JP2017528457A - Abiraterone acetate formulation and method of use - Google Patents

Abstract

Described are pharmaceutical compositions (including unit dosage forms) comprising abiraterone acetate and methods of making and using such compositions. [Selection figure] None

Description

  The present disclosure relates to pharmaceutical compositions (including unit dosage forms) comprising abiraterone acetate and methods of making and using such compositions.

Abiraterone ((3β) -17- (pyridin-3-yl) androsta-5,16-dien-3-ol; CAS #: 154229-19-3; Formula: C ₂₄ H ₃₁ NO; Molecular weight: 349.5 g / Mol) is an inhibitor of CYP17 and thus interferes with androgen synthesis in testicular, adrenal, and prostate tumor tissues. Abiraterone prodrug abiraterone acetate (17- (3-pyridyl) androsta-5, acetate; CAS # 154229-18-2) is approved in the United States for the treatment of castration-resistant prostate cancer. Abiraterone acetate is considered poorly water-soluble.

  Zytiga® tablets (250 mg; National Drug Code No. 57894-150; NDA202379) are approved in the United States for use with prednisone for the treatment of patients with metastatic castration resistant prostate cancer. According to the prescribing information of Zytiga (registered trademark), it is recommended that 1,000 mg (4 × 250 mg tablet) be orally administered once a day together with oral administration of prednisone (5 mg) twice a day. Has been. In Europe, Zytiga® is approved for co-administration with prednisone or prednisolone.

Zytiga® prescription information states that it must be taken on an empty stomach and that food should not be taken for at least 2 hours before taking and at least 1 hour after taking. The prescribing information includes a steady state value of Cmax (mean ± SD) of 226 ± 178 ng / mL and a steady state value of AUC (mean ±±) at a daily dose of 1,000 mg in patients with metastatic castration resistant prostate cancer. SD) is 1,173 ± 690 ng. It is described as hr / mL. In a single dose (1,000 mg) crossover study of Zytiga® in healthy subjects, it was found that systemic exposure to abiraterone increased when Zytiga® was administered with food. Specifically, the C _max and AUC _0-∞ of abiraterone when Zytiga® is administered with a low fat diet (7% fat, 300 calories) are each about as compared to when administered in a fasted state. 7 times and about 5 times higher. The abiraterone C _max and AUC _0-∞ when Zytiga® was administered with a high fat diet (57% fat, 825 calories) were about 17 times and about 10 times, respectively, when administered in the fasted state. It was twice as expensive.

A unit dosage form of abiraterone acetate, wherein the unit dosage form at a dose of 500 mg is bioequivalent to a dose of 1,000 mg of Zytiga® in a fasting healthy male subject. Described in the specification. Also, the geometry of AUC _(0-∞) for a dose of 500 mg administered to a fasted healthy male subject compared to a dose of 1,000 mg of Zytiga® administered to a fasted healthy male subject. Average log ratio is selected from 0.6-1.4, 0.7-1.3, 0.8-1.2, and 0.9-1.1; fasted healthy male subject The ratio of the geometric mean logarithm of C (max) for a dose of 500 mg administered to a fasting healthy male subject compared to a dose of 1,000 mg of Zytiga® administered in Also described are unit dosage forms of abiraterone acetate selected from 1.4, 0.7-1.3, 0.8-1.2, and 0.9-1.1.

  In some cases, [D90] of abiraterone acetate is greater than 300 nm and 7,500 nm, 7,000 nm, 6,000 nm, 5,000 nm, 4,500 nm, 4,000 nm, 3,000 nm, 2,000 nm, 900 nm , 800 nm, and less than one of 700 nm; [D50] of abiraterone acetate is greater than 100 nm and 3,500 nm, 3,000 nm, 2,500 nm, 1,600 nm, 1,400 nm, 1,200 nm, 1 Less than one of 2,000, 800, 500, 400, and 300 nm; [D4,3] of abiraterone acetate is greater than 300 nm and 7,000 nm, 6,000 nm, 5,000 nm, 4,000 nm, 3 nm , 2,000 nm, 2500 nm, 2,400 nm, 2,200 nm, , 1,000 nm, 1,900 nm, 1,700 nm, 1,500 nm, 1,300 nm, 1,100 nm, 900 nm, and 800 nm; the dissolution rate of abiraterone acetate in the unit dosage form is 0 When testing a sample containing 100 mg of abiraterone acetate in a 900 mL pH 4.5 phosphate buffer containing 1% sodium lauryl sulfate using USP apparatus II at 75 rpm, at least 70% of said abiraterone acetate was The dissolution rate is 5-15 minutes or 5-10 minutes; the dissolution rate of abiraterone acetate in the unit dosage form is pH 4.5 phosphate buffer containing 0.12% sodium lauryl sulfate Containing 125 mg of abiraterone acetate fine particles using USP apparatus II at 75 rpm in 900 mL When the sample was tested for, at least 70% of the abiraterone acetate can be rate such eluting with 5 to 15 minutes, or 5 minutes to 10 minutes; the unit dosage form contains abiraterone acetate 125 mg.

  A unit dosage form of a pharmaceutical composition comprising abiraterone acetate, wherein the average plasma Cmax is 50 ng / mL to 120 ng / mL when a dose of 500 mg is orally administered to a population of healthy male subjects in a fasted state Also describe the shape. In some cases, when a dose of 500 mg is orally administered to a population of fasting healthy male subjects, the median plasma tmax is between 1 hour and 2.5 hours. A unit dosage form of a pharmaceutical composition comprising abiraterone acetate, wherein a mean plasma AUC (0-∞) of 240 h * ng / mL to 650 h * when a dose of 500 mg is orally administered to a population of fasting healthy male subjects Unit dosage forms that are ng / mL are described herein. In some cases, the unit dosage form contains 125 mg of abiraterone acetate.

  A unit dosage form of a pharmaceutical composition comprising abiraterone acetate, wherein when a dose of 500 mg is administered to a fasting healthy male subject, the 90% confidence interval of mean plasma Cmax is a value between 50 ng / mL and 120 ng / mL A unit dosage form of a pharmaceutical composition comprising abiraterone acetate, wherein a 90% confidence interval of mean plasma AUC (0-∞) when a dose of 500 mg is administered to a fasting healthy male subject A unit dosage form with a value of 240 h * ng / mL to 650 h * ng / mL is also described.

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

  A method of treating castration resistant prostate cancer comprising administering to a patient in need thereof a therapeutically effective amount (eg, 500 mg) of a unit dosage form of abiraterone acetate described herein and a glucocorticoid Methods that include doing are also described herein. In various embodiments, the glucocorticoid is selected from the group consisting of prednisone, prednisolone, and methylprednisolone; the therapeutically effective amount is 500 mg / day; the therapeutically effective amount is 100 mg, 125 mg of abiraterone acetate, or Administered using a dosage form containing 150 mg; the 500 mg dose is administered using one, two, three, four, five, or six unit dosage forms.

  A method of making a composition comprising abiraterone acetate, comprising grinding a composition comprising abiraterone acetate, a comminuteable comminuting compound, an accelerator, and one or both of an antioxidant and a sequestering agent. A method for reducing the particle size of the abiraterone acetate by dry milling is described herein, comprising dry milling in a mill for a time sufficient to produce a composition comprising the abiraterone acetate prepared.

  In some cases of the preparation method, [D90] of abiraterone acetate in the pulverized composition is greater than 400 nm and 7,500 nm, 7,000 nm, 6,000 nm, 5,000 nm, 4,500 nm, 4, Less than one of 000 nm, 3,000 nm, 2,000 nm, 900 nm, 800 nm, and 700 nm; [D50] of abiraterone acetate in the milled composition is greater than 100 nm and less than 3,500 nm, 3, 000 nm, 2,500 nm, 1,600 nm, less than 1,400 nm, less than 1,200 nm, less than 1,000 nm, less than 800 nm, less than 500 nm, less than 400 nm, less than 300 nm; of abiraterone acetate in the milled composition Elution rate is pH 4.5 phosphate buffer with 0.1% sodium lauryl sulfate When testing a sample containing 100 mg of abiraterone acetate using USP apparatus II at 75 rpm in 900 mL, at least 70% of said abiraterone acetate elutes in 5-15 minutes or 5-10 minutes The dissolution rate of abiraterone acetate in the milled composition was 125 mg of abiraterone acetate using USP apparatus II at 75 rpm in 900 mL of pH 4.5 phosphate buffer containing 0.12% sodium lauryl sulfate. Is at a rate such that at least 70% of the abiraterone acetate elutes in 5 to 15 minutes or 5 to 10 minutes; the abiraterone acetate in the milled composition [ D50] is greater than 200 nm and less than 6,500 nm, 6,000 nm, 5,50 nm, less than 5,000 nm, less than 4,000 nm, less than 3,000 nm, or less than 2,000 nm; the method comprises one or more pharmaceutically acceptable diluents comprising a composition comprising microparticles of abiraterone acetate; It further includes preparing a unit dosage form with a disintegrant, lubricant, lubricant, or dispersant.

In various embodiments, the particles of abiraterone acetate in the pharmaceutical composition (or used to prepare the pharmaceutical composition) are 5,000 nm, 4,000 nm, 3,000 nm, 2,500 nm, 2,400 nm, 2,300 nm, 2,200 nm, 2,200 nm, 2,100 nm, 2,000 nm, 1,900 nm, 1,800 nm, 1,700 nm, 1,600 nm, 1,500 nm, 1,400 nm, 1,300 nm, 1, Median particle size ([D ₅₀ ]) determined on the basis of particle volume below the particle size selected from the group consisting of 200 nm, 1,100 nm, 1,000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, and 200 nm Or D _[50] or [D50]). In some embodiments, [D50] is 25 nm or 100 nm or even 500 nm or more. In various embodiments, [D50] is 5,000 nm to 100 nm, 3,500 nm to 100 nm, 2,500 nm to 100 nm, 1,500 nm to 100 nm, 1,200 nm to 100 nm, 1,100 nm to 100 nm, 1,000 nm. -100 nm, 800 nm to 100 nm, 700 nm to 100 nm, 600 nm to 100 nm, 500 nm to 100 nm. D [4,3] (volume average diameter) in various embodiments is less than 7,000 nm, less than 5,000 nm, less than 3,500 nm, less than 3,000 nm, less than 2,000 nm, less than 1,000 nm, or 300 nm Is less than. For example, in various cases, such as those already described, D [4,3] is greater than 100 nm or greater than 200 nm. In some cases, D [4,3] (volume average diameter) is 7,000 nm to 1,000 nm, 6,000 nm to 200 nm, 5,000 nm to 1,000 nm, 4,000 nm to 1,000 nm, 3 1,000 nm to 1,000 nm, 2,000 nm to 1,000 nm, 1,800 nm to 1,000 nm, 1,600 nm to 1,000 nm, 1,500 nm to 1,000 nm, 1,500 nm to 500 nm, 4,000 nm to 2 2,000 nm, 4,000 nm to 100 nm, 25,000 nm to 500 nm, 700 nm to 100 nm, 600 nm to 100 nm, 500 nm to 100 nm, 1,000 nm to 200 nm, 900 nm to 200 nm, 800 nm to 200 nm, 700 nm to 200 nm. [D90] in various embodiments _{([D 90]} or _{D [90])} is less than 8,000 nm, less than 7,500Nm, less 7,000Nm, less 6,000Nm, less than 4,000 nm, less than 2,000nm , Less than 1,000 nm and less than 500 nm. In some cases, D90 is from 5,500 nm to 300 nm, 5,000 nm to 500 nm, 4,500 nm to 500 nm, 4,000 nm to 200 nm, 4,500 nm to 750 nm, and 3,500 nm to 500 nm. In various embodiments described herein, the [D90] of abiraterone acetate is less than 5,000 nm or less than 4,000 nm. In some embodiments, [D ₉₀ ] is from 6,000 nm to 500 nm, 5,500 nm to 500 nm, or 5,000 nm to 500 nm, and 4,000 nm to 400 nm.

  In another embodiment, the crystallinity profile of abiraterone acetate is at least 40% of abiraterone acetate, wherein at least 20% of abiraterone acetate is crystalline, and at least 30% of abiraterone acetate is crystalline. % Is crystalline, at least 50% of abiraterone acetate is crystalline, at least 60% of abiraterone acetate is crystalline, at least 70% of abiraterone acetate is crystalline, acetic acid At least 75% of abiraterone is crystalline, at least 85% of abiraterone acetate is crystalline, at least 90% of abiraterone acetate is crystalline, at least 95% of abiraterone acetate is crystalline Crystalline and at least 98% of abiraterone acetate It is selected from the group consisting of a crystalline. In some embodiments, the crystallinity profile of abiraterone acetate is substantially equal to the crystallinity profile of abiraterone acetate prior to subjecting the abiraterone acetate to the methods described herein.

  In another embodiment, the amorphous content of abiraterone acetate is less than 80% of abiraterone acetate is amorphous, less than 70% of abiraterone acetate is amorphous, Less than 60% is amorphous, less than 50% of abiraterone acetate is amorphous, less than 40% of abiraterone acetate is amorphous, less than 30% of abiraterone acetate is non- Crystalline, less than 25% of abiraterone acetate is amorphous, less than 15% of abiraterone acetate is amorphous, less than 10% of abiraterone acetate is amorphous, Selected from the group consisting of less than 5% of abiraterone acetate being amorphous and less than 2% of abiraterone acetate being amorphous. In some embodiments, abiraterone acetate does not significantly increase the amorphous content after subjecting abiraterone acetate to the dry milling process described herein.

  In some embodiments, abiraterone acetate particles are prepared by dry milling abiraterone acetate with a comminuteable compound and an accelerator in the presence of a mill. Additional components may be present during grinding, and the various components present during grinding (except for abiraterone acetate and ground) are referred to as the comminuted matrix. In some cases, milling results in particles of abiraterone acetate that are significantly reduced in size dispersed in the comminuted matrix. Since all of the components in the comminuted matrix are pharmaceutically acceptable, a pharmaceutical composition can be prepared using a mixture of abiraterone acetate and comminuted matrix made by grinding. In some cases, some or all of the components of the comminuted matrix are reduced during grinding. In some cases, additional pharmaceutically acceptable ingredients may be added to the mixture of abiraterone acetate and comminuted matrix after grinding. In some embodiments, dry milling is performed in the presence of a milled body, and in other cases by milling in the absence of a milled body, for example, a jet mill or another type of mill, such as In a mill that can reduce particle size and / or increase the solubility of abiraterone acetate when milling abiraterone acetate in the presence of a millable comminuting compound that may or may not reduce its own particle size Particles are produced by grinding with.

