KR102617537B1 - Abiraterone acetate formulation and methods of use - Google Patents

Abstract

Pharmaceutical compositions, including unit dosage forms, comprising abiraterone acetate, and methods of making and using the compositions are described.

Description

ABIRATERONE ACETATE FORMULATION AND METHODS OF USE}

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 the synthesis of androgens in testicular, adrenal and prostate tumor tissues. Abiraterone acetate (17-(3-pyridyl)androsta-5, acetate; CAS #154229-18-2), a prodrug of abiraterone, causes castration-resistant prostate cancer in the United States. It is approved for treatment. Abiraterone acetate is considered to be poorly water soluble.

Zytiga® tablets (250 mg; National Drug Code Number 57894-150; NDA 202379) are approved in the United States for use in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer. It was received. Prescribing information for Zytiga tablets recommends 1,000 mg (4 x 250 mg tablets) administered orally once daily in combination with prednisone (5 mg) administered orally twice daily. Europe has approved its administration in combination with either prednisone or prednisolone.

The prescribing information for Zytiga tablets states that Zytiga tablets should be taken on an empty stomach and that no food should be eaten for at least 2 hours before taking the dose and 1 hour after taking the dose. Prescribing information indicates that at a dose of 1,000 mg/day in patients with metastatic castration-resistant prostate cancer, the steady-state C _max value (mean ± SD) was 226 ± 178 ng/mL and the AUC value was 1,173 ± 690 ng.hr/mL. Explain. A cross-over study of a single dose (1,000 mg) of Zytiga in healthy subjects showed that systemic exposure to abiraterone increased when Zytiga was administered with food. Specifically, abiraterone C _max and AUC _0-∞ were approximately 7-fold and 5-fold, respectively, when Zytiga was administered with a low-fat diet (7% fat, 300 calories) compared to administration in the fasting state. It was twice higher. Abiraterone C _max and AUC _0-∞ were approximately 17- and 10-fold higher, respectively, when Zytiga was administered with a high-fat (57% fat, 825 calories) diet compared to administration in the fasting state. .

The present disclosure features pharmaceutical compositions comprising unit dosage forms comprising abiraterone acetate, as well as methods of making and using such compositions.

Described herein is a unit dosage form of abiraterone acetate, wherein a 500 mg dose unit dosage form is bioequivalent to a 1,000 mg dose of Zytiga in fasting healthy male subjects. The log ratio of the geometric mean of AUC _(0-∞) for a 1,000 mg dose of Zytiga administered to fasting healthy male subjects versus a 500 mg dose administered to fasting healthy male subjects was 0.6 to 1.4 and 0.7 to 1.3. , 0.8 to 1.2 and 0.9 to 1.1, a unit dosage form of abiraterone acetate; The log ratio of the geometric mean of C(max) for a 1,000 mg dose of Zytiga administered to fasting healthy male subjects versus a 500 mg dose administered to fasting healthy male subjects was 0.6 to 1.4, 0.7 to 1.3, and 0.8. Unit dosage forms of abiraterone acetate selected from 1.2 to 0.9 and 0.9 to 1.1 are also described.

In some cases, the [D90] of abiraterone acetate is greater than 300 nm, including 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. is less than one value of nm; Abiraterone acetate has a [D50] greater than 100 nm and is one of 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. is less than the value; The [D4,3] of abiraterone acetate is greater than 300 nm, 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, 1,900 nm, 1,700 nm, 1,500 nm. is less than one of the following values: nm, 1,300 nm, 1,100 nm, 900 nm, and 800 nm; The dissolution rate of abiraterone acetate in unit dosage forms was determined by dissolving a sample containing 100 mg of abiraterone acetate in 900 ml of phosphate buffer, pH 4.5 containing 0.1% sodium lauryl sulfate, using a USP Apparatus II at 75 °C. When tested at rpm, at least 70% of the abiraterone acetate dissolves within 5 to 15 minutes or within 5 to 10 minutes; The dissolution rate of abiraterone acetate in unit dosage form was determined by dissolving a sample containing 125 mg of particulate abiraterone acetate in 900 ml of phosphate buffer, pH 4.5, containing 0.12% sodium lauryl sulfate using a USP Apparatus II. When tested at 75 rpm, at least 70% of the abiraterone acetate dissolves within 5 to 15 minutes or within 5 to 10 minutes; The unit dosage form contains 125 mg of abiraterone acetate.

A unit dosage form of a pharmaceutical composition comprising abiraterone acetate is also described, wherein a 500 mg dose provides a mean plasma C _max of 50-120 ng/ml when administered orally to a population of healthy male subjects in a fasting state. . In some cases, when administered orally to a population of fasting healthy male subjects, a 500 mg dose provides a median plasma t _max of 1 to 2.5 hours. Disclosed herein is a pharmaceutical comprising abiraterone acetate, wherein a 500 mg dose provides a mean plasma AUC (0-∞) of 240-650 h*ng/ml when administered orally to a population of fasting healthy male subjects. The unit dosage form of the composition is described. 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 500 mg dose is administered to a fasting healthy male subject, the 90% confidence interval for the mean plasma C _max is a value of 50 to 120 ng/ml; A pharmaceutical composition comprising abiraterone acetate, wherein the 90% confidence interval for the mean plasma AUC (0-∞) is a value of 240 to 650 h*ng/ml when a 500 mg dose is administered to healthy male subjects in fasting state. The unit dosage form is also described.

The unit dosage forms described herein may contain antioxidants (e.g., one or both BHA and BHT).

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

Disclosed herein is a composition comprising abiraterone acetate, a millable grinding compound, an accelerator, and one or both of an antioxidant and a metal ion sequestering agent in a mill for a period of time sufficient to produce a composition comprising milled abiraterone acetate. Dry milling, wherein the particle size of abiraterone acetate is reduced by dry milling.

In some instances of the manufacturing method, the [D90] of abiraterone acetate in the milled composition is greater than 400 nm, 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, is less than one of 800 nm, and 700 nm; The [D50] of abiraterone acetate in the milled composition is greater than 100 nm, less than 3,500 nm, less than 3,000 nm, less than 2,500 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; The dissolution rate of abiraterone acetate in the milled composition was determined by dissolving a sample containing 100 mg of abiraterone acetate in 900 ml of phosphate buffer pH 4.5 containing 0.1% sodium lauryl sulfate using a USP Apparatus II at 75 °C. When tested at rpm, at least 70% of the abiraterone acetate dissolves within 5 to 15 minutes or within 5 to 10 minutes; The dissolution rate of abiraterone acetate in the milled composition was determined by dissolving a sample containing 125 mg of abiraterone acetate in 900 ml of phosphate buffer pH 4.5 containing 0.12% sodium lauryl sulfate using a USP Apparatus II at 75 °C. When tested at rpm, at least 70% of the abiraterone acetate dissolves within 5 to 15 minutes or within 5 to 10 minutes; The [D50] of abiraterone acetate in the milled composition is greater than 200 nm, less than 6,500 nm, less than 6,000 nm, less than 5,500 nm, less than 5,000 nm, less than 4,000 nm, less than 3,000 nm, or less than 2,000 nm; The method further includes combining the composition comprising particulates of abiraterone acetate with one or more pharmaceutically acceptable diluents, disintegrants, lubricants, glidants or dispersants to prepare a unit dosage form.

In various embodiments, the median particle size of the particles of abiraterone acetate in the pharmaceutical composition (or used to prepare the pharmaceutical composition), as measured on a particle volume basis ([D ₅₀ ] or D _[50] or [D 50 ]) is 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, 1,400nm , 1,300 nm, 1,200 nm, 1,100 nm, 1,000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, and 200 nm. In some embodiments, [D50] is at least 25 nm or 100 nm or even 500 nm. In various embodiments, [D50] is 5,000 nm to 100 nm, 3,500 nm and 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 to 100 nm. , 800 nm to 100 nm, 700 nm to 100 nm, 600 nm to 100 nm, 500 nm to 100 nm. In various embodiments, D[4,3] (volume average diameter) 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 less than 300 nm. In various cases, for example as described above, 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, 3,000 nm to 1,000 nm, 2,000 nm to 1,000 nm. 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 2,000 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. In various embodiments, [D90] ([ _D90 ] or D _[90] ) is less than 8,000 nm, less than 7,500 nm, less than 7,000 nm, less than 6,000 nm, less than 4,000 nm, less than 2,000 nm, less than 1,000 nm, less than 500 nm. It is less than. In some cases, D90 is 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 6,000 nm-500 nm, 5,500 nm-500 nm, or 5,000 nm-500 nm, and 4,000-400 nm.

In another embodiment, the crystallinity profile of the abiraterone acetate is such that at least 20% of the abiraterone acetate is crystalline, at least 30% of the abiraterone acetate is crystalline, and at least 40% of the abiraterone acetate is crystalline. , more than 50% of abiraterone acetate is crystalline, more than 60% of abiraterone acetate is crystalline, more than 70% of abiraterone acetate is crystalline, more than 75% of abiraterone acetate This is crystalline, 85% or more of abiraterone acetate is crystalline, 90% or more of abiraterone acetate is crystalline, 95% or more of abiraterone acetate is crystalline, and abiraterone acetate It is selected from the group consisting of those that are at least 98% crystalline. In some embodiments, the crystallinity profile of abiraterone acetate is substantially the same as the crystallinity profile of abiraterone acetate prior to subjecting the material to a method as described herein.

In another embodiment, the amorphous content of abiraterone acetate is such that less than 80% of abiraterone acetate is amorphous, less than 70% of abiraterone acetate is amorphous, or less than 60% of abiraterone acetate 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 amorphous, Less than 25% of the abiraterone acetate is amorphous, less than 15% of the abiraterone acetate is amorphous, less than 10% of the abiraterone acetate is amorphous, less than 5% of the abiraterone acetate is amorphous, and Avira. Theron acetate is selected from the group consisting of less than 2% of the acetate being amorphous. In some embodiments, after subjecting the material to the dry milling method described herein, the amorphous content of abiraterone acetate does not substantially increase.

In some embodiments, particles of abiraterone acetate are prepared by dry milling abiraterone acetate with a millable grinding compound and an accelerator in the presence of a milling body. Additional components may be present during milling, and the various components present together during milling (except abiraterone acetate and milling bodies) are referred to as the grinding matrix. In some cases, milling produces significantly reduced size abiraterone acetate particles dispersed in a grinding matrix. Since all of the components in the grinding matrix are pharmaceutically acceptable, pharmaceutical compositions can be prepared using a mixture of abiraterone acetate and a grinding matrix prepared by milling. In some cases, some or all of the components of the grinding matrix are reduced in size during milling. In some cases, additional pharmaceutically acceptable ingredients may be added to the mixture of abiraterone acetate and grinding matrix after milling. In some embodiments, dry milling is performed in the presence of a milling body; In other cases, the particles may or may not themselves be reduced in particle size by milling in the absence of a milling body, e.g., a jet mill or another type of mill, e.g., abiraterone acetate. It is prepared by milling in a mill that can reduce the particle size and/or increase the solubility of abiraterone acetate when milled in the presence of a millable grinding compound.

