calcium dodecylbenzenesulfonate (branched); diisopropyl naphthalene sulfonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; a naphthalenesulfonic acid-formaldehyde condensate; nonylphenol ethoxylate, POE-30; phosphate esters, tristyrylphenol ethoxylate, free acids; polyoxyethylene (15) tallow alkylamine; sodium alkylnaphthalene sulfonate; sodium alkylnaphthalenesulfonate condensates; sodium alkyl benzene sulfonate; sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; a formaldehyde sulfonate; n-butylnaphthalene sulfonic acid sodium salt; tridecyl alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate; triethanolamine tristyryl phosphate; tristyrylphenol ethoxylate sulfate; bis (2-hydroxyethyl) tallow alkylamine.

(g) Xylitol or a combination of xylitol and at least one substance selected from the group consisting of: lactose monohydrate; anhydrous lactose; mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; d, L-malic acid; sodium pentane sulfate; sodium stearyl sulfate; polyoxyethylene 100 stearyl ether; polyoxyethylene 10 stearyl ether; n-lauroyl sarcosine sodium; lecithin; docusate sodium; polyoxyethylene-40-stearic acid; hydrophobic colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants having chain lengths between C5 and C18; polyvinylpyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG6000, sodium lauryl sulfate and PEG8000, sodium lauryl sulfate and PEG10000, sodium lauryl sulfate and polyoxyethylene 100 stearyl ether, sodium lauryl sulfate and poloxamer 407, sodium lauryl sulfate and poloxamer 338, sodium lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer 338, poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate blend; calcium dodecylbenzenesulfonate (branched); diisopropyl naphthalene sulfonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; a naphthalenesulfonic acid-formaldehyde condensate; nonylphenol ethoxylate, POE-30; phosphate esters, tristyrylphenol ethoxylate, free acids; polyoxyethylene (15) tallow alkylamine; sodium alkylnaphthalene sulfonate; sodium alkylnaphthalenesulfonate condensates; sodium alkyl benzene sulfonate; sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; a formaldehyde sulfonate; n-butylnaphthalene sulfonic acid sodium salt; tridecyl alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate; triethanolamine tristyryl phosphate; tristyrylphenol ethoxylate sulfate; bis (2-hydroxyethyl) tallow alkylamine.

(h) Tartaric acid or tartaric acid in combination with at least one substance selected from the group consisting of: lactose monohydrate; anhydrous lactose; mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; trisodium citrate dihydrate; d, L-malic acid; sodium pentane sulfate; sodium stearyl sulfate; polyoxyethylene 100 stearyl ether; polyoxyethylene 10 stearyl ether; n-lauroyl sarcosine sodium; lecithin; docusate sodium; polyoxyethylene-40-stearate; hydrophobic colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants having chain lengths between C5 and C18; polyvinylpyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG6000, sodium lauryl sulfate and PEG8000, sodium lauryl sulfate and PEG10000, sodium lauryl sulfate and polyoxyethylene 100 stearyl ether, sodium lauryl sulfate and poloxamer 407, sodium lauryl sulfate and poloxamer 338, sodium lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer 338, poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate blend; calcium dodecylbenzenesulfonate (branched); diisopropyl naphthalene sulfonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; a naphthalenesulfonic acid-formaldehyde condensate; nonylphenol ethoxylate, POE-30; phosphate esters, tristyrylphenol ethoxylate, free acids; polyoxyethylene (15) tallow alkylamine; sodium alkylnaphthalene sulfonate; sodium alkylnaphthalenesulfonate condensates; sodium alkyl benzene sulfonate; sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; a formaldehyde sulfonate; n-butylnaphthalene sulfonic acid sodium salt; tridecyl alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate; triethanolamine tristyryl phosphate; tristyrylphenol ethoxylate sulfate; bis (2-hydroxyethyl) tallow alkylamine.

(i) Microcrystalline cellulose or microcrystalline cellulose in combination with at least one substance selected from the group consisting of: lactose monohydrate; xylitol; anhydrous lactose; mannitol; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; d, L-malic acid; sodium pentane sulfate; sodium stearyl sulfate; polyoxyethylene 100 stearyl ether; polyoxyethylene 10 stearyl ether; n-lauroyl sarcosine sodium; lecithin; docusate sodium; polyoxyethylene-40-stearic acid; hydrophobic colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants having chain lengths between C5 and C18; polyvinylpyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG6000, sodium lauryl sulfate and PEG8000, sodium lauryl sulfate and PEG10000, sodium lauryl sulfate and polyoxyethylene 100 stearyl ether, sodium lauryl sulfate and poloxamer 407, sodium lauryl sulfate and poloxamer 338, sodium lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer 338, poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate blend; calcium dodecylbenzenesulfonate (branched); diisopropyl naphthalene sulfonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; a naphthalenesulfonic acid-formaldehyde condensate; nonylphenol ethoxylate, POE-30; phosphate esters, tristyrylphenol ethoxylate, free acids; polyoxyethylene (15) tallow alkylamine; sodium alkylnaphthalene sulfonate; sodium alkylnaphthalenesulfonate condensates; sodium alkyl benzene sulfonate; sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; a formaldehyde sulfonate; n-butylnaphthalene sulfonic acid sodium salt; tridecyl alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate; triethanolamine tristyryl phosphate; tristyrylphenol ethoxylate sulfate; bis (2-hydroxyethyl) tallow alkylamine.

(j) Kaolin in combination with at least one material selected from the group consisting of: lactose monohydrate; xylitol; anhydrous lactose; mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; d, L-malic acid; sodium pentane sulfate; sodium stearyl sulfate; polyoxyethylene 100 stearyl ether; polyoxyethylene 10 stearyl ether; n-lauroyl sarcosine sodium; lecithin; docusate sodium; polyoxyethylene-40-stearate; hydrophobic colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants having chain lengths between C5 and C18; polyvinylpyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG6000, sodium lauryl sulfate and PEG8000, sodium lauryl sulfate and PEG10000, sodium lauryl sulfate and polyoxyethylene 100 stearyl ether, sodium lauryl sulfate and poloxamer 407, sodium lauryl sulfate and poloxamer 338, sodium lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer 338, poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate blend; calcium dodecylbenzenesulfonate (branched); diisopropyl naphthalene sulfonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; a naphthalenesulfonic acid-formaldehyde condensate; nonylphenol ethoxylate, POE-30; phosphate esters, tristyrylphenol ethoxylate, free acids; polyoxyethylene (15) tallow alkylamine; sodium alkylnaphthalene sulfonate; sodium alkylnaphthalenesulfonate condensates; sodium alkyl benzene sulfonate; sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; a formaldehyde sulfonate; n-butylnaphthalene sulfonic acid sodium salt; tridecyl alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate; triethanolamine tristyryl phosphate; tristyrylphenol ethoxylate sulfate; bis (2-hydroxyethyl) tallow alkylamine.

(k) Talc in combination with at least one member selected from the group consisting of: lactose monohydrate; xylitol; anhydrous lactose; mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; d, L-malic acid; sodium pentane sulfate; sodium stearyl sulfate; polyoxyethylene 100 stearyl ether; polyoxyethylene 10 stearyl ether; n-lauroyl sarcosine sodium; lecithin; docusate sodium; polyoxyethylene-40-stearate; hydrophobic colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants having chain lengths between C5 and C18; polyvinylpyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG6000, sodium lauryl sulfate and PEG8000, sodium lauryl sulfate and PEG10000, sodium lauryl sulfate and polyoxyethylene 100 stearyl ether, sodium lauryl sulfate and poloxamer 407, sodium lauryl sulfate and poloxamer 338, sodium lauryl sulfate and poloxamer 188; poloxamer 407, poloxamer 338, poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate blend; calcium dodecylbenzenesulfonate (branched); diisopropyl naphthalene sulfonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; a naphthalenesulfonic acid-formaldehyde condensate; nonylphenol ethoxylate, POE-30; phosphate esters, tristyrylphenol ethoxylate, free acids; polyoxyethylene (15) tallow alkylamine; sodium alkylnaphthalene sulfonate; sodium alkylnaphthalenesulfonate condensates; sodium alkyl benzene sulfonate; sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; a formaldehyde sulfonate; n-butylnaphthalene sulfonic acid sodium salt; tridecyl alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate; triethanolamine tristyryl phosphate; tristyrylphenol ethoxylate sulfate; bis (2-hydroxyethyl) tallow alkylamine.

In some embodiments, abiraterone acetate is dry milled with one or more additional substances selected from the group consisting of: are considered "generally regarded as safe" (GRAS) materials for pharmaceutical products.