  In some cases, the abiraterone acetate is one or more pulverizable comminuted compounds selected from lactose (eg, lactose monohydrate or anhydrous lactose) and mannitol, and 1 selected from sodium lauryl sulfate and povidone. It grind | pulverizes with the above promoter. In some cases, milling reduces the particle size of one or more components of the comminuted matrix in addition to reducing the particle size of abiraterone acetate. Thus, in some cases, pulverization reduces one or more particles of a substance (eg, lactose) used as a pulverizable comminution compound. In some cases, abiraterone acetate is ground with lactose (eg, lactose monohydrate) and sodium lauryl sulfate. In some cases, during dry milling, abiraterone acetate may be present at 20% to 60% (w / w), lactose may be present at 80% (w / w) or less, and mannitol is 80% (w / w). w) may be present below, and povidone and sodium lauryl sulfate may each (or both) be present at 1% to 10% (w / w).

  In some embodiments, abiraterone acetate includes one or more antioxidants and / or one or more sequestering agents (ie, sequestering ions, in addition to at least one comminuteable compound and at least one accelerator). For example, dry grinding is performed in the presence of an agent that may be a metal ion. Thus, one or more of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, fumaric acid, tartaric acid, and citric acid (eg, anhydrous citric acid), or mixtures thereof are being dry milled May be present. In some cases, both at least one antioxidant and at least one sequestering agent are present during milling. During grinding, ascorbic acid, fumaric acid, tartaric acid, and citric acid (e.g., anhydrous citric acid) are 8% or less on a w / w basis (e.g., 7% -0.1%, 1%- 0.1% or 0.2%), and BHT and BHA may be 0.5% or less (eg, 0.5% to 0.01%, 0.2% to 0, respectively or in combination) 0.08%, 0.15% to 0.05%, or 0.1%). After grinding is complete, one or more additional antioxidants and / or one or more additional sequestering agents may be added to the ground material.

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

  Also, a method of treating a patient, comprising: 1 in the form of a pharmaceutical composition described herein (eg, by administering one or more unit dosage forms described herein comprising abiraterone acetate) Abiraterone acetate (e.g. 900 mg, 850 mg, 800 mg, 750 mg, 700 mg, 650 mg, 600 mg, 550 mg, 525 mg, 500 mg, 475 mg, 450 mg, 425 mg, 400 mg, 375 mg, 350 mg, 325 mg, 300 mg, 275 mg) , 250 mg, 225 mg, 200 mg, 150 mg, 100 mg, 90 mg, 80 mg, 70 mg, 60 mg, or 50 mg), wherein the abiraterone acetate has a particle size profile as described herein and / or the agent But also a method having the dissolution profiles described herein described herein. A patient may also be treated with a glucocorticoid such as prednisone, prednisolone, or dexamethasone. Alternatively, for example, 5 mg / day to 15 mg / day (eg, 5 mg / day, 6 mg / day, 7 mg / day, 8 mg / day, 9 mg / day, 10 mg / day, eg, 2 × 4 mg dose / day) of methylprednisolone The patient may be treated with In some cases, a patient, eg, a patient not suffering from liver damage, is treated at 500 mg / day by administering four 125 mg unit dosage forms of abiraterone acetate described herein.

In some cases, for the dosage forms described herein, when administered with a low fat diet (7% fat, 300 calories), a single dose of the unit dosage form described herein (or its effectiveness) AUC _0-∞ in an amount (eg, 4 × 125 mg) is 4 times lower (3 times lower, 2 times lower, 1.5 times lower) than when administered in a fasted state.

In some cases, for the dosage forms described herein, when administered with a high fat diet (57% fat, 825 calories), a single dose of the unit dosage form described herein (or its effectiveness) AUC _0-∞ (or AUC _0-t ) in an amount, for example 4 × 125 mg, is 8 times or less (7 times or less, 5 times or less, 3 times or less, 2 times or less) than when administered in a fasted state. 1.5 times or less) High.

In some cases, for the dosage forms described herein, when administered with a high fat diet (57% fat, 825 calories), a single dose of the unit dosage form described herein (or its effectiveness) C _max of the amount, for example 4 × 125 mg, is 15 times or less (13 times or less, 12 times or less, 11 times or less, 10 times or less, 9 times or less, 8 times or less) than when administered in a fasted state, 2 times or less, 6 times or less, 5 times or less) high.

  In some cases, for the dosage forms described herein, when administered with a low fat diet (7% fat, 300 calories), a single dose of the unit dosage form described herein (or its approval) The amount of Cmax, for example 4 × 125 mg, is 6 times or less (5 times or less, 4 times or less, 3 times or less, 2 times or less, 1.5 times or less) higher than when administered in a fasted state.

  The dissolution rate of tablets containing 100 mg or 125 mg of abiraterone acetate was measured using a USP apparatus II of 75 rpm in 900 mL of pH 4.5 phosphate buffer containing 0.1% to 0.12% sodium lauryl sulfate (respectively). At least 90% or at least 95% of the abiraterone acetate is 20 minutes or less (eg, 19 minutes or less, 18 minutes or less, 17 minutes or less, 16 minutes or less, 15 minutes or less, 14 minutes or less, The rate of elution is 1 minute or less, 11 minutes or less, 9 minutes or less). For example, 90% can elute in 9 to 19 minutes. If the tablet contains more than 125 mg of abiraterone acetate or less than 100 mg, the dissolution rate is determined for the portion (or multiple smaller tablets) of the larger tablet that gives 100 mg to 125 mg of abiraterone acetate. In some cases, at least 80% or at least 85% of abiraterone acetate is 15 minutes or less (eg, 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 than 7 minutes). For example, 85% can elute in 7 to 14 minutes.

  In some cases, at least 80% or at least 85% of abiraterone acetate in a 125 mg dosage form after storage at 25 ° C., 60% RH for 4 weeks or more (eg, 8 weeks or 12 weeks) for 15 minutes or less ( For example, elution is performed for 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). In some cases, after storage at 40 ° C. and 75% RH for 3 weeks or more (eg, 6 weeks or 9 weeks), at least 95% of abiraterone acetate is 15 minutes or less (eg, 14 minutes or less, 13 minutes or less) 11 minutes or less, 9 minutes or less). For example, 95% can elute in 8 minutes to 14 minutes. Again, if the tablet contains more than 125 mg or less than 100 mg of abiraterone acetate, the dissolution rate is determined for the portion (or multiple smaller tablets) of the larger tablet that gives 100 mg to 125 mg of abiraterone acetate.

  In certain embodiments, the coefficient of variation observed for a pharmaceutical composition described herein in one or more of Cmax, AUC (0-t), and AUC (0-∞) is a healthy state in a fasted state Less than 60%, less than 50%, less than 40%, less than 30%, less than 25%, or less than 20% when administered to a patient. In some embodiments, a pharmaceutical composition described herein (125 mg unit dosage form, or a 500 mg unit dosage form, eg, 4 × 125 mg) is administered in a comparative pharmacokinetic study, eg, Zytiga®. ) Smaller than one or more of Cmax, AUC (0-t), and AUC (0-∞) as compared to a 250 mg dosage form (or a Zytiga® 250 mg dosage form at a dose of 1,000) Showing fluctuations.

  In some cases, the hardness of the abiraterone tablet is 100N to 190N (eg, 110N to 180N).

  Pharmaceutical intermediates can be prepared by dry milling the following materials: (A) 5% to 60% by weight of abiraterone acetate, 30% to 95% by weight of lactose (eg, lactose monohydrate) Sodium lauryl sulfate 0.1 wt% to 15 wt%; BHA 0.001 wt% to 1 wt%, and BHT 0.001 wt% to 1 wt%; (B) abiraterone acetate 10 wt% to 50 wt%, lactose ( For example, lactose monohydrate) 40 wt% to 80 wt%, sodium lauryl sulfate 0.5 wt% to 10 wt%; BHA 0.01 wt% to 0.8 wt%, and BHT 0.01 wt% to 0. 8% by weight; (C) abiraterone acetate 20% to 40% by weight, lactose (eg, lactose monohydrate) 50% to 70% by weight, sodium lauryl sulfate BHA 0.05 wt% to 0.5 wt%, and BHT 0.05 wt% to 0.5 wt%; (D) Abiraterone acetate 25 wt% to 35 wt%, lactose (eg, lactose Monohydrate) 60 wt% to 70 wt%, sodium lauryl sulfate 4 wt% to 8 wt%; BHA 0.05 wt% to 0.15 wt%, and BHT 0.05 wt% to 0.15 wt%; (E) Abiraterone acetate 30% by weight, lactose (eg lactose monohydrate) 63.8% by weight, sodium lauryl sulfate 6% by weight; BHA 0.1% by weight, and BHT 0.1% by weight.

  The pharmaceutical intermediate can be processed into tablets having the following materials: (A) 5% to 50% by weight of abiraterone acetate, 5% to 80% by weight of lactose (eg, lactose monohydrate), Sodium lauryl sulfate 0.1 wt% to 10 wt%, BHA 0.001 wt% to 1 wt%, BHT 0.001 wt% to 1 wt%, microcrystalline cellulose 5 wt% to 80 wt%, croscarmellose sodium 0 5 wt% to 20 wt%, and sodium stearyl fumarate 0.01 wt% to 10 wt%; (B) abiraterone acetate 8 wt% to 40 wt%, lactose (e.g., lactose monohydrate) 10 wt% -60 wt%, sodium lauryl sulfate 0.5 wt% -8 wt%, BHA 0.01 wt% -0.05 wt%, BHT 0.01 wt% -0.5 wt% 10% to 70% by weight of microcrystalline cellulose, 1% to 15% by weight of croscarmellose sodium, and 0.05% to 5% by weight of sodium stearyl fumarate; (C) 10% to 30% by weight of abiraterone acetate %, Lactose (e.g., lactose monohydrate) 20% to 40%, sodium lauryl sulfate 1% to 5%, BHA 0.01% to 0.2%, BHT 0.01% to 0% 2 wt%, microcrystalline cellulose 20 wt% to 60 wt%, croscarmellose sodium 2 wt% to 10 wt%, and sodium stearyl fumarate 0.1 wt% to 2 wt%; (D) abiraterone acetate 12 % To 17% by weight, lactose (eg lactose monohydrate) 25% to 35% by weight, sodium lauryl sulfate 2% to Wt%; BHA 0.01 wt% to 0.2 wt%, BHT 0.01 wt% to 0.2 wt%, microcrystalline cellulose 35 wt% to 50 wt%, croscarmellose sodium 5 wt% to 9 wt% And (E) abiraterone acetate 14.29% by weight, lactose (eg lactose monohydrate) 30.38% by weight, sodium lauryl sulfate 3 21 wt%; BHA 0.05 wt%, BHT 0.05 wt%, microcrystalline cellulose 44 wt% to 53 wt%, croscarmellose sodium 7 wt%, and sodium stearyl fumarate 0.5 wt%.

  In some embodiments, the dry crusher used to dry crush abiraterone acetate is an attritor mill (horizontal or vertical), nutation mill, tower mill, pearl mill, planetary mill, vibration mill, eccentric vibration mill, gravity dependent A mill selected from the group consisting of a die ball mill, a rod mill, a roller mill, and a crusher mill. In some embodiments, the dry pulverizer used to dry pulverize abiraterone acetate is a mill selected from the group consisting of a jet mill, a spiral jet mill, a micronizer, or a pulverizer. Preferably, the method is adapted to produce abiraterone acetate in a swing batch or continuous mode.

  In some embodiments, when the mill uses a pulverized body, the pulverized body in the pulverizer is mechanically agitated by one, two, or three rotating shafts. The pulverized body may be formed of a material selected from the group consisting of ceramic, glass, steel, polymer, ferromagnet, and metal, as well as other suitable materials. In some embodiments, the crushed body is a steel ball having a diameter selected from the group consisting of 1 mm to 20 mm, 2 mm to 15 mm, and 3 mm to 10 mm. In various embodiments of the dry grinding method, the ground body is a zirconium oxide ball having a diameter selected from the group consisting of 1 mm to 20 mm, 2 mm to 15 mm, and 3 mm to 10 mm.

  In another embodiment, the grinding time is 10 minutes to 6 hours, 10 minutes to 2 hours, 10 minutes to 90 hours, 10 minutes to 1 hour, 10 minutes to 45 minutes, 10 minutes to 30 minutes, 5 minutes to 30 minutes. It is a range selected from the group consisting of 1 minute to 2 minutes, 5 minutes to 20 minutes, 2 minutes to 10 minutes, 2 minutes to 5 minutes, and 1 minute to 2 minutes.