In some cases, abiraterone acetate is milled with one or more millable grinding compounds selected from lactose (e.g., lactose monohydrate or lactose anhydrous) and mannitol, and one or more accelerators selected from sodium lauryl sulfate and povidone. do. In some cases, in addition to reducing the particle size of the abiraterone acetate, milling also reduces the particle size of one or more components of the grinding matrix. Accordingly, in some cases, milling reduces particles of one or more of the substances (eg, lactose) used as the millable grinding compound. In some cases, abiraterone acetate is milled with lactose (eg, lactose monohydrate) and sodium lauryl sulfate. In some cases, during dry milling, abiraterone acetate up to 20-60% (w/w), lactose up to 80% (w/w), mannitol up to 80% (w/w), and povidone and sodium lauryl sulfate may each (or both) be present at 1-10% (w/w).

In some embodiments, the abiraterone acetate, in addition to at least one millable grinding compound and at least one accelerator, is comprised of one or more antioxidants and/or one or more metal ion sequestering agents (i.e., capable of sequestering ions, such as metal ions). It is dry milled in the presence of a certain agent). Accordingly, one or more of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, fumaric acid, tartaric acid and citric acid (e.g., citric anhydride) or mixtures thereof may be present during dry milling. . In some cases, both at least one antioxidant and at least one metal ion sequestering agent are present during milling. During milling, ascorbic acid, fumaric acid, tartaric acid, and citric acid (e.g., anhydrous citric acid) are kept at no more than 8% on a w/w basis (e.g., 7%-0.1%, 1%-0.1%, or 0.2%, individually or in combination). may be present, and BHT and BHA may be present at no more than 0.5% (e.g., individually or in combination, e.g., 0.5%-0.01%, 0.2%-0.08%, 0.15%-0.05%, or 0.1%). One or more additional antioxidants and/or one or more additional metal ion sequestering agents may be added to the milled material after milling is complete.

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

Also described herein are abiraterone acetate in daily doses of 1,000 mg to 50 mg (e.g., 900, 850, 800, 750, 700, 650, 600, 550, 525, 500, 475, 450, 425, 400, 375, 350 , 325, 300, 275, 250, 225, 200, 150, 100, 90, 80, 70, 60, or 50 mg) in the form of a pharmaceutical composition described herein (e.g., abiraterone comprising administering in one or more units the unit dosage form described herein comprising acetate, wherein the abiraterone acetate has a size profile described herein and/or the dosage form is described herein. Describes a method of treating a patient, wherein the method has a dissolution profile of Patients may also be treated with glucocorticoids, such as prednisone, prednisolone, or dexamethasone. Alternatively, the patient may also take methylprednisolone, e.g., 5-15 mg/day (e.g., 5, 6, 7, 8, 9, 10 mg/day, e.g., 4 mg doses/day over two doses). (day) can be treated. In some cases, patients, such as patients not suffering from hepatic impairment, are treated with 500 mg/day of the 125 mg abiraterone acetate unit dosage form described herein by administering four times.

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 an effective dose thereof, e.g., 4 The AUC _0-∞ for 125 mg) is up to 4 times (up to 3 times, up to 2 times, up to 1.5 times) higher than when administered in the fasting 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 an effective dose thereof, e.g., 4 AUC _0-∞ (or AUC _0-t ) for 125 mg) is 8 times or less (7 times or less, 5 times or less, 3 times or less, 2 times or less, 1.5 times or less) than when administered in an empty stomach. 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 an effective dose thereof, e.g., 4 C _max for 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, 7 times or less, 6 times or less) than when administered in an empty stomach. , 5 times or less) is higher.

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 an effective dose thereof, e.g., 4 C _max for 125 mg) is up to 6 times (up to 5 times, up to 4 times, up to 3 times, up to 2 times, up to 1.5 times) higher than when administered in the fasting state.

Contains 100 mg or 125 mg of abiraterone acetate when tested at 75 rpm using USP Apparatus II in 900 ml of phosphate buffer, pH 4.5, containing 0.1%-0.12% sodium lauryl sulfate (each). The dissolution rate of the tablet is that at least 90% or at least 95% of the abiraterone acetate is within 20 minutes (e.g., within 19 minutes, within 18 minutes, within 17 minutes, within 16 minutes, within 15 minutes, within 14 minutes, and within 13 minutes. It dissolves within 11 minutes, within 9 minutes). For example, 90% can be dissolved within 9-19 minutes. If a tablet contains more than 125 mg or less than 100 mg of abiraterone acetate, the dissolution rate given is relative to the fraction of the larger tablet (or multiple smaller tablets) giving 100-125 mg of abiraterone acetate will be. In some cases, at least 80% or at least 85% of the abiraterone acetate is administered within 15 minutes (e.g., within 14 minutes, within 13 minutes, within 12 minutes, within 11 minutes, within 10 minutes, within 9 minutes, within 8 minutes, or within 7 minutes). For example, 85% can be dissolved within 7-14 minutes.

In some cases, after storage at 25°C, 60% RH for at least 4 weeks (e.g., 8 or 12 weeks), at least 80% or at least 85% of the abiraterone acetate in the 125 mg unit dosage form is lost within 15 minutes (e.g., dissolves within 14 minutes, within 13 minutes, within 12 minutes, within 11 minutes, within 10 minutes, within 9 minutes, within 8 minutes, or within 7 minutes). In some cases, after storage at 40°C, 75% RH for at least 3 weeks (e.g., 6 or 9 weeks), at least 95% of the abiraterone acetate is released within 15 minutes (e.g., within 14 minutes, within 13 minutes, within 11 minutes). It dissolves within 9 minutes). For example, 95% can be dissolved within 8-14 minutes. Here also, if the tablet contains less than 125 mg or 100 mg of abiraterone acetate, the given dissolution rate is the fraction of the larger tablet (or multiple smaller tablets) giving 100-125 mg of abiraterone acetate. It's about.

In certain embodiments, the coefficient of variation observed for a pharmaceutical composition described herein in one or more of C _max , AUC(0-t), and AUC(0-∞) when administered to healthy patients in a fasting state is 60%. It will be less than, less than 50%, less than 40%, less than 30%, less than 25%, or less than 20%. In some embodiments, the pharmaceutical composition described herein (either in a 125 mg unit dosage form or in a 500 mg dose, e.g., 4 x 125 mg) is used in a pharmacokinetic property comparison experiment, e.g., as a dosage form of 250 mg Zytiga. (or 1,000 doses of the 250 mg Zytiga dosage form) compared to one or more of C _max , AUC(0-t), and AUC(0-∞).

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

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

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

In some embodiments, the dry milling device used to dry mill abiraterone acetate is an attritor mill (horizontal or vertical), a nutating mill, a tower mill, a pearl mill, etc. The milling machine is selected from the group consisting of a milling machine, a planetary milling machine, a vibrating milling machine, an eccentric vibrating milling machine, a gravity-dependent ball milling machine, a rod milling machine, a roller milling machine, and a crusher milling machine. In some embodiments, the dry milling device used to dry mill 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 configured to produce abiraterone acetate in swing batch or continuous mode.

In some embodiments, when the mill uses a milling body, the milling body within the milling device is mechanically agitated by one, two or three rotating axes. The milling body may be formed from a material selected from ceramics, glass, steel, polymers, ferromagnets and metals and other suitable materials. In some embodiments, the milling body is a steel ball having a diameter selected from the group consisting of 1 to 20 mm, 2 to 15 mm, and 3 to 10 mm. In various embodiments of the dry milling method, the milling bodies are zirconium oxide balls having a diameter selected from the group consisting of 1 to 20 mm, 2 to 15 mm and 3 to 10 mm.

In another embodiment, the milling period is 10 minutes to 6 hours, 10 minutes to 2 hours, 10 minutes to 90 minutes, 10 minutes to 1 hour, 10 minutes to 45 minutes, 10 minutes to 30 minutes, 5 minutes to 30 minutes. , 5 minutes to 20 minutes, 2 minutes to 10 minutes, 2 minutes to 5 minutes, and 1 minute to 2 minutes.

Additional milling matrices and accelerators

In embodiments, the grinding matrix is a single material or a mixture of two or more materials in any ratio. In some embodiments, a single substance or a mixture of two or more substances is mannitol, sorbitol, isomalt, xylitol, maltitol, lactitol, erythritol, arabitol, ribitol, glucose, fructose, mannose, galactose, It is selected from the group consisting of anhydrous lactose, lactose monohydrate, sucrose, maltose, trehalose, and maltodextrin. In some embodiments, a single substance or a mixture of two or more substances is selected from the group consisting of dextrin, inulin, dextrose, polydextrose, starch, wheat flour, corn flour, rice flour, rice starch, tapioca flour, tapioca starch, potato flour, potato starch, and other Flours and starches, milk powder, skim milk powder, other milk solids and derivatives, soy flour, soy wheat or other soy products, cellulose, microcrystalline cellulose, co-blended materials based on microcrystalline cellulose, pregelatinized ( or partially gelatinized) starch, hypromellose, carboxymethyl cellulose, hydroxypropyl cellulose, citric acid, tartaric acid, malic acid, maleic acid, fumaric acid, ascorbic acid, succinic acid, sodium citrate, sodium tartrate, sodium malate, ascorbic acid. Sodium, potassium citrate, potassium tartrate, potassium malate, sodium acetate, potassium ascorbate, sodium carbonate, potassium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, sodium sulfate, sodium chloride, Sodium metabisulfite, sodium thiosulfate, ammonium chloride, Glauber's salt, ammonium carbonate, sodium bisulfate, magnesium sulfate, alum, potassium chloride, sodium bisulfate, sodium hydroxide, crystalline hydroxide, bicarbonate, ammonium chloride, methylamine. Hydrochloride, ammonium bromide, silica, thermal silica, alumina, titanium dioxide, talc, chalk, mica, kaolin, bentonite, hectorite, magnesium trisilicate, clay-based substances or aluminum silicate, sodium lauryl sulfate, sodium stearyl sulphate. Pate, Sodium Cetyl Sulfate, Sodium Cetostearyl Sulfate, Sodium Docusate, Sodium Deoxycholate, N-Lauroylsarcosine Sodium Salt, Glyceryl Monostearate, Glycerol 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 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 Free, 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, Sorbitan 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 taurodeoxycholate, taurodeoxycholic acid, soy lecithin, phosphatidylcholine, phosphatidylethanolamine, Phosphatidylserine, phosphatidylinositol, PEG4000, PEG6000, PEG8000, PEG10000, PEG2,0000, alkyl naphthalene sulfonate condensate/lignosulfonate blend, calcium dodecylbenzene sulfonate, sodium dodecylbenzene sulfonate, diiso Propyl naphthalenesulfonate, erythritol distearate, naphthalene sulfonate formaldehyde condensate, nonylphenol ethoxylate (poe-30), tristyrylphenol ethoxylate, polyoxyethylene (15) tallowalkylamine, sodium Alkyl Naphthalene Sulfonate, Sodium Alkyl Naphthalene Sulfonate Condensate, Sodium Alkylbenzene Sulfonate, Sodium Isopropyl Naphthalene Sulfonate, Sodium Methyl Naphthalene Formaldehyde Sulfonate, Sodium n-Butyl Naphthalene Sulfonate, Tridecyl Alcohol Ethoxylate (POE) -18), triethanolamine isodecanol phosphate ester, triethanolamine tristyryl phosphate ester, tristyrylphenol ethoxylate sulfate, and bis(2-hydroxyethyl)tallowalkylamine.

