CN106687112A

CN106687112A - Abiraterone acetate formulation and methods of use

Info

Publication number: CN106687112A
Application number: CN201580050453.8A
Authority: CN
Inventors: M·墨菲; P·内梅斯; H·W·伯士; M·卡拉汉; S·布哈米迪帕蒂; J·科勒曼; C·希尔; M·诺雷特
Original assignee: Iceutica Inc
Current assignee: Iceutica Inc
Priority date: 2014-09-18
Filing date: 2015-09-18
Publication date: 2017-05-17
Also published as: KR102491439B1; IL250270B; EP3193857A1; BR112017003219A2; PH12017500239A1; TN2018000318A1; KR20230014878A; WO2016044701A1; AP2017009804A0; EA201790650A1; MX2017003525A; TN2017000098A1; CO2017002472A2; JP2017528457A; CA2958316A1; KR102617537B1; EP3193857A4; IL250270A0; AU2015317466A1; SG11201701139YA

Abstract

Pharmaceutical compositions, including unit dosage forms, comprising abiraterone acetate and methods for producing and using such compositions are described.

Description

Abiraterone acetate preparation and using method

Background technology

Abiraterone ((3 β) -17- (pyridin-3-yl) androstane -5,16- dien-3-ols；CAS#：154229-19-3；Molecule Formula：C₂₄H₃₁NO；Molecular weight：349.5g/mol) be CYP17 therefore inhibitor and interference testis, adrenal gland and tumor of prostate Androgenic synthesis in tissue.Abiraterone acetate (17- (3- pyridine radicals) androstane -5, acetic acid esters；CAS#154229-18-2) (prodrug of abiraterone) is approved for treating castration-resistant prostate cancer (castration-resistant in the U.S. prostate cancer).Abiraterone acetate is considered as poorly water-soluble.

Tablet (250mg；National drug numbering 57894-150；NDA 202379) go through and sprinkle in the U.S. Buddhist nun pine is combined for patient of the treatment with metastatic castration-resistant prostate cancer.The prescription information of tablet is built Orally administered 1,000mg (4 × 250mg tablets) once a day is discussed, is mutually tied with twice daily Orally administered metacortandracin (5mg) Close.Europe approvalFor with metacortandracin or prednisolone administering drug combinations.

Prescription information explanation, it must be taking on an empty stomach, and before medication at least 2 hours Dietary intake is not answered with after medication at least 1 hour.Prescription information is illustrated, with metastatic, castration-resistant prostate cancer Patient in, under the dosage of daily 1000mg, C_maxSteady-state value (mean value ± SD) be 226 ± 178ng/mL, and AUC Steady-state value is 1173 ± 690ng.hr/mL.Single dose (1000mg) crossing research in health volunteer is sent out It is existing, whenWhen applying together with food, the Systemic exposure of abiraterone is increased.Specifically, whenWhen applying together with low fat diet (7% is fatty, 300 calories), compared with applying under fasted conditions, Ah ratio Special dragon C_maxAnd AUC_0-∞High about 7 times and 5 times respectively.WhenWith high fat diet (57% is fatty, 825 calories) together During administration, compared with applying under fasted conditions, abiraterone C_maxAnd AUC_0-∞Difference is high about 17 and 10 times.

The content of the invention

The present disclosure describes the pharmaceutical composition of Abiraterone acetate is wherein included, including unit dosage forms, and for making It is standby and using the method for such composition.

Described herein is the unit dosage forms of Abiraterone acetate, wherein in the healthy male subjects in fasted conditions The unit dosage forms bioequivalence of middle 500mg dosage is in 1000mg dosageAlso describe：Abiraterone acetate Unit dosage forms, wherein for the healthy male subjects to fasted conditions apply 500mg dosage and to the health under fasted conditions Male subject applies 1000mg dosageCompare, AUC_(0-∞)The ratio of logarithm of geometric average be selected from：0.6 To 1.4,0.7 to 1.3,0.8 to 1.2 and 0.9 to 1.1；The unit dosage forms of Abiraterone acetate, wherein for fasted conditions Healthy male subjects apply 500mg dosage and apply 1000mg dosage with to the healthy male subjects under fasted conditionsCompare, C_(max)The ratio of logarithm of geometric average be selected from：0.6 to 1.4,0.7 to 1.3,0.8 to 1.2 and 0.9 To 1.1.

In some cases：[the D of Abiraterone acetate₉₀] more than 300nm and less than one below：7500nm、7000nm、 6000nm, 5000nm, 4500nm, 4000nm, 3000nm, 2000nm, 900nm, 800nm and 700nm；Abiraterone acetate [D₅₀] more than 100nm and less than one below：3500nm、3000nm、2500nm、1600nm、1400nm、1200nm、1000nm、 800nm, 500nm, 400nm and 300nm；[the D of Abiraterone acetate_4,3] more than 300nm and less than one below：7000nm、 6000nm、5000nm、4000nm、3000nm、2500nm、2400nm、2200nm、2000nm、1900nm、1700nm、1500nm、 1300nm, 1100nm, 900nm and 800nm；The dissolution rate of Abiraterone acetate is caused when using USP instruments in unit dosage forms II is tested in the phosphate buffers of pH 4.5 containing 0.1% lauryl sodium sulfate of 900ml with 75rpm and contained During the sample of 100mg Abiraterone acetates, at least 70% Abiraterone acetate between 5 and 15 minutes or 5 and 10 minutes it Between dissolution；The dissolution rate of Abiraterone acetate is caused to work as and uses USP apparatus IIs with 75rpm in 900ml in the unit dosage forms The phosphate buffers of pH 4.5 containing 0.12% lauryl sodium sulfate in test contain 125mg fine grained acetic acid Ah ratios During the sample of special dragon, at least 70% Abiraterone acetate is between 5 and 15 minutes or dissolution between 5 and 10 minutes；The unit Formulation contains the Abiraterone acetate of 125mg.