In additional grinding matrix and accelerator embodiments, the grinding matrix is a single substance or a mixture of two or more substances in any ratio. In some embodiments, the single substance or mixture of two or more substances is mannitol, sorbitol, isomalt, xylitol, maltitol, lactitol, erythritol, arabitol, ribitol, glucose, fructose, mannose, galactose, anhydrous lactose, Selected from the group consisting of lactose monohydrate, sucrose, maltose, trehalose, and maltodextrin. In some embodiments, the single substance or mixture of two or more substances is dextrin, inulin, dextrate, polydextrose, starch, wheat flour, corn flour, rice flour, rice starch, tapioca flour, tapioca starch, potato flour Potato starch, other flours and starches, milk powder, skim milk powder, other solid milks and derivatives, soybean flour, soybean meal or other soybean products, cellulose, microcrystalline cellulose, blended materials based on microcrystalline cellulose, gelatinization (Or partial gelatinization) starch, hypromellose, carboxymethylcellulose, hydroxypropylcellulose, citric acid, tartaric acid, malic acid, maleic acid, fumaric acid, ascorbic acid, succinic acid, sodium citrate, sodium tartrate, sodium malate, ascorbine Acid Lithium, potassium citrate, potassium tartrate, potassium malate, sodium acetate, potassium ascorbate, sodium carbonate, potassium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium carbonate, dicalcium phosphate, tricalcium phosphate, sodium sulfate , Sodium chloride, sodium metabisulfite, sodium thiosulfate, ammonium chloride, Gruber salt, ammonium carbonate, sodium bisulfate, magnesium sulfate, potassium alum, potassium chloride, sodium hydrogensulfate, sodium hydroxide, crystalline hydroxide, carbonic acid Hydrogen salt, ammonium chloride, methylamine hydrochloride, ammonium bromide, silica, anhydrous silica, alumina, titanium dioxide, talc, chalk, mica, kaolin, bentonite, hectorite, three Magnesium silicate, clay-based material or aluminum silicate, sodium lauryl sulfate, sodium stearyl sulfate, sodium cetyl sulfate, sodium cetostearyl sulfate, sodium docusate, sodium deoxycholate, sodium N-lauroyl sarcosine, glyceryl monostearate, Glyceryl distearate, glyceryl palmitostearate, glyceryl behenate, glyceryl caprylate, glyceryl oleate, benzalkonium chloride, cetrimonium bromide, cetrimonium chloride, cetrimide, cetylpyridinium chloride, cetylpyridinium bromide, benzethonium chloride, PEG 40 stearate, PEG 100 stearate, poloxamer 188, poloxamer 338, poloxamer 407, polyoxyl 2 ester Allyl ether, polyoxyl 100 stearyl ether, polyoxyl 20 stearyl ether, polyoxyl 10 stearyl ether, polyoxyl 20 cetyl ether, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polyoxyl 35 castor oil, polyoxyl 40 castor oil , Polyoxyl 60 castor oil, polyoxyl 100 castor oil, polyoxyl 200 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil, polyoxyl 100 hydrogenated castor oil, polyoxyl 200 hydrogenated castor oil, cetostearyl alcohol, macrogel 15 Hydroxystearate, Sorbitan monopalmitate, Sorbi monostearate , Sorbitan trioleate, sucrose palmitate, sucrose stearate, sucrose distearate, sucrose laurate, glycocholic acid, sodium glycolate, cholic acid, sodium cholate, sodium deoxycholate, deoxycholic acid, sodium taurocholate , Taurocholic acid, sodium taurodeoxycholic acid, taurodeoxycholic acid, soybean lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkyl naphthalenesulfonate / lignosulfonate blend , Calcium dodecylbenzenesulfonate, dodecylbenzene Sodium sulfonate, diisopropyl naphthalenesulfonate, erythritol distearate, formaldehyde condensate naphthalenesulfonate, nonylphenol ethoxylate (poe-30), tristyrylphenol ethoxylate, polyoxyethylene (15) tallow alkylamine, sodium alkylnaphthalenesulfonate , Sodium alkylnaphthalenesulfonate, sodium alkylbenzenesulfonate, sodium isopropylnaphthalenesulfonate, sodium methylnaphthalene formaldehydesulfonate, sodium n-butylnaphthalenesulfonate, tridecyl alcohol ethoxylate (poe-18), triethanolamine iso Decanol phosphate, triethanolamine tristyryl phosphorus It is selected from the group consisting of acid esters, tristyrylphenol ethoxylate sulfate, bis (2-hydroxyethyl) tallow alkylamine.

  In some embodiments, the concentration of the single (or first) material of the comminuted matrix is 5% w / w to 99% w / w, 10% w / w to 95% w / w, 15% w / w to 85% w / w, 20% w / w to 80% w / w, 25% w / w to 75% w / w, 30% w / w to 60% w / w, 40% w / Selected from the group consisting of w-50% w / w. In some embodiments, the concentration of the second or even less material of the comminuted matrix is 5% w / w to 50% w / w, 5% w / w to 40% w / w, 5% w. / W-30% w / w, 5% w / w-20% w / w, 10% w / w-40% w / w, 10% w / w-30% w / w, 10% w / w Selected from the group consisting of -20% w / w, 20% w / w -40% w / w, or 20% w / w -30% w / w, or the second substance or less Is a surfactant or a water-soluble polymer, the concentrations are 0.1% w / w to 10% w / w, 0.1% w / w to 5% w / w, 0.1% w / w -2.5% w / w, 0.1% w / w-2% w / w, 0.1% w / w-1% w / w, 0.5% w / w-5% w / w 0.5% w / w to 3% w / w, 0.5% w / w to 2% w / w 0.5% w / w to 1.5% w / w, 0.5% w / w to 1% w / w, 0.75% w / w to 1.25% w / w, 0.75% It is selected from w / w to 1% w / w and 1% w / w.

In some embodiments, abiraterone acetate is ground in the presence of:
(A) Lactose monohydrate or a combination of lactose monohydrate and 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 octadecyl sulfate; polyoxyl 100 stearyl ether; polyoxyl 10 stearyl ether; sodium n-lauroyl sarcosinate; Lecithin; sodium docusate; polyoxyl-40-stearate; hydrophobic colloidal silica; sodium lauryl sulfate, or other alkyl sulfate surfactants with chain lengths C5 to C18; polyvinylpyrrolidone; lauryl sulfate sodium Um and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG 6000, sodium lauryl sulfate and PEG 8000, sodium lauryl sulfate and PEG 10000, sodium lauryl sulfate and polyoxyl 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, naphthalene sulfonate alkyl condensate / lignosulfonate blend; calcium dodecylbenzene sulfonate (branched) ; Naphth Diisopropyl stearate; erythritol distearate; linear and branched dodecylbenzenesulfonic acid; naphthalenesulfonic acid formaldehyde condensate; nonylphenol ethoxylate, POE-30; phosphate ester, tristyrylphenol ethoxylate, free acid; polyoxyethylene ( 15) Tallow alkylamine; sodium alkylnaphthalenesulfonate; sodium alkylnaphthalenesulfonate condensate; sodium alkylbenzenesulfonate; sodium isopropylnaphthalenesulfonate; sodium methylnaphthalene; formaldehyde sulfonate; sodium salt of n-butylnaphthalenesulfonate; tridecyl Alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate Ter; triethanolamine tristyryl phosphate; tristyrylphenol ethoxylate sulfate; bis (2-hydroxyethyl) tallow alkylamine.
(B) anhydrous lactose or a combination of anhydrous lactose and at least one substance selected from the group consisting of: lactose monohydrate; xylitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; Malic acid; trisodium citrate dihydrate; D, L-malic acid; sodium pentane sulfate; sodium octadecyl sulfate; polyoxyl 100 stearyl ether; polyoxyl 10 stearyl ether; sodium n-lauroyl sarcosinate; lecithin; Polyacetate Sodium; Polyoxyl-40-Stearate; Hydrophobic Colloidal Silica; Sodium Lauryl Sulfate, or Other Alkyl Sulfate Surfactants with Chain Lengths C5 to C18; Polyvinylpyrrolidone; And polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG 6000, sodium lauryl sulfate and PEG 8000, sodium lauryl sulfate and PEG 10000, sodium lauryl sulfate and polyoxyl 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; calcium dodecylbenzene sulfonate (branched); Naphthalene Diisopropyl sulfonate; erythritol distearate; linear and branched dodecylbenzenesulfonic acid; naphthalenesulfonic acid formaldehyde condensate; nonylphenol ethoxylate, POE-30; phosphate ester, tristyrylphenol ethoxylate, free acid; polyoxyethylene ( 15) Tallow alkylamine; sodium alkylnaphthalenesulfonate; sodium alkylnaphthalenesulfonate condensate; sodium alkylbenzenesulfonate; sodium isopropylnaphthalenesulfonate; sodium methylnaphthalene; formaldehyde sulfonate; sodium salt of n-butylnaphthalenesulfonate; tridecyl Alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate Triethanolamine tristyryl phosphate; tristyrylphenol ethoxylate sulfate; bis (2-hydroxyethyl) tallow alkylamine.
(C) Mannitol or a combination of mannitol and at least one substance selected from the group consisting of: lactose monohydrate; xylitol; anhydrous lactose; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; Calcium carbonate; malic acid; trisodium citrate dihydrate; D, L-malic acid; sodium pentane sulfate; sodium octadecyl sulfate; polyoxyl 100 stearyl ether; polyoxyl 10 stearyl ether; sodium n-lauroyl sarcosate; Polyoxyl-40-stearate; Hydrophobic colloidal silica; Sodium lauryl sulfate or other alkyl sulfate surfactants with chain lengths C5-C18; Polyvinylpyrrolidone; Lauryl Sodium sulfate and polyethylene glycol 40 stearate, Sodium lauryl sulfate and polyethylene glycol 100 stearate, Sodium lauryl sulfate and PEG 3000, Sodium lauryl sulfate and PEG 6000, Sodium lauryl sulfate and PEG 8000, Sodium lauryl sulfate and PEG 10000, Sodium lauryl sulfate and polyoxyl 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; calcium dodecylbenzene sulfonate (branched ) Diisopropyl naphthalenesulfonate; erythritol distearate; linear and branched dodecylbenzenesulfonic acid; naphthalenesulfonic acid formaldehyde condensate; nonylphenol ethoxylate, POE-30; phosphate ester, tristyrylphenol ethoxylate, free acid; polyoxyethylene (15) Tallow alkylamine; sodium alkylnaphthalenesulfonate; sodium alkylnaphthalenesulfonate condensate; sodium alkylbenzenesulfonate; sodium isopropylnaphthalenesulfonate; sodium methylnaphthalene; formaldehyde sulfonate; sodium salt of n-butylnaphthalenesulfonate; Decyl alcohol ethoxylate, POE-18; triethanolamine isodecanol Acid ester; triethanolamine tristyryl phosphate; tristyrylphenol ethoxylate sulfate; bis (2-hydroxyethyl) tallow alkylamine.
(D) Sucrose or a combination of sucrose and at least one substance selected from the group consisting of: lactose monohydrate; anhydrous lactose; mannitol; microcrystalline cellulose; glucose; sodium chloride; talc; kaolin; Malic acid; tartaric acid; trisodium citrate dihydrate; D, L-malic acid; sodium pentane sulfate; sodium octadecyl sulfate; polyoxyl 100 stearyl ether; polyoxyl 10 stearyl ether; sodium n-lauroyl sarcosate; lecithin; Polyacetate Sodium; Polyoxyl-40-Stearate; Hydrophobic Colloidal Silica; Sodium Lauryl Sulfate or Other Alkyl Sulfate Surfactants with Chain Lengths C5 to C18; Polyvinylpyrrolidone; And polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG 6000, sodium lauryl sulfate and PEG 8000, sodium lauryl sulfate and PEG 10000, sodium lauryl sulfate and polyoxyl 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, naphthalene sulfonate alkyl condensate / lignosulfonate blend; calcium dodecylbenzene sulfonate (branched) ; Naphthale Diisopropyl sulfonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acid; naphthalene sulfonic acid formaldehyde condensate; nonylphenol ethoxylate, POE-30; phosphate ester, tristyrylphenol ethoxylate, free acid; polyoxyethylene ( 15) Tallow alkylamine; sodium alkylnaphthalenesulfonate; sodium alkylnaphthalenesulfonate condensate; sodium alkylbenzenesulfonate; sodium isopropylnaphthalenesulfonate; sodium methylnaphthalene; formaldehyde sulfonate; sodium salt of n-butylnaphthalenesulfonate; tridecyl Alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester Triethanolamine tristyryl phosphate; tristyrylphenol ethoxylate sulfate; bis (2-hydroxyethyl) tallow alkylamine.
(E) Glucose or a combination of glucose and at least one substance selected from the group consisting of: lactose monohydrate; anhydrous lactose; mannitol; microcrystalline cellulose; sucrose; sodium chloride; talc; kaolin; Calcium, malic acid, tartaric acid, trisodium citrate dihydrate, D, L-malic acid, sodium pentane sulfate, sodium octadecyl sulfate, polyoxyl 100 stearyl ether, polyoxyl 10 stearyl ether, sodium n-lauroyl sarcosate; lecithin; Polyoxyl-40-stearate; Hydrophobic colloidal silica; Sodium lauryl sulfate or other alkyl sulfate surfactants with chain lengths C5 to C18; Polyvinylpyrrolidone; Sodium lauryl sulfate Um and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG 6000, sodium lauryl sulfate and PEG 8000, sodium lauryl sulfate and PEG 10000, sodium lauryl sulfate and polyoxyl 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, naphthalene sulfonate alkyl condensate / lignosulfonate blend; calcium dodecylbenzene sulfonate (branched) ; Naphth Diisopropyl stearate; erythritol distearate; linear and branched dodecylbenzenesulfonic acid; naphthalenesulfonic acid formaldehyde condensate; nonylphenol ethoxylate, POE-30; phosphate ester, tristyrylphenol ethoxylate, free acid; polyoxyethylene ( 15) Tallow alkylamine; sodium alkylnaphthalenesulfonate; sodium alkylnaphthalenesulfonate condensate; sodium alkylbenzenesulfonate; sodium isopropylnaphthalenesulfonate; sodium methylnaphthalene; formaldehyde sulfonate; sodium salt of n-butylnaphthalenesulfonate; tridecyl Alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate Ter; triethanolamine tristyryl phosphate; tristyrylphenol ethoxylate sulfate; bis (2-hydroxyethyl) tallow alkylamine.
(F) Sodium chloride or a combination of sodium chloride and at least one substance 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 octadecyl sulfate; polyoxyl 100 stearyl ether; polyoxyl 10 stearyl ether; sodium n-lauroyl sarcosinate; Docusate sodium; polyoxyl-40-stearate; hydrophobic colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants with chain lengths C5-C18; polyvinylpyrrolidone; lauryl sulfate Thorium and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG 6000, sodium lauryl sulfate and PEG 8000, sodium lauryl sulfate and PEG 10000, sodium lauryl sulfate and polyoxyl 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, naphthalene sulfonate alkyl condensate / lignosulfonate blend; calcium dodecylbenzene sulfonate (branched) ; Na Diisopropyl talene sulfonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acid; naphthalene sulfonic acid formaldehyde condensate; nonylphenol ethoxylate, POE-30; phosphate ester, tristyrylphenol ethoxylate, free acid; polyoxyethylene (15) Tallow alkylamine; sodium alkylnaphthalenesulfonate; sodium alkylnaphthalenesulfonate condensate; sodium alkylbenzenesulfonate; sodium isopropylnaphthalenesulfonate; sodium methylnaphthalene; formaldehyde sulfonate; sodium salt of n-butylnaphthalenesulfonate; Decyl alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate Ester; 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; Calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D, L-malic acid; sodium pentane sulfate; sodium octadecyl sulfate; polyoxyl 100 stearyl ether; polyoxyl 10 stearyl ether; sodium n-lauroyl sarcosinate; Lecithin; docusate sodium; polyoxyl-40-stearate; hydrophobic colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants with chain lengths C5-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 PEG 6000, sodium lauryl sulfate and PEG 8000, sodium lauryl sulfate and PEG 10000, sodium lauryl sulfate and polyoxyl 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 / lignosulfonate blend; calcium dodecylbenzene sulfonate Branched); diisopropyl naphthalenesulfonate; erythritol distearate; linear and branched dodecylbenzenesulfonic acid; naphthalenesulfonic acid formaldehyde condensate; nonylphenol ethoxylate, POE-30; phosphate ester, tristyrylphenol ethoxylate, free acid; Polyoxyethylene (15) tallow alkylamine; sodium alkylnaphthalenesulfonate; sodium alkylnaphthalenesulfonate condensate; sodium alkylbenzenesulfonate; sodium isopropylnaphthalenesulfonate; sodium methylnaphthalene; formaldehyde sulfonate; sodium n-butylnaphthalenesulfonate Salt; tridecyl alcohol ethoxylate, POE-18; triethanolamine isodeca Nol phosphate ester; Triethanolamine tristyryl phosphate ester; Tristyrylphenol ethoxylate sulfate; Bis (2-hydroxyethyl) tallow alkylamine.
(H) Tartaric acid or a combination of tartaric acid and at least one substance selected from the group consisting of: lactose monohydrate; anhydrous lactose; mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; Calcium carbonate; malic acid; trisodium citrate dihydrate; D, L-malic acid; sodium pentane sulfate; sodium octadecyl sulfate; polyoxyl 100 stearyl ether; polyoxyl 10 stearyl ether; sodium n-lauroyl sarcosate; Polyoxyl-40-stearate; Hydrophobic colloidal silica; Sodium lauryl sulfate or other alkyl sulfate surfactants with chain lengths C5 to 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 PEG 6000, sodium lauryl sulfate and PEG 8000, sodium lauryl sulfate and PEG 10000, sodium lauryl sulfate and polyoxyl 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; calcium dodecylbenzene sulfonate (branched); Naphthalene Diisopropyl sulfonate; erythritol distearate; linear and branched dodecylbenzenesulfonic acid; naphthalenesulfonic acid formaldehyde condensate; nonylphenol ethoxylate, POE-30; phosphate ester, tristyrylphenol ethoxylate, free acid; polyoxyethylene ( 15) Tallow alkylamine; sodium alkylnaphthalenesulfonate; sodium alkylnaphthalenesulfonate condensate; sodium alkylbenzenesulfonate; sodium isopropylnaphthalenesulfonate; sodium methylnaphthalene; formaldehyde sulfonate; sodium salt of n-butylnaphthalenesulfonate; tridecyl Alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate Triethanolamine tristyryl phosphate; tristyrylphenol ethoxylate sulfate; bis (2-hydroxyethyl) tallow alkylamine.
(I) Microcrystalline cellulose, or a combination of microcrystalline cellulose and 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 octadecyl sulfate, polyoxyl 100 stearyl ether, polyoxyl 10 stearyl ether, n-lauroyl sarcosine Lecithin; sodium docusate; polyoxyl-40-stearate; hydrophobic colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants with chain lengths C5-C18; 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 PEG 6000, sodium lauryl sulfate and PEG 8000, sodium lauryl sulfate and PEG 10000, sodium lauryl sulfate and Polyoxyl 100 stearyl ether, sodium lauryl sulfate and poloxamer 407, sodium lauryl sulfate and poloxamer 338, sodium lauryl sulfate and poloxamer 188; Cal Bis (branched); diisopropyl naphthalene sulfonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acid; naphthalene sulfonic acid formaldehyde condensate; nonylphenol ethoxylate, POE-30; phosphate ester, tristyrylphenol ethoxylate, free Polyoxyethylene (15) tallow alkylamine; sodium alkylnaphthalenesulfonate; sodium alkylnaphthalenesulfonate condensate; sodium alkylbenzenesulfonate; sodium isopropylnaphthalenesulfonate; sodium methylnaphthalene; formaldehyde sulfonate; n-butylnaphthalenesulfonate Sodium salt of tridecyl alcohol ethoxylate, POE-18; triethanolamine Sodecanol phosphate; triethanolamine tristyryl phosphate; tristyrylphenol ethoxylate sulfate; bis (2-hydroxyethyl) tallow alkylamine.
(J) A combination of kaolin and at least one substance selected from the group consisting of: lactose monohydrate; xylitol; anhydrous lactose; mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; Calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D, L-malic acid; sodium pentane sulfate; sodium octadecyl sulfate; polyoxyl 100 stearyl ether; polyoxyl 10 stearyl ether; sodium n-lauroyl sarcosinate; Docusate sodium; polyoxyl-40-stearate; hydrophobic colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants with chain lengths C5 to C18; polyvinylpyrrolidone; lauryl Sodium sulfate and polyethylene glycol 40 stearate, Sodium lauryl sulfate and polyethylene glycol 100 stearate, Sodium lauryl sulfate and PEG 3000, Sodium lauryl sulfate and PEG 6000, Sodium lauryl sulfate and PEG 8000, Sodium lauryl sulfate and PEG 10000, Sodium lauryl sulfate and polyoxyl 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; calcium dodecylbenzene sulfonate (branched ) Diisopropyl naphthalenesulfonate; erythritol distearate; linear and branched dodecylbenzenesulfonic acid; naphthalenesulfonic acid formaldehyde condensate; nonylphenol ethoxylate, POE-30; phosphate ester, tristyrylphenol ethoxylate, free acid; polyoxyethylene (15) Tallow alkylamine; sodium alkylnaphthalenesulfonate; sodium alkylnaphthalenesulfonate condensate; sodium alkylbenzenesulfonate; sodium isopropylnaphthalenesulfonate; sodium methylnaphthalene; formaldehyde sulfonate; sodium salt of n-butylnaphthalenesulfonate; Decyl alcohol ethoxylate, POE-18; triethanolamine isodecanol Acid ester; briethanolamine tristyrylphosphate ester; tristyrylphenol ethoxylate sulfate; bis (2-hydroxyethyl) tallow alkylamine.
(K) A combination of talc and at least one substance selected from the group consisting of: lactose monohydrate; xylitol; anhydrous lactose; mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; kaolin; Malic acid; tartaric acid; trisodium citrate dihydrate; D, L-malic acid; sodium pentane sulfate; sodium octadecyl sulfate; polyoxyl 100 stearyl ether; polyoxyl 10 stearyl ether; sodium n-lauroyl sarcosate; Polyacetate Sodium; Polyoxyl-40-Stearate; Hydrophobic Colloidal Silica; Sodium Lauryl Sulfate or Other Alkyl Sulfate Surfactants with Chain Lengths C5 to C18; Polyvinylpyrrolidone; And polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulfate and PEG 6000, sodium lauryl sulfate and PEG 8000, sodium lauryl sulfate and PEG 10000, sodium lauryl sulfate and polyoxyl 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, naphthalenesulfonic acid alkyl condensate / lignosulfonate blend; calcium dodecylbenzenesulfonate ; Naphthale Diisopropyl sulfonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acid; naphthalene sulfonic acid formaldehyde condensate; nonylphenol ethoxylate, POE-30; phosphate ester, tristyrylphenol ethoxylate, free acid; polyoxyethylene ( 15) Tallow alkylamine; sodium alkylnaphthalenesulfonate; sodium alkylnaphthalenesulfonate condensate; sodium alkylbenzenesulfonate; sodium isopropylnaphthalenesulfonate; sodium methylnaphthalene; formaldehyde sulfonate; sodium salt of n-butylnaphthalenesulfonate; tridecyl Alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester 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 substances that are considered “generally regarded as safe” (GRAS) as pharmaceuticals.