In some embodiments, the concentration of a single (or first) component of the grinding matrix is 5-99% w/w, 10-95% w/w, 15-85% w/w, 20-80% w/w, It is selected from the group consisting of 25-75% w/w, 30-60% w/w, and 40-50% w/w. In some embodiments, the concentration of the second or subsequent component of the grinding matrix is 5-50% w/w, 5-40% w/w, 5-30% w/w, 5-20% w/w, 10- 40% w/w, 10-30% w/w, 10-20% w/w, 20-40% w/w, or 20-30%, or the second or subsequent material is selected from the group consisting of For active agents or water-soluble polymers, the concentrations are 0.1-10% w/w, 0.1-5% w/w, 0.1-2.5% w/w, 0.1-2% w/w, 0.1-1%, 0.5-5%. w/w, 0.5-3% w/w, 0.5-2% w/w, 0.5-1.5%, 0.5-1% w/w, 0.75-1.25% w/w, 0.75-1% and 1% w/ is selected from w.

In some embodiments, abiraterone acetate is milled in the presence of (a)-(k) below:

(a) lactose monohydrate, or xylitol; lactose anhydrous; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaoline; 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 sarcosine; lecithin; docusate sodium; polyoxyl-40-stearate; hydrophobic colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length of C5 to C18; polyvinyl pyrrolidone; 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 Samer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate blend; Calcium dodecylbenzene sulfonate (branched); diisopropyl naphthalenesulfonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acid; naphthalene sulfonate formaldehyde condensate; Nonylphenol ethoxylate, POE-30; Phosphate esters, tristyrylphenol ethoxylate, free acid; polyoxyethylene (15) tallowalkylamine; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; Sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; formaldehyde sulfonate; Sodium salt of n-butyl naphthalene sulfonate; Tridecyl alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate ester; Triethanolamine tristyryl phosphate ester; tristyrylphenol ethoxylate sulfate; Lactose monohydrate in combination with at least one substance selected from the group consisting of bis(2-hydroxyethyl)tallowalkylamine.

(b) lactose anhydrous, or lactose monohydrate; xylitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaoline; 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 sarcosine; lecithin; docusate sodium; polyoxyl-40-stearate; hydrophobic colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length of C5 to C18; polyvinyl pyrrolidone; 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 Samer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate blend; Calcium dodecylbenzene sulfonate (branched); diisopropyl naphthalenesulfonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acid; naphthalene sulfonate formaldehyde condensate; Nonylphenol ethoxylate, POE-30; Phosphate esters, tristyrylphenol ethoxylate, free acid; polyoxyethylene (15) tallowalkylamine; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; Sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; formaldehyde sulfonate; Sodium salt of n-butyl naphthalene sulfonate; Tridecyl alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate ester; Triethanolamine tristyryl phosphate ester; tristyrylphenol ethoxylate sulfate; Lactose anhydrous in combination with at least one substance selected from the group consisting of bis(2-hydroxyethyl)tallowalkylamine.

(c) mannitol, or lactose monohydrate; xylitol; lactose anhydrous; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaoline; 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 sarcosine; lecithin; docusate sodium; polyoxyl-40-stearate; hydrophobic colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length of C5 to C18; polyvinyl pyrrolidone; 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 Samer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate blend; Calcium dodecylbenzene sulfonate (branched); diisopropyl naphthalenesulfonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acid; naphthalene sulfonate formaldehyde condensate; Nonylphenol ethoxylate, POE-30; Phosphate esters, tristyrylphenol ethoxylate, free acid; polyoxyethylene (15) tallowalkylamine; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; Sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; formaldehyde sulfonate; Sodium salt of n-butyl naphthalene sulfonate; Tridecyl alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate ester; Triethanolamine tristyryl phosphate ester; tristyrylphenol ethoxylate sulfate; Mannitol in combination with at least one substance selected from the group consisting of bis(2-hydroxyethyl)tallowalkylamine.

(d) sucrose, or lactose monohydrate; lactose anhydrous; Mannitol; microcrystalline cellulose; glucose; sodium chloride; talc; kaoline; 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 sarcosine; lecithin; docusate sodium; polyoxyl-40-stearate; hydrophobic colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length of C5 to C18; polyvinyl pyrrolidone; 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 Samer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate blend; Calcium dodecylbenzene sulfonate (branched); diisopropyl naphthalenesulfonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acid; naphthalene sulfonate formaldehyde condensate; Nonylphenol ethoxylate, POE-30; Phosphate esters, tristyrylphenol ethoxylate, free acid; polyoxyethylene (15) tallowalkylamine; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; Sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; formaldehyde sulfonate; Sodium salt of n-butyl naphthalene sulfonate; Tridecyl alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate ester; Triethanolamine tristyryl phosphate ester; tristyrylphenol ethoxylate sulfate; Sucrose in combination with at least one substance selected from the group consisting of bis(2-hydroxyethyl)tallowalkylamine.

(e) glucose, or lactose monohydrate; lactose anhydrous; Mannitol; microcrystalline cellulose; sucrose; sodium chloride; talc; kaoline; 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 sarcosine; lecithin; docusate sodium; polyoxyl-40-stearate; hydrophobic colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length of C5 to C18; polyvinyl pyrrolidone; 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 Samer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate blend; Calcium dodecylbenzene sulfonate (branched); diisopropyl naphthalenesulfonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acid; naphthalene sulfonate formaldehyde condensate; Nonylphenol ethoxylate, POE-30; Phosphate esters, tristyrylphenol ethoxylate, free acid; polyoxyethylene (15) tallowalkylamine; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; Sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; formaldehyde sulfonate; Sodium salt of n-butyl naphthalene sulfonate; Tridecyl alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate ester; Triethanolamine tristyryl phosphate ester; tristyrylphenol ethoxylate sulfate; Glucose in combination with at least one substance selected from the group consisting of bis(2-hydroxyethyl)tallowalkylamine.

(f) sodium chloride, or lactose monohydrate; lactose anhydrous; Mannitol; microcrystalline cellulose; sucrose; glucose; talc; kaoline; 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 sarcosine; lecithin; docusate sodium; polyoxyl-40-stearate; hydrophobic colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length of C5 to C18; polyvinyl pyrrolidone; 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 Samer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate blend; Calcium dodecylbenzene sulfonate (branched); diisopropyl naphthalenesulfonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acid; naphthalene sulfonate formaldehyde condensate; Nonylphenol ethoxylate, POE-30; Phosphate esters, tristyrylphenol ethoxylate, free acid; polyoxyethylene (15) tallowalkylamine; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; Sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; formaldehyde sulfonate; Sodium salt of n-butyl naphthalene sulfonate; Tridecyl alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate ester; Triethanolamine tristyryl phosphate ester; tristyrylphenol ethoxylate sulfate; Sodium chloride in combination with at least one substance selected from the group consisting of bis(2-hydroxyethyl)tallowalkylamine.

(g) xylitol, or lactose monohydrate; lactose anhydrous; Mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaoline; 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 sarcosine; lecithin; docusate sodium; polyoxyl-40-stearate; hydrophobic colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length of C5 to C18; polyvinyl pyrrolidone; 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 Samer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate blend; Calcium dodecylbenzene sulfonate (branched); diisopropyl naphthalenesulfonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acid; naphthalene sulfonate formaldehyde condensate; Nonylphenol ethoxylate, POE-30; Phosphate esters, tristyrylphenol ethoxylate, free acid; polyoxyethylene (15) tallowalkylamine; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; Sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; formaldehyde sulfonate; Sodium salt of n-butyl naphthalene sulfonate; Tridecyl alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate ester; Triethanolamine tristyryl phosphate ester; tristyrylphenol ethoxylate sulfate; Xylitol in combination with at least one substance selected from the group consisting of bis(2-hydroxyethyl)tallowalkylamine.

(h) tartaric acid, or lactose monohydrate; lactose anhydrous; Mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaoline; 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 sarcosine; lecithin; docusate sodium; polyoxyl-40-stearate; hydrophobic colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length of C5 to C18; polyvinyl pyrrolidone; 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 Samer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate blend; Calcium dodecylbenzene sulfonate (branched); diisopropyl naphthalenesulfonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acid; naphthalene sulfonate formaldehyde condensate; Nonylphenol ethoxylate, POE-30; Phosphate esters, tristyrylphenol ethoxylate, free acid; polyoxyethylene (15) tallowalkylamine; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; Sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; formaldehyde sulfonate; Sodium salt of n-butyl naphthalene sulfonate; Tridecyl alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate ester; Triethanolamine tristyryl phosphate ester; tristyrylphenol ethoxylate sulfate; Tartaric acid in combination with at least one substance selected from the group consisting of bis(2-hydroxyethyl)tallowalkylamine.

(i) microcrystalline cellulose, or lactose monohydrate; xylitol; lactose anhydrous; Mannitol; sucrose; glucose; sodium chloride; talc; kaoline; 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 sarcosine; lecithin; docusate sodium; polyoxyl-40-stearate; hydrophobic colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length of C5 to C18; polyvinyl pyrrolidone; 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 Samer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate blend; Calcium dodecylbenzene sulfonate (branched); diisopropyl naphthalenesulfonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acid; naphthalene sulfonate formaldehyde condensate; Nonylphenol ethoxylate, POE-30; Phosphate esters, tristyrylphenol ethoxylate, free acid; polyoxyethylene (15) tallowalkylamine; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; Sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; formaldehyde sulfonate; Sodium salt of n-butyl naphthalene sulfonate; Tridecyl alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate ester; Triethanolamine tristyryl phosphate ester; tristyrylphenol ethoxylate sulfate; Microcrystalline cellulose in combination with at least one material selected from the group consisting of bis(2-hydroxyethyl)tallowalkylamine.