In some embodiments, the dry milling of abiraterone acetate is performed in the presence of a promoting agent or a combination of promoting agents. In some embodiments, the facilitating agent is selected from a glidant, a surfactant, a polymer, and/or a lubricant. In some embodiments, the facilitating agent is selected from: colloidal silicon dioxide, sodium stearate and talc. In some embodiments, the facilitating agent is selected from: benzethonium chloride, docusate sodium, polyvinyl alkyl ether, sodium lauryl sulfate, glyceryl trioctanoate, alpha-tocopherol, glyceryl monooleate, myristyl alcohol, poloxamer, polyoxyethylene alkyl ether, polyoxyethylene stearate, polyoxyethylene castor oil derivative, polyoxyethylene 15hydroxystearate, polyoxyethylene glyceryl ester, polysorbate, propylene glycol dilaurate, sorbitan ester, sucrose palmitate, vitamin E polyethylene glycol succinate, polyethylene glycol (PEG), poloxamer, poloxamine, sarcosinate surfactants, polysorbate, aliphatic alcohols, alkyl and aryl sulfates, alkyl and aryl polyether sulfonates and other sulfate surfactants, trimethylammonium surfactants, lecithin and other phospholipids, bile salts, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitol fatty acid esters, sodium lauryl sulfate, glyceryl trioctanoate, alpha-tocopherol, glyceryl monooleate, glyceryl monostearate, propylene glycol dilaurate, sorbitan esters, glyceryl monostearate, polyoxyethylene glycollate, Sorbitan fatty acid esters, sucrose fatty acid esters, alkylpyranosides, alkylpyramaltosides, glycerol fatty acid esters, alkylbenzenesulfonic acids, alkylethercarboxylic acids, alkyl and aryl phosphates, alkyl and aryl sulfates, alkyl and aryl sulfonic acids, alkylphenol phosphates, alkylphenol sulfates, alkyl and aryl phosphates, alkyl polysaccharides, alkylamine ethoxylates, alkylnaphthalenesulfonate formaldehyde condensates, sulfosuccinates, lignosulfonates, cetearyl alcohol ethoxylates, condensed naphthalene sulfonates, dialkyl and alkyl naphthalene sulfonates, dialkyl sulfosuccinates, ethoxylated nonylphenols, glycol esters, fatty alcohol alkoxylates, hydrogenated tallow alkylamines, monoalkyl sulfosuccinamates, nonylphenol ethoxylates, sodium oleyl N-methyltaurate, tallow alkylamines, straight and branched dodecylbenzene sulfonic acid.

In some embodiments, the facilitating agent is selected from the group consisting of sodium stearyl sulfate, sodium stearyl fumarate, magnesium stearate, talc, myristic acid, sodium cetyl sulfate, sodium cetostearyl sulfate, docusate sodium, sodium deoxycholate, sodium N-lauroylsarcosine sodium salt, glyceryl monostearate, glyceryl distearate, glyceryl palmitostearate, glyceryl behenate, glyceryl caprylate, glyceryl oleate, benzalkonium chloride, cetyl trimethylammonium bromide, cetyl trimethylammonium chloride, cetrimide, cetylpyridinium chloride, cetylpyridinium bromide, benzethonium chloride, polyethylene glycol 40 stearate, polyethylene glycol 100 stearate, poloxamer 188, poloxamer 338, poloxamer 407, polyoxyethylene 2 stearyl ether, polyoxyethylene 100 stearyl ether, polyoxyethylene 20 stearyl ether, polyoxyethylene 10 stearyl ether, glyceryl monostearate, glyceryl behenate, glyceryl stearate, glyceryl oleate, benzalkonium chloride, cetyl trimethylammonium bromide, cetyltrimethylammonium chloride, cetylpyridinium bromide, benz, Polyoxyethylene 20 cetyl ether, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polyoxyethylene 35 castor oil, polyoxyethylene 40 castor oil, polyoxyethylene 60 castor oil, polyoxyethylene 100 castor oil, polyoxyethylene 200 castor oil, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 60 hydrogenated castor oil, polyoxyethylene 100 hydrogenated castor oil, polyoxyethylene 200 hydrogenated castor oil, cetostearyl alcohol, polyethylene glycol 15-hydroxystearate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate, sucrose palmitate, sucrose stearate, sucrose distearate, sucrose laurate, glycocholic acid, sodium glycocholate, cholic acid sodium, deoxycholate, deoxycholic acid, sodium taurocholate, taurocholic acid, sodium taurocholic acid, polysorbate 60 hydrogenated castor oil, polyoxyethylene 100 hydrogenated castor oil, polyoxyethylene 200 hydrogenated castor oil, polyoxyethylene stearyl alcohol, polyoxyethylene 15-hydroxystearate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate, sucrose palmitate, sucrose stearate, Taurodeoxycholic acid sodium salt, taurodeoxycholic acid, soybean lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkylnaphthalenesulfonate condensate/lignosulfonate blend, calcium dodecylbenzenesulfonate, sodium dodecylbenzenesulfonate, diisopropylnaphthalenesulfonate, erythritol distearate, naphthalenesulfonate formaldehyde condensate, nonylphenol ethoxylate (POE-30), tristyrylphenol ethoxylate, polyoxyethylene (15) tallow alkylamine, sodium alkylnaphthalenesulfonate condensate, sodium alkylbenzenesulfonate, sodium isopropylnaphthalenesulfonate, sodium methylnaphthalenesulfonate, sodium n-butylnaphthalenesulfonate, tridecanol ethoxylate (POE-18), triethanolamine isodecanol phosphate, triethanolamine tristyryl phosphate, triethanolamine triphenylethylene phosphate, phosphatidylethanolamine, sodium salt of sodium alkylnaphthalenesulfonate, sodium dodecylnaphthalenesulfonate, diisopropyl naphthalenesulfonate, erythritol distearate, naphthalenesulfonate, Tristyrylphenol ethoxylate sulfate, bis (2-hydroxyethyl) tallow alkylamine.

In some embodiments, the facilitating agent is selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinyl alcohol, copolymers of acrylic acid-based polymers and acrylic acid.

In some embodiments, the facilitating agent has a concentration during dry-milling selected from the group consisting of: 0.1-10% w/w, 0.1-5% w/w, 0.1-2.5% w/w, 0.1-2% w/w, 0.1-1%, 0.5-5% w/w, 0.5-3% w/w, 0.5-2% w/w, 0.5-1.5%, 0.5-1% w/w, 0.75-1.25% w/w, 0.75-1% and 1% w/w.

In some embodiments, a facilitating agent or combination of facilitating agents is used during dry milling. In some embodiments, the facilitating agent is added during dry milling. In some embodiments, the facilitating agent is added to the dry mill at a time selected from the group consisting of: when 1-5% of the total grinding time remains, 1-10% of the total grinding time remains, 1-20% of the total grinding time remains, 1-30% of the total grinding time remains, 2-5% of the total grinding time remains, 2-10% of the total grinding time remains, 5-20% of the total grinding time remains, and 5-20% of the total grinding time remains.

Reasons for including the facilitating agent include, but are not limited to, providing better dispersibility, controlling aggregation, releasing or retaining the active particles from the delivery matrix. Examples of facilitating agents include, but are not limited to: sodium lauryl sulfate, crosslinked PVP (crospovidone), croscarmellose sodium (croscarmellose sodium), sodium starch glycolate, povidone (PVP), povidone K12, povidone K17, povidone K25, povidone K29/32 and povidone K30, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, sodium stearyl lactate, zinc stearate, sodium stearate or lithium stearate, other solid fatty acids such as oleic acid, lauric acid, palmitic acid, erucic acid, behenic acid or derivatives (such as esters and salts), amino acids such as leucine, isoleucine, lysine, valine, methionine, phenylalanine, aspartame or acesulfame potassium.

In another aspect, the disclosure includes a method of treating a human in need of such treatment comprising the step of administering to the human an effective amount of a pharmaceutical composition as described herein for treating castration-resistant prostate cancer. Treatment may include administration of 500mg of abiraterone acetate per day (e.g., at 1 or 2 or 4 equal doses (e.g., one unit dose containing 500mg, two unit doses each containing 250mg of abiraterone acetate or four unit doses each containing 125mg of abiraterone acetate). patients may also be treated with a glucocorticoid, such as prednisone, dexamethasone, or prednisolone (e.g., 5mg, twice daily).

The disclosure also includes methods of treating breast cancer (e.g., metastatic breast cancer) and ovarian cancer (e.g., epithelial ovarian cancer) using the compositions described herein.

In another aspect, the disclosure includes the use of a pharmaceutical composition described herein in the manufacture of a medicament for treating a human in need of such treatment.

In another aspect, the present disclosure includes a method for preparing a pharmaceutical composition as described herein, comprising the steps of: the composition containing abiraterone acetate prepared by the methods described herein or as described herein is combined with one of a diluent, lubricant, excipient, disintegrant, wetting agent to produce a pharmaceutically acceptable dosage form.

The disclosure described herein may include one or more ranges of values (e.g., size, concentration, etc.). A range of values will be understood to include all values within the range, including the values defining the range, as well as values adjacent to the range that result in the same or substantially the same result as the values immediately adjacent to the value defining the boundary of the range.

The entire disclosures of all publications (including patents, patent applications, journal articles, laboratory manuals, books, or other documents) cited herein are hereby incorporated by reference. The inclusion does not constitute an admission that any of the references form part of the common general knowledge of those skilled in the art or working in the field to which the disclosure relates.

Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. It should also be noted that in this disclosure, particularly in the claims and/or paragraphs, terms such as "comprising," "including," "containing," and the like may have the meaning attributed to it in U.S. patent law; for example, they may mean "including", "containing", and the like.

As used herein, "therapeutically effective amount" with respect to methods of treatment and particularly dosage of a drug shall mean a dosage that provides the particular pharmacological response for which the drug is administered in a large number of subjects in need of such treatment. It is emphasized that a "therapeutically effective amount" administered to a particular subject under particular circumstances is not always effective in treating the diseases described herein, even if the dose is considered by those skilled in the art to be a "therapeutically effective amount". It is further understood that the drug dose is in certain cases measured as an oral dose or relative to the drug level measured in the blood.

Throughout the specification, unless the context requires otherwise, the phrase "dry milling" or variations such as "dry milling" should be understood to mean milling in the at least substantial absence of liquid. If liquids are present, they are present in an amount such that the contents of the mill retain the characteristics of a dry powder.

The term "abradable" means that the abrasive substrate is capable of being reduced in size under the dry-milling conditions of the disclosed method. In one embodiment of the present disclosure, the milled grinding matrix has a particle size comparable to abiraterone acetate. In another embodiment of the present disclosure, the particle size of the matrix is significantly reduced, but not as small as abiraterone acetate.

Those skilled in the art will appreciate that variations and modifications of the disclosure described herein may be made in addition to those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The disclosure also includes all of the steps, features, compositions and materials referred to or indicated in the specification, individually or collectively, and any and all combinations or any two or more of the steps or features.