  In some embodiments, the dry milling of abiraterone acetate is performed in the presence of an accelerator or combination of accelerators. In some embodiments, the accelerator is selected from the group consisting of a lubricant, a surfactant, a polymer, and / or a lubricant. In some embodiments, the accelerator is selected from the group consisting of colloidal silicon dioxide, sodium stearate, and talc. In some embodiments, the accelerator is benzethonium chloride, docusate sodium, polyethylene alkyl ether, sodium lauryl sulfate, tricaprylin, alpha tocopherol, glyceryl monooleate, myristyl alcohol, poloxamer, polyoxyethylene alkyl ether, polyoxy Ethylene stearate, polyoxyethylene castor oil derivative, polyoxy-15 hydroxystearate, polyoxyglyceride, polysorbate, propylene glycol dilaurate, sorbitan ester, sucrose palmitate, vitamin E polyethylene glycol succinate, polyethylene glycol (PEG), Poloxamer, Poloxamine, Sarcosine type surfactant, Polysorbate, Aliphatic alcohol, Alkyl And aryl sulfates, alkyl and aryl polyether sulfonates, and other sulfate type surfactants, trimethyl ammonium type surfactants, lecithin and other phospholipids, bile salts, polyoxyethylene castor oil derivatives, poly Oxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, alkyl glucopyranoside, alkyl maltopyranoside, glycerol fatty acid ester, alkylbenzene sulfonic acid, alkyl ether carboxylic acid, alkyl and aryl phosphate ester, alkyl and aryl sulfate ester, alkyl And aryl sulfonic acids, alkylphenol phosphates, alkylphenol sulfates, alkyl and aryl phosphates, alkyl polysaccharides, alkylamine ethoxylates , Alkyl-naphthalene sulfonic acid formaldehyde condensate, sulfosuccinate, lignosulfonate, cet-oleyl alcohol ethoxylate, condensed naphthalene sulfonate, dialkyl and alkyl naphthalene sulfonate, dialkyl sulfosuccinate, ethoxylated nonylphenol, ethylene glycol ester , Aliphatic alcohol alkoxylate, hydrogenated tallow alkylamine, mono-alkylsulfosuccinamidate, nonylphenol ethoxylate, sodium oleyl N-methyl taurate, tallow alkylamine, linear and branched dodecylbenzenesulfonic acid Selected from the group.

  In some embodiments, the accelerator is sodium stearyl sulfate, sodium stearyl fumarate, magnesium stearate, talc, myristic acid, sodium cetyl sulfate, sodium cetostearyl sulfate, docusate sodium, sodium deoxycholate, N-lauroyl. Sarcosine sodium salt, glyceryl monostearate, glyceryl distearate, glyceryl palmitostearate, glyceryl behenate, glyceryl caprylate, glyceryl oleate, benzalkonium chloride, cetyltrimethylammonium bromide, cetyltrimethylammonium chloride, cetrimide, chloride Cetylpyridinium, cetylpyridinium bromide, benzethonium chloride, PEG 40 stearate, PEG 100 stearate, poloxamer 188 Poloxamer 338, poloxamer 407, polyoxyl 2 stearyl ether, polyoxyl 100 stearyl ether, polyoxyl 20 stearyl ether, polyoxyl 10 stearyl ether, polyoxyl 20 cetyl ether, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polyoxyl 35 castor oil, polyoxyl 40 castor oil, polyoxyl 60 castor oil, polyoxyl 100 castor oil, polyoxyl 200 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil, polyoxyl 100 hydrogenated castor oil, polyoxyl 200 hydrogenated castor oil Oil, cetostearyl alcohol, macrogel 15 hydroxyste Rate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate, sucrose palmitate, sucrose stearate, sucrose distearate, sucrose laurate, glycocholic acid, sodium glycolate, cholic acid, sodium cholate, deoxychol Sodium acid, deoxycholic acid, sodium taurocholate, taurocholic acid, sodium taurodeoxycholate, taurodeoxycholic acid, soybean lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, Naphthalenesulfonic acid alkyl condensate / lignosulfonatebrene , Calcium dodecylbenzenesulfonate, sodium dodecylbenzenesulfonate, diisopropyl naphthalenesulfonate, erythritol distearate, formaldehyde condensate of naphthalenesulfonate, nonylphenol ethoxylate (POE-30), tristyrylphenol ethoxylate, polyoxyethylene (15 ) Tallow alkyl amine, sodium alkyl naphthalene sulfonate, sodium alkyl naphthalene sulfonate condensate, sodium alkyl benzene sulfonate, sodium isopropyl naphthalene sulfonate, sodium methyl naphthalene formaldehyde sulfonate, sodium n-butyl naphthalene sulfonate, tridecyl alcohol ethoxylate (Poe-18), triethanolamine isode Norurin acid ester, triethanolamine tristyryl phosphates esters, tristyrylphenol ethoxylate sulfates are selected from the group consisting of bis (2-hydroxyethyl) tallow alkyl amine.

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

  In some embodiments, the concentration of the accelerator during dry milling is 0.1% w / w to 10% w / w, 0.1% w / w to 5% w / w, 0.1% w. / W to 2.5% w / w, 0.1% w / w to 2% w / w, 0.1% w / w to 1% w / w, 0.5% w / w to 5% w / W, 0.5% w / w to 3% w / w, 0.5% w / w to 2% w / w, 0.5% w / w to 1.5% w / w, 0.5 Selected from the group consisting of ˜1% w / w, 0.75% w / w to 1.25% w / w, 0.75% w / w to 1% w / w, and 1% w / w .

  In some embodiments, accelerators are used during dry milling or a combination of accelerators is used. In some embodiments, the accelerator is added during dry milling. In some embodiments, the accelerator is 1% to 20% of the total grinding time, 1% to 5% of the total grinding time, 1% to 10% of the total grinding time remains. When 1% to 30% of the total grinding time remains, 2% to 5% of the total grinding time remains, 2% to 10% of the total grinding time remains At a time selected from the group consisting of 5% to 20% of the total grinding time remaining and 5% to 20% of the total grinding time remaining.

  Reasons for including an accelerator include, but are not limited to, providing better dispersibility, controlling agglomerates, releasing or retaining active particles from the delivery matrix. Examples of accelerators include sodium lauryl sulfate, crosslinked PVP (crospovidone), crosslinked sodium carboxymethylcellulose (croscarmellose 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; oleic acid, lauric acid, palmitic acid, erucic acid, Other solid state fatty acids such as behenic acid or derivatives (such as esters and salts); leucine, isoleucine, lysine, valine, methionine, phenylalanine, aspa Thame, or amino acids such as acesulfame K include, but are not limited to.