(j) lactose monohydrate; xylitol; lactose anhydrous; Mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaoline; 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 sarcosine; lecithin; docusate sodium; polyoxyl-40-stearate; hydrophobic colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length of C5 to C18; polyvinyl pyrrolidone; 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 Samer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate blend; Calcium dodecylbenzene sulfonate (branched); diisopropyl naphthalenesulfonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acid; naphthalene sulfonate formaldehyde condensate; Nonylphenol ethoxylate, POE-30; Phosphate esters, tristyrylphenol ethoxylate, free acid; polyoxyethylene (15) tallowalkylamine; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; Sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; formaldehyde sulfonate; Sodium salt of n-butyl naphthalene sulfonate; Tridecyl alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate ester; Triethanolamine tristyryl phosphate ester; tristyrylphenol ethoxylate sulfate; Kaolin in combination with at least one material selected from the group consisting of bis(2-hydroxyethyl)tallowalkylamine.

(k) lactose monohydrate; xylitol; lactose anhydrous; Mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; kaoline; 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 sarcosine; lecithin; docusate sodium; polyoxyl-40-stearate; hydrophobic colloidal silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length of C5 to C18; polyvinyl pyrrolidone; 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 Samer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/lignosulfonate blend; Calcium dodecylbenzene sulfonate (branched); diisopropyl naphthalenesulfonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acid; naphthalene sulfonate formaldehyde condensate; Nonylphenol ethoxylate, POE-30; Phosphate esters, tristyrylphenol ethoxylate, free acid; polyoxyethylene (15) tallowalkylamine; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; Sodium isopropyl naphthalene sulfonate; sodium methyl naphthalene; formaldehyde sulfonate; Sodium salt of n-butyl naphthalene sulfonate; Tridecyl alcohol ethoxylate, POE-18; triethanolamine isodecanol phosphate ester; Triethanolamine tristyryl phosphate ester; tristyrylphenol ethoxylate sulfate; Talc in combination with at least one substance selected from the group consisting of bis(2-hydroxyethyl)tallowalkylamine.

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

In some embodiments, 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 glidants, surfactants, polymers, and/or lubricants. 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, polyoxyethylene stearate, polyoxyethylene castor oil derivative, polyoxyl 15 hydroxystearate, polyoxylglyceride, polysorbate, propylene glycol dilaurate, sorbitan ester, sucrose palmitate, vitamin E polyethylene glycol. Succinates, polyethylene glycol (PEG), poloxamers, poloxamines, sarcosine-based surfactants, polysorbates, aliphatic alcohols, alkyl and aryl sulfates, alkyl and aryl polyether sulfonates and other sulfate surfactants, trimethyl ammonium-based Surfactants, lecithin and other phospholipids, bile salts, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters sucrose fatty acid esters, alkyl glucopyranosides, alkyl maltopyranosides, glycerol fatty acid esters. , alkyl benzene sulfonic acids, alkyl ether carboxylic acids, alkyl and aryl phosphate esters, alkyl and aryl sulfate esters, alkyl and aryl sulfonic acids, alkyl phenol phosphate esters, alkyl phenol sulfate esters, alkyl and aryl phosphates, alkyl polysaccharides, Alkylamine ethoxylates, alkyl-naphthalene sulfonate formaldehyde condensates, sulfosuccinates, lignosulfonates, ceto-oleyl alcohol ethoxylates, condensed naphthalene sulfonates, dialkyl and alkyl naphthalene sulfonates, dialkyl Sulfosuccinate, ethoxylated nonylphenol, ethylene glycol ester, fatty alcohol alkoxylate, hydrogenated tallowalkylamine, mono-alkyl sulfosuccinamate, nonyl phenol ethoxylate, sodium oleyl N-methyl taurate. , tallowalkylamines, linear and branched dodecylbenzene sulfonic acids.

In some embodiments, the accelerator is sodium stearyl sulfate, sodium stearyl fumarate, magnesium stearate, talc, myristic acid, sodium cetyl sulfate, sodium cetostearyl sulfate, sodium docusate, sodium deoxycholate, N-Lauroylsarcosine Sodium Salt, Glyceryl Monostearate, Glycerol Distearate Glyceryl Palmitostearate, Glyceryl Behenate, Glyceryl Caprylate, Glyceryl Oleate, Benzalkonium Chloride, Cetyl Trimethyl Ammonium Bromide, Cetyl Trimethyl Ammonium Chloride, Cetrimide, Cetylpyridinium Chloride, 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, Poly Oxyl 60 Hydrogenated Castor Oil, Polyoxyl 100 Hydrogenated Castor Oil, Polyoxyl 200 Hydrogenated Castor Oil, Cetostearyl Alcohol, Macrogel 15 Hydroxystearate, Sorbitan Monopalmitate, Sorbitan 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 taurodeoxycholate, taurodeoxycholic acid, soy lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkyl naphthalene sulfonate condensate/ Lignosulfonate blend, calcium dodecylbenzene sulfonate, sodium dodecylbenzene sulfonate, diisopropyl naphthalenesulfonate, erythritol distearate, naphthalene sulfonate formaldehyde condensate, nonylphenol ethoxylate (POE-30) ), Tristyrylphenol ethoxylate, polyoxyethylene (15) tallowalkylamine, sodium alkyl naphthalene sulfonate, sodium alkyl naphthalene sulfonate condensate, sodium alkylbenzene sulfonate, sodium isopropyl naphthalene sulfonate, sodium methyl Naphthalene Formaldehyde Sulfonate, Sodium n-Butyl Naphthalene Sulfonate, Tridecyl Alcohol Ethoxylate (POE-18), Triethanolamine Isodecanol Phosphate Ester, Triethanolamine Tristyryl Phosphate Ester, Tristyrylphenol Ethoxylate Sulfur pate, bis(2) hydroxyethyl)tallowalkylamine.

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

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

In some embodiments, an accelerator is used during dry milling, or a combination of accelerators is used. In some embodiments, an accelerator is added during dry milling. In some embodiments, the accelerator is 1-5% of the total milling time remaining, 1-10% of the total milling time remaining, 1-20% of the total milling time remaining, 1-30% of the total milling time remaining, It is added to dry milling at a time selected from the group consisting of 2-5% of the time, 2-10% of the total milling time remaining, 5-20% of the total milling time remaining, and 5-20% of the total milling time remaining. .

Reasons for including accelerators include, but are not limited to, providing better dispersibility, control of agglomeration, release or retention of active particles from the delivery matrix. Examples of accelerators include sodium lauryl sulfate, cross-linked PVP (crospovidone), cross-linked sodium carboxymethylcellulose (croscarmellose sodium), sodium starch glycolate, povidone (PVP), povidone K12, povidone K17, povidone K25, Povidone K29/32 and povidone K30, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, sodium stearyl lactylate, zinc stearate, sodium or lithium stearate, other solid state fatty acids such as Oleic acid, lauric acid, palmitic acid, erucic acid, behenic acid, or derivatives (such as esters and salts), amino acids such as leucine, isoleucine, lysine, valine, methionine, phenylalanine, aspartame or acesulfame K Including, but not limited to.

In another aspect, the disclosure includes a method of treating a human in need of treatment for castration-resistant prostate cancer, comprising administering to the human an effective amount of a pharmaceutical composition as described herein. . Treatment consists of 500 mg of abiraterone acetate (e.g., in 1 or 2 or 4 equal doses (e.g., 1 unit dose containing 500 mg, 2 units each containing 250 mg of abiraterone acetate) dose, or in four unit doses each containing 125 mg of abiraterone acetate. The patient may also be administered a glucocorticoid, such as prednisone, dexamethasone or prednisolone (e.g., 5 mg daily). (2 times daily). Alternatively, the patient may be treated with methylprednisolone (e.g., 4 mg, twice daily). The patient may also be treated with other chemotherapy agents for the treatment of cancer (e.g., prostate cancer). Or you may be treated with other agents.

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

In another aspect, the disclosure includes the use of a pharmaceutical composition as described herein in the manufacture of a medicament for the treatment of 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 combination with one of a diluent, lubricant, excipient, disintegrant, or wetting agent. A method of preparing a pharmaceutical composition as described herein comprising preparing a pharmaceutically acceptable dosage form.

The disclosure described herein may include one or more ranges of values (eg, size, concentration, etc.). A range of values is defined by the value that defines that value, and the boundaries of that value by defining all values within that range, including values immediately adjacent to that value that are equal to or lead to substantially the same result. It will be understood as containing a value.

The entire disclosures of all publications (including patents, patent applications, journal articles, laboratory manuals, books, or other documents) cited herein are incorporated herein by reference. Inclusion is not to be construed as an admission that any of the references constitute prior art or are part of the common general knowledge of those skilled in the art to which the disclosure pertains.

Throughout this specification, unless the context dictates otherwise, the word "comprise" or its derivatives, e.g., "comprises," "comprising," refers to any other integer or group of integers. It should be understood as implying that it does not exclude, but includes the mentioned integer or group of integers. In this disclosure, particularly in the claims and/or paragraphs, the terms "comprises," "comprised," "comprising," and the like are attributed to them under U.S. patent law. It can have the meaning of being; For example, it should be noted that this may have the meaning of “includes,” “included,” “including,” etc.

As used herein in relation to methods of treatment and particularly drug dosages, "therapeutically effective amount" means the dosage of drug administered to provide a specific pharmacological response in a significant number of subjects in need of such treatment. shall. Although the above dosages are considered to be "therapeutically effective amounts" by those skilled in the art, it is emphasized that a "therapeutically effective amount" administered to a particular patient in a particular case may not always be effective in treating the condition described herein. do. It is further to be understood that the drug dosage is in certain cases measured as an oral dose or in relation to drug levels as measured in the blood.

It is to be understood that throughout this specification, unless the context otherwise requires, the phrase “dry mill” or derivatives such as “dry milling” mean milling that takes place at least substantially in the presence of a liquid. If liquid is present, it is present in an amount such that the contents of the mill retain the characteristics of a dry powder.

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

Those skilled in the art will understand that the disclosure described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the disclosure includes all such variations and modifications. The disclosure also includes all of the steps, features, compositions and materials mentioned, or specified, individually or collectively herein, and any combination of any two or more of the steps or features.