The present disclosure is not to be limited in scope by the specific embodiments described herein, which are for illustrative purposes only. Functionally equivalent products, compositions and methods are clearly within the scope of the disclosure described herein.

Other aspects and advantages of the disclosure will become apparent to those skilled in the art upon reading the following description.

Drawings

Figure 1 is a graph of the results of particle size analysis of unmilled abiraterone acetate and of the abiraterone acetates of formula 1 and formula 2 of example 1.

Figure 2 is a graph of the dissolution rate measurements for abiraterone acetate tablets as described in example 3.

Fig. 3A and 3B are graphs depicting the results of the stability study described in example 6.

Detailed Description

Particle size

For measurements made using laser diffraction, the term "median particle diameter" is defined as the median particle diameter determined on an equivalent spherical particle volume basis. Where the term median is used, it is understood to describe the particle size that divides the population in half such that 50% of the population on a volume basis is greater or less than that size. The median particle diameter is written as: [ D ]₅₀]Or D_[50]Or [ D50]]D50, D (0.50) or D [0.5 ]]Or the like. As used herein [ D₅₀]Or D_[50]Or [ D50]]D50, D (0.50) or D [0.5 ]]Or the like, shall be taken to mean the median particle diameter.

The term "Dx of the particle size distribution" refers to a distribution based on volumeThe xth percentile; thus, D90 refers to the 90 th percentile, D95 refers to the 95 th percentile, and so on. Taking D90 as an example, this can be written as [ D ] in general₉₀]Or D_[90]Or [ D90]]D (0.90) or D [0.9 ]]Or the like. With respect to median particle diameter and Dx, capital D or lowercase D are interchangeable and have the same meaning. Another common way to describe the particle size distribution as measured by laser diffraction or equivalent methods known in the art is to describe how much% of the distribution is below or above a specified size. The term "percent less" is also written as%<", is defined as the percentage of the particle size distribution at the indicated size, e.g. -%, by volume<1000 nm. The term "greater than percent", also written as%>", defined as the percentage of the particle size distribution by volume that exceeds the specified size, e.g."%)>1000 nm. The term D (3,2) is referred to as the area weighted average size or Sauter diameter; the term D (4,3) is referred to as the volume weighted average size. Detailed descriptions of how to calculate these values are known in the art and can be found, for example, in ISO 9276-2:2014 (E).

Particle size can be readily measured for many materials subjected to the methods of the present disclosure. When the active substance has poor water solubility and the matrix in which it is milled has good water solubility, the powder can simply be dispersed in an aqueous solvent. In this case, the matrix dissolves leaving the active dispersed in the solvent. The suspension can then be measured by techniques such as PCS or laser diffraction.

Suitable methods for measuring the exact particle size in the case of active substances with substantial water solubility or matrices with low solubility in water-based dispersants are outlined below.

1. In cases where insoluble matrices such as microcrystalline cellulose prevent measurement of the active, separation techniques such as filtration or centrifugation can be used to separate the insoluble matrix from the active particles. Other ancillary techniques are needed to determine whether any active is removed by the separation technique so that it can be taken into account.

2. In the case of active substances that are too soluble in water, other solvents can be evaluated to determine particle size. In case a solvent can be found in which the active substance is poorly soluble but which is a good solvent for the matrix, the measurement will be relatively simple. If it is difficult to find such a solvent, another method is to measure the aggregation of the matrix and the active material in a solvent in which neither is soluble (e.g., isooctane). The powder is then measured in another solvent in which the active material is soluble but the matrix is insoluble. Thus, by measuring the matrix particle size and measuring the size of the matrix and the active together, knowledge of the active particle size can be obtained.

3. In some cases, image analysis may be used to obtain information about the particle size distribution of the active. Suitable image measurement techniques may include Transmission Electron Microscopy (TEM), Scanning Electron Microscopy (SEM), optical microscopy, and confocal microscopy. In addition to these standard techniques, there is a need to distinguish the active material from the matrix particles in parallel using some additional technique. Possible techniques may be elemental analysis, raman spectroscopy, FTIR spectroscopy or fluorescence spectroscopy, depending on the chemical composition of the materials involved.

Improved dissolution characteristics

The process results in abiraterone acetate having improved dissolution characteristics. Improved dissolution profiles have significant advantages, including, in some cases, improved bioavailability of abiraterone acetate in vivo. Standard methods for determining the in vitro dissolution profile of a material are available in the art. A suitable method of determining improved dissolution characteristics in vitro may include determining the concentration of sample material in solution over a period of time and comparing the results from the sample material to a control sample. The observation that the peak solution concentration of the sample material is achieved in a shorter time compared to the control sample indicates that the sample material has improved dissolution characteristics. The test sample may be a unit dosage form containing abiraterone acetate and grinding matrix and/or other additives that have been subjected to the methods of the present disclosure described herein, as well as excipients to prepare the final dosage form. Herein, the control sample may be a sample corresponding to the measurement sampleThe same physical properties of the components in (a), and the same relative proportions of active, matrix and/or additive as the measured sample. The control sample may also be a commercially available dosage form,a tablet cut to exhibit an equivalent amount of abiraterone acetate to the test sample. Standard methods for determining the improved dissolution profile of a material in vivo are available in the art.

Crystal characteristics

Methods for determining the crystallization characteristics of abiraterone acetate are widely available in the art. Suitable methods may include X-ray diffraction, differential scanning calorimetry and raman or IR spectroscopy.

Amorphous character

Methods for determining the amorphous content of abiraterone acetate are widely available in the art. Suitable methods may include X-ray diffraction, differential scanning calorimetry and raman or IR spectroscopy.

Abrasive matrix

As will be described subsequently, selection of an appropriate abrasive matrix provides a particularly advantageous application for the methods of the present disclosure. Again, as will be described subsequently, a highly advantageous aspect of the present disclosure is that certain abrasive matrices suitable for use in the methods of the present disclosure are also suitable for use in pharmaceuticals. The present disclosure includes methods for producing a medicament containing both abiraterone acetate and a grinding matrix or in some cases abiraterone acetate and a portion of a grinding matrix, medicaments so produced, and methods of treatment using the medicaments. The drug may include only the milled abiraterone acetate and the milled grind matrix or, more preferably, the milled abiraterone acetate and the milled grind matrix may be combined with one or more pharmaceutically acceptable carriers and any required excipients or other similar agents commonly used in the manufacture of drugs.

In some cases, at least one component of the grinding matrix is harder than abiraterone acetate and is therefore capable of reducing the particle size of abiraterone acetate under the dry grinding conditions of the present disclosure. Also without wishing to be bound by theory, in these cases, it is believed that the millable abrasive matrix provides the advantages of the present disclosure through a second pathway in which smaller particles of the abrasive matrix produced under dry milling conditions are able to achieve greater interaction with abiraterone acetate. The amount of abrasive matrix relative to the amount of abiraterone acetate and the extent of physical degradation of the abrasive matrix is sufficient to inhibit reaggregation of the particles of active material. In some embodiments, the amount of grinding matrix relative to the amount of abiraterone acetate and the extent of reduction in the size of the grinding matrix is sufficient to inhibit reaggregation of the active agent particles. As noted above, the abrasive matrix may include one or more antioxidants and/or one or more chelating agents.

In some embodiments, the abrasive matrix has a low tendency to aggregate during dry-grinding. While it is difficult to objectively quantify the tendency for agglomeration during grinding, it is possible to obtain a subjective measurement by observing the level of "caking" of the grinding substrate in the grinding chamber of the mill as dry grinding proceeds.

The grinding matrix may be inorganic or organic.

Grinding body

In the methods of the present disclosure, when abrasive bodies are used, the abrasive bodies are preferably chemically inert and rigid. The term "chemically inert" as used herein means that the abrasive body does not chemically react with abiraterone acetate or the abrasive matrix.

As mentioned above, the abrasive body is substantially resistant to fracture and erosion during the abrading process.

The abrasive body is preferably provided in the form of a body which may have any of a variety of smooth, regular shapes, flat or curved surfaces, and which has no sharp or raised edges. For example, suitable abrasive bodies may be in the form of bodies having an elliptical, oval, spherical or right circular cylindrical shape. In some embodiments, the abrasive bodies are provided in the form of one or more beads, balls, spheres, rods, right cylinders, drums, or right cylinders with a radius (i.e., right cylinders with a hemispherical bottom having the same radius as the cylinder).

Depending on the nature of the abiraterone acetate and the grinding matrix, the grinding bodies desirably have an effective average diameter of between about 0.1 and 30mm, more preferably between about 1 and about 15mm, still more preferably between about 3 and 10 mm.

The abrasive body may comprise various substances in particulate form, such as ceramics, glass, metals or polymer compositions. Suitable metal abrasive bodies are generally spherical and generally have good hardness (i.e., RHC 60-70), roundness, high wear resistance, and a narrow size distribution, and may include, for example, balls made from type 52100 chromium steel, type 304, 316, or 440C stainless steel, or type 1065 high carbon steel.

For example, the ceramics may be selected from a wide variety of ceramics, which desirably have sufficient hardness and fracture resistance to enable them to avoid chipping or crushing during grinding and also have a sufficiently high density. Suitable densities for the abrasive body may range from about 1 to 15g/cm³Preferably from about 1 to 8g/cm³. The ceramic may be selected from the group consisting of saponite, alumina, zirconia-silica, yttria-stabilized zirconia, magnesia-stabilized zirconia, silicon nitride, silicon carbide, cobalt-stabilized tungsten carbide, and the like, and mixtures thereof.