  In another aspect, the disclosure provides a method of treating a human in need of treatment for castration resistant prostate cancer, wherein the human composition comprises an effective amount of a pharmaceutical composition described herein for performing such treatment. A method comprising the step of administering to: The treatment is (eg one or two or four equal doses (eg one unit dose containing 500 mg, two unit doses each containing 250 mg abiraterone acetate, or 4 each containing 125 mg abiraterone acetate) One unit dose) may include daily administration of 500 mg of abiraterone acetate The patient may be treated with a glucocorticoid, such as prednisone, dexamethasone, or prednisolone (eg, 5 mg, twice daily). Alternatively, the patient may be treated with methylprednisolone (eg, 4 mg twice a day) The patient may be treated with other chemotherapeutic agents or other agents to treat cancer (eg, prostate cancer). May be treated.

  The disclosure also includes methods of treating breast cancer (eg, metastatic breast cancer) and ovarian cancer (eg, ovarian epithelial 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 provides a composition comprising abiraterone acetate prepared by a method described herein or a composition described herein in a diluent, lubricant, excipient, disintegrant, A method of making a pharmaceutical composition as described herein comprising the step of making a pharmaceutically acceptable dosage form with one of the wetting agents.

  The disclosure described herein may include a range of one or more values (eg, particle size, concentration, etc.). A range of values is close to the range leading to the same or substantially the same result as all values within the range, including the value defining the range, and the value adjacent to the value defining the range limit. It will be understood to include values that

  The entire disclosure of all publications (including patents, patent applications, papers, laboratory manuals, books, or other documents) cited herein are hereby incorporated by reference. Inclusion is not an admission that any of the references constitutes prior art or is part of the general knowledge of one of ordinary skill in the art to which this invention pertains.

  Throughout this specification, unless the context suggests otherwise, a term such as “include”, or “included” or “included” is intended to include the specified integer or group of integers. It is understood that it does not exclude any other integer or group of integers. Also, in this disclosure, particularly in the claims and / or paragraphs, terms such as “include”, “included”, “include” may have the meaning ascribed to them in US Patent Law; , These can mean “include”, “included”, “included” and the like.

  A “therapeutically effective amount” as used herein in relation to the therapeutic method and the dosage of a particular medicament is the purpose of administering the medicament in a significant number of subjects in need of such treatment. It shall mean a dose that produces a specific pharmacological response. A “therapeutically effective amount” to be administered to a particular subject in a particular case is described herein even if such dose is recognized as a “therapeutically effective amount” by those skilled in the art. Emphasize that it is not always effective in the treatment of disease. Furthermore, it should be understood that the dosage of the medicament is optionally measured as an oral dosage or related to the concentration of the medicament measured in the blood.

  Throughout this specification, unless the context suggests otherwise, the phrase “dry milling” or variations such as “dry milling” refers to milling in the absence of liquid at least substantially. It should be understood as pointing. When present, the liquid is present in an amount such that the contents of the mill retain the dry powder characteristics.

  The term “millable” means that the size of the comminuted matrix can be reduced under the dry milling conditions of the disclosed method. In one embodiment of the present disclosure, the comminuted matrix has a particle size comparable to that of abiraterone acetate. In another embodiment of the present disclosure, the particle size of the matrix is substantially reduced, but not as small as abiraterone acetate.

  Those skilled in the art will appreciate that changes and modifications may be made to the disclosure described herein other than those specifically described. It is to be understood that this disclosure includes all such changes and modifications. In addition, the present disclosure also includes, individually or collectively, all of the steps, mechanisms, compositions, and materials mentioned or indicated in the specification, and any and all combinations or any of the steps or mechanisms. Of two or more.

  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 present disclosure will become apparent to those skilled in the art upon a better understanding of the following description.

FIG. 1 is a graph of particle size analysis results for unmilled abiraterone acetate and abiraterone acetate in Formula 1 and Formula 2 of Example 1. FIG. 2 is a graph of the dissolution rate measurement results of the abiraterone acetate tablet described in Example 3. 3A is a graph showing the results of the stability test described in Example 6. FIG. FIG. 3B is a graph showing the results of the stability test described in Example 6.

Particle Size In measurements made using laser diffraction, the term “median particle size” is defined as the median particle size determined based on the volume of equivalent spherical particles. When the term center is used, it should be understood to describe the granularity that divides the population in half so that 50% of the population is larger or smaller than this granularity on a volume basis. The median particle size is described as [D ₅₀ ] or D _[50] or [D50], D50, D (0.50), D [0.5], or the like. As used herein, [D ₅₀ ] or D _[50] or [D50], D50, D (0.50), or D [0.5] etc. are taken to mean “medium granularity”. Shall.

The term “Dx of particle size distribution” refers to the xth percentile of the distribution on a volume basis. Thus, D90 refers to the 90th percentile, D95 refers to the 95th percentile, and so on. Taking D90 as an example, this can often be described as [D ₉₀ ] or D _[90] or [D90], D (0.90) or D [0.9], etc. With respect to the median granularity and Dx, the capital letter D or lowercase letter d is used interchangeably and has the same meaning. Another commonly used method for describing the particle size distribution measured by laser diffraction or equivalent methods known in the art is what percentage of the distribution is smaller or larger than the specified particle size. Is to describe. The term “percentage less than” is also described as “% <” and is defined as the percentage of particles smaller than the specified particle size in the particle size distribution by volume, eg,% <1,000 nm. . The term “percentage” is also described as “%>” and is defined as the percentage of particles larger than the specified particle size in the particle size distribution by volume, eg,%> 1,000 nm. . The term D (3,2) is referred to as area weighted average particle size or Sauter diameter; the term D (4,3) is referred to as volume weighted average particle size. Details of how to calculate these values are known in the art and can be found, for example, in ISO92776-2: 2014 (E).

  For many of the materials subjected to the method of the present invention, the particle size can be easily measured. If the water solubility of the active substance is low and the matrix in which the active substance is ground is high in water, the powder may simply be dispersed in an aqueous solvent. In this scenario, the matrix dissolves, leaving the active substance dispersed in the solvent. This suspension can then be measured by techniques such as PCS or laser diffraction.

A suitable method for measuring the correct particle size when the active substance is substantially water soluble or when the matrix is poorly soluble in aqueous dispersants is outlined below:
1. In situations where an insoluble matrix such as microcrystalline cellulose interferes with the measurement of the active substance, a separation technique such as filtration or centrifugation can be used to separate the insoluble matrix from the active substance particles. Other ancillary techniques are needed to determine if any active material has been removed by the separation technique so that this method can be considered.
2. If the water solubility of the active substance is too high, other solvents for measuring particle size may be evaluated. If the solubility of the active substance is low but a solvent that is a good solvent for the matrix can be found, the measurement will be relatively easy. If it is difficult to find such a solvent, another approach is used to measure the aggregate of the matrix and active agent in a solvent in which both the matrix and the active agent are insoluble (such as isooctane). The powder is then measured in another solvent in which the active substance is soluble but the matrix is insoluble. Thereby, an understanding of the particle size of the active substance can be obtained using the measured value of the matrix particle size and the measured value of the particle size of the matrix and the active substance.
3. In some situations, image analysis can be used to obtain information regarding the particle size distribution of the active agent. Suitable image measurement techniques include transmission electron microscope (TEM), scanning electron microscope (SEM), optical microscope, and confocal microscope. In addition to these standard techniques, it is necessary to use several additional techniques in parallel with the identification of active substances and matrix particles. Depending on the chemical composition of the contained material, elemental analysis, Raman spectroscopy, FTIR spectroscopy, or fluorescence spectroscopy may be possible.

Improving the dissolution profile The process yields abiraterone acetate with an improved dissolution profile. Improved elution profiles have significant advantages, including in some cases, improved bioavailability of abiraterone acetate in vivo. Standard methods for determining the elution profile of substances in vitro are available in the art. A suitable method for determining an improvement in elution profile in vitro may include measuring the concentration of the sample material in solution over a period of time and comparing the result of the sample material to a control sample. The finding that the sample material reached peak solution concentration in a shorter time than the control sample indicates that the elution profile of the sample material has been improved. The test sample contains excipients for manufacturing the final dosage form in addition to abiraterone acetate and comminuted matrix and / or other additives subjected to the process of the present disclosure described herein. Unit dosage form. As used herein, a control sample may be a physical mixture of components in a measurement sample that includes the same relative proportions of active substances, matrices, and / or additives as the measurement sample. The control sample may be a commercial dosage form, Zytiga® tablet, cut to an equivalent amount to abiraterone acetate as the test sample. Standard methods for determining an improved dissolution profile of a substance in vivo are available in the art.

Crystallization Profile Methods for determining the crystallinity profile of abiraterone acetate are widely available in the art. Suitable methods include X-ray diffraction, differential scanning calorimetry, Raman spectroscopy, or IR spectroscopy.

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

Grinding Matrix As described below, the method of the present disclosure is particularly beneficially applied by selecting an appropriate grinding matrix. Also, as described below, a highly advantageous aspect of the present disclosure is that certain comminuted matrices suitable for use in the disclosed methods are also suitable for use in medicine. The present disclosure provides a method for preparing a medicament comprising both abiraterone acetate and a comminuted matrix, or in some cases, a method for producing a medicament comprising abiraterone acetate and a portion of a comminuted matrix, as described above. The medicine to be produced and the treatment method using the medicine are included. The medicament may comprise only abiraterone acetate milled with a milled comminuted matrix, or more preferably, the milled abiraterone acetate and milled comminuted matrix may be one or more pharmaceutically acceptable. Possible carriers and any desired excipients commonly used in the preparation of medicaments or other similar agents may be combined.

  In some cases, the particle size of abiraterone acetate can be reduced under the dry milling conditions of the present disclosure because at least one component of the comminuted matrix is harder than abiraterone acetate. Also, without being bound by theory, under these circumstances, a pulverizable comminuted matrix is more interactive with abiraterone acetate by producing smaller particles of the comminuted matrix under dry milling conditions. It is believed that the advantages of the present disclosure are provided via a second route that allows the action. The amount of comminuted matrix relative to the amount of abiraterone acetate and the degree of physical degradation of the comminuted matrix are sufficient to inhibit reagglomeration of the active agent particles. In some embodiments, the amount of comminuted matrix relative to the amount of abiraterone acetate and the degree of particle size reduction of the comminuted matrix is sufficient to inhibit reagglomeration of the active agent particles. As detailed above, the comminuted matrix may include one or more antioxidants and / or one or more sequestering agents.

  In some embodiments, the comminuted matrix is less prone to agglomeration during dry milling. Although it is difficult to objectively quantify the tendency to agglomerate during grinding, a subjective measure can be established by observing the level of “caking” of the grinding matrix in the mill grinding chamber as dry grinding proceeds. It is possible to get.

  The comminuted matrix may be an inorganic material or an organic material.

Grinded body In the method of the present disclosure, when a ground body is used, the ground body is preferably chemically inert and rigid. The term “chemically inert” as used herein means that the grind does not chemically react with abiraterone acetate or a comminuted matrix.

  As mentioned above, the pulverized body is inherently resistant to crushing and polishing in the pulverization process.

  The grind is desirably provided in a form that may have any of a variety of smooth, regular shapes, flat or curved surfaces, and no sharp or protruding edges. For example, suitable grinding bodies may be in the form of an oval, oval, spherical, or right circular cylinder. In some embodiments, the grind is one of beads, balls, spheres, rods, right cylinders, drums, or radius end right prisms (ie, right cylinders with a hemispherical base having the same radius as the cylinder). It is provided in the above form.

  Depending on the nature of the abiraterone acetate and comminuted matrix, the comminuted body desirably has an effective average diameter of about 0.1 mm to about 30 mm, more preferably about 1 mm to about 15 mm, and even more preferably about 3 mm to about 10 mm. Have.

  The pulverized body may contain various substances such as ceramic, glass, metal, or polymer composition in particulate form. Suitable metal grinds are typically spherical, generally have good hardness (ie RHC 60-70), roundness, high wear resistance, and narrow particle size distribution, For example, mention may be made of balls made from 52100 type chrome steel, 304 type, 316 type, or 440C type stainless steel, or 1065 type high carbon steel.

The ceramic may be selected from a wide range of ceramics, for example, having sufficient hardness and resistance to crushing so as not to chip or crush during milling, and desirably sufficiently dense. it can. A suitable density for the grind may be from about 1 g / cm ³ to about 15 g / cm ³ , preferably from about 1 g / cm ³ to about 8 g / cm ³ . The ceramic is selected from a mixture of these in addition to steatite, aluminum oxide, zirconium oxide, zirconia-silica, yttria stabilized zirconium oxide, magnesia stabilized zirconium oxide, silicon nitride, silicon carbide, cobalt stabilized tungsten carbide, etc. be able to.

  The glass pulverized body is spherical (for example, beads), has a narrow particle size distribution and is durable, and examples thereof include lead-free soda lime glass and borosilicate glass. The polymer grind is preferably substantially spherical and has sufficient hardness and friability so that it does not chip or crush during milling, minimizing wear that causes product contamination. Can be selected from a wide range of polymer resins that are wear resistant and free of impurities such as metals, solvents, and residual monomers.

The pulverized body may be formed from a polymer resin. For example, the polymer resin is from cross-linked polystyrene such as polystyrene cross-linked with divinylbenzene, styrene copolymer, polyacrylate such as polymethyl methacrylate, polycarbonate, polyacetal, vinyl chloride polymer and copolymer, polyurethane, polyamide, high density polyethylene, polypropylene, etc. You can choose. The use of polymer grinds to break materials to very small particle sizes (as opposed to mechanochemical synthesis) is described, for example, in US Pat. Nos. 5,478,705 and 5,500, No. 331. The density of the polymer resin can typically be from about 0.8 g / cm ³ to about 3.0 g / cm ³ . In general, high density polymer resins are preferred. Alternatively, the pulverized body may be a composite including a high-density core body to which a polymer resin is attached. The core particles may be selected from materials known to be useful as pulverized bodies such as glass, alumina, zirconia, silica, zirconium oxide, and stainless steel. The density of the core material is greater than about 2.5 g / cm ³ .

  In one embodiment of the present disclosure, the pulverized body is formed from a ferromagnetic material to facilitate removal of contaminants resulting from wear of the crushed body by using magnetic separation techniques.