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

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

Figure 1 is a graph showing the particle size analysis results of unmilled abiraterone acetate and abiraterone acetate of Formulation 1 and Formulation 2 of Example 1.
Figure 2 is a graph showing the dissolution rate measurement results for the abiraterone acetate tablet described in Example 3.
3A and 3B are graphs showing the results of the stability study described in Example 6.

particle size

For measurements performed using laser diffraction, the term “median particle size” is defined as the median particle diameter measured based on equivalent spherical particle volume. When the term median is used, it is understood that the particle size divides the population in half, stating that 50% of the population by volume is larger or smaller than that size. The median particle size is written as: [D ₅₀ ] or D _[50] or [D50], D50, D(0.50) or D[0.5], etc. As used herein, [D ₅₀ ] or D _[50] or [D50], D50, D(0.50) or D[0.5] etc. should be considered to mean the median particle size.

The term “Dx of particle size distribution” refers to the xth percentile of the distribution by volume; Accordingly, D90 refers to the 90th percentile, D95 refers to the 95th percentile, etc. Considering D90 as an example, it can be written as [ _D90 ] or D _[90] or [D90], D(0.90) or D[0.9], etc. With respect to particle size median and Dx, the uppercase D or lowercase d are interchangeable and have the same meaning. Another commonly used method of describing particle size distributions measured by laser diffraction or equivalent methods known in the art is to describe what percentage of the distribution is below or above a specified size. The term "% less than", also written as "%<", for example, % <1,000 nm, is defined as the proportion of the particle size distribution below a specified size, by volume. The term “% greater than”, also written as “%>”, for example, % > 1,000 nm, is defined as the proportion of the particle size distribution above a specified size, by volume. The term D(3,2) is referred to as the area-weighted average size or Sauter diameter; The term D(4,3) refers to the volume-weighted average size. Detailed descriptions of how these values are calculated are known in the art and can be found, for example, in ISO 9276-2:2014(E).

For many materials subject to the methods of this disclosure, particle size can be readily measured. If the active material is poorly water-soluble and the milled matrix has good water solubility, the powder can simply be dispersed in an aqueous solvent. In this scenario, the matrix dissolves and the active material remains dispersed in the solvent. The suspension can then be measured by techniques such as PCS or laser diffraction.

When the active material has substantial water solubility or the matrix has low solubility in aqueous dispersants, suitable methods for determining the correct particle size are outlined below.

1. In situations where an insoluble matrix, such as microcrystalline cellulose, interferes with the determination of the active material, separation techniques such as filtration or centrifugation can be used to separate the insoluble matrix from the active material particles. Other auxiliary techniques will also be required to determine whether any active material has been removed by the separation technique so that this can be taken into account.

2. If the active material is highly water soluble, other solvents can be evaluated for determination of particle size. If the solvent can be determined such that the active material is poorly soluble in the solvent, but highly soluble in the matrix, the determination will be relatively simple. If such a solvent is difficult to find, another approach would be to measure the ensemble of matrix and active material in a solvent (e.g. isooctane) in which both matrix and active material are insoluble. The powder will then be measured in another solvent in which the active substance is soluble, but the matrix is insoluble. Accordingly, an understanding of the active material particle size can be achieved together with the measurement of the matrix particle size and the size of the matrix and the active material.

3. In some cases, image analysis may be used to obtain information about the particle size distribution of the active material. Suitable imaging techniques may include transmission electron microscopy (TEM), scanning electron microscopy (SEM), optical microscopy, and confocal microscopy. In addition to the above standard techniques, some additional techniques may be required to be used in parallel to distinguish between active material and matrix particles. Depending on the chemical composition of the substances involved, possible techniques may be elemental analysis, Raman spectroscopy, FTIR spectroscopy or fluorescence spectroscopy.

Improved dissolution profile

This process improves the dissolution profile of abiraterone acetate. In some cases, the improved dissolution profile has significant advantages, including improved bioavailability of abiraterone acetate in vivo. Standard methods for determining the in vitro dissolution profile of a material are available in the art. A suitable method for determining an improved dissolution profile in vitro may include measuring the concentration of a sample material in solution over a period of time and comparing the results from the sample material to a control sample. The observation that the maximum solution concentration for the sample material was achieved in less time than the control sample would suggest that the dissolution profile of the sample material was improved. The test sample may be a unit dosage form containing abiraterone acetate and a grinding matrix and/or other additives upon which the process of the disclosure described herein is performed, as well as excipients to prepare the final dosage form. As used herein, a control sample may be a substance comprised of components in the measurement sample, including active substances, matrix, and/or additives in the same relative proportions as the measurement sample. The control sample can also be a commercially available dosage form, Zytiga tablets, cut to represent an equivalent amount of abiraterone acetate as the test sample. Standard methods for determining the improved dissolution profile of a material in vivo are available in the art.

crystallization profile

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

amorphous profile

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

crushing matrix

As described later, selection of an appropriate grinding matrix provides particularly advantageous applications of the methods of the present disclosure. Additionally, as will be described later, a very advantageous aspect of the present disclosure is that certain grinding matrices suitable for use in the methods of the present disclosure are also suitable for use in medicine. The present disclosure provides methods for making medicaments incorporating both abiraterone acetate and a grinding matrix, or, in some cases, a portion of abiraterone acetate and a grinding matrix, medicaments so prepared, and treatments using said medicaments. Includes methods. The medicament may comprise only milled abiraterone acetate together with the milled grinding matrix, or, more preferably, the milled abiraterone acetate and the milled grinding matrix may comprise one or more pharmaceutically acceptable carriers as well as any It may be combined with the desired excipients or other similar agents commonly used in the manufacture of pharmaceuticals.

In some cases, at least one component of the grinding matrix may be of greater rigidity than the abiraterone acetate, thereby reducing the particle size of the abiraterone acetate under the dry milling conditions of the present disclosure. Additionally, and without wishing to be bound by theory, millable grinding matrices under such circumstances provide the benefits of the present disclosure via a second route, wherein smaller particles of grinding matrix are prepared under dry milling conditions. is believed to be able to interact more significantly with abiraterone acetate. The amount of grinding matrix relative to the amount of abiraterone acetate, and the degree of physical decomposition of the grinding matrix, are sufficient to inhibit re-agglomeration of particles of the active material. In some embodiments, the amount of grinding matrix relative to the amount of abiraterone acetate, and the degree of size reduction of the grinding matrix, are sufficient to inhibit re-agglomeration of particles of the active material. As described above, the grinding matrix may include one or more antioxidants and/or one or more metal ion sequestering agents.

In some embodiments, the grinding matrix has a low tendency to agglomerate during dry milling. Although it is difficult to objectively quantify the tendency to agglomerate during milling, a subjective measure can be obtained by observing the level of "caking" of the grinding matrix in the milling chamber of the mill as dry milling proceeds.

The grinding matrix may be an inorganic or organic material.

milling body

In the methods of the present disclosure, if a milling body is used, the milling body is preferably chemically inert and rigid. As used herein, the term “chemically inert” means that the milling body does not chemically react with abiraterone acetate or the grinding matrix.

As described above, milling bodies are inherently resistant to fracture and corrosion during the milling process.

The milling body is preferably provided in the form of a body that can have any of a variety of smooth, regularly shaped, flat or curved surfaces and has no sharp or raised edges. For example, suitable milling bodies may be in the form of oval, oval, spherical or vertically cylindrical bodies. In some embodiments, the milling body is provided in the form of a bead, ball, sphere, rod, vertical cylinder, drum, or radius-tipped vertical cylinder (i.e., a vertical cylinder having a hemispherical base with the same radius as the cylinder).

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

The milling body may comprise various materials in particulate form, such as ceramics, glass, metals or polymer compositions. Suitable metal milling bodies are typically spherical and generally have good hardness (i.e. RHC 60-70), roundness, high wear resistance, and narrow size distribution, e.g. Type 52100 Chrome Steel, Type 304 , 316 or 440C stainless steel, or type 1065 high carbon steel.

The ceramic may, for example, be selected from a wide array of ceramics that preferably have sufficient hardness and resistance to fracture to prevent chipping or crushing during milling, and also have a sufficiently high density. Suitable densities for milling bodies may range from about 1 to 15 g/cm3, preferably from about 1 to 8 g/cm3. The ceramic may be selected from steatite, aluminum oxide, zirconium oxide, zirconia-silica, yttria-stabilized zirconium oxide, magnesia-stabilized zirconium oxide, silicon nitride, silicon carbide, cobalt-stabilized tungsten carbide, etc., as well as mixtures thereof. You can.

Glass milling bodies are spherical (e.g., beads), have a narrow size distribution, are durable, and include, for example, lead-free soda lime glass and borosilicate glass. The polymer milling body is preferably substantially spherical, has sufficient hardness and friability to prevent breaking or spalling during milling, is wear-resistant to minimize abrasion that causes contamination of the product, and is free from, for example, metals, solvents, and residual monomers. It can be selected from a wide variety of polymer resins that do not have impurities such as.

The milled body can be formed from polymer resin. Polymeric resins include, for example, crosslinked polystyrenes, such as polystyrene crosslinked with divinylbenzene, styrene copolymers, polyacrylates, such as polymethylmethacrylate, polycarbonates, polyacetals, vinyl chloride polymers and copolymers. It may be selected from polymer, polyurethane, polyamide, high density polyethylene, polypropylene, etc. The use of polymer milling bodies to grind materials to very small particle sizes (as opposed to mechanochemical synthesis) is disclosed, for example, in US Patents 5,478,705 and 5,500,331. Polymeric resins may typically have a density ranging from about 0.8 to 3.0 g/cm3. Higher density polymer resins are generally preferred. Alternatively, the milling body may be a composite body comprising a dense core body onto which a polymeric resin is adhered. The core particles may be selected from materials known to be useful as milling bodies, such as glass, alumina, zirconia silica, zirconium oxide, stainless steel, etc. The core material has a density greater than about 2.5 g/cm3.

In one embodiment of the present disclosure, the milling body is formed from a ferromagnetic material, thereby facilitating the removal of contaminants resulting from wear of the milling body using magnetic separation techniques.

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

dry milling

In the dry milling process of the present disclosure, abiraterone acetate in the form of crystals, powder, etc. and a grinding matrix are mechanically agitated for a predetermined period of time with a predetermined agitation intensity in a milling chamber with or without a plurality of milling bodies. Combine in appropriate proportions. Typically, a milling device applies various translational, rotational or reversal motions, or a combination thereof, to the milling chamber and its contents by external application of agitation, a dry gas stream or other force, or through a rotating axis of a blade, propeller, impeller or It is used to impart mobility to the contents of the mill, including any milling body, by internal application of agitation terminating in paddles, or by a combination of both.