The glass abrasive bodies are spherical (e.g., beads), have a narrow size distribution, are durable, and include, for example, lead-free soda-lime glass and borosilicate glass. The polymeric milling bodies are preferably substantially spherical and may be selected from a wide range of polymeric resins, which have sufficient hardness and brittleness such that they can avoid chipping or crushing during milling, sufficient abrasion resistance to minimize abrasion leading to product contamination, and absence of impurities such as metals, solvents, and residual monomers.

The abrasive body may be formed of a polymer resin. The polymer resin may be selected, for example, from crosslinked polystyreneFor example, polystyrene crosslinked with divinylbenzene, styrene copolymers, polyacrylates such as polymethylmethacrylate, polycarbonate, polyacetal, vinyl chloride polymers and copolymers, polyurethane, polyamide, high density polyethylene, polypropylene, and the like. The use of polymeric milling bodies to mill materials to very small particle sizes (as opposed to mechanochemical synthesis) is disclosed, for example, in U.S. Pat. nos. 5,478,705 and 5,500,331. The polymer resin may generally have a range of from about 0.8 to 3.0g/cm³The density of (c). Higher density polymer resins are generally preferred. Alternatively, the abrasive body may be a composite body comprising a dense core to which a polymeric resin is adhered. The core particles may be selected from materials known to be useful as abrasive bodies, such as glass, alumina, zirconia silica, zirconia, stainless steel, and the like. The core material has a density of greater than about 2.5g/cm³The density of (c).

In one embodiment of the invention, the abrasive body is formed of a ferromagnetic substance, thereby facilitating the removal of contaminants resulting from the wear of the abrasive body by using a magnetic separation technique.

Each type of abrasive body has its own advantages. For example, metals have the highest specific gravity, which improves grinding efficiency due to increased impact energy. Metal costs range from low to high, but metal contamination of the final product can be a problem. Glass is advantageous from the standpoint of low cost and availability of bead sizes as low as 0.004 mm. However, the specific gravity of glass is lower than other abrasive bodies and requires significantly more grinding time. Finally, ceramics are advantageous from the point of view of low wear and contamination, easy cleaning and high hardness.

Dry milling

In the dry milling method of the present disclosure, abiraterone acetate in the form of crystals, powder, etc. and milling substrate are combined in a suitable ratio in a mechanically agitated milling chamber, with or without a plurality of milling bodies, wherein the mechanical agitation c is a predetermined agitation intensity for a predetermined time. Typically, a milling apparatus is used to impart motion to the contents of the mill containing any milling bodies by externally applied agitation, drying gas flow or other force, thereby applying various translational, rotational or counter-rotational motions, or combinations thereof, to the milling chamber and its contents; or by imparting motion through the application of agitation internally via a rotating shaft terminating in a blade, propeller, impeller, or paddle; or by a combination of both actions.

During the milling process, the motion imparted to the milling bodies or the gas flowing through the milling system may result in the application of shear forces and various impacts or collisions of significant strength between the milling components, any milling bodies used, and the particles of abiraterone acetate and the milling matrix. The nature and intensity of the force applied to the abiraterone acetate and abrasive matrix is influenced by a variety of processing parameters including: the type of grinding equipment; the strength of the force generated; kinematic aspects of the process; the size, density, shape and composition of any abrasive body used; the weight ratio of abiraterone acetate and grinding matrix mixture to any grinding bodies used; a duration of grinding; physical properties of both abiraterone acetate and the grinding matrix; the atmosphere present during milling; and other factors.

Advantageously, the mill is capable of repeatedly or continuously applying mechanical compressive and shear stresses to the abiraterone acetate and the grinding matrix. In the remainder of the description, reference will be made to dry milling by means of a ball mill. Examples of mills of this type are attritors, nutation mills, tower mills, planetary mills, vibration mills, gravity-dependent ball mills, jet mills, rod mills, roller mills or crushers, jet mills and pulverizers. It should be understood that dry milling according to the methods of the present disclosure may also be accomplished by any suitable milling method or means.

In some cases, the particle size of the abiraterone acetate prior to dry-milling according to the methods described herein is less than about 1000 μm, as determined by sieve analysis. If the particle size of the abiraterone acetate is greater than about 1000 μm, then preferably another method of particle size reduction is used to reduce the particle size of the abiraterone acetate matrix to less than 1000 μm prior to dry-milling according to the methods described herein.

Aggregate of processed abiraterone acetate

Aggregates comprising abiraterone acetate particles having a particle size within the ranges specified herein should be understood to fall within the scope of the present disclosure, whether or not the aggregates exceed the ranges specified above.

Time of treatment

In some embodiments, the minimum time required to dry grind the abiraterone acetate and grinding matrix is to minimize any possible contamination from the grinding process and/or any grinding bodies used. This time varies widely depending on the abiraterone acetate and grinding matrix, and can range from as short as 1 minute to several hours.

The appropriate stirring rate and total milling time are adjusted for the type and size of milling equipment, the type and size of any milling media used, the weight ratio of the abiraterone acetate and milling matrix mixture to the plurality of milling bodies that may be used, the chemical and physical properties of the abiraterone acetate and milling matrix, and other parameters that may be optimized empirically.

In some embodiments, the grinding matrix (the material that is ground with the abiraterone acetate) is not separated from the abiraterone acetate, but remains with the abiraterone acetate in the final product. In some embodiments, the abrasive matrix is considered Generally Regarded As Safe (GRAS) for pharmaceutical products.

In an alternative aspect, the grinding matrix is separated from the abiraterone acetate. In one aspect, when the grinding matrix is not sufficiently ground, the unground grinding matrix is separated from the abiraterone acetate. In another aspect, at least a portion of the milled grinding matrix is separated from the abiraterone acetate.

Any portion of the abrasive matrix can be removed, including but not limited to 10%, 25%, 50%, 75%, or substantially all of the abrasive matrix.

In some embodiments of the present disclosure, a majority of the milled grinding matrix may contain particles similar in size and/or smaller than the particles containing abiraterone acetate. Separation techniques based on particle size distribution are not applicable when the portion of the milled grinding matrix to be separated from the abiraterone acetate-containing particles comprises particles of a size similar to and/or smaller than the abiraterone acetate-containing particles. In these cases, the methods of the present disclosure may involve separating at least a portion of the milled grinding matrix from abiraterone acetate by techniques including, but not limited to, electrostatic separation, magnetic separation, centrifugation (density separation), hydrodynamic separation, and froth flotation. Advantageously, the step of removing at least a portion of the milled grinding matrix from the abiraterone acetate may be carried out by methods such as selective dissolution, washing or sublimation.

In some cases, an abrasive matrix having two or more components may be used, wherein at least one component is water soluble and at least one component has a low solubility in water. In this case, washing may be used to remove the water-soluble matrix component, while allowing the abiraterone acetate to disperse in the remaining matrix component. In a highly advantageous aspect of the present disclosure, the matrix with low solubility is a functional excipient.

In some cases, abrasive matrices suitable for use in the methods of the present disclosure are also pharmaceutically acceptable, and thus suitable for use in medicine. When the methods of the present disclosure do not involve complete separation of the milling matrix from the abiraterone acetate, the present disclosure includes methods for producing a medicament comprising abiraterone acetate and at least a portion of the milled milling matrix, the medicament so produced, and methods of treating animals (including humans) with a therapeutically effective amount of the abiraterone acetate by the medicament.

Abiraterone acetate and composition

The present disclosure includes pharmaceutically acceptable materials produced according to the methods of the present disclosure, compositions including such materials, including compositions including such materials and abrasive matrices, facilitating agents, with or without abrasive aids, with at least a portion of the abrasive matrices or separated from the abrasive matrices.

Medicine

The medicaments of the present disclosure may contain pharmaceutically acceptable materials, optionally together with the grinding matrix or at least a portion of the grinding matrix, with or without grinding aids, facilitating agents, in combination with one or more pharmaceutically acceptable carriers and other agents commonly used in the preparation of pharmaceutically acceptable compositions.

As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. In some embodiments, the carrier is suitable for parenteral, intravenous, intraperitoneal, intramuscular, sublingual, pulmonary, transdermal or oral administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The use of such media and agents for the preparation of medicaments is well known in the art. Except insofar as any conventional media or agent is incompatible with the pharmaceutically acceptable materials, its use in the preparation of pharmaceutical compositions according to the disclosure is contemplated.

Pharmaceutically acceptable carriers according to the present disclosure may include one or more of the following examples:

(1) surfactants and polymers including, but not limited to, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), sodium lauryl sulfate, polyvinyl alcohol, crospovidone, polyvinylpyrrolidone-polyvinylacrylate copolymer, cellulose derivatives, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl ethylcellulose, hydroxypropyl methylcellulose phthalate, polyacrylates and polymethacrylates, urea, sugars, polyols and their polymers, emulsifiers, sugar gums, starches, organic acids and their salts, vinyl pyrrolidone, and vinyl acetate;

(2) binders such as various celluloses and crosslinked polyvinylpyrrolidone, microcrystalline cellulose; and/or

(3) Fillers such as lactose monohydrate, anhydrous lactose, microcrystalline cellulose and various starches; and/or

(4) Lubricants, for example agents acting on the flowability of the powder to be compressed, including colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, colloidal silica; and/or

(5) A sweetener, such as any natural or artificial sweetener, including sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acesulfame K; and/or

(6) A flavoring agent; and/or

(7) Preservatives, such as potassium sorbate, methyl paraben, propyl paraben, benzoic acid and its salts, other esters of parahydroxybenzoic acid, such as butyl paraben, alcohols, such as ethanol or benzyl alcohol, phenolic chemicals, such as phenol, or quaternary ammonium compounds, such as benzalkonium chloride; and/or

(8) A buffering agent; and/or

(9) Diluents, such as pharmaceutically acceptable inert fillers, e.g. microcrystalline cellulose, lactose, dibasic calcium phosphate, sugars and/or mixtures of any of the foregoing; and/or

(10) Wetting agents such as cereal starch, potato starch, corn starch and modified starches and mixtures thereof; and/or

(11) A disintegrant; such as croscarmellose sodium, crospovidone, sodium starch glycolate; and/or

(12) Effervescent agents, such as Effervescent couples (e.g., organic acids (e.g., citric, tartaric, malic, fumaric, adipic, succinic, and alginic acids and anhydrides and acid salts), or carbonates (e.g., sodium, potassium, magnesium, glycine, L-lysine, and arginine carbonates) or bicarbonates (e.g., sodium or potassium bicarbonate); and/or

(13) Other pharmaceutically acceptable excipients.