The unit dosage forms of the pharmaceutical composition containing Abiraterone acetate are also described, wherein when in fasted conditions During the Orally administered 500mg dosage of the colony of healthy male subjects, there is provided the average blood plasma C of 50-120ng/ml_max.At some In the case of：When the Orally administered 500mg dosage of the colony to the healthy male subjects in fasted conditions, there is provided 1 to 2.5 The median plasma t of hour_max.This document describes the unit dosage forms of the pharmaceutical composition containing Abiraterone acetate, wherein when to place When the colony of the healthy male subjects of fasted conditions Orally administered 500mg dosage, there is provided 240-650h*ng/ml's is flat Equal plasma A UC_(0-∞).In some cases, unit dosage forms contain 125mg Abiraterone acetates.

Also describe：The unit dosage forms of the pharmaceutical composition containing Abiraterone acetate, wherein when to the strong of fasted conditions When health male subject applies 500mg dosage, average blood plasma C_max90% confidential interval be 50-120ng/ml between value；With The unit dosage forms of the pharmaceutical composition containing Abiraterone acetate, wherein when the healthy male subjects to fasted conditions are applied During 500mg dosage, average blood plasma AUC_(0-∞)90% confidential interval be value between 240 to 650h*ng/ml.

Unit dosage forms as herein described can contain antioxidant (for example, in BHA and BHT one or two).

There is also described herein the method for treating castration-resistant prostate cancer, it includes being applied to patient in need The Abiraterone acetate unit dosage forms as herein described and glucocorticoid for the treatment of effective dose (for example, 500mg).In various realities In applying mode：The glucocorticoid is selected from metacortandracin, prednisolone and methylprednisolone；The treatment effective dose is 500mg/ days；Treatment effective dose is applied using the formulation containing following dosage：The acetic acid Ah ratio of 100mg, 125mg or 150mg Special dragon；500mg dosage is applied using 1,2,3,4,5 or 6 unit dosage forms.

This document describes a kind of method for producing the composition containing Abiraterone acetate, methods described includes： In grinder by containing Abiraterone acetate, polishing compounds can be ground, promoted in reagent and antioxidant and chelating agent One or two composition is dry grinded one section and be enough to produce the time of the composition containing the Abiraterone acetate milled, wherein leading to Overdrying wears away the particle diameter of the little Abiraterone acetate.

In the certain situation of production method：[the D of Abiraterone acetate in the composition milled₉₀] more than 400nm and Less than one below：7500nm、7000nm、6000nm、5000nm、4500nm、4000nm、3000nm、2000nm、900nm、 800nm and 700nm；[the D of Abiraterone acetate in the composition milled₅₀] more than 100nm and less than 3500nm, 3000nm, 2500nm, less than l600nm, less than 1400nm, less than 1200nm, less than 1000nm, less than 800nm, less than 500nm, be less than 400nm, less than 300nm；In the composition milled the dissolution rate of Abiraterone acetate cause when use USP apparatus IIs with 75rpm contains in the phosphate buffers of pH 4.5 of 0.1% lauryl sodium sulfate test containing 100mg acetic acid in 900ml During the sample of abiraterone, at least 70% Abiraterone acetate is between 5 and 15 minutes or dissolution between 5 and 10 minutes； The dissolution rate of Abiraterone acetate is caused to work as and contained in 900ml with 75rpm using USP apparatus IIs in the composition milled The sample containing 125mg Abiraterone acetates is tested in the phosphate buffers of pH 4.5 of 0.12% lauryl sodium sulfate When, at least 70% Abiraterone acetate is between 5 and 15 minutes or dissolution between 5 and 10 minutes；In the composition milled [the D of Abiraterone acetate₅₀] more than 200nm and less than 6500nm, 6000nm, 5500nm, less than 5000nm, less than 4000nm, Less than 3000nm or less than 2000nm；And methods described also includes：Will containing the fine grain composition of Abiraterone acetate with One or more pharmaceutically acceptable diluent, disintegrant, lubricant, glidant or dispersant package are preparing unit dose Type.