During milling, the motility imparted to the milling bodies or the gases flowing through the milling system can cause multiple impacts or collisions of considerable intensity between the mill components, any milling bodies used and the particles of the abiraterone acetate and grinding matrix. Shear force can be applied. The nature and intensity of the force applied to abiraterone acetate and the grinding matrix will depend on the type of milling device; intensity of forces generated, dynamic aspects of the process; The size, density, shape and composition of any milling bodies used; weight ratio of abiraterone acetate and grinding matrix mixture to any milling bodies used; milling duration; Physical properties of both abiraterone acetate and grinding matrix; Atmosphere present during milling; and other factors.

Advantageously, the mill can repeatedly or continuously apply mechanical compressive forces and shear stresses to the abiraterone acetate and grinding matrix. Throughout the remainder of this specification, reference will be made to dry milling performed by a ball mill. Examples of mills of this type are attritor mills, nutating mills, tower mills, planetary mills, vibratory mills, gravity-dependent ball mills, jet mills, rod mills, roller or crusher mills, jet mills and differential mills. . It will be appreciated that dry milling according to the present disclosure may also be accomplished by any suitable milling method and 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 sieve analysis. If the particle size of the abiraterone acetate is greater than about 1,000 μm, then another particle size reduction method may be used to reduce the particle size of the abiraterone acetate substrate to less than 1,000 μm prior to dry milling according to the method described herein. It is desirable to reduce it to .

Agglomerates of abiraterone acetate after processing

It is to be understood that aggregates comprising particles of abiraterone acetate whose particle size is within the ranges specified herein are included within the scope of this disclosure, regardless of whether the aggregates exceed the ranges specified above.

processing time

In some embodiments, abiraterone acetate and grinding matrix are dry milled for the shortest period of time necessary to minimize any possible contamination from any milling bodies and/or milling processes used. This period varies greatly depending on the abiraterone acetate and grinding matrix and can range from as little as 1 minute to several hours.

Suitable agitation speeds and total milling times will depend on the type and size of the milling device, the type and size of any milling media used, the weight ratio of the abiraterone acetate and grinding matrix mixture to the plurality of milling bodies that may be used, the abiraterone acetate and It is adjusted to the chemical and physical properties of the grinding matrix and other parameters that can be optimized experimentally.

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

In an alternative aspect, the grinding matrix is separated from abiraterone acetate. In one aspect, if the grinding matrix is not completely milled, the unmilled grinding matrix is separated from the abiraterone acetate. In a further aspect, at least a portion of the milled grinding matrix is separated from the abiraterone acetate.

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

In some embodiments of the present disclosure, a significant portion of the milled grinding matrix may include particles of similar size and/or smaller than the particles comprising abiraterone acetate. Separation techniques based on size distribution, when the portion of the milled grinding matrix to be separated from the particles comprising abiraterone acetate contains particles of similar and/or smaller size than the particles comprising abiraterone acetate. is not applicable. In this context, the methods of the present disclosure allow for the separation of acetate milled from abiraterone acetate by techniques including, but not limited to, electrostatic separation, magnetic separation, centrifugation (density separation), hydrodynamic separation, and foam flotation. It may include separating at least a portion of the grinding matrix. Advantageously, the step of removing at least part of the milled grinding matrix from abiraterone acetate can be carried out by means such as selective dissolution, washing or sublimation.

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

In some cases, grinding matrices suitable for use in the methods of the present disclosure are also pharmaceutically acceptable and therefore suitable for use in medicine. Where the methods of the present disclosure do not involve complete separation of the grinding matrix from the abiraterone acetate, the present disclosure provides a method for preparing a medicament incorporating both abiraterone acetate and at least a portion of the milled grinding matrix. Methods, medicaments thus prepared, and methods of treating animals, including humans, using a therapeutically effective amount of the abiraterone acetate by the medicaments.

Abiraterone acetate and compositions

The present disclosure includes at least a portion of a grinding matrix, including a grinding matrix and a composition comprising such materials, with or without pharmaceutically acceptable materials, milling aids, and accelerators prepared according to the methods of the present disclosure. , or separated from the grinding matrix, and compositions comprising such materials.

medicine

The medicament of the present disclosure may be prepared in a milling matrix or milling matrix, optionally with or without milling aids, accelerators, in combination with one or more pharmaceutically acceptable carriers, as well as other agents commonly used in the manufacture of pharmaceutically acceptable compositions. It may include pharmaceutically acceptable substances along with at least a portion of.

As used herein, “pharmaceutically acceptable carrier” includes any and all physiologically compatible solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic agents, absorption delaying agents, and the like. In some embodiments, the carrier is suitable for parenteral administration, intravenous, intraperitoneal, intramuscular, sublingual, pulmonary, transdermal, or oral administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The use of such media and agents in the preparation of medicaments is well known in the art. Except in cases where any conventional media or agent is incompatible with pharmaceutically acceptable materials, its use in preparing pharmaceutical compositions 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), polyvinylpyrrolidone (PVP), sodium lauryl sulfate, polyvinyl alcohol, crospovidone, polyvinylpyrrolidone-polyvinyl acrylate copolymer, cellulose derivative, hydroxypropyl Methyl cellulose, hydroxypropyl cellulose, carboxymethylethyl cellulose, hydroxypropylmethyl cellulose phthalate, polyacrylates and polymethacrylates, ureas, sugars, polyols, and polymers thereof, emulsifiers, sugar gums, starch, organic acids and salts thereof. , surfactants and polymers including, but not limited to, vinyl pyrrolidone and vinyl acetate.

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

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

(4) lubricants such as agents that affect the fluidity of the powder to be compacted, including colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, and silica gel; and/or

(5) sweetening agents, such as any natural or artificial sweetener, including sucrose, 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, other esters of parahydroxybenzoic acid, such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quaternaries. compounds such as preservatives such as benzalkonium chloride; and/or

(8) Buffering agent; and/or

(9) diluents such as pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and/or mixtures of any of the foregoing; and/or

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

(11) disintegrant; For example, croscarmellose sodium, crospovidone, sodium starch glycolate, and/or

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

(13) Other pharmaceutically acceptable excipients.

The actual dosage levels of abiraterone acetate of the present disclosure will depend on the properties of abiraterone acetate as well as the potential increased efficacy attributable to providing and administering abiraterone acetate (e.g., increased solubility, faster dissolution, abiraterone It may vary depending on the increase in surface area of acetate, etc.). Accordingly, as used herein, “therapeutically effective amount” will mean the amount of abiraterone acetate necessary to produce a therapeutic response in the animal. Amounts effective for this use include a variety of factors including the desired therapeutic effect; route of administration; Efficacy of abiraterone acetate; desired duration of treatment; Stage and severity of the disease being treated; the patient's weight and general health; and will vary depending on the judgment of the attending physician.

Pharmacokinetic properties of abiraterone acetate composition

Fast onset of absorption

In some embodiments, the abiraterone acetate compositions of the present disclosure are rapidly absorbed. In one example, the abiraterone acetate composition of the present disclosure, when administered to a fasting adult male, produces a t _max of less than about 2.5 hours (about 3 hours to about 2 hours), less than about 2.0 hours, less than about 1.75 hours. , less than about 1.5 hours, less than about 1.25 hours, and greater than about 1.0 hours, such as 1.5 to 2.0 hours.

Increased bioavailability

The abiraterone acetate compositions of the present disclosure exhibit increased bioavailability (AUC) compared to prior conventional compositions (e.g., Zytiga) administered at the same dose and require smaller doses. In some cases, similar AUC and/or C _max to Zytiga can be achieved at lower doses than for Zytiga. Accordingly, in some cases, pharmaceutical compositions described herein, administered at lower doses than Zytiga, provide similar systemic exposure. For example, a 500 mg dose may be bioequivalent to a 1,000 mg dose of Zytiga. Any drug composition can have harmful side effects. Therefore, lower doses of the drug that can achieve the same or better therapeutic effects than those observed with larger doses of conventional compositions are desirable. Because the greater bioavailability observed with the present compositions compared to conventional drug formulations means that smaller amounts of drug are needed to achieve the desired therapeutic effect, the lower dosages allow the compositions of the present disclosure to be used. It can be realized by using it.

The pharmacokinetic profile of the compositions of the present disclosure may be affected to a lesser extent by the fed or fasting state of the subject taking the composition.

The present disclosure includes an abiraterone acetate composition, wherein, compared to Zytiga, the pharmacokinetic profile of the composition is less affected by the fed or fasting state of the subject taking the composition. This means that when the composition is administered with food, the difference in the quantitative amount or absorption rate of the composition is small compared to the fasting state. Accordingly, in some cases, when compared to Zytiga, the compositions of the present disclosure reduce the effect of food on the pharmacokinetic properties of the composition.

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

In some cases, the geometric mean coefficient of variation in one or more of C _max , AUC0-t and AUC0-∞ may be smaller for the abiraterone acetate dosage forms described herein than for Zytiga. Therefore, the geometric mean coefficient of variation in one or more of C _max , AUC0-t and AUC0-∞ may be 10%-50% smaller than that for Zytiga (at least 10% smaller, or 10%-30% smaller, or may be 10%-20% smaller). (Calculated as CV (Zytiga)-CV (this dosage form)/CV (Zytiga) x 100%).

Pharmacokinetic Protocol

After administration of the composition, the plasma concentration profile in humans can be measured using any standard pharmacokinetic protocol, thereby establishing whether the composition meets the pharmacokinetic criteria described herein. For example, a randomized, single-dose crossover study can be conducted using a group of healthy adult human subjects. The number of subjects should be sufficient to provide adequate control of variation in the statistical analysis, and is typically about 10 or more, although smaller groups may be sufficient for certain purposes. Each subject receives a single dose (e.g., 100 mg) of the test composition formulation by oral administration at time zero, usually approximately 8 am, after an overnight fast. The subject continues to remain fasted and remains in an upright position for approximately 4 hours after administration of the composition. Blood samples are collected from each subject before administration (e.g., 15 minutes before) and at various intervals after administration. For this purpose, several samples are collected within an initial time point and less frequently thereafter. Exemplarily, blood samples may be collected at 15, 30, 45, 60, and 90 minutes after administration, and then every hour from 2 to 10 hours after administration. Additional blood samples may also be taken thereafter, for example, at 12, 24, 36 and 48 hours post administration. If the same subjects are used for the study of a second test agent, a period of at least 7 days must elapse before administration of the second agent. Plasma is separated from the blood sample by centrifugation, and the separated plasma is analyzed for composition by effective high-performance liquid chromatography (HPLC) or liquid chromatography mass spectrometry (LCMS) methods. Plasma concentration of a composition as referenced herein is intended to mean the total concentration including both the free composition and the bound composition.

Mode of administration of medicaments containing abiraterone acetate

The medicament of the present disclosure can be administered to animals, including humans, in any pharmaceutically acceptable manner, such as orally, rectally, pulmonaryly, vaginally, topically (powder, ointment or drops), transdermally, parenterally. It can be administered by intravenous, intraperitoneal, intramuscular, sublingual or buccal or nasal spray.