Actual dosage levels of the disclosed abiraterone acetate may vary depending on the nature of the abiraterone acetate and the potentially improved efficacy (e.g., increased solubility, more rapid dissolution, increased surface area of the abiraterone acetate, etc.) due to the advantages of providing and administering the abiraterone acetate. Thus, a "therapeutically effective amount" as used herein refers to the amount of abiraterone acetate required to achieve a therapeutic response in an animal. The amount effective for such an application will depend on: the desired therapeutic effect; the route of administration; efficacy of abiraterone acetate; the desired duration of treatment; the stage and severity of the disease being treated; the weight and general health of the patient; and the judgment of the prescribing physician.

Pharmacokinetic properties of abiraterone acetate compositions

Rapid onset of absorption

In some embodiments, the abiraterone acetate compositions of the present disclosure are rapidly absorbed. In one example, an abiraterone acetate composition of the present disclosure has a T of less than about 2.5 hours (about 3 hours to about 2 hours), less than about 2.0 hours, less than about 1.75 hours, less than about 1.5 hours, less than about 1.25 hours, and greater than about 1.0 hour, e.g., between 1.5 and 2.0 hours, when administered to an adult male in a fasted state_max。

Enhanced bioavailability

As with existing conventional compositions administered at the same dosage (e.g.,) In contrast, the abiraterone acetate compositions of the present disclosure exhibit improved bioavailability (AUC) and require smaller doses. In some cases, the ratio may be inAt lower doses, the achievement is similar toAUC and/or Cmax of. Thus, in some cases, the ratioThe pharmaceutical compositions described herein, administered at low doses, provide comparable systemic exposure. For example, a 500mg dose may be bioequivalent to a 1,000mg doseAny pharmaceutical composition may have adverse side effects. Thus, lower drug doses that achieve the same or better therapeutic effect as observed with larger doses of conventional compositions are desirable. Such lower doses can be achieved with the compositions of the present disclosure, because the higher bioavailability observed with the compositions compared to conventional pharmaceutical formulations means that smaller drug doses are required to achieve the desired therapeutic effect.

The pharmacokinetic properties of the compositions of the present disclosure may be less affected by the fed or fasted state of a subject ingesting the composition

The present disclosure includes abiraterone acetate compositions, whereinThe pharmacokinetic profile of the composition is less affected by the fed or fasted state of the subject ingesting the composition than by the fed or fasted state of the subject. This means that there is less difference in the amount of the composition or the rate of absorption of the composition when the composition is administered in a fed versus fasted state. Thus, in some cases, withIn contrast, the compositions of the present disclosure reduce the influence of food on the pharmacokinetics of the composition.

The pharmacokinetic properties of the compositions of the present disclosure may exhibit reduced inter-patient variability

In some cases, for the abiraterone acetate dosage forms described herein, wherein C is_max、AUC_0-tAnd AUC_0-∞May be less thanThus, C_max、AUC_0-tAnd AUC_0-∞The geometric mean coefficient of variation of one or more of may be comparedBy 10% -50% (by at least 10%, by 10% -30%, or by 10% -20%). (calculated as CV)CV (dosage form of the invention)/CV×100％)。

Pharmacokinetic study protocol

Any standard pharmacokinetic protocol can be used to determine the plasma concentration profile in a human after administration of the composition and thereby determine whether the composition meets the pharmacokinetic criteria described herein. For example, a randomized single dose crossover study can be performed using a group of healthy adult subjects. The number of subjects should be sufficient to provide adequate control of variation in the statistical analysis, and is typically about 10 or more, although for some purposes a smaller group may be sufficient. Each subject, typically at about 8 am after an overnight fast, received a single dose (e.g., 100mg) of the test composition formulation by oral administration at time point 0. Subjects continued to fast and remained in an upright position for about 4 hours after administration of the composition. Blood samples were collected from each subject prior to administration (e.g., 15 minutes) and at several time intervals after administration. For this purpose, several samples are taken within the first hour and then sampled at a lower frequency. Illustratively, blood samples may be collected at 15, 30, 45, 60 and 90 minutes after administration, and then collected every hour from 2 to 10 hours after administration. Additional blood samples may also be collected subsequently, e.g., at 12, 24, 36, and 48 hours post-dose. If the same subject is used for the study of the second test formulation, a period of at least 7 days should elapse before administration of the second formulation. Plasma was separated from the blood sample by centrifugation and the composition of the separated plasma was analyzed by validated High Performance Liquid Chromatography (HPLC) or Liquid Chromatography Mass Spectrometry (LCMS) methods. Reference herein to plasma concentrations of the compositions is meant to include the total concentration of free and bound compositions.

Administration mode of drug containing abiraterone acetate

The medicaments of the present disclosure may be administered to animals, including humans, in any pharmaceutically acceptable manner, e.g., orally, rectally, pulmonarily, intravaginally, topically (powders, ointments or drops), transdermally, parenterally, intravenously, intraperitoneally, intramuscularly, sublingually, or as a buccal or nasal spray.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, pellets and granules. In addition, incorporation of any commonly used excipients, such as those listed above, and typically 5-95% of the biologically active agent, and more preferably at a concentration of 10% -75%, will form a pharmaceutically acceptable non-toxic oral composition.

However, if abiraterone acetate is used in a liquid suspension, the particles containing abiraterone acetate may need to be further stabilized once the solid carrier is substantially removed to ensure that particle aggregation is eliminated or at least minimised.

Examples

Example 1 preparation of Fine particle Abiraterone acetate powder blend

Abiraterone acetate was dry milled in the presence of lactose monohydrate and sodium lauryl sulfate at the percentages shown in table 1 to produce the drug product intermediate for use in the preparation of tablets. Two batches of material were ground in a Union Process 1S attritor with a 0.5 gallon jacketed cooling tank. 200g of the batch were ground with a grinding body for 40 minutes.

Table 1: pharmaceutical product intermediates for the preparation of tablets

Example 2: particle size analysis of milled and unmilled abiraterone acetate

The particle size distribution of abiraterone acetate in the two drug product intermediate material batches described in example 1 was measured by light scattering using a malz 3000 Malvern Mastersizer 3000 particle size analyzer fitted with a Hydro MV wet sample dispersion apparatus. In addition, an unmilled blend of abiraterone acetate, lactose monohydrate and sodium lauryl sulfate was measured. All three samples were measured using the following method: the dispersant used was a 0.1% aqueous solution of povidone K30. About 20mg of sample powder and 5mL of dispersant were added to a plastic centrifuge tube. The tube was rotated to disperse the powder and then sonicated (Branson digital sonicator 250, equipped with a model 102C sonic probe) at 20% amplitude for 1 minute with a sonication cycle of 5 seconds on and 15 seconds off. Particle size analyzer sample dispersion device was filled with dispersant and sample was pipetted into the reservoir until 5-15% target occlusion was reached and held constant. The stirrer was run at 1500rpm and data was collected for 10 seconds. Three measurements were made and the average value of each particle size parameter was reported. Table 2 and figure 1 show the particle size distribution; the data shows a particle size reduction of more than 10 fold.

TABLE 2 particle size distribution of unmilled and milled abiraterone acetate

Example 3: preparation of tablets and comparative dissolution Studies

The milled drug product intermediate is combined with intragranular excipients and dry granulated using roller compaction and milling. The granules were mixed with extragranular excipients and compressed in a rotary tablet press to give 100mg abiraterone acetate tablets having the composition shown in table 3.

TABLE 3 Abiraterone acetate 100mg tablet composition

The dissolution rate of the tablets prepared as described above was measured using the method listed on the FDA website for abiraterone acetate tablets, 250 mg; USP apparatus II, 50rpm, in 900mL of pH4.5 buffer with 0.25% sodium dodecyl sulfate. The samples were analyzed by UV at 270 nm. In addition, for comparison purposes, the test was performed under the same dissolution conditionsAnd (4) tablets. The results of this analysis are shown in table 4 and fig. 2. For both tablet formulations containing milled abiraterone acetate, complete dissolution was achieved within 10-20 minutes: (>85% dissolution) compared to complete dissolution in 60 minutes (>85% dissolution) of

TABLE 4 dissolution of Abiraterone acetate tablets

Example 4: abiraterone acetate tablets for initial phase I study

Abiraterone acetate was dry milled in the presence of lactose monohydrate and sodium lauryl sulfate in the amounts shown in table 5 to produce the drug product intermediate used to prepare the tablets used in the phase I trial. The material was ground in a Union Process 1S attritor with a 1.5 gallon jacketed cooling tank. The material was ground with a grinding body for 40 minutes.