In various embodiments, in pharmaceutical composition the Abiraterone acetate of (or for preparing pharmaceutical composition) Grain has based on particle volume ([D₅₀] or D_[50]Or [D50]) determine equal to or less than selected from following size intermediate value grain Footpath：5000nm、4000nm、3000nm、2500nm、2400nm、2300nm、2200nm、2200nm、2100nm、2000nm、 1900nm、1800nm、1700nm、1600nm、1500nm、1400nm、1300nm、1200nm、1100nm、1000nm、900nm、 800nm, 700nm, 600nm, 500nm, 400nm, 300nm and 200nm.In some embodiments, [D50] is equal to or more than 25nm or 100nm or or even 500nm.In various embodiments, [D50] be between 5000nm and 100nm, 3500nm and Between 100nm, between 2500nm and 100nm, between 1500nm and 100nm, between 1200nm and 100nm, 1100nm and 100nm Between, between 1000nm and 100nm, between 800nm and 100nm, between 700nm and 100nm, between 600nm and 100nm, Between 500nm and 100nm.In various embodiments, D [4,3] (volume mean diameter) is：Less than 7000nm, it is less than 5000nm, less than 3500nm, less than 3000nm, less than 2000nm, less than 1000 or less than 300nm.In all cases, for example It is described above those, D [4,3] is more than 100nm or more than 200nm.In some cases, D [4,3] (volume mean diameter) Between：Between 7000nm and 1000nm, between 6000nm and 200nm, between 5000nm and 1000nm, 4000nm and 1000nm it Between, between 3000nm and 1000nm, between 2000nm and 1000nm, between 1800nm and 1000nm, 1600nm and 1000nm it Between, between 1500nm and 1000nm, between 1500nm and 500nm, between 4000nm and 2000nm, between 4000nm and 100nm, Between 25000nm and 500nm, between 700nm and 100nm, between 600nm and 100nm, between 500nm and 100nm, 1000nm And 200nm between, between 900nm and 200nm, between 800nm and 200nm, between 700nm and 200nm.In various embodiments In, [D90] ([D₉₀] or D_[90]) be：Less than 8000nm, less than 7500nm, less than 7000nm, less than 6000nm, be less than 4000nm, less than 2000nm, less than 1000nm, less than 500nm.In some cases, D90 between 5500nm and 300nm, Between 5000nm and 500nm, between 4500nm and 500nm, between 4000nm and 200nm, between 4500nm and 750nm and Between 3500nm and 500nm.In various embodiments described herein, [D90] of Abiraterone acetate less than 5000nm or Less than 4000nm.In some embodiments, [D₉₀] be：6000nm-500nm, 5500nm-500nm or 5000nm-500nm and 4000-400nm。

In another embodiment, the degree of crystallinity characteristic of Abiraterone acetate is selected from：At least 20% acetic acid Ah's bit Dragon is crystal, and at least 30% Abiraterone acetate is crystal, and at least 40% Abiraterone acetate is crystal, at least 50% Abiraterone acetate is crystal, and at least 60% Abiraterone acetate is crystal, and at least 70% Abiraterone acetate is crystal, At least 75% Abiraterone acetate is crystal, and at least 85% Abiraterone acetate is crystal, at least 90% acetic acid Ah ratio Special dragon is crystal, and at least 95% Abiraterone acetate is crystal, and at least 98% Abiraterone acetate is crystal.At some In embodiment, the degree of crystallinity characteristic of Abiraterone acetate is substantially equal to the vinegar before material experiences method as described herein The degree of crystallinity characteristic of sour abiraterone.

In another embodiment, the content of amorphous of Abiraterone acetate is selected from：Acetic acid Ah's bit less than 80% Dragon is amorphous, and the Abiraterone acetate less than 70% is amorphous, and the Abiraterone acetate less than 60% is amorphous, is less than 50% Abiraterone acetate is amorphous, and the Abiraterone acetate less than 40% is amorphous, the acetic acid Ah ratio less than 30% Special dragon is amorphous, and the Abiraterone acetate less than 25% is amorphous, and the Abiraterone acetate less than 15% is amorphous, few It is amorphous in 10% Abiraterone acetate, the Abiraterone acetate less than 5% is amorphous, and the acetic acid Ah less than 2% Bit dragon is amorphous.In some embodiments, after making the material experience dry grinding method as herein described, acetic acid Ah The content of amorphous of bit dragon is not dramatically increased.

In some embodiments, by the presence of abrasive body by Abiraterone acetate with can grind polishing compounds Dry grind to prepare the particle of Abiraterone acetate together with promotion reagent.There may be other component during grinding, and The various components (in addition to Abiraterone acetate and abrasive body) existed during grinding are collectively known as grinding matrix.One In the case of a little, grinding produces the Abiraterone acetate particle that the size being dispersed in grinding matrix is substantially reduced.Because grinding base All components in matter are pharmaceutically acceptable, it is possible to use the Abiraterone acetate produced by grinding and grinding matrix Mixture is preparing pharmaceutical composition.In some cases, some or all of components of grinding matrix size during grinding subtracts It is little.In some cases, can after milling by other pharmaceutically acceptable component be added to Abiraterone acetate and In the mixture of grinding matrix.In some embodiments, dry grinded in the presence of abrasive body；In other cases, Particle is produced by grinding in the case where there is no abrasive body, such as by jet mill or by other types Grinder grinding, for example can reduce particle diameter and/or increase Abiraterone acetate solubility grinder (as acetic acid Ah ratio Special dragon exist can grind polishing compounds in the case of grind when, can grind polishing compounds particle diameter itself can reduce or not Reduce).

In some cases, by Abiraterone acetate together with one or more selected from following ground polishing compounds Grinding：Lactose (such as lactose monohydrate or Lactis Anhydrous) and mannitol and selected from the one of lauryl sodium sulfate and PVP Plant or various promotion reagents.In some cases, in addition to reducing the particle diameter of Abiraterone acetate, grinding also reduces grinding base The particle diameter of one or more component of matter.Therefore, in some cases, grinding is reduced as triturable polishing compounds The particle of one or more material (such as lactose).In some cases, by Abiraterone acetate and lactose (for example, lactose one Hydrate) and lauryl sodium sulfate grind together.In some cases, during dry grinding, Abiraterone acetate can be deposited At 20-60% (w/w), lactose is up to 80% (w/w), and mannitol is up to 80% (w/w) and polyvinylpyrrolidone and dodecyl Sodium sulphate each (or both) be 1-10% (w/w).