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

However, when abiraterone acetate is used as a liquid suspension, once the solid carrier has been substantially removed so as to reliably eliminate, or at least minimize, particle agglomeration, the particles comprising abiraterone acetate may be further removed. Stabilization may be necessary.

Example 1. Preparation of particulate abiraterone acetate powder blend

The drug product intermediate for use in tablet manufacturing was prepared by dry milling abiraterone acetate in the presence of lactose monohydrate and sodium lauryl sulfate in the ratios shown in Table 1 below. Both lots of material were milled on a Union Process 1S attritor mill equipped with a 0.5 gallon jacketed cooled tank. A 200 g batch was milled with a milling body for 40 minutes.

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

Abiraterone from two drug product intermediate lots described in Example 1 by light scattering using a Malvern Mastersizer 3000 model MAZ3000 particle size analyzer configured with a Hydro MV wet sample dispersion device. The particle size distribution of acetate was measured. Additionally, 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 an aqueous solution of 0.1% povidone K30. Approximately 20 mg of sample powder and 5 mL of dispersant were added to a plastic centrifuge tube. The tube was vortexed to disperse the powder and then sonicated at 20% amplitude for 1 minute with a sonication cycle of 5 seconds on and 15 seconds off (Branson Digital Sonifier equipped with sonic probe model 102C). ) 250). The particle size analyzer sample dispersant was charged with dispersant and the sample was pipetted into the reservoir until a target obscuration of 5-15% was reached and held constant. The stirrer was run at 1,500 rpm and data was collected for 10 seconds. Measurements were made three times, and the average value of each particle size parameter was recorded. Table 2 and Figure 1 below present the particle size distribution; The data indicates that the particle size was reduced by more than 10-fold.

Example 3: Comparative study on tablet preparation and dissolution

The milled drug product intermediate was combined with intragranular excipients and dry granulated using roller compaction and milling. The granules were blended with extragranular excipients and compressed in a rotary tablet press to prepare 100 mg abiraterone acetate tablets with the composition shown in Table 3 below.

Method listed on the FDA website for abiraterone acetate tablets, 250 mg: as described above using USP Apparatus II, 50 rpm in 900 ml of buffer containing 0.25% sodium lauryl sulfate, pH 4.5. The dissolution rate of the tablets prepared together was measured. Samples were analyzed by UV at 270 nm. Additionally, for comparative purposes, Zytiga tablets were tested using identical dissolution conditions. The results of this analysis are presented in Table 4 and Figure 2 below. Compared to 60 minutes for Zytiga to completely dissolve (>85% dissolved), the two tablet formulations containing milled abiraterone acetate took 10-20 minutes to completely dissolve (>85% dissolved). It took minutes.

Example 4: Abiraterone Acetate Tablets for Initial Phase I Study

The drug product intermediate for use in the manufacture of tablets for Phase I trials was prepared by dry milling abiraterone acetate in the presence of lactose monohydrate and sodium lauryl sulfate in the amounts shown in Table 5 below. The material was milled on a Union Process 1S Attritor mill equipped with a 1.5 gallon jacketed cooled tank. The material was milled with the milling body for 40 minutes.

The particle size distribution of abiraterone acetate in the milled drug product intermediate was determined using a Micromeritics Saturn Digisizer II 5205 particle size analyzer configured with an AquaPrep II sample cell. The device sample reservoir was filled with dispersant solution (0.1% povidone K30). Samples were prepared by adding 100 mg of milled powder and 20 mL of dispersant to a 30 mL glass bottle. After dispersing the particles by stirring with a pipette, the capped bottle was placed in an ultrasonic bath (Branson ultrasonic bath, model 5510-MT, power 135 W, 42 KHz) so that the bath water level rose halfway up the side of the bottle. The sample was then sonicated for 30 minutes. The dispersed sample was added dropwise to the reservoir of the liquid sample processing device until the obscuration value reached approximately 7%. The built-in sonic probe was operated at 100% intensity for 300 seconds and the sample was cycled for 120 seconds prior to data collection. Data were collected in an environment with a beam angle of 65° when the shielding value was 5 to 10%. Each measurement was repeated in triplicate, and the average of the three measurements was recorded. Particle size data obtained from the milled powders are reported in Table 6 below.

The milled drug product intermediate was combined with intragranular excipients and dry granulated using roller compaction and milling. The granules were blended with extragranular excipients and compressed in a rotary tablet press to prepare 100 mg abiraterone acetate tablets with the composition shown in Table 7 below.

The dissolution rate of tablets prepared as described above was measured using a USP Apparatus II, 75 rpm in 900 ml of buffer containing 0.1% SLS, pH 4.5. Samples were analyzed by HPLC. Additionally, for comparative purposes, Zytiga tablets were tested using identical dissolution conditions. Since the Zytiga tablets weigh 250 mg, which is close to the dissolution limit of the dissolution medium, the tablets were cut into weights equivalent to 100 mg of abiraterone acetate. Zytiga samples were measured at 270 nm using UV. The results of this analysis are presented in Table 8 below; While the prepared tablets took 5 minutes to completely dissolve (>85% dissolved), the Zytiga tablets took 20 minutes to dissolve.

Example 5: Phase I study of abiraterone acetate formulations at doses of 100, 200, and 400 mg compared to 1,000 mg of Zytiga

Abiraterone acetate 100 mg tablet formulation prepared as described in Example 4 was administered in doses of 100 mg, 200 mg, and 400 mg (1, 2, or 4 x 100 mg tablets, respectively) in healthy male patients under fasting conditions. tested. In the same study, a 1,000 mg dose of Zytiga (4 x 250 mg tablets) was tested. The results of this study are presented in Table 9 below.

Example 6: Stability of Abiraterone Acetate Powder Blends and Tablets

After dry milling abiraterone acetate with lactose monohydrate and sodium lauryl sulfate, an increase in total impurities of 0.2-0.6% AUC was detected by HPLC. When the milled abiraterone acetate powder blend (or drug product intermediate; “DPI”) was further processed into tablets, impurity levels were observed to be greater than about 0.5-1.1%. The stability test results showed that impurities increased at 25℃/60%RH and 40℃/75%RH, but did not increase at 2-8℃. Additionally, impurities increased more rapidly in tablets than in milled DPI. Table 10 below and Figures 3A and 3B (diamonds, 5°C; squares, 25°C/60% RH; and triangles, 40°C/75% RH) show the stability of milled DPI and tablet lots in accelerated stability experiments. Provides an overview of impurity levels. Although refrigerated tablets have acceptable low levels of impurities, it may be desirable to have a formulation that can be stored under ambient conditions.

The increase in impurities in DPIs and tablets containing particulate abiraterone acetate is due to oxidative degradation of abiraterone acetate. Old Zytiga (abiraterone acetate) tablets were tested for purity and the level of impurities was observed to be much lower than older tablets containing particulate abiraterone acetate. The faster rate of disintegration in tablets containing particulate abiraterone acetate can be attributed to a number of reasons, including, but not limited to, the larger surface area of the API, the higher ratio of excipients to API, and excipient differences. It may be happening. Further studies revealed that the API decomposed some in the presence of excipients, but once the mixture was milled, the decomposition was greatly accelerated. The data is presented in Table 11 below.

Example 7: Milling of abiraterone with antioxidants or sequestering agents

Dry milling of abiraterone acetate was performed in the presence of lactose monohydrate and sodium lauryl sulfate and various antioxidants and/or metal ion sequestrants. In one study, dry milling included a combination of ascorbic acid and fumaric acid, or butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT); The formulations are presented in Table 12 below. Each lot was milled on a Union Process 1S attritor mill equipped with a 0.5 gallon jacketed cooled tank. A 200 g batch was milled with a milling body for 40 minutes. When tested according to the light scattering method described in Example 2, both DPI formulations contained abiraterone acetate with a D ₉₀ of less than 1,000 nm.

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

The stability of two tablet formulations was tested under accelerated conditions. Table 14 below shows that when compared to the formulation that did not contain antioxidants, both tablet formulations containing antioxidants had significantly improved stability after 3 months of storage at 40°C/75%RH, and the BHA/BHT formulation had significantly improved stability. Includes data demonstrating that all degradation is virtually halted. This demonstrates that adding antioxidants and/or metal ion sequestrants during milling can significantly improve stability.

The dissolution rate of abiraterone acetate in tablet formulation ascorbic acid/fumaric acid and tablet formulation BHA/BHT was tested using USP Apparatus II at 75 rpm in 900 ml of phosphate buffer, pH 4.5 containing 0.1% SLS. For all three types of tablets, the tablets were completely dissolved (>85% of abiraterone acetate dissolved) within 10 minutes.

Example 8: Abiraterone Acetate Tablets for Additional Phase I Study

Additional drug product intermediate formulations were prepared by dry milling abiraterone acetate, lactose monohydrate, sodium lauryl sulfate, BHA and BHT. The composition of the material that was milled to form the intermediate is shown in Table 15 below. The formulation was milled in a commercial jacket-cooled 62 gallon attritor mill; The powder blend was milled with a milling body for 72 minutes.

The particle size distribution of abiraterone acetate in the drug product intermediate was determined by light scattering using a Malvern Mastersizer 3000 Model MAZ3000 particle size analyzer configured with a Hydro MV wet sample dispersion device. As described below, particle size distribution was measured using two different methods:

Method 1: The dispersant used was an aqueous solution of 0.1% povidone K30. Approximately 20 mg of sample powder and 5 mL of dispersant were added to a plastic centrifuge tube. The tube was vortexed to disperse the powder and then sonicated at 20% amplitude for 1 minute with a sonication cycle of 5 seconds on and 15 seconds off (Branson Digital Sonifier 250 equipped with sonic probe Model 102C). The particle size analyzer sample dispersant was charged with dispersant and the sample was pipetted into the reservoir until target coverage reached 5-15% and remained constant. The stirrer was run at 1,500 rpm and data was collected for 10 seconds. Measurements were made three times, and the average value of each particle size parameter was recorded.

Method 2: The dispersant used was an aqueous solution containing 0.1% Poloxamer 338 and 0.1% calcium chloride, filtered through a 0.2 μm nylon filter prior to use. Approximately 20 mg of sample powder and 5 mL of dispersant solution were added to a glass vial. The vial was capped and vortexed to disperse the powder particles. The vial cap was then opened and the vial was placed in the center of the sonic bath (Elma Elmsonic P30H ultrasonic bath). The vial was submerged so that the bath liquid level was higher than the level of the dispersant in the vial, but the vial did not touch the bottom of the bath. Samples were sonicated at 37 kHz at 100% power for 10 minutes. The particle size analyzer sample dispersant was charged with dispersant and the sample was pipetted into the reservoir until a 5-15% shielding was achieved and this remained constant. The stirrer was run at 1,500 rpm and data was collected for 10 seconds. Measurements were made three times, and the average value of each particle size parameter was recorded.