Table 5: pharmaceutical product intermediates for preparing tablets for phase I testing

Ingredient name and rating	Weight percent of	Batch/lot (g)
			Abiraterone acetate	30.00	300.0
Lactose monohydrate, USP	67.75	677.5
			Sodium dodecyl sulfate, NF	2.25	22.5
Total up to	100.00	1000.0

The particle size distribution of abiraterone acetate in the milled drug product intermediate was measured using a Micromeritics Saturn DigiSizer II 5205 particle size analyzer equipped with AquaPrep II sample cell. The sample reservoir of the instrument was filled with a dispersant solution (0.1% povidone K30). The sample was prepared by adding 100mg of the milled powder and 20mL of the dispersant to a 30mL glass vial. The particles were dispersed by stirring with a pipette and then the capped bottle was placed in an ultrasonic water bath (Branson ultrasonic bath, model 5510-MT, output 135W, 42KHz) so that the level of the bath water was located halfway to the side of the bottle. The samples were then sonicated for 30 minutes. The dispersed sample was added drop-wise to the reservoir of the liquid sample processing unit until a shading value of about 7% was reached. The internal acoustic probe was run at 100% intensity for 300 seconds, and then the sample was cycled 120 seconds before data collection. When the shading value is between 5 and 10%, data is collected at a beam angle setting of 65 °. Each measurement was repeated three times and the average of the three measurements was reported. Particle size data from the milled powders are reported in table 6.

Table 6: milled abiraterone acetate particle size

Particle size parameter	Results (micron)
		D10	0.105
D50	0.387
		D90	1.308
D4,3	0.588
		D3,2	0.247

The milled drug product intermediate is combined with intragranular excipients and dry granulated using roller compaction and milling. The granules were mixed with extragranular excipients and compressed in a rotary tablet press to give 100mg abiraterone acetate tablets having the composition shown in table 7.

Table 7: abiraterone acetate 100mg tablet composition for initial phase 1 trials

Composition (I)	％w/w	mg/tablet
			Abiraterone acetate	14.29	100.0
Lactose monohydrate, NF	32.26	225.8
			Sodium dodecyl sulfate, NF	1.42	10.0
Microcrystalline cellulose, NF	44.53	311.7
			Croscarmellose sodium, NF	7.00	49.0
Sodium stearyl fumarate, NF	0.50	3.5
			Total up to	100.00	700.0

The dissolution rate of the tablets prepared as described above was measured in 900mL of pH4.5 buffer with 0.1% SLS in USP apparatus II, 75 rpm. Samples were analyzed by HPLC. In addition, for comparison purposes, the test was performed under the same dissolution conditionsAnd (4) tablets. Because of the fact thatThe tablet is 250mg, which is near the solubility limit of the dissolution medium, so the tablet is cut to a weight equivalent to 100mg abiraterone acetate. Measurement at 270nm using UVAnd (3) sampling. The results of this analysis are shown in table 8; complete dissolution of the prepared tablets was achieved within 5 minutes: (>85% dissolution) of the solution, andtablet dissolution was achieved within 20 minutes.

Table 8: dissolution of 100mg abiraterone acetate tablet

Example 5: and 1000mg ofPhase I study comparing 100, 200 and 400mg doses of abiraterone acetate formulation

100mg tablet formulations of abiraterone acetate prepared as described in example 4 were tested in healthy male patients under fasting conditions for 100mg, 200mg and 400mg doses (1, 2 or 4 × 100mg tablets respectively.) in the same study, a 1000mg dose (4 × 250mg tablets) was testedThe results of this study are shown inIn table 9.

Table 9: 100mg pharmacokinetic data (arithmetic mean) of Abiraterone acetate tablets

Observed differences were highly significant in four treatments (p <0.0001, ANOVA).

The observed differences are significant (p)<0.05, Wilcoxon signed rank test), with 1,000mgAnd (4) comparing.

Example 6: stability of abiraterone acetate powder blends and tablets

After dry milling of abiraterone acetate with lactose monohydrate and sodium dodecyl sulfate, a total impurity increase of 0.2-0.6% AUC was detected by HPLC. When the milled abiraterone acetate powder blend (or drug product intermediate; "DPI") was further processed into tablets, higher impurity levels, about 0.5-1.1%, were found. Stability tests showed that the impurities grew at 25 ℃/60% RH and 40 ℃/75% RH, but did not grow at 2-8 ℃. Furthermore, the impurities in the tablet grow faster than in the milled DPI. Table 10 and figures 3A and 3B (diamond, 5 ℃, square, 25 ℃/60% RH; and triangle, 40 ℃/75% RH) provide a summary of the impurity levels in DPI batches and tablets milled in the accelerated stability test. The frozen stored tablets have acceptably low levels of impurities, but it is desirable to have a formulation that can be stored at ambient conditions.

TABLE 10 Abiraterone acetate stability (Total impurities)

The increase in impurities in DPI and tablets containing fine particle abiraterone acetate is due to oxidative degradation of the abiraterone acetate. Test agedThe purity of the (abiraterone acetate) tablets and the impurity levels were found to be much lower than the aged tablets containing fine particles of abiraterone acetate. The faster degradation of tablets containing fine particles of abiraterone acetate may result from a number of sources, including but not limited to: greater API surface area, higher excipient ratios relative to API, and differences in excipients. Further studies found that the API had some degradation in the presence of excipients, but degradation was greatly accelerated once the mixture was milled. The data are provided in table 11.

TABLE 11 Abiraterone acetate stability

Example 7: milling abiraterone with antioxidant or chelating agent

The dry milling of abiraterone acetate was carried out in the presence of lactose monohydrate and sodium lauryl sulphate and various antioxidants and/or chelating agents. In one study, dry milling included a combination of ascorbic acid and fumaric acid or a combination of Butylated Hydroxyanisole (BHA) and Butylated Hydroxytoluene (BHT): the formulation is shown in table 12. Each batch is provided withMilling in a 0.5 gallon jacketed chilled tank Union Process 1S attritor. 200g of the batch were ground with a grinding body for 40 minutes. When the light scattering test was passed according to the method described in example 2, both DPI formulations contained D₉₀Abiraterone acetate less than 1000 nm.

Table 12: DPI formulations containing antioxidants or chelating agents

Two different corresponding tablet formulations as detailed in table 13 were prepared using two different DPI formulations by adding the indicated excipients to the DPI formulation, dry granulation and tableting.

Table 13: tablet formulation containing an antioxidant or a chelating agent

Both tablet formulations were tested for stability under accelerated conditions. Table 14 contains data demonstrating that both tablet formulations with antioxidant have significantly improved stability after 3 months storage at 40 ℃/75% RH, and that the formulation with BHA/BHT stops almost all degradation, compared to the formulation without antioxidant. This indicates that the addition of antioxidants and/or chelating agents during milling can significantly improve stability.

TABLE 14 stability data for tablets with and without antioxidant

The dissolution rates of tablet formulation ascorbic/fumaric acid and abiraterone acetate in tablet formulation BHA/BHT were tested using USP apparatus II at 75rpm in 900ml of pH4.5 phosphate buffer containing 0.1% SLS. All three types of tablets were completely dissolved in 10 minutes (> 85% abiraterone acetate dissolved).

Example 8: abiraterone acetate tablets for additional phase I study

Additional pharmaceutical product intermediate formulations were prepared by dry milling abiraterone acetate, lactose monohydrate, sodium lauryl sulfate, BHA and BHT. The composition of the material milled to form this intermediate is shown in table 15. Milling the formulation in a custom jacketed 62 gallon attritor; the powder blend was milled with milling bodies for 72 minutes.

Table 15: milled drug product intermediates containing BHA and BHT for phase 1 clinical studies

Composition (I)	Weight percent of	Batch/lot (g)
			Abiraterone acetate	30.0	8.400
Lactose monohydrate, USP	63.8	17.886
			Sodium dodecyl sulfate, NF	6.0	1.680
BHA	0.1	0.028
			BHT	0.1	0.028
Total up to	100	28.000

The particle size distribution of abiraterone acetate in the drug product intermediate was measured by light scattering using a Malvern Mastersizer 3000 particle size analyzer model MAZ3000 equipped with a Hydro MV wet sample dispersion unit. The particle size distribution was measured using two different methods, as follows:

the method comprises the following steps: the dispersant used was a 0.1% aqueous solution of povidone K30. About 20mg of sample powder and 5mL of dispersant were added to a plastic centrifuge tube. The tube was rotated to disperse the powder and then sonicated (Branson digital sonicator 250 with a type 102C sonic probe) at 20% amplitude for 1 minute with a sonication cycle of 5 seconds on and 15 seconds off. Particle size analyzer sample dispersion unit is filled with dispersant and sample is pipetted into the reservoir until 5-15% of the target shade is reached and held constant. The stirrer was run at 1500rpm and data was collected for 10 seconds. Three measurements were made and the average of each particle size parameter is reported.

The method 2 comprises the following steps: the dispersant used was an aqueous solution containing 0.1% poloxamer 338 and 0.1% calcium chloride, which was filtered through a 0.2 μm nylon filter before use. About 20mg of sample powder and 5mL of dispersant solution were added to a glass vial. The vial was capped and swirled to disperse the powder particles. The vial cap was then loosened and the vial was placed in the center of a sonic bath (ElmaElmsonic P30H ultrasonic bath). The vial was immersed so that the bath level was above the level of dispersant in the vial, but the vial did not contact the bath floor. The samples were sonicated at 37kHz, 100% power for 10 minutes. Particle size analyzer sample dispersion unit is filled with dispersant and sample is pipetted into the reservoir until 5-15% shielding is obtained and held constant. The stirrer was run at 1500rpm and data was collected for 10 seconds. Three measurements were made and the average value of each particle size parameter was reported.

Table 16 presents a comparison of the particle size values of abiraterone acetate in the Drug Product Intermediate (DPI) described in table 15 before and after milling using methods 1 and 2 above.

Table 16: particle size distribution data for Abiraterone acetate DPI containing BHA and BHT

The milled drug product intermediate is combined with intragranular excipients and dry granulated using roller compaction and milling. The granules were blended with extragranular excipients and compressed in a rotary tablet press to give 125mg abiraterone acetate tablets having the composition shown in table 17.