In some embodiments, except at least one triturable polishing compounds and it is at least one promote reagent it Outward, Abiraterone acetate (that is, can chelating ion, such as gold in one or more antioxidant and/or one or more chelating agent Category ion reagent) in the presence of dry grind.Therefore, there may be butylated hydroxyanisol (BHA), butylation in dry milled process In hydroxy-methylbenzene (BHT), ascorbic acid, fumaric acid, tartaric acid and citric acid (such as anhydrous citric acid) or its mixture one Plant or various.In some cases, there is at least one antioxidant and at least one chelating agent simultaneously during grinding.Grinding During mill, ascorbic acid, fumaric acid, tartaric acid and citric acid (such as anhydrous citric acid) can be based on w/w with 8% or lower (such as 7%-0.1%, 1%-0.1% or 0.2%, each or in combination) is present, and BHT and BHA can be with 0.5% or more Few (for example, 0.5%-0.01%, 0.2%-0.08%, 0.15%-0.05% or 0.1%, each or in combination) is present.Grinding After the completion of mill, one or more other antioxidant and/or one or more other chelating agent can be added to grinding Material in.

Pharmaceutical composition can be unit dosage forms, for example containing 50-500mg Abiraterone acetates (for example, 50,55,60, 65、70、75、80、85、90、95、100、110、115、120、125、130、135、140、145、150、175、200、225、250、 275th, 300,325,350,375,400,425,450,475 or 500mg) capsule or tablet, wherein the Abiraterone acetate There is stripping curve as herein described with Size Distribution as herein described and/or formulation.

There is also described herein the method for treating patient, it includes (the example in the form of pharmaceutical composition as herein described Such as, by applying the unit dosage forms as herein described containing Abiraterone acetate of one or more units) apply daily dosage The Abiraterone acetate of 1000mg to 50mg is (for example, 900,850,800,750,700,650,600,550,525,500,475, 450th, 425,400,375,350,325,300,275,250,225,200,150,100,90,80,70,60 or 50mg), wherein institute There is Size Distribution as herein described and/or the formulation to have stripping curve as herein described to state Abiraterone acetate.Patient Can also be with glucocorticoid such as metacortandracin, prednisolone or dexamethasone in treatment.Or, patient can also sprinkle Buddhist nun with methyl Song Long is treated, for example with 5-15mg/ days (such as 5,6,7,8,9,10mg/ days, such as 4mg dosage/day twice) treatment.At some In the case of, by applying four 125mg Abiraterone acetates unit dosage forms as described herein with 500mg/ days treatment patients, example Such as the patient that there is no hepatic lesion.

In some cases, for formulation as herein described, when applying together with low fat diet (7% is fatty, 300 calories) Used time, the AUC of the unit dosage forms described herein (or its effective dose, such as 4 × 125mg) of single dose_0-∞Than under fasted conditions High 4 times or less during administration (3 times or less, 2 times or less, 1.5 times or less).

In some cases, for formulation as herein described, when with high fat diet (57% is fatty, 825 calories) together During administration, the AUC of the unit dosage forms as herein described of single dose (or its effective dose, such as 4 × 125mg)_0-∞(or AUC_0-t) High 8 times or less (7 times or less, 5 times or less, 3 times or less, 2 times or less, 1.5 times during than being administered under fasted conditions Or following).

In some cases, for formulation as herein described, when with high fat diet (57% is fatty, 825 calories) together During administration, the C of the unit dosage forms as herein described of single dose (or its effective dose, such as 4 × 125mg)_maxThan in fasted conditions High 15 times or less during lower administration (13 times or less or 12 times or less, 11 times or less, 10 times or less, 9 times or with Under, 8 times or less, 7 times or less, 6 times or less, 5 times or less).

In some cases, for formulation as herein described, when applying together with low fat diet (7% is fatty, 300 calories) Used time, the C of the unit dosage forms as herein described (or it ratifies dosage, such as 4 × 125mg) of single dose_maxThan under fasted conditions High 6 times or less during administration (5 times or less or 4 times or less, 3 times or less, 2 times or less, 1.5 times or less).

When using USP apparatus IIs with 75rpm the lauryl sodium sulfate containing 0.1%-0.12% (difference) 900ml The phosphate buffers of pH 4.5 in when testing, the dissolution rate of the tablet containing 100mg or 125mg Abiraterone acetates is to make At least 90% or at least 95% Abiraterone acetate in 20 minutes or shorter time (for example, 19 minutes or shorter, 18 minutes Or it is shorter, 17 minutes or it is shorter, 16 minutes or it is shorter, 15 minutes or it is shorter, 14 minutes or it is shorter, 13 minutes or it is shorter, 11 points Clock or shorter, 9 minutes or shorter time) interior dissolution.For example, 90% can the dissolution within 9-19 minutes.Contain in tablet and have more than In the case of the Abiraterone acetate of 125mg or less than 100mg, the dissolution rate for being given is for offer 100-125mg acetic acid A part (or multiple smaller pieces agent) for the larger tablet of abiraterone.In some cases, at least 80% or at least 85% Abiraterone acetate was at (such as 14 minutes or shorter, 13 minutes or shorter, 12 minutes or shorter, 11 minutes 15 minutes or shorter Or it is shorter, 10 minutes or it is shorter, 9 minutes or it is shorter, 8 minutes or it is shorter or 7 minutes or shorter) dissolution in the time.For example, 85% can the dissolution within 7-14 minutes.

In some cases, at 25 DEG C, store 4 weeks under 60%RH or after the longer time (such as 8 weeks or 12 weeks), 125mg In unit dosage forms at least 80% or at least 85% Abiraterone acetate 15 minutes or shorter (such as 14 minutes or shorter, 13 Minute or it is shorter, 12 minutes or it is shorter, 11 minutes or it is shorter, 10 minutes or it is shorter, 9 minutes or it is shorter, 8 minutes or it is shorter or 7 minutes are shorter) dissolution in the time.In some cases, at 40 DEG C, store 3 weeks under 75%RH or (for example, 6 weeks longer time Or 9 weeks) after, at least 95% Abiraterone acetate 15 minutes or shorter (for example, 14 minutes or shorter, 13 minutes or shorter, 11 minutes or shorter, 9 minutes are shorter) dissolution in the time.For example, 95% can the dissolution within 8-14 minutes.In addition, in tablet In the case of the Abiraterone acetate more than 125mg or less than 100mg, the dissolution rate for being given is for offer 100- A part (or multiple smaller pieces agent) for the larger tablet of 125mg Abiraterone acetates.