  Various pulverized bodies have unique advantages. For example, since metal has the highest specific gravity, increasing the impact energy increases the grinding efficiency. Metal costs vary 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 diameters as small as 0.004 mm. However, since the specific gravity of glass is lower than that of other pulverized bodies, a significantly long pulverization time is required. Finally, ceramic is advantageous from the standpoint of low wear and contamination, easy cleaning, and high hardness.

Dry grinding In the dry grinding process of the present disclosure, abiraterone acetate in the form of crystals, powders and the like and a pulverized matrix together with a plurality of pulverized bodies in a pulverization chamber that is mechanically stirred at a predetermined stirring intensity for a predetermined time. Match at a suitable ratio without grinding. Typically, stirring, drying gas flow, or other forces are applied externally to apply various translational, rotational, or reverse motions, or a combination thereof to the grinding chamber and its contents. Alternatively, the agitation is applied internally using a rotating shaft with a blade, propeller, impeller, or paddle at the end, or a combination of both actions to move the contents of the mill, including any comminution For this purpose, a grinding device is used.

  During milling, in addition to the application of shear forces by movement transferred to the mill or gas stream through the milling system, between the milling components, i.e. between any mills utilized and the particles of abiraterone acetate and the milling matrix Multiple impacts or collisions of considerable strength can occur. The nature and strength of the force applied to abiraterone acetate and the comminution matrix are affected by a wide range of processing parameters including: type of grinding device; strength of force generated; kinematic aspect of the process; used The size, density, shape and composition of any milled body; the weight ratio of the abiraterone acetate and comminuted matrix mixture to any grind used; the milling time; the physical properties of the abiraterone acetate and milled matrix; present during milling Atmosphere; and other factors.

  Conveniently, the mill can apply mechanical compressive forces and shear stress repeatedly or continuously to abiraterone acetate and the comminuted matrix. Throughout the rest of the specification, reference will be made to dry grinding carried out using a ball mill. Examples of this type of mill are attritor mills, nutation mills, tower mills, planetary mills, vibration mills, gravity dependent ball mills, jet mills, rod mills, roller mills, or crusher mills, jet mills and fine grinding mills. It will also be understood that the dry grinding according to the method of the present disclosure can be achieved by any suitable grinding method or means.

  In some cases, the particle size of abiraterone acetate prior to dry milling according to the methods described herein is less than about 1,000 μm as determined by sieving analysis. If the particle size of abiraterone acetate is greater than about 1,000 μm, use another particle size reduction method to reduce the particle size of the abiraterone acetate base to less than 1,000 μm before dry milling according to the method described herein. It is preferable to reduce it.

Aggregates of abiraterone acetate after processing Agglomerates comprising particles of abiraterone acetate having a particle size within the range specified herein may be present regardless of whether the agglomerate exceeds the range specified above. It should be understood that it is within the scope of the disclosure.

Processing Time In some embodiments, the abiraterone acetate and comminuted matrix are dry milled for the shortest time necessary to minimize the possibility of any contamination from the milling process and / or any milled body utilized. . This time varies greatly depending on the abiraterone acetate and comminuted matrix, and can vary from as little as one minute to several hours.

  Suitable agitation speeds and total grinding time include the type and size of the grinding device, the type and size of any grinding media utilized, the weight ratio of the abiraterone acetate and the grinding matrix mixture to the available grinding bodies, It is tuned by the chemical and physical properties of abiraterone acetate and comminuted matrix, as well as other parameters that can be optimized empirically.

  In some embodiments, the comminuted matrix (the material that is ground with abiraterone acetate) is not separated from the abiraterone acetate and is maintained with the abiraterone acetate in the final product. In some embodiments, the comminuted matrix is considered generally accepted as safe (GRAS) for pharmaceuticals.

  In another aspect, the comminuted matrix is separated from abiraterone acetate. In one embodiment, if the comminuted matrix is not completely comminuted, the unmilled comminuted matrix is separated from abiraterone acetate. In a further embodiment, at least a portion of the milled comminuted matrix is separated from abiraterone acetate.

  Any proportion of the comminuted matrix may be removed, including but not limited to 10%, 25%, 50%, 75%, or substantially all of the comminuted matrix.

  In some embodiments of the present disclosure, a significant portion of the milled comminution matrix may comprise particles that are similar in size to particles comprising abiraterone acetate and / or smaller in size than particles comprising abiraterone acetate. . If the portion of the milled comminuted matrix to be separated from the particles containing abiraterone acetate contains particles of similar particle size and / or smaller particle size than particles containing abiraterone acetate, based on the particle size distribution Separation techniques are not applicable. In these situations, the disclosed method may include electrostatic separation, magnetic separation, centrifugation (density separation), hydrodynamic separation, floss flotation, but techniques that are not limited thereto, and are pulverized to a comminuted matrix. Separating at least a portion of from abiraterone acetate. Conveniently, the step of removing at least a portion of the milled comminuted matrix from the abiraterone acetate may be performed using means such as selective dissolution, washing, or sublimation.

  In some cases, a comminuted matrix having two or more components where at least one component is water soluble and at least one component is poorly water soluble may be used. In this case, the water-soluble matrix component can be removed using washing to leave abiraterone acetate dispersed in the remaining matrix component. In a highly advantageous aspect of the present disclosure, the poorly soluble matrix is a functional excipient.

  In some cases, comminuted matrices that are suitable for use in the disclosed methods are also pharmaceutically acceptable and therefore suitable for use in medicine. Where the method of the present disclosure does not include complete separation of the comminuted matrix from abiraterone acetate, the present disclosure provides a method of making a medicament that combines both abiraterone acetate and at least a portion of the comminuted comminuted matrix; And a method of treating animals, including humans, with a medicament prepared as described above and a therapeutically effective amount of abiraterone acetate via the medicament.

Abiraterone Acetate and Compositions The present disclosure relates to pharmaceutically acceptable substances made according to the methods of the present disclosure, compositions comprising such substances (at least part of the comminuted matrix, with or without grinding aids, accelerators) Or a composition comprising such a material with a comminuted matrix).

Pharmaceuticals The pharmaceuticals of the present disclosure optionally include one or more pharmaceutically acceptable carriers and pharmaceutically acceptable, with or without at least a portion of a comminuted matrix or comminuted matrix, with or without grinding aids, accelerators. Pharmaceutically acceptable materials may be included in combination with other agents commonly used in the preparation of the compositions.

  As used herein, “pharmaceutically acceptable carrier” refers to physiologically compatible solvents, dispersion media, coatings, antibacterial agents, antifungal agents, isotonic agents, absorption delaying agents, and the like. Includes any and all. In some embodiments, the carrier is suitable for parenteral administration, intravenous, intraperitoneal, intramuscular, sublingual, intrapulmonary, 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 dispersion. The use of such media and agents for the manufacture of a medicament is well known in the art. Except insofar as any conventional medium or agent is incompatible with the pharmaceutically acceptable substance, the use of said medium or agent in the manufacture of a pharmaceutical composition according to the present disclosure is contemplated.

Pharmaceutically acceptable carriers according to the present disclosure may include one or more of the following examples:
(1) Polyethylene glycol (PEG), polyvinyl pyrrolidone (PVP), polyvinyl alcohol, sodium lauryl sulfate, crospovidone, polyvinyl pyrrolidone-polyvinyl acrylate copolymer, cellulose derivative, hydroxypropyl methylcellulose, hydroxypropylcellulose, carboxymethylethylcellulose, hydroxypropylmethylcellulose Surfactants and polymers including, but not limited to, phthalates, polyacrylates and polymethacrylates, ureas, sugars, polyols and polymers thereof, emulsifiers, sugar gums, starches, organic acids and salts thereof, 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 And / or (4) lubricants such as colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, silica gel and other agents that affect the fluidity of the compressed powder; and / or (5) sucrose, Sweeteners such as any natural or artificial sweeteners including xylitol, sodium saccharin, cyclamate, aspartame, and acesulfame K; and / or (6) flavoring agents; and / or (7) potassium sorbate, methylparaben, propylparaben , Benzoic acid and its salts, parahydroxyl such as butylparaben Preservatives such as other esters of benzoic acid, alcohols such as ethyl alcohol or benzyl alcohol, phenolic chemicals such as phenol, or quaternary compounds such as benzalkonium chloride; and / or (8) buffering agents; and / or Or (9) diluents such as microcrystalline cellulose, lactose, dicalcium phosphate, sugar, and / or pharmaceutically acceptable inert fillers such as any mixture of the aforementioned substances; and / or (10) Wetting agents such as corn starch, potato starch, corn starch, and modified starch, mixtures thereof; and / or (11) disintegrants such as croscarmellose sodium, crospovidone, sodium starch glycolate; and / or (12) Organic acids (eg citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid And alginic acid, and their anhydrides and acid salts) or carbonates (eg, sodium carbonate, potassium carbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate) or bicarbonates (eg, bicarbonate) Effervescent agents such as effervescent couples such as sodium or potassium bicarbonate; and / or (13) other pharmaceutically acceptable excipients.

  The actual dosage level of the disclosed abiraterone acetate, in addition to the properties of abiraterone acetate, can be enhanced due to the benefits of providing and administering abiraterone acetate (eg, the solubility of abiraterone acetate) Increase, elution rate increase, surface area increase, etc.). Thus, as used herein, “therapeutically effective amount” refers to the amount of abiraterone acetate necessary to affect a therapeutic response in an animal. Effective amounts for such use depend on the desired therapeutic effect, route of administration, efficacy of abiraterone acetate, the desired duration of treatment, the stage and severity of the disease being treated, the patient's weight and general health, and the judgment of the prescribing physician. Dependent.

Pharmacokinetic Properties of Abiraterone Acetate Composition Rapid Onset of Absorption In some embodiments, the abiraterone acetate composition of the present disclosure is rapidly absorbed. In one example, an abiraterone acetate composition of the present disclosure when administered to a fasted adult male is less than about 2.5 hours (about 3 hours to about 2 hours), less than about 2.0 hours, about 1. It has a T _max of less than 75 hours, less than about 1.5 hours, less than about 1.25 hours, and greater than about 1.0 hour, eg, 1.5 hours to 2.0 hours.

Improved Bioavailability The abiraterone acetate composition of the present disclosure exhibits high bioavailability (AUC) and requires a lower dose compared to conventional compositions (eg, Zytiga®) administered at the same dose. In some cases, AUC and / or Cmax similar to Zytiga (R) can be achieved at lower doses than Zytiga (R). Thus, in some cases, a pharmaceutical composition described herein that is administered at a lower dose than Zytiga provides comparable systemic exposure. For example, a dose of 500 mg can be biologically equivalent to a dose of 1,000 mg of Zytiga®. Any drug can have deleterious side effects. Therefore, it is desirable to be able to achieve the same or better therapeutic effect with lower doses as seen with higher doses of conventional compositions. By using the composition of the present disclosure, such a low dose can be realized because the composition exhibits high bioavailability compared to conventional pharmaceutical preparations, and has a desired therapeutic effect. This is because it means that the dose of the drug necessary to obtain is small.

The pharmacokinetic profile of the composition of the present disclosure may not be significantly affected by whether the subject taking the composition is in a fed state or in a fasted state. Abiraterone acetate compositions are less affected by the pharmacokinetic profile of the composition depending on whether the ingested subject is in the fed or fasted state compared to Zytiga®. This means that there is no significant difference in the amount of the composition or the absorption rate of the composition between when the composition is administered in the fed state and when it is administered in the fasted state. Thus, in some cases, the compositions of the present disclosure reduce the effect of food on the pharmacokinetics of the composition as compared to Zytiga®.

The pharmacokinetic profile of the compositions of the present disclosure may have less patient-to-patient variation. In some cases, the geometric mean coefficient of variation in one or more of Cmax, AUC0-t, and AUC0-∞ is Zytiga ( The abiraterone acetate dosage form described herein can be lower than the registered trademark. Accordingly, the geometric mean coefficient of variation in one or more of Cmax, AUC0-t, and AUC0-∞ is 10% to 50% (at least 10%, 10% to 30%, or 10%) than Zytiga®. (~ 20%) may be lower (calculated as CV (Zytiga®) -CV (present dosage form) / CV (Zytiga®) × 100%).

Pharmacokinetic Protocols Measure plasma concentration profiles in humans after administration of the composition using any standard pharmacokinetic protocol to determine whether the composition meets the pharmacokinetic criteria described herein can do. For example, a randomized single dose crossover test may be performed using a group of healthy adult human subjects. The number of subjects should be sufficient to adequately control the variation in the statistical analysis and is typically about 10 or more, but for specific purposes, a smaller group is sufficient In some cases. Each subject is given a single dose (eg, 100 mg) of a test formulation of the composition by oral administration at time 0, but this administration is usually performed around 8 am after an overnight fast. About 4 hours after administration of the composition, the subject continues to fast and remains standing. Blood samples are collected from each subject prior to administration (eg, 15 minutes before) and several times after administration. For the purposes of this study, samples are taken several times within the first hour, and then the sampling frequency is reduced. For example, blood samples are collected at 15 minutes, 30 minutes, 45 minutes, 60 minutes, and 90 minutes after administration, and thereafter, once every hour for 2 to 10 hours after administration. It's okay. Thereafter, further blood samples may be taken, for example, 12 hours, 24 hours, 36 hours, and 48 hours after administration. If the same subject is used for testing a second test formulation, it must be at least 7 days before administering the second test formulation. Plasma is separated from the blood sample by centrifugation and the composition of the separated plasma is analyzed by validated high performance liquid chromatography (HPLC) or liquid chromatography mass spectrometry (LCMS) procedures. The plasma concentration of the compositions described herein is intended to mean the total concentration including both the free composition and the binding composition.

Method of administering a medicament containing abiraterone acetate The medicament of the present disclosure can be administered orally, rectally, pulmonarily, vaginally, topically (powder, ointment, or drop), transdermal, parenteral, intravenous It can be administered to animals, including humans, by any pharmaceutically acceptable method, such as administration, intraperitoneal administration, intramuscular administration, sublingual administration, or as a buccal or intranasal spray.

  Solid dosage forms for oral administration include capsules, tablets, pills, powders, pellets, and granules. In addition, any of the commonly used excipients as described above and generally from 5% to 95% biologically active substance, more preferably from 10% to 75% concentration of biologically active substance. In combination, a pharmaceutically acceptable non-toxic oral composition is formed.

  However, when abiraterone acetate is utilized in a liquid suspension, once the solid support has been substantially removed to ensure that agglomeration of particles containing abiraterone acetate is prevented or at least minimized, the particles are It may be necessary to further stabilize.