Table 17: 125mg composition of ground abiraterone acetate tablet

Components	％w/w	mg/tablet
			Abiraterone acetate	14.37	125.00
Lactose monohydrate, NF	30.56	265.83
			Sodium dodecyl sulfate, NF	2.87	25.00
BHA (butylated hydroxyanisole), NF	0.05	0.42
			BHT (butylated hydroxytoluene), NF	0.05	0.42
Microcrystalline cellulose, NF	44.60	388.06
			Croscarmellose sodium, NF	7.00	60.90
Sodium stearyl fumarate, NF	0.50	4.38
			Total up to	100.00	870.00

The dissolution rate of these tablets was measured in pH4.5 buffer with 0.12% SLS in USP apparatus II, 75 rpm. Samples were analyzed by HPLC. The results of this analysis are shown in table 18; complete dissolution (> 85% dissolution) was achieved in 10 min.

Table 18: dissolution of abiraterone acetate tablets

Time (minutes)	% dissolved abiraterone acetate	％RSD
			5	53	6.6
10	86	3.4
			15	93	3.5
30	95	2.9
			45	95	3.1
60	95	3.0

Example 11: abiraterone acetate formulations at 125mg, 500mg and 625mg doses compared to 1000mgPhase I study

Abiraterone acetate 125mg tablets prepared as described in example 10 were tested in healthy male patients under fasting conditions at doses of 125mg, 500mg and 625mg (1, 4 or 5 × 125mg tablets, respectively.) in the same study, a 1000mg dose (4 × 250mg tablets) was testedThe results of this study are shown in table 19.

Table 19: 125mg pharmacokinetic data (arithmetic mean) of abiraterone acetate tablets

Example 12: additional abiraterone acetate powders and tablets

Additional pharmaceutical product intermediate formulations were prepared by dry milling abiraterone acetate, lactose monohydrate, sodium lauryl sulfate, BHA and BHT. The composition of the material milled to form this intermediate is shown in table 16. The two batches were milled using different processing conditions, resulting in slightly different particle sizes.

Table 16: additional milled drug product intermediates

The particle size distribution of abiraterone acetate in the two batches of drug product intermediates was measured by light scattering using a Malvern Mastersizer 3000 particle size analyzer model MAZ3000 fitted with a Hydro MV wet sample dispersion unit. The particle size distributions shown in table 17 were obtained using method 1 described in example 8.

Table 17: additional particle size distribution data for abiraterone acetate DPI

Milled drug product intermediate from batch 1 was combined with intragranular excipients and dry granulated using roller compaction and milling. The granules were blended with extra-granular excipients and compressed in a rotary tablet press to give 100mg abiraterone acetate tablets having the composition shown in table 18.

Table 18: 100mg composition of ground abiraterone acetate tablets

The dissolution rate of these tablets was measured in pH4.5 buffer with 0.1% SLS in USP apparatus II, 75 rpm. The samples were analyzed by UV at 270 nm. The results of this analysis are shown in table 19; complete dissolution (> 85% dissolution) was achieved in 10 min.

Table 19: 100mg of abiraterone acetate tablet is dissolved out

Example 13: stability of the tablet

Additional pharmaceutical product intermediate formulations were prepared by dry milling abiraterone acetate, lactose monohydrate, sodium lauryl sulfate, BHA and BHT. The composition of the material milled to form this intermediate is shown in table 20.

Table 20: milled drug product intermediates containing BHA and BHT

Composition (I)	Weight percent of	Batch/lot (kg)
			Abiraterone acetate	30.00	7.44
Lactose monohydrate, USP	63.8	15.82
			Sodium dodecyl sulfate, NF	6.0	1.49
Butylated Hydroxytoluene (BHT)	0.10	0.025
			Butylated Hydroxyanisole (BHA)	0.10	0.025
Total up to	100.00	24.80

The particle size distribution of abiraterone acetate in the drug product intermediate was measured by light scattering using a Malvern Mastersizer 3000 particle size analyzer model MAZ3000 equipped with a Hydro MV wet sample dispersion unit. The particle size distributions shown in table 21 were obtained using method 1 described in example 8.

Table 21: additional particle size distribution data for Abiraterone acetate DPI containing BHA and BHT

The milled drug product intermediate is combined with intragranular excipients and dry granulated using roller compaction and milling. The granules were blended with extragranular excipients and compressed in a rotary tablet press to give 125mg abiraterone acetate tablets having the composition shown in table 22.

Table 22: 125mg composition of ground abiraterone acetate tablet

Composition (I)	％w/w	mg/tablet
			Abiraterone acetate	14.34	125.00
Lactose monohydrate, USP	30.49	265.83
			Butylated Hydroxytoluene (BHT)	0.05	0.42
Butylated Hydroxyanisole (BHA)	0.05	0.42
			Sodium dodecyl sulfate, NF	2.87	25.00
Microcrystalline cellulose, NF	44.69	389.63
			Croscarmellose sodium, NF	7.02	61.25
Sodium stearyl fumarate, NF	0.50	4.38
			Total up to	100.00	871.92

The tablets were packaged and loaded at 40 ℃ and 75% relative humidity for accelerated stability. Impurities were measured by stability indicating HPLC method. The dissolution rate of these tablets was measured in pH4.5 buffer with 0.12% SLS in USP apparatus II, 75 rpm. The results are shown in Table 23. No impurity growth was observed at 40 ℃/75% RH over 3 months, and the dissolution remained unchanged over 3 months at 40 ℃/75% RH, with complete dissolution (> 85% dissolution) within 10 minutes.

TABLE 23 stability of Abiraterone acetate tablets 125mg

Example 14: effect of eating or fasting State

The effect of high fat diet on oral bioavailability of a 500mg dose of 125mg milled abiraterone tablets was evaluated in a single-center, single dose, randomized, open-label, 2-phase, 2-treatment cross-pharmacokinetic study. In the first dosing period, about half of the subjects were administered the test article with 240mL of water after 10 hours of fasting. The remaining subjects were given about 30 minutes after taking the standard FDA high-fat breakfastAnd (6) testing the sample. After a seven day washout period, each subject was crossed over for another treatment. Plasma samples were drawn immediately prior to administration of the test article and at 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 18.0, 24.0, and 48.0 hours after administration of the test article. The samples were analyzed for abiraterone concentration, and the results were used to calculate pharmacokinetic parameters (AUC) for each subject and treatment_0-∞、AUC_0-tAnd C_max). AUC when test article is administered in fed state_0-∞、AUC_0-tAnd C_maxAre 1444.1 ng.h/mL, 1393.4 ng.h/mL and 443.7ng/mL, respectively, whereas the geometric mean values of these same parameters when administered in the fasting state are 322.7 ng.h/mL, 301.0 ng.h/mL and 67.9 ng/mL. AUC_0-∞、AUC_0-tAnd C_maxThe ratios of (fed/fasted) were 4.48, 4.63 and 6.53, respectively.

Claims (56)

1. A unit dosage form of abiraterone acetate comprises a unit dosage form of 500mg and a unit dosage form of 1000mgBioequivalence in healthy male subjects in the fasted state.

2. The unit dosage form of abiraterone acetate of claim 1, wherein a 500mg dose is administered to healthy male subjects in the fasted stateAdministered to healthy male subjects in the fasted state in a dose of 1000mgIn contrast, AUC_(0-∞)The ratio of the logarithms of the geometric means of (a) is selected from: 0.6 to 1.4, 0.7 to 1.3, 0.8 to 1.2, and 0.9 to 1.1.

3. The unit dosage form of abiraterone acetate of claim 1, wherein the 500mg dose is administered to healthy male subjects in the fasted state and the 1000mg dose is administered to healthy male subjects in the fasted stateCompared with C_(max)The ratio of the logarithms of the geometric means of (a) is selected from: 0.6 to 1.4, 0.7 to 1.3, 0.8 to 1.2, and 0.9 to 1.1.

4. The unit dosage form of abiraterone acetate of claim 1, wherein the [ D90] of the abiraterone acetate is greater than 300nm and less than one of: 7500nm, 7000nm, 6000nm, 5000nm, 4500nm, 4000nm, 3000nm, 2000nm, 900nm, 800nm and 700 nm.

5. The unit dosage form of abiraterone acetate of claim 1, wherein the [ D50] of the abiraterone acetate is greater than 100nm and less than one of: 3500nm, 3000nm, 2500nm, 1600nm, 1400nm, 1200nm, 1000nm, 800nm, 500nm, 400nm and 300 nm.

6. The unit dosage form of abiraterone acetate of claim 1, wherein the [ D4,3] of the abiraterone acetate is greater than 300nm and less than one of: 7000nm, 6000nm, 5000nm, 4000nm, 3000nm, 2500nm, 2400nm, 2200nm, 2000nm, 1900nm, 1700nm, 1500nm, 1300nm, 1100nm, 900nm and 800 nm.

7. The unit dosage form of abiraterone acetate of claim 1, wherein the dissolution rate of the abiraterone acetate in the unit dosage form is such that when a sample containing 100mg of abiraterone acetate is tested in 900ml of phosphate buffer ph4.5 with 0.1% sodium dodecyl sulfate using USP apparatus II at 75rpm, at least 70% of the abiraterone acetate dissolves in between 5 and 15 minutes or between 5 and 10 minutes.

8. The unit dosage form of abiraterone acetate of claim 1, wherein the dissolution rate of the abiraterone acetate in the unit dosage form is such that when a sample containing 125mg of abiraterone acetate is tested in 900ml of ph4.5 phosphate buffer containing 0.12% sodium lauryl sulfate using USP apparatus II at 75rpm, at least 70% of the abiraterone acetate dissolves in between 5 and 15 minutes or between 5 and 10 minutes.