In some embodiments, when the healthy patients of fasted conditions are applied to, for medicine group as herein described Compound observe in C_max、AUC_(0-t)And AUC_(0-∞)In the coefficient of variation of one or more will less than 60%, less than 50%, Less than 40%, less than 30%, less than 25% or less than 20%.In some embodiments, pharmaceutical composition as herein described (unit dosage forms of 125mg unit dosage forms or 500mg dosage, such as 4 × 125mg) relative to for example, 250mg formulations(or the 250mg formulations of 1000 dosage) in suitable pharmacokinetics test in C_max、 AUC_(0-t)And AUC_(0-∞)One or more in show small change.

In some cases, the hardness of abiraterone tablet (for example, 110N to 180N) between 100N to 190N.

Pharmaceutical product intermediate can be prepared by dry grinding following material：(A) Abiraterone acetate of 5-60 weight %, The lactose (such as lactose monohydrate) of 30-95 weight %, the lauryl sodium sulfate of 0.1-15 weight %；0.001-1 weights The BHT of BHA and 0.001-1 weight % of amount %；(B) Abiraterone acetate of 10-50 weight %, the lactose of 40-80 weight % (such as lactose monohydrate), the lauryl sodium sulfate of 0.5-10 weight %；The BHA and 0.01-0.8 of 0.01-0.8 weight % The BHT of weight %；(C) Abiraterone acetate of 20-40 weight %, the lactose (such as lactose monohydrate) of 50-70 weight %, The lauryl sodium sulfate of 2-8 weight %；The BHA of 0.05-0.5 weight %, and the BHT of 0.05-0.5 weight %；(D)25-35 The Abiraterone acetate of weight %, the lactose (such as lactose monohydrate) of 60-70 weight %, the dodecyl of 4-8 weight % Sodium sulphate；The BHA of 0.05-0.15 weight %, and the BHT of 0.05-0.15 weight %；(E) acetic acid Ah's bit of 30 weight % Dragon, the lactose (such as lactose monohydrate) of 63.8 weight %, the lauryl sodium sulfate of 6 weight %；The BHA of 0.1 weight %, The BHT of 0.1 weight %.

Said medicine product Intermediate can be processed to the tablet with following material：(A) acetic acid of 5-50 weight % Abiraterone, the lactose (such as lactose monohydrate) of 5-80 weight %, the lauryl sodium sulfate of 0.1-10 weight %, The BHT of the BHA of 0.001-1 weight %, 0.001-1 weight %, the microcrystalline cellulose of 5-80 weight %, the friendship of 0.5-20 weight % The sodium stearyl fumarate of connection sodium carboxymethylcellulose and 0.01-10 weight %；(B) Abiraterone acetate of 8-40 weight %, The lactose (such as lactose monohydrate) of 10-60 weight %, the lauryl sodium sulfate of 0.5-8 weight %, 0.01-0.05 weights The BHA of amount %, the BHT of 0.01-0.5 weight %, the microcrystalline cellulose of 10-70 weight %, the cross-linked carboxymethyl of 1-15 weight % The sodium stearyl fumarate of sodium cellulosate and 0.05-5 weight %；(C) Abiraterone acetate of 10-30 weight %, 20-40 weights The lactose (such as lactose monohydrate) of amount %, the lauryl sodium sulfate of 1-5 weight %；The BHA of 0.01-0.2 weight %, The microcrystalline cellulose of the BHT of 0.01-0.2 weight %, 20-60 weight %, the Ac-Di-Sol of 2-10 weight % and The sodium stearyl fumarate of 0.1-2 weight %；(D) Abiraterone acetate of 12-17 weight %, the lactose (example of 25-35 weight % Such as lactose monohydrate), the lauryl sodium sulfate of 2-5 weight %；The BHA of 0.01-0.2 weight %, 0.01-0.2 weight % BHT, the microcrystalline cellulose of 35-50 weight %, the Ac-Di-Sol of 5-9 weight % and 0.2-0.8 weight % Sodium stearyl fumarate；(E) Abiraterone acetate of 14.29 weight %, lactose (such as water of lactose one of 30.38 weight % Compound), the lauryl sodium sulfate of 3.21 weight %；The BHA of 0.05 weight %, the BHT of 0.05 weight %, 44-53 weight % Microcrystalline cellulose, the sodium stearyl fumarate of the Ac-Di-Sol of 7 weight % and 0.5 weight %.

In some embodiments, the dry grinding equipment for Abiraterone acetate of dry grinding is selected from following grinding machine：Grind Grinding machine (attritor mill) (level is vertical), nutating grinding machine, tower mill, ball mill (pearl mill), planetary mill Machine, vibrating mill, eccentric vibrating grinding machine, gravity dependent form ball mill, rod mill, roller mill and broken mill.In some enforcements In mode, the dry grinding equipment for Abiraterone acetate of dry grinding is selected from following grinding machine：Jet mill, spiral spray mill Machine, atomizer or pulverizer.Preferably, the method is configured to be produced to wave batch (swing batch) or continuation mode Raw Abiraterone acetate.