Example 1. Preparation of Fine Abiraterone Acetate Powder Blend Abiraterone acetate was dry milled in the presence of the proportions of lactose monohydrate and sodium lauryl sulfate shown in Table 1 to prepare a pharmaceutical intermediate for use in tablet preparation. Both lots of material were ground in a Union Process 1S attritor mill equipped with a 0.5 gallon jacketed cooling bath. A batch of 200 g was ground with a mill for 40 minutes.

Example 2: Particle size analysis of milled and unmilled abiraterone acetate The particle size distribution of abiraterone acetate in the two pharmaceutical intermediate lots described in Example 1 was measured using a Malvern Mastersizer 3000 model MAZ3000 particle size analyzer equipped with a Hydro MV wet sample dispersion unit. And measured by light scattering. 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% povidone K30 aqueous solution. About 20 mg of sample powder and 5 mL of dispersant were added to a plastic centrifuge tube. The tube was swirled to disperse the powder and then sonicated for 1 minute at 20% amplitude using a sonication cycle of 5 seconds on and 15 seconds off (Branson Digital Sonifier 250 with Sonic Probe Model 102C). ). The sample dispersion unit of the particle size analyzer was filled with dispersant and the sample was pipetted into the reservoir until the target obscuration reached 5-15% and remained constant. The stirrer was operated at 1,500 rpm and data was collected for 10 seconds. Three measurements were taken and the average value of each particle size parameter was reported. Table 2 and FIG. 1 show the particle size distribution and the data show a particle size reduction greater than 10 times.

Example 3: Tablet Preparation and Comparative Dissolution Test The milled pharmaceutical intermediate was combined with an intragranular excipient and dry granulated using roller compression and milling. The granulation was blended with extragranular excipients and compressed on a rotary tableting machine to make 100 mg abiraterone acetate tablets having the composition shown in Table 3.

  As described above using the method described on the FDA website for 250 mg of abiraterone acetate tablets in a 900 mL pH 4.5 buffer containing 0.25% sodium lauryl sulfate using a USP apparatus II at 50 rpm. The dissolution rate of the prepared tablets was measured. Samples were analyzed by 270 nm UV. In addition, for comparison purposes, Zytiga® tablets were tested under the same dissolution conditions. The results of this analysis are shown in Table 4 and FIG. Two tablet formulations containing milled abiraterone acetate dissolved completely (> 85% dissolution) from 10 minutes to 20 minutes compared to Zytiga® fully dissolved (> 85% dissolution) in 60 minutes .

Example 4: Abiraterone Acetate Tablets for Initial Phase I Testing Abiraterone acetate is dry milled in the presence of the amounts of lactose monohydrate and sodium lauryl sulfate shown in Table 5 to produce tablets for use in phase I testing. A pharmaceutical intermediate was prepared for use in the preparation. The material was ground in a Union Process 1S attritor mill equipped with a 1.5 gallon jacket cooling bath. The material was pulverized with the pulverized body for 40 minutes.

  The particle size distribution of abiraterone acetate in the milled pharmaceutical intermediate was measured using a Micromeritics Satur DigiSizer II 5205 particle size analyzer equipped with an AquaPrep II sample cell. The sample reservoir of the device was filled with a dispersant solution (0.1% povidone K30). Samples were prepared by adding 100 mg of ground powder and 20 mL of dispersant to a 30 mL glass bottle. Disperse the particles by agitating with a pipette, and then place the capped bottle in an ultrasonic water bath (Branson Ultrasonic bath, model 5510-MT, output 135 W, so that the water level of the ultrasonic water bath is half of the side of the bottle. , 42 KHz). The sample was then sonicated for 30 minutes. The dispersed sample was dropped into the reservoir of the liquid sample handling unit until the obscuration value reached about 7%. The internal ultrasound probe was operated at 100% intensity for 300 seconds and then the sample was circulated for 120 seconds before data collection. When the obscuration value reached 5% to 10%, data was collected with the beam angle set to 65 °. Each measurement was repeated three times and the average of the three measurements was reported. The particle size data obtained from the milled powder is reported in Table 6.

  The milled pharmaceutical intermediate was combined with an intragranular excipient and dry granulated using roller compaction and milling. The granulation was blended with extragranular excipients and compressed on a rotary tableting machine to make 100 mg abiraterone acetate tablets having the composition shown in Table 7.

  The dissolution rate of the tablets prepared as described above was measured using a USP apparatus II at 75 rpm in 900 mL of pH 4.5 buffer containing 0.1% SLS. Samples were analyzed by HPLC. In addition, for comparison purposes, Zytiga® tablets were tested under the same dissolution conditions. The Zytiga® tablet is 250 mg, which is close to the dissolution limit of the dissolution medium, so the tablet was cut to a weight equal to 100 mg of abiraterone acetate. Zytiga® samples were measured using 270 nm UV. The results of this analysis are shown in Table 8. Zytiga® tablets dissolved in 20 minutes, whereas prepared tablets dissolved completely (> 85% dissolution) in 5 minutes.

Example 5: Phase I study of 100 mg, 200 mg, and 400 mg of abiraterone acetate formulation compared to 1,000 mg of Zytiga® Dose 100 mg, 200 mg, and 400 mg (1, 2, or 4 × 100 mg tablets, respectively) The abiraterone acetate 100 mg tablet formulation prepared as described in Example 4) was tested in healthy male patients under fasting conditions. In the same study, a dose of 1,000 mg of Zytiga® was tested (4 × 250 mg tablets). The results of this test are shown in Table 9.

Example 6: Stability of abiraterone acetate powder blends and tablets After dry milling abiraterone acetate with lactose monohydrate and sodium lauryl sulfate, HPLC detected a total impurity increase of 0.2% to 0.6% AUC. It was. When milled abiraterone acetate powder blend (or pharmaceutical intermediate; “DPI”) is further processed into tablets, it has been found that the concentration of impurities increases (from about 0.5% to about 1.1%). . Stability testing showed that impurities increased at 25 ° C./60% RH and 40 ° C./75% RH but not at 2 ° C. to 8 ° C. Furthermore, the impurity increase in the tablets was faster than the milled DPI. Table 10 and FIGS. 3A and 3B (diamond, 5 ° C .; square, 25 ° C./60% RH; and triangle, 40 ° C./75% RH) show the impurities in the milled DPI and tablet lots during the accelerated stability test. An outline of the concentration is shown. The impurity concentration of refrigerated tablets was acceptable to a low level, but a formulation that can be stored under ambient conditions is desirable.

  The increase in impurities in DPI and tablets containing microparticulate abiraterone acetate is due to oxidative degradation of abiraterone acetate. Aged Zytiga® (aviraterone acetate) tablets were tested for purity and found to have a much lower impurity concentration than tablets containing aged particulate abiraterone acetate. Fast degradation in tablets containing particulate abiraterone acetate is due to a number of causes including, but not limited to, high API surface area, high excipient to API ratio, and excipient differences. There is a case. Further testing has found that API degrades slightly in the presence of excipients, but degradation is greatly accelerated once the mixture is ground. The data is shown in Table 11.

Example 7: Milling of abiraterone with an antioxidant or sequestering agent Dry milling of abiraterone acetate in the presence of lactose monohydrate and sodium lauryl sulfate and various antioxidants and / or sequestering agents was performed. In one test, dry milling included a combination of ascorbic acid and fumaric acid, or a combination of butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT): the formulations are shown in Table 12. Each lot was pulverized in a Union Process 1S attritor mill equipped with a 0.5 gallon jacket cooling bath. A batch of 200 g was ground with a mill for 40 minutes. Both DPI formulations contained abiraterone acetate having a D ₉₀ of less than 1,000 nm when tested according to the light scattering method described in Example 2.

  Two different corresponding tablet formulations detailed in Table 13 were prepared using two different DPI formulations by adding the specified excipients to the DPI formulation, dry granulating and tableting.

  The stability of the two tablet formulations was tested under accelerated conditions. Table 14 shows that both tablet formulations with antioxidants have dramatically improved stability after 3 months storage at 40 ° C./75% RH compared to formulations without antioxidants. / BHT formulation contains data indicating that almost all degradation has stopped. This shows that stability can be dramatically improved by adding antioxidants and / or sequestering agents during grinding.

  The dissolution rate of abiraterone acetate in tablet formulation ascorbic / fumaric acid and tablet formulation BHA / BHT was tested using USP apparatus II at 75 rpm in 900 mL pH 4.5 phosphate buffer containing 0.1% SLS. did. All three tablets dissolved completely within 10 minutes (> 85% of abiraterone acetate dissolved).

Example 8: Abiraterone Acetate Tablets for Additional Phase I Studies Additional pharmaceutical intermediate formulations were prepared by dry milling abiraterone acetate, lactose monohydrate, sodium lauryl sulfate, BHA, and BHT. Table 15 shows the composition of the material ground to form this intermediate. The formulation was ground in a 62 gallon custom jacket cooled attritor mill; the powder blend was ground with the mill for 72 minutes.

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

  Method 1: The dispersant used was a 0.1% povidone K30 aqueous solution. About 20 mg of sample powder and 5 mL of dispersant were added to a plastic centrifuge tube. The tube was swirled to disperse the powder and then sonicated for 1 minute at 20% amplitude using a sonication cycle of 5 seconds on and 15 seconds off (Branson Digital Sonifier 250 with Sonic Probe Model 102C). ). The sample dispersion unit of the particle size analyzer was filled with dispersant and the sample was pipetted into the reservoir until the target obscuration reached 5-15% and remained constant. The stirrer was operated at 1,500 rpm and data was collected for 10 seconds. Three measurements were taken and the average value of each particle size parameter was reported.

  Method 2: 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 20 mg of sample powder and 5 mL of dispersant solution were added to a glass vial. The vial was capped and swirled to disperse the powder particles. The vial lid was then loosened and the vial was placed in the center of an ultrasonic bath (Elma Elmsonic P30H ultrasonic bath). The vial was immersed so that the water level in the bath exceeded the dispersant in the vial but the vial did not touch the bottom of the bath. The sample was sonicated for 10 minutes at 37 kHz and 100% output. The sample dispersion unit of the particle size analyzer was filled with the dispersant and the sample was pipetted into the reservoir until the obscuration reached 5-15% and remained constant. The stirrer was operated at 1,500 rpm and data was collected for 10 seconds. Three measurements were taken and the average value of each particle size parameter was reported.

  Table 16 shows a comparison of the particle size values of abiraterone acetate in the pharmaceutical intermediate (DPI) described in Table 15 before and after milling using methods 1 and 2 above.

  The milled pharmaceutical intermediate was combined with an intragranular excipient and dry granulated using roller compaction and milling. The granulation was blended with extragranular excipients and compressed on a rotary tableting machine to make 125 mg abiraterone acetate tablets having the composition shown in Table 17.

  The dissolution rate of these tablets was tested using a USP apparatus II at 75 rpm in a pH 4.5 buffer containing 0.12% SLS. Samples were analyzed by HPLC. The results of this analysis are shown in Table 18; complete elution (> 85% elution) in 10 minutes.

Example 11: Phase I study of 125 mg, 500 mg, and 625 mg of abiraterone acetate formulation compared to 1,000 mg of Zytiga® Dose 125 mg, 500 mg, and 625 mg (1, 4, or 5 × 125 mg tablets, respectively) The abiraterone acetate 125 mg tablet formulation prepared as described in Example 10) was tested in healthy male patients under fasting conditions. In the same study, a dose of 1,000 mg of Zytiga® was tested (4 × 250 mg tablets). The results of this test are shown in Table 19.

Example 12: Additional abiraterone acetate powder and tablets Additional pharmaceutical intermediate formulations were prepared by dry milling abiraterone acetate, lactose monohydrate, sodium lauryl sulfate, BHA, and BHT. The composition of the material ground to form this intermediate is shown in Table 16. When the two batches were ground under various processing conditions, slightly different particle sizes were obtained.

  The particle size distribution of abiraterone acetate in both lots of pharmaceutical intermediates was measured by light scattering using a Malvern Mastersizer 3000 model MAZ3000 particle size analyzer equipped with a Hydro MV wet sample dispersion unit. Using Method 1 described in Example 8, the particle size distribution shown in Table 17 was obtained.

  Batch 1's ground pharmaceutical intermediate was combined with intragranular excipients and dry granulated using roller compaction and grinding. The granulation was blended with extragranular excipients and compressed on a rotary tableting machine to make 100 mg abiraterone acetate tablets having the compositions shown in Table 18.

  The dissolution rate of these tablets was tested using a USP apparatus II at 75 rpm in a pH 4.5 buffer containing 0.1% SLS. Samples were analyzed by 270 nm UV. The results of this analysis are shown in Table 19; complete elution (> 85% elution) in 10 minutes.

Example 13: Tablet Stability Additional pharmaceutical intermediate formulations were prepared by dry milling abiraterone acetate, lactose monohydrate, sodium lauryl sulfate, BHA, and BHT. Table 20 shows the composition of the material pulverized to form this intermediate.

  The particle size distribution of abiraterone acetate in this pharmaceutical intermediate was measured by light scattering using a Malvern Mastersizer 3000 model MAZ3000 particle size analyzer equipped with a Hydro MV wet sample dispersion unit. Using Method 1 described in Example 8, the particle size distribution shown in Table 21 was obtained.

  The milled pharmaceutical intermediate was combined with an intragranular excipient and dry granulated using roller compaction and milling. The granulation was blended with extragranular excipients and compressed on a rotary tableting machine to make 125 mg abiraterone acetate tablets having the compositions shown in Table 22.

  The tablets were packaged and subjected to accelerated stability testing at 40 ° C. and 75% relative humidity. Impurities were measured by a stability indicating HPLC method. The dissolution rate of these tablets was measured using a USP apparatus II at 75 rpm in a pH 4.5 buffer containing 0.12% SLS. The results are shown in Table 23; no increase in impurities was observed over 3 months at 40 ° C./75% RH, elution remained unchanged, and 10 minutes over 3 months at 40 ° C./75% RH. Elution within (> 85% elution).