9. The unit dosage form of abiraterone acetate of claim 1, containing 125mg of abiraterone acetate.

10. The unit dosage form of abiraterone acetate of claim 1, wherein a 500mg dose, when orally administered to a population of healthy male subjects in the fasted state, provides a mean plasma Cmax of 50-120ng/ml_max。

11. The unit dosage form of claim 10, wherein a 500mg dose, when orally administered to a population of healthy male subjects in the fasted state, provides a median plasma t of 1 to 2.5 hours_max。

12. The unit dosage form of abiraterone acetate of claim 1, wherein the mean plasma AUC of 240-_(0-∞)。

13. The unit dosage form of claim 1, containing 125mg of abiraterone acetate.

14. The unit dosage form of abiraterone acetate of claim 1, wherein the mean plasma Cmax when a 500mg dose is administered to healthy male subjects in the fasted state_maxThe 90% confidence interval of (A) is a value between 50 and 120 ng/ml.

15. The unit dosage form of abiraterone acetate of claim 1, wherein the mean plasma AUC when administered to a 500mg dose to healthy male subjects in the fasted state_(0-∞)The 90% confidence interval of (c) is a value between 240 and 650h ng/ml.

16. The unit dosage form of claim 14, containing 125mg of abiraterone acetate.

17. The unit dosage form according to any of claims 1, further comprising an antioxidant.

18. A unit dosage form of abiraterone acetate containing 125mg of abiraterone acetate, wherein the median particle size of the abiraterone acetate based on the volume of the particles is between 2000nm and 100 nm.

19. The unit dosage form of claim 18, wherein the dissolution rate of the abiraterone acetate in the unit dosage form is such that when a sample containing 125mg of abiraterone acetate is tested in 900ml of pH4.5 phosphate buffer with 0.12% sodium lauryl sulfate using USP apparatus II at 75rpm, at least 70% of the abiraterone acetate dissolves in between 5 and 15 minutes or between 5 and 10 minutes.

20. The unit dosage form of claim 18, wherein the administration is to a healthy male subject in the fasted stateMean plasma AUC at 500mg dose_(0-∞)The 90% confidence interval of (c) is a value between 240 and 650h ng/ml.

21. The unit dosage form of claim 18, wherein the mean plasma Cmax when a 500mg dose is administered to healthy male subjects in the fasted state_maxThe 90% confidence interval of (A) is a value between 50 and 120 ng/ml.

22. A method for treating castration-resistant prostate cancer comprising administering to a patient in need thereof a daily 500mg dose of an abiraterone acetate dosage form and a glucocorticoid, wherein the 500mg dose is in combination with a 1000mg dose in healthy male subjects in the fasted stateAnd (4) bioequivalence.

23. The method of claim 22, wherein the glucocorticoid is selected from the group consisting of prednisone, prednisolone, and methylprednisolone.

24. A method for producing a composition comprising nanoparticles of abiraterone acetate, the method comprising:

dry milling a composition comprising abiraterone acetate, an abradable milling compound, an accelerating agent and one or both of an antioxidant and a chelating agent in a mill comprising a plurality of milling bodies for a time sufficient to produce a composition comprising fine particles of abiraterone acetate,

wherein the particle size of the abiraterone acetate is reduced by dry milling.

25. The method of claim 24, wherein [ D ] of abiraterone acetate is present in the composition comprising fine particles of abiraterone acetate₉₀]Greater than 100nm and less than one of: 3000nm, 2000nm, 900nm, 800nm, 700nm, 600nm, 500nm, 400nm, 300nm and200nm。

26. the method of claim 24 or claim 25, wherein the milling is performed in the presence of one or both of an antioxidant and a chelating agent.

27. The method of claim 3, wherein the antioxidant is selected from ascorbic acid, BHA, and BHT.

28. The method of claim 26, wherein the chelating agent is selected from fumaric acid, tartaric acid, and citric acid.

29. The method according to any one of claims 23-28, wherein [ D ] of the fine particles of abiraterone acetate in the composition containing the fine particles of abiraterone acetate₅₀]Greater than 100nm and less than 2000nm, less than 1600nm, less than 1400nm, less than 1200nm, less than 1000nm, less than 800nm, less than 500nm, less than 400nm, or less than 300 nm.

30. The method according to any one of claims 23-29, wherein [ D ] of the fine particles of abiraterone acetate in the composition containing the fine particles of abiraterone acetate_4,3]Greater than 100nm and less than one of: 2500nm, 2400nm, 2200nm, 2000nm, 1900nm, 1700nm, 1500nm, 1300nm, 1100nm, 1000nm, 900nm, 800nm, 700nm, 600nm, 500nm, 400nm and 300 nm.

31. A process for preparing a unit dosage composition comprising: preparing a composition comprising fine particles of abiraterone acetate according to the process of any of the preceding claims, combining the composition comprising fine particles of abiraterone acetate with one or more pharmaceutically acceptable diluents, disintegrants, lubricants, glidants or dispersants.

32. The method of claim 31, wherein the unit dosage composition is a tablet or capsule.

33. The method of claim 32, wherein the unit dosage composition contains 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, or 400mg of abiraterone acetate.

34. The method of claim 33, wherein the dissolution rate of the abiraterone acetate in the unit dosage composition is such that when a sample containing 100mg of abiraterone acetate is tested in 900ml of pH4.5 phosphate buffer (0.1% SLS) using USP apparatus II at 75rpm, at least 70% of the abiraterone acetate dissolves in between 5 and 15 minutes or between 5 and 10 minutes.

35. The method of claim 33 or 34, wherein the unit dosage composition is a tablet and the dissolution rate is such that when the tablet is tested in 900ml of phosphate buffer pH4.5 (0.1% SLS) using USP apparatus II at 75rpm, at least 80% of the abiraterone acetate dissolves in between 5 and 15 minutes or between 5 and 10 minutes.

36. A unit dose pharmaceutical composition comprising abiraterone acetate, wherein [ D ] of the abiraterone acetate in said composition₉₀]Greater than 100nm and less than one of: 5,000nm, 4500nm, 4000nm, 3000nm, 2000nm, 900nm, 800nm, 700nm, 600nm, 500nm, 400nm, 300nm, and 200 nm.

37. The unit dose pharmaceutical composition of claim 36, wherein the [ D ] of abiraterone acetate₅₀]Greater than 100nm and less than 2000nm, less than 1600nm, less than 1400nm, less than 1200nm, less than 1000nm, less than 800nm, less than 500nm, smallAt 400nm and below 300 nm.

38. The unit dose pharmaceutical composition according to claim 36 or claim 37, wherein the [ D of abiraterone acetate_4,3]Greater than 100nm and less than one of: 2500nm, 2400nm, 2200nm, 2000nm, 1900nm, 1700nm, 600nm, 500nm, 400nm, and 300 nm.

39. The unit dosage composition of any one of claims 36-38, wherein the dissolution rate of the abiraterone acetate in the unit dosage composition is such that when a sample containing 100mg of abiraterone acetate is tested in 900ml of pH4.5 phosphate buffer (0.1% SLS) using USP apparatus II at 75rpm, at least 70% of the abiraterone acetate dissolves in between 5 and 15 minutes or between 5 and 10 minutes.

40. The unit dosage composition of any one of claims 36-39, wherein the average AUC of the unit dosage composition when administered to an adult male with a low fat diet (7% fat, 300 calories)_0-∞Is 2-fold or less higher than when administered in the fasted state.

41. The unit dosage composition of any one of claims 36-40, wherein the mean AUC of the unit dosage composition when administered to an adult male with a high-fat diet (57% fat, 825 calories)_0-∞Is 2-fold or less higher than when administered in the fasted state.

42. The unit dosage composition of any one of claims 36-41, wherein the average C of the unit dosage composition, when administered to an adult male with a low-fat diet (7% fat, 300 calories)_maxIs 2-fold or less higher than when administered in the fasted state.

43. The unit dosage composition of any one of claims 36-42, wherein the average C of the unit dosage composition when administered to an adult male consuming a high-fat diet (57% fat, 825 calories)_maxIs 5-fold or less higher than when administered in the fasted state.

44. The unit dosage composition of any one of claims 36-42, wherein for C in a healthy male patient when administered in the fasted state_maxAnd AUC_0-tOne or both, a 500mg dose of the unit dosage composition is bioequivalent to a 1,000mg dose of Zytiga.

45. The unit dosage composition of any one of claims 36-44, wherein for C in a healthy male patient when administered in the fasted state_maxAnd AUC_0-tBoth, a 500mg dose of the unit dosage composition is bioequivalent to a 1000mg dose of Zytiga.

46. The unit dosage composition of any one of claims 36-45, wherein said unit dosage composition contains 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, or 400mg of abiraterone acetate.

47. A method for treating castration-resistant prostate cancer comprising administering an abiraterone acetate in a daily dose of 100-700mg, wherein the [ D ] of the abiraterone acetate_4,3]Greater than 100nm and less than one of: 2500nm, 2400nm, 2200nm, 2000nm, 1900nm, 1700nm, 600nm, 500nm, 400nm, and 300 nm.

48. The method of claim 47 comprising administering 200 and 600mg of abiraterone acetate.

49. The method as claimed in claim 48, which comprises administering 300 and 600mg of abiraterone acetate.

50. A method for the treatment of castration-resistant prostate cancer comprising administering a daily dose of 100-700mg of abiraterone acetate in a unit dosage form as defined in any one of claims 36-47.

51. The method according to claim 50, wherein the daily dose is 500mg of abiraterone acetate.

52. The method of any one of claims 48-51, further comprising administering a glucocorticoid.

53. The method of claim 52, wherein the glucocorticoid is prednisone.

54. The method of claim 52, wherein the glucocorticoid is prednisolone.

55. The method of claim 52, wherein the glucocorticoid is methylprednisolone.

56. A pharmaceutical composition prepared by a process comprising the method of any one of claims 23-34.