In some embodiments, when grinding machine uses abrasive body, the abrasive body in milling apparatus is by 1,2 or 3 rotations Rotor axis mechanical is stirred.Abrasive body can be by forming selected from following material：Ceramics, glass, steel, polymer, ferromagnetic material and Metal and other suitable materials.In some embodiments, abrasive body is that have the steel ball selected from diameter below：1 To 20mm, 2 to 15mm and 3 to 10mm.In the various embodiments of dry grind process, abrasive body is that have selected from following straight The zirconia ball in footpath：1 to 20mm, 2 to 15mm and 3 to 10mm.

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

Other grinding matrix and promotion reagent

In embodiments, the mixing that matrix is two or more materials of homogenous material or any ratio is ground Thing.In some embodiments, the mixture of the homogenous material or the material of two or more is selected from：Mannitol, sorb Alcohol, isomalt, xylitol, maltitol, lactitol, erythrite, arabitol, ribitol, glucose, fructose, sweet dew Sugar, galactolipin, Lactis Anhydrous, lactose monohydrate, sucrose, maltose, trehalose and maltodextrin.In some embodiments In, the mixture of the homogenous material or two or more materials is selected from：Dextrin, inulin, dextrates, poly- grape Sugar, starch, wheat flour, corn flour, rice meal, rice starch, tapioca starch, tapioca, potato flour, farina, Other flour and starch, milk powder, skimmed milk powder, other milk solids and derivative, soy meal, Soybean Meal or other soybean prods, Cellulose, microcrystalline cellulose, microcrystalline cellulose base intermingling material, pregelatinated (or part gel) starch, Hydroxypropyl methylcellulose, carboxylic Methylcellulose, hydroxypropyl cellulose, citric acid, tartaric acid, malic acid, maleic acid, fumaric acid, ascorbic acid, butanedioic acid, lemon Lemon acid sodium, sodium tartrate, natrium malicum, sodium ascorbate, potassium citrate, potassium tartrate, potassium malate, sodium acetate, Vitamin C Sour potassium, sodium carbonate, potassium carbonate, magnesium carbonate, sodium acid carbonate, saleratus, calcium carbonate, calcium monohydrogen phosphate, calcium phosphate, sodium sulphate, chlorine Change sodium, sodium pyrosulfite, sodium thiosulfate, ammonium chloride, saltcake, ammonium carbonate, niter cake, magnesium sulfate, arcanite, potassium chloride, sulphur Sour hydrogen sodium, NaOH, crystalline hydroxides, bicarbonate, ammonium chloride, methylamine hydrochloride, ammonium bromide, silica, heat two Silica, aluminum oxide, titanium dioxide, talcum, chalk, mica, kaolin, bentonite, hectorite, magnesium trisilicate, clay-based Material or alumina silicate, lauryl sodium sulfate, stearyl sodium sulphate, cetyl sulfate, sodium cetostearyl sulphate, many storehouse esters Sodium, NaTDC, N- sodium lauroyl sarcosine salt, glycerin monostearate, distearin, palmitic, stearic are sweet Grease, Compritol 888 ATO, glycerol caprylate, olein, benzalkonium chloride, cetrimonium bromide, cetrimonium chloride, bromine palm fibre front three Ammonium, cetylpyridinium chloride, brocide, benzethonium chloride, the stearate of polyethylene glycol 40, polyethylene glycol 100 Stearate, PLURONICS F87, Pluronic/Lutrol F 108, poloxamer188, the stearyl ether of polyoxyethylene 2, polyoxyethylene 100 are hard It is aliphatic radical ether, the stearyl ether of polyoxyethylene 20, the stearyl ether of polyoxyethylene 10, the spermaceti alcohol ether of polyoxyethylene 20, polysorbate 20, poly- Sorb ester 40, polysorbate 60, polysorbate 61, polysorbate 65, polyoxyethylene sorbitan monoleate, Emulsifier EL-35, polyoxy second The castor oil of alkene 40, Emulsifier EL-60, Emulsifier EL-100, the castor oil of polyoxyethylene 200, the hydrogen of polyoxyethylene 40 Change castor oil, Cremophor RH60, the rilanit special of polyoxyethylene 100, the rilanit special of polyoxyethylene 200, whale Wax stearyl alcohol, Solutol HS15 (macrogel 15hydroxystearate), anhydro sorbitol list palm Acid esters, Arlacel-60, sorbitan trioleate, sucrose palmitate, stearic acid sucrose ester, sucrose two Stearate, Surfhope SE Cosme C 1216, glycocholic acid, NaGC, cholic acid, sodium taurocholate, NaTDC, deoxycholic acid, ox Sulphur sodium taurocholate, taurocholate, sodium taurodeoxycholate, tauroursodeoxycholic acid, soybean lecithin, phosphatid ylcholine, phosphatidyl second Hydramine, phosphatidylserine, phosphatidylinositols, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkylnaphthalene Sulfonate condensation product/lignosulfonates blend, calcium dodecyl benzene sulfonate, neopelex, diisopropyl naphthalene Sulfonate, erythrite distearate, naphthalenesulfonate formaldehyde condensation compound, nonyl phenol ethoxylate (poe-30), triphenylethylene Base phenol elhoxylate (tristyrylphenol ethoxylate), polyoxyethylene (15) tallow alkylamine, alkylnaphthalene sulphur Sour sodium, Negel condensation product, sodium alkyl benzene sulfonate, isopropyl naphthalene sulfonate, methyl naphthalene formaldehyde sulfonate, normal-butyl naphthalene Sodium sulfonate, tridecyl alcohol ethoxylate (poe-18), triethanolamine isodecanol phosphate, triethanolamine triphenylethylene base phosphoric acid Ester, tristyrylphenol ethoxylates sulfate, double (2- ethoxys) tallow alkylamines.