Table 16 below shows a comparison of particle size values before and after milling for abiraterone acetate in the drug product intermediate (DPI) described in Table 15, performed using Methods 1 and 2 described above.

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

The dissolution rate of the tablets was measured in USP Apparatus II, 75 rpm in buffer containing 0.12% SLS, pH 4.5. Samples were analyzed by HPLC. The results of this analysis are presented in Table 18 below; Complete dissolution (>85% dissolution) took 10 minutes.

Example 9: Phase I study of abiraterone acetate formulations at doses of 125, 500, and 625 mg compared to 1,000 mg of Zytiga

Abiraterone acetate 125 mg tablet formulation prepared as described in Example 8 was administered in doses of 125 mg, 500 mg, and 625 mg (1, 4, or 5 x 125 mg tablets, respectively) in healthy male patients under fasting conditions. tested. In the same study, a 1,000 mg dose of Zytiga (4 x 250 mg tablets) was tested. The results of this study are presented in Table 19 below.

Example 12: Additional Abiraterone Acetate Powder and Tablets

Additional drug product intermediate formulations were prepared by dry milling abiraterone acetate, lactose monohydrate, sodium lauryl sulfate, BHA and BHT. The composition of the material that was milled to form the intermediate is shown in Table 16 below. Two batches were milled using various processing conditions to obtain slightly different particle sizes.

[Table 16]

The particle size distribution of abiraterone acetate of both drug product intermediate lots was determined by light scattering using a Malvern Mastersizer 3000 Model MAZ3000 particle size analyzer configured with a Hydro MV wet sample dispersion device. Method 1 described in Example 8 was used to obtain particle size distributions as shown in Table 17 below.

[Table 17]

The milled drug product intermediate from batch 1 was combined with intragranular excipients and dry granulated using roller compaction and milling. The granules were blended with extragranular excipients and compressed in a rotary tablet press to prepare 100 mg abiraterone acetate tablets with the composition shown in Table 18 below.

[Table 18]

The dissolution rate of the tablets was measured in USP Apparatus II, 75 rpm in buffer containing 0.1% SLS, pH 4.5. Samples were analyzed by UV at 270 nm. The results of this analysis are presented in Table 19 below; Complete dissolution (>85% dissolution) took 10 minutes.

[Table 19]

Example 13: Stability of tablets

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

The particle size distribution of abiraterone acetate in the drug product intermediate was determined by light scattering using a Malvern Mastersizer 3000 Model MAZ3000 particle size analyzer configured with a Hydro MV wet sample dispersion device. Method 1 described in Example 8 was used to obtain particle size distributions as shown in Table 21 below.

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

Tablets were packaged and subjected to accelerated stability at 40° C. and 75% relative humidity. Impurities were measured by HPLC method, which shows stability. The dissolution rate of the tablets was measured in USP Apparatus II, 75 rpm in buffer containing 0.12% SLS, pH 4.5. The results are presented in Table 23 below; No increase in impurities was observed even after 3 months at 40℃/75%RH, and dissolution remained unchanged. After 3 months at 40℃/75%RH, it was completely dissolved (>85% dissolved) within 10 minutes. .

Example 14: Effect of fed or fasted state

In a single-center, single-dose, randomized, open-label, 2-period, 2-treatment crossover pharmacokinetic study, a high-fat diet was administered orally to a 500 mg dose of 125 mg milled abiraterone mg tablets. The effect on bioavailability was evaluated. During the first dosing period, approximately half of the subjects received test article with 240 mL of water after a 10-hour fast. The remaining subjects received the test article approximately 30 minutes after consuming a standard FDA high-fat breakfast. After a washout period of 7 days, each subject was switched to a different treatment group. Plasma samples were collected immediately prior to dosing and at 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 18.0, 24.0, and 48.0 hours after test article administration. Samples were analyzed for abiraterone concentration and the results were used to calculate pharmacokinetic parameters (AUC _0-∞ , AUC _0-t , and C _max ) for each subject and treatment group. The geometric mean values for AUC _0-∞ , AUC _0-t , and C _max when the test article was administered with food were 1,444.1 ng·h/mL, 1,393.4 ng·h/mL, and 443.7 ng/mL, respectively. On the other hand, the geometric mean values for the same parameters when the drug was administered in a fasting state were 322.7 ng·h/mL, 301.0 ng·h/mL, and 67.9 ng/mL. The ratios for AUC _0-∞ , AUC _0-t , and C _max (fed state/fasted state) were 4.48, 4.63, and 6.53, respectively.

Claims (19)

Contains 125 mg of abiraterone acetate,
[D ₅₀ ], determined based on the particle volume of abiraterone acetate, is greater than 100 nm and less than 1200 nm;
The unit dosage form is
(i) one or more millable grinding compounds selected from lactose monohydrate, lactose anhydrate and mannitol,
(ii) microcrystalline cellulose,
(iii) sodium lauryl sulfate,
(iv) croscarmellose sodium,
(v) sodium stearyl fumarate,
(vi) ascorbic acid, and
(vii) further comprising fumaric acid;
A 500 mg dose _solid oral unit dosage form was compared with a _1,000 mg dose Zytiga® tablet (250 mg; It is bioequivalent to National Drug Code No. 57894-150; USFDA NDA 202379);
The dissolution rate of abiraterone acetate in unit dosage form is greater than 70% when tested at 75 rpm using a USP Apparatus II in 900 ml of phosphate buffer, pH 4.5, containing 0.12% sodium lauryl sulfate. Terone acetate dissolves within 5 to 15 minutes;
When administered orally to a population of fasting healthy male subjects, a 500 mg dose provides a mean plasma C _max of 50-120 ng/ml and a mean plasma AUC _(0-∞) of 240-650 h*ng/ml. Phosphorus, a solid oral unit dosage form of abiraterone acetate. The method of claim 1, wherein a 1,000 mg dose of Zytiga tablets (250 mg; National Drug Code No. 57894-150; USFDA NDA 202379) administered to healthy male subjects in a fasting state versus 500 mg administered to healthy male subjects in a fasting state. A solid oral unit dosage form of abiraterone acetate, wherein the log ratio of the geometric mean of AUC _{(0-∞) to} dose is 0.6 to 1.4. The method of claim 2, wherein a 1,000 mg dose of Zytiga tablets (250 mg; National Drug Code No. 57894-150; USFDA NDA 202379) administered to healthy male subjects in a fasting state versus 500 mg administered to healthy male subjects in a fasting state. A solid oral unit dosage form of abiraterone acetate, wherein the log ratio of the geometric mean of AUC _{(0-∞) to} dose is 0.7 to 1.3. The method of claim 3, wherein a 1,000 mg dose of Zytiga tablets (250 mg; National Drug Code No. 57894-150; USFDA NDA 202379) administered to healthy male subjects in a fasting state versus 500 mg administered to healthy male subjects in a fasting state. A solid oral unit dosage form of abiraterone acetate, wherein the log ratio of the geometric mean of AUC _{(0-∞) to} dose is 0.8 to 1.2. The method of claim 4, wherein a 1,000 mg dose of Zytiga tablets (250 mg; National Drug Code No. 57894-150; USFDA NDA 202379) administered to healthy male subjects in a fasting state versus 500 mg administered to healthy male subjects in a fasting state. A solid oral unit dosage form of abiraterone acetate, wherein the log ratio of the geometric mean of AUC _{(0-∞) to} dose is 0.9 to 1.1. The method of claim 1, wherein a 1,000 mg dose of Zytiga tablets (250 mg; National Drug Code No. 57894-150; USFDA NDA 202379) administered to healthy male subjects in a fasting state versus 500 mg administered to healthy male subjects in a fasting state. A solid oral unit dosage form of abiraterone acetate, wherein the log ratio of the geometric mean of C _max to dose is 0.6 to 1.4. The method of claim 6, wherein a 1,000 mg dose of Zytiga tablets (250 mg; National Drug Code No. 57894-150; USFDA NDA 202379) administered to healthy male subjects in a fasting state versus 500 mg administered to healthy male subjects in a fasting state. A solid oral unit dosage form of abiraterone acetate, wherein the log ratio of the geometric mean of C _max to dose is 0.7 to 1.3. The method of claim 7, wherein a 1,000 mg dose of Zytiga tablets (250 mg; National Drug Code No. 57894-150; USFDA NDA 202379) administered to healthy male subjects in a fasting state versus 500 mg administered to healthy male subjects in a fasting state. A solid oral unit dosage form of abiraterone acetate, wherein the log ratio of the geometric mean of C _max to dose is 0.8 to 1.2. The method of claim 8, wherein a 1,000 mg dose of Zytiga tablets (250 mg; National Drug Code No. 57894-150; USFDA NDA 202379) administered to healthy male subjects in a fasting state versus 500 mg administered to healthy male subjects in a fasting state. A solid oral unit dosage form of abiraterone acetate, wherein the log ratio of the geometric mean of C _max to dose is 0.9 to 1.1. The method of claim 1, wherein the [D ₉₀ ] determined based on the particle volume of the abiraterone acetate is greater than 100 nm and is less than 4,500 nm and/or the [D _{50 ]} determined based on the particle volume of the abiraterone acetate. ] is greater than 100 nm and less than 1,000 nm. 2. The method of claim 1, wherein the dissolution rate of the abiraterone acetate in the unit dosage form is such that the unit dosage form comprising 125 mg of abiraterone acetate is dissolved in 900 ml of pH 4.5 containing 0.12% sodium lauryl sulfate. A solid oral unit dosage form of abiraterone acetate, wherein at least 70% of the abiraterone acetate dissolves within 5 to 10 minutes when tested at 75 rpm using a USP Apparatus II in phosphate buffer. The method of claim 1, wherein when administered orally to a population of healthy male subjects in a fasting state, a 500 mg dose produces a plasma t _max of 1 to 2.5 hours. Solid oral unit dosage form, providing median values. The solid oral unit dosage form of abiraterone acetate according to claim 1, wherein when a 500 mg dose is administered to fasting healthy male subjects, the 90% confidence interval for the mean plasma C _max is a value of 50 to 120 ng/ml. 2. The method of claim 1, wherein the 90% confidence interval for the mean plasma AUC _(0-∞) is 240 to 650 h*ng/ml when a 500 mg dose is administered to healthy male subjects in a fasting state. Solid oral unit dosage form. 2. The solid oral unit dosage form of abiraterone acetate according to claim 1, wherein the millable grinding compound is lactose monohydrate. delete delete delete delete