Example 14: Effect of fed or fasted state The effect of a high fat diet on the oral bioavailability of a 500 mg dose of 125 mg ground abiraterone mg tablets was compared to a single center, single dose, randomized, open-label, 2 period, 2 treatment cross. Evaluated in an over-pharmacokinetic study. During the first dosing period, after 10 hours of fasting, approximately half of the subjects were administered test articles with 240 mL of water. The remaining subjects received the test article approximately 30 minutes after ingesting a standard FDA high fat breakfast. After a 7-day withdrawal period, each subject was replaced with another treatment. Immediately before administration of the test article and 0.25 hours, 0.5 hours, 1.0 hour, 1.5 hours, 2.0 hours, 3.0 hours, 4.0 hours after administration. Plasma samples were collected after 6.0 hours, 8.0 hours, 12.0 hours, 18.0 hours, 24.0 hours, and 48.0 hours. Samples were analyzed for abiraterone concentrations and the results were used to calculate pharmacokinetic parameters (AUC _0-∞ , AUC _0-t , and C _max ) for each subject and treatment. The geometric mean values of AUC _0-∞ , AUC _0-t , and C _max when the test article is administered in the fed state are 1444.1 ng · h / mL, 1393.4 ng · h / mL, and 443, respectively. On the other hand, the geometric mean values of the same parameters when the drug was administered in the fasted state were 322.7 ng · h / mL, 301.0 ng · h / mL, and 67.9 ng / mL. It was. The ratios of AUC _0-∞ , AUC _0-t , and C _max (feeding / fasting) were 4.48, 4.63, and 6.53, respectively.

Claims (56)

  Abiraterone acetate unit dosage form, wherein the unit dosage form of 500 mg is bioequivalent to a dose of 1,000 mg of Zytiga® in a fasted healthy male subject Unit dosage form. Geometric mean of AUC _(0−∞) for a dose of 500 mg administered to a fasting healthy male subject compared to a dose of 1,000 mg of Zytiga® administered to a fasted healthy male subject. The abiraterone acetate according to claim 1, wherein the log ratio is selected from 0.6 to 1.4, 0.7 to 1.3, 0.8 to 1.2, and 0.9 to 1.1. Unit dosage form.   Logarithm of the geometric mean of C (max) for a dose of 500 mg administered to a fasted healthy male subject compared to a dose of 1,000 mg of Zytiga® administered to a fasted healthy male subject. The abiraterone acetate unit agent according to claim 1, wherein the ratio is selected from 0.6 to 1.4, 0.7 to 1.3, 0.8 to 1.2, and 0.9 to 1.1. form.   [D90] of the abiraterone acetate is greater than 300 nm and 7,500 nm, 7,000 nm, 6,000 nm, 5,000 nm, 4,500 nm, 4,000 nm, 3,000 nm, 2,000 nm, 900 nm, 800 nm, and 700 nm A unit dosage form of abiraterone acetate according to claim 1, wherein the unit dosage form is less than one of   [D50] of the abiraterone acetate is more than 100 nm and is selected from 3,500 nm, 3,000 nm, 2,500 nm, 1,600 nm, 1,400 nm, 1,200 nm, 1,000 nm, 800 nm, 500 nm, 400 nm, and 300 nm The unit dosage form of abiraterone acetate according to claim 1, wherein the unit dosage form is less than 1.   [D4,3] of the abiraterone acetate is more than 300 nm and 7,000 nm, 6,000 nm, 5,000 nm, 4,000 nm, 3,000 nm, 2,500 nm, 2,400 nm, 2,200 nm, 2,000 nm, The unit dosage form of abiraterone acetate according to claim 1, wherein the unit dosage form is less than one of 1,900 nm, 1,700 nm, 1,500 nm, 1,300 nm, 1,100 nm, 900 nm, and 800 nm.   Sample containing 100 mg of abiraterone acetate using USP apparatus II at 75 rpm in 900 mL of pH 4.5 phosphate buffer containing 0.1% sodium lauryl sulfate in elution rate of the abiraterone acetate in the unit dosage form The unit dosage form of abiraterone acetate according to claim 1, wherein the unit dosage form of abiraterone acetate is at a rate such that at least 70% of the abiraterone acetate elutes in 5 to 15 minutes or 5 to 10 minutes.   Sample containing 125 mg of abiraterone acetate using USP apparatus II at 75 rpm in 900 mL of pH 4.5 phosphate buffer containing 0.12% sodium lauryl sulfate in elution rate of the abiraterone acetate in the unit dosage form The unit dosage form of abiraterone acetate according to claim 1, wherein the unit dosage form of abiraterone acetate is at a rate such that at least 70% of the abiraterone acetate elutes in 5 to 15 minutes or 5 to 10 minutes.   A unit dosage form of abiraterone acetate according to claim 1 containing 125 mg of abiraterone acetate.   The unit dosage form of abiraterone acetate according to claim 1, wherein the average plasma Cmax is 50 ng / mL to 120 ng / mL when orally administered to a population of healthy male subjects in a fasted state at a dose of 500 mg.   11. A unit dosage form according to claim 10, wherein the median plasma tmax is 1 hour to 2.5 hours when administered at a dose of 500 mg orally to a population of healthy male subjects in a fasted state.   The unit of abiraterone acetate according to claim 1, wherein when the dose of 500 mg is orally administered to a population of healthy male subjects in a fasted state, the average plasma AUC (0-∞) is 240 h * ng / mL to 650 h * ng / mL. Dosage form.   A unit dosage form according to claim 1 containing 125 mg of abiraterone acetate.   The unit dosage form of abiraterone acetate according to claim 1, wherein when a dose of 500 mg is administered to a fasting healthy male subject, the 90% confidence interval of mean plasma Cmax is a value of 50 ng / mL to 120 ng / mL.   The 90% confidence interval of mean plasma AUC (0-∞) is a value of 240 h * ng / mL to 650 h * ng / mL when administered at a dose of 500 mg to a fasting healthy male subject. Abiraterone acetate unit dosage form.   15. A unit dosage form according to claim 14 containing 125 mg of abiraterone acetate.   The unit dosage form of claim 1, further comprising an antioxidant.   A unit dosage form of abiraterone acetate containing 125 mg of abiraterone acetate, wherein the median particle size of the abiraterone acetate is 2,000 nm to 100 nm on a particle volume basis.   Sample containing 125 mg of abiraterone acetate using USP apparatus II at 75 rpm in 900 mL of pH 4.5 phosphate buffer containing 0.12% sodium lauryl sulfate in elution rate of the abiraterone acetate in the unit dosage form 19. The unit dosage form of claim 18, wherein the unit dosage form is at a rate such that at least 70% of the abiraterone acetate elutes in 5 to 15 minutes or 5 to 10 minutes when tested.   19. The 90% confidence interval for mean plasma AUC (0-∞) when administered at a dose of 500 mg to a fasted healthy male subject is a value between 240 h * ng / mL and 650 h * ng / mL. Unit dosage form.   19. The unit dosage form of claim 18, wherein when a dose of 500 mg is administered to a fasted healthy male subject, the 90% confidence interval for mean plasma Cmax is a value between 50 ng / mL and 120 ng / mL.   A method of treating castration resistant prostate cancer, wherein a patient in need thereof is treated with a daily dose that is bioequivalent to a dose of 1,000 mg of Zytiga® in a fasted healthy male subject. Administering 500 mg of abiraterone acetate dosage form and a glucocorticoid.   23. The method of claim 22, wherein the glucocorticoid is selected from the group consisting of prednisone, prednisolone, and methylprednisolone. A method of making a composition comprising nanoparticles of abiraterone acetate, comprising:
A composition comprising abiraterone acetate, a pulverizable comminution compound, an accelerator, and one or both of an antioxidant and a sequestering agent is sufficient to produce a composition comprising said abiraterone acetate microparticles. Including dry pulverization in a mill including a plurality of pulverized bodies,
A method wherein the particle size of the abiraterone acetate is reduced by dry milling. [D ₉₀ ] of the abiraterone acetate in the composition containing the fine particles of the abiraterone acetate is more than 100 nm and 3,000 nm, 2,000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, and 200 nm 25. The method of claim 24, wherein the number is less than one.   26. A method according to any of claims 24 to 25, wherein the grinding is performed in the presence of one or both of an antioxidant and a sequestering agent.   4. The method of claim 3, wherein the antioxidant is selected from ascorbic acid, BHA, and BHT.   27. The method of claim 26, wherein the sequestering agent is selected from fumaric acid, tartaric acid, and citric acid. [D ₅₀ ] of the fine particles of abiraterone acetate in the composition containing the fine particles of abiraterone acetate is more than 100 nm and less than 2,000 nm, less than 1,600 nm, less than 1,400 nm, less than 1,200 nm, less than 1,000 nm 29. A method according to any of claims 23 to 28, less than 800 nm, less than 500 nm, less than 400 nm, or less than 300 nm. [D _4,3 ] of the fine particles of abiraterone acetate in the composition containing the fine particles of abiraterone acetate is more than 100 nm and 2,500 nm, 2,400 nm, 2,200 nm, 2,000 nm, 1,900 nm, 1, 30. Any of the claims 23-29, less than one of 700nm, 1,500nm, 1,300nm, 1,100nm, 1,000nm, 900nm, 800nm, 700nm, 600nm, 500nm, 400nm, and 300nm. the method of.   A method for preparing a unit dose composition comprising: preparing a composition comprising microparticles of abiraterone acetate according to the method of any of claims 24 to 30; and a composition comprising the microparticles of abiraterone acetate. Combining with one or more pharmaceutically acceptable diluents, disintegrants, lubricants, lubricants, or dispersants.   32. The method of claim 31, wherein the unit dose composition is a tablet or capsule.   The unit dose composition is abiraterone acetate 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 250 mg, 275 mg, 300 mg, 325 mg, 35. The method of claim 32, comprising 350 mg, 375 mg, or 400 mg.   Sample containing 100 mg of abiraterone acetate using USP apparatus II at 75 rpm in 900 mL of pH 4.5 phosphate buffer (0.1% SLS), the dissolution rate of the abiraterone acetate in the unit dose composition 34. The method of claim 33, wherein at a rate such that at least 70% of the abiraterone acetate elutes in 5 to 15 minutes or 5 to 10 minutes when tested.   When the unit dose composition is a tablet and the tablet is tested in 900 mL of pH 4.5 phosphate buffer (0.1% SLS) using a 75 rpm USP apparatus II, of the abiraterone acetate 35. A method according to any of claims 33 to 34, wherein the elution rate is such that at least 80% of the elution occurs at 5 to 15 minutes or at 5 to 10 minutes. A unit dose pharmaceutical composition comprising abiraterone acetate, wherein the [D ₉₀ ] of the abiraterone acetate in the composition is greater than 100 nm and 5,000 nm, 4,500 nm, 4,000 nm, 3,000 nm, 2, A unit dose pharmaceutical composition characterized by being less than one of 000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, and 200 nm. [D ₅₀ ] of the abiraterone acetate is greater than 100 nm and less than 2,000 nm, less than 1,600 nm, less than 1,400 nm, less than 1,200 nm, less than 1,000 nm, less than 800 nm, less than 500 nm, less than 400 nm, less than 300 nm 37. A unit dose pharmaceutical composition according to claim 36. [D _4,3 ] of the abiraterone acetate is greater than 100 nm and is selected from 2,500 nm, 2,400 nm, 2,200 nm, 2,000 nm, 1,900 nm, 1,700 nm, 600 nm, 500 nm, 400 nm, and 300 nm 38. A unit dose pharmaceutical composition according to any of claims 36 to 37, wherein there are less than one.   The elution rate of the abiraterone acetate in the unit dose composition was obtained by subjecting a sample containing 100 mg of the abiraterone acetate to a pH 4.5 phosphate buffer (0.1% SLS) 900 mL at 75 rpm USP apparatus II. 39. A unit dose according to any of claims 36 to 38, wherein the unit dosage is such an elution rate that at least 70% of said abiraterone acetate elutes in 5 minutes to 15 minutes or 5 minutes to 10 minutes when tested with Composition. The average AUC _0-∞ of the unit dosage composition when administered to an adult male fed a low fat diet (7% fat, 300 calories) is no more than twice as high as when administered in a fasted state. 40. A unit dose composition according to any of 36 to 39. The average AUC _0-∞ of the unit dosage composition when administered to an adult male fed a high fat diet (57% fat, 825 calories) is less than twice as high as when administered in a fasted state. 41. A unit dose composition according to any of 36 to 40.   42. When administered to an adult male fed a low fat diet (7% fat, 300 calories), the mean Cmax of the unit dosage composition is no more than twice as high as when administered in a fasted state. A unit dose composition according to any of the above.   43. When administered to an adult male fed a high fat diet (57% fat, 825 calories), the average Cmax of the unit dosage composition is no more than 5 times higher than when administered in a fasted state. A unit dose composition according to any of the above.   A dose of 500 mg of the unit dose composition is bioequivalent to a dose of 1,000 mg of Zytiga for one or both of Cmax and AUC0-t in healthy male patients when administered in a fasted state. 43. A unit dose composition according to any of 36 to 42.   45. The dose of 500 mg of the unit dose composition is biologically equivalent to a dose of 1,000 mg of Zytiga for both Cmax and AUC0-t in healthy male patients when administered in the fasted state. A unit dose composition according to any one of the above.   The unit dose composition is abiraterone acetate 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg 46. A unit dose composition according to any of claims 36 to 45, containing 375 mg or 400 mg. A method of treating castration resistant prostate cancer comprising administering a daily dose of 100 mg to 700 mg of abiraterone acetate, wherein [D _4,3 ] of the abiraterone acetate is greater than 100 nm and 2,500 nm, 2, Less than one of 400 nm, 2,200 nm, 2,000 nm, 1,900 nm, 1,700 nm, 600 nm, 500 nm, 400 nm, and 300 nm.   48. The method of claim 47, comprising administering 200 mg to 600 mg of abiraterone acetate.   49. The method of claim 48, comprising administering 300 mg to 600 mg of abiraterone acetate.   48. A method for treating castration resistant prostate cancer comprising administering a daily dosage of 100 mg to 700 mg of abiraterone acetate in the unit dosage form of any of claims 36 to 47. Method.   51. The method of claim 50, wherein the daily dose is 500 mg abiraterone acetate.   52. The method according to any of claims 48 to 51, further comprising administering a glucocorticoid.   53. The method of claim 52, wherein the glucocorticoid is prednisone.   53. The method of claim 52, wherein the glucocorticoid is prednisolone.   53. The method of claim 52, wherein the glucocorticoid is methylprednisolone.   35. A pharmaceutical composition prepared by a method comprising the method of any of claims 23-34.