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

In some embodiments, Abiraterone acetate grinds in the presence of following material：

(a) lactose monohydrate or lactose monohydrate be selected from following at least one combinations of substances：Xylitol；Nothing Water and milk sugar；Microcrystalline cellulose；Sucrose；Glucose；Sodium chloride；Talcum；Kaolin；Calcium carbonate；Malic acid；The water of trisodium citrate two Compound；D, L MALIC ACID；Pentane sodium sulphate；Sodium stearyl sulfate；The stearyl ether of polyoxyethylene 100；The stearyl ether of polyoxyethylene 10； N- sodium N-lauroyl sarcosinates；Lecithin；Docusate sodium；Polyoxyethylene -40- stearic acid；Hydrophobic colloid silica；Dodecane Base sodium sulphate or other alkyl sulfate surfactants with the chain length between C5 to C18；Polyvinylpyrrolidone；12 Sodium alkyl sulfate and the stearate of polyethylene glycol 40, lauryl sodium sulfate and the stearate of polyethylene glycol 100, dodecyl sulphur Sour sodium and PEG 3000, lauryl sodium sulfate and PEG 6000, lauryl sodium sulfate and PEG 8000, dodecyl sulphate Sodium and PEG 10000, lauryl sodium sulfate and the stearyl ether of polyoxyethylene 100, lauryl sodium sulfate and poloxamer188, Lauryl sodium sulfate and Pluronic/Lutrol F 108, lauryl sodium sulfate and PLURONICS F87；Poloxamer188, poloxamer 338th, PLURONICS F87, alkylnaphthalene sulfonate condensation product/lignosulphonates blend；Calcium dodecyl benzene sulfonate (branch)； Diisopropyl naphthalene sulfonic acids；Erythrite distearate；Straight chain and branched dodecylbenzene sulfonic acid；Naphthalene sulfonic acid-formaldehyde condensation product；Nonyl Base phenol ethoxylate, POE-30；Phosphate, tristyrylphenol ethoxylates, free acid；Polyoxyethylene (15) butter Alkylamine；Negel；Negel condensation product；Sodium alkyl benzene sulfonate；Isopropyl naphthalene sulfonate；Methyl naphthalene sodium； Formaldehyde sulphonic acid ester；Normal-butyl naphthalene sulfonate salt；Tridecyl alcohol ethoxylate, POE-18；Triethanolamine isodecanol phosphate； Triethanolamine triphenylethylene base phosphate；Tristyrylphenol ethoxylates sulfate；Two (2- ethoxys) tallow alkyls Amine.

(b) Lactis Anhydrous or Lactis Anhydrous be selected from following at least one combinations of substances：Lactose monohydrate；Wood sugar Alcohol；Microcrystalline cellulose；Sucrose；Glucose；Sodium chloride；Talcum；Kaolin；Calcium carbonate；Malic acid；Trisodium citrate two is hydrated Thing；D, L MALIC ACID；Pentane sodium sulphate；Sodium stearyl sulfate；The stearyl ether of polyoxyethylene 100；The stearyl ether of polyoxyethylene 10；n- Sodium N-lauroyl sarcosinate；Lecithin；Docusate sodium；Polyoxyethylene -40- stearic acid；Hydrophobic colloid silica；Dodecyl Sodium sulphate or other alkyl sulfate surfactants with the chain length between C5 to C18；Polyvinylpyrrolidone；Dodecane Base sodium sulphate and the stearate of polyethylene glycol 40, lauryl sodium sulfate and the stearate of polyethylene glycol 100, dodecyl sulphate Sodium and PEG 3000, lauryl sodium sulfate and PEG 6000, lauryl sodium sulfate and PEG 8000, lauryl sodium sulfate With PEG 10000, lauryl sodium sulfate and the stearyl ether of polyoxyethylene 100, lauryl sodium sulfate and poloxamer188, ten Sodium dialkyl sulfate and Pluronic/Lutrol F 108, lauryl sodium sulfate and PLURONICS F87；Poloxamer188, poloxamer 338th, PLURONICS F87, alkyl naphthalene sulfonic acid ester condensates/lignosulphonates blend；Calcium dodecyl benzene sulfonate (side chain)； Diisopropyl napsylate；Erythrite distearate；Straight chain and branched dodecylbenzene sulfonic acid；Naphthalene sulfonic acid-formaldehyde condensation product； Nonyl phenol ethoxylate, POE-30；Phosphate, tristyrylphenol ethoxylates, free acid；Polyoxyethylene (15) ox Oily alkylamine；Negel；Negel condensation product；Sodium alkyl benzene sulfonate；Isopropyl naphthalene sulfonate；Methyl naphthalene Sodium；Formaldehyde sulphonic acid ester；Normal-butyl naphthalene sulfonate salt；Tridecyl alcohol ethoxylate, POE-18；Triethanolamine isodecanol phosphoric acid Ester；Triethanolamine triphenylethylene base phosphate；Tristyrylphenol ethoxylates sulfate；Two (2- ethoxys) tallow alkane Base amine.

(c) mannitol or mannitol be selected from following at least one combinations of substances：Lactose monohydrate；Xylitol； Lactis Anhydrous；Microcrystalline cellulose；Sucrose；Glucose；Sodium chloride；Talcum；Kaolin；Calcium carbonate；Malic acid；Trisodium citrate two Hydrate；D, L MALIC ACID；Pentane sodium sulphate；Sodium stearyl sulfate；The stearyl ether of polyoxyethylene 100；Polyoxyethylene 10 is stearic Ether；N- sodium N-lauroyl sarcosinates；Lecithin；Docusate sodium；Polyoxyethylene -40- stearic acid；Hydrophobic colloid silica；Ten Sodium dialkyl sulfate or other alkyl sulfate surfactants with the chain length between C5 to C18；Polyvinylpyrrolidone； Lauryl sodium sulfate and the stearate of polyethylene glycol 40, lauryl sodium sulfate and the stearate of polyethylene glycol 100, dodecane Base sodium sulphate and PEG 3000, lauryl sodium sulfate and PEG 6000, lauryl sodium sulfate and PEG 8000, dodecyl Sodium sulphate and PEG 10000, lauryl sodium sulfate and the stearyl ether of polyoxyethylene 100, lauryl sodium sulfate and poloxamer 407th, lauryl sodium sulfate and Pluronic/Lutrol F 108, lauryl sodium sulfate and PLURONICS F87；Poloxamer188, pool Lip river Husky nurse 338, PLURONICS F87, alkyl naphthalene sulfonic acid ester condensates/lignosulphonates blend；Calcium dodecyl benzene sulfonate (side chain )；Diisopropyl naphthalene sulfonic acids；Erythrite distearate；Straight chain and branched dodecylbenzene sulfonic acid；Naphthalenesulfonateformaldehyde formaldehyde is condensed Thing；Nonyl phenol ethoxylate, POE-30；Phosphate, tristyrylphenol ethoxylates, free acid；Polyoxyethylene (15) tallow alkylamine；Negel；Negel condensation product；Sodium alkyl benzene sulfonate；Isopropyl naphthalene sulfonate；First Base naphthalene sodium；Formaldehyde sulphonic acid ester；Normal-butyl naphthalene sulfonate salt；Tridecyl alcohol ethoxylate, POE-18；Triethanolamine isodecanol Phosphate；Triethanolamine triphenylethylene base phosphate；Tristyrylphenol ethoxylates sulfate；Two (2- ethoxys) oxen Fat alkylamine.

(d) sucrose or sucrose be selected from following at least one combinations of substances：Lactose monohydrate；Lactis Anhydrous；It is sweet Dew alcohol；Microcrystalline cellulose；Glucose；Sodium chloride；Talcum；Kaolin；Calcium carbonate；Malic acid；Tartaric acid；The water of trisodium citrate two Compound；D, L MALIC ACID；Pentane sodium sulphate；Sodium stearyl sulfate；The stearyl ether of polyoxyethylene 100；The stearyl ether of polyoxyethylene 10； N- sodium N-lauroyl sarcosinates；Lecithin；Docusate sodium；Polyoxyethylene -40- stearic acid；Hydrophobic colloid silica；Dodecane Base sodium sulphate or other alkyl sulfate surfactants with the chain length between C5 to C18；Polyvinylpyrrolidone；12 Sodium alkyl sulfate and the stearate of polyethylene glycol 40, lauryl sodium sulfate and the stearate of polyethylene glycol 100, dodecyl sulphur Sour sodium and PEG 3000, lauryl sodium sulfate and PEG 6000, lauryl sodium sulfate and PEG 8000, dodecyl sulphate Sodium and PEG 10000, lauryl sodium sulfate and the stearyl ether of polyoxyethylene 100, lauryl sodium sulfate and poloxamer188, Lauryl sodium sulfate and Pluronic/Lutrol F 108, lauryl sodium sulfate and PLURONICS F87；Poloxamer188, poloxamer 338th, PLURONICS F87, alkyl naphthalene sulfonic acid ester condensates/lignosulphonates blend；Calcium dodecyl benzene sulfonate (side chain)； Diisopropyl napsylate；Erythrite distearate；Straight chain and branched dodecylbenzene sulfonic acid；Naphthalene sulfonic acid-formaldehyde condensation product； Nonyl phenol ethoxylate, POE-30；Phosphate, tristyrylphenol ethoxylates, free acid；Polyoxyethylene (15) ox Oily alkylamine；Negel；Negel condensation product；Sodium alkyl benzene sulfonate；Isopropyl naphthalene sulfonate；Methyl naphthalene Sodium；Formaldehyde sulphonic acid ester；Normal-butyl naphthalene sulfonate salt；Tridecyl alcohol ethoxylate, POE-18；Triethanolamine isodecanol phosphoric acid Ester；Triethanolamine triphenylethylene base phosphate；Tristyrylphenol ethoxylates sulfate；Two (2- ethoxys) tallow alkane Base amine.

(e) glucose or glucose be selected from following at least one combinations of substances：Lactose monohydrate；Anhydrous lactitol Sugar；Mannitol；Microcrystalline cellulose；Sucrose；Sodium chloride；Talcum；Kaolin；Calcium carbonate；Malic acid；Tartaric acid；Trisodium citrate Dihydrate；D, L MALIC ACID；Pentane sodium sulphate；Sodium stearyl sulfate；The stearyl ether of polyoxyethylene 100；Polyoxyethylene 10 is hard Fat ether；N- sodium N-lauroyl sarcosinates；Lecithin；Docusate sodium；Polyoxyethylene -40- stearic acid；Hydrophobic colloid silica； Lauryl sodium sulfate or other alkyl sulfate surfactants with the chain length between C5 to C18；Polyvinylpyrrolidine Ketone；Lauryl sodium sulfate and the stearate of polyethylene glycol 40, lauryl sodium sulfate and the stearate of polyethylene glycol 100, ten Sodium dialkyl sulfate and PEG 3000, lauryl sodium sulfate and PEG 6000, lauryl sodium sulfate and PEG 8000,12 Sodium alkyl sulfate and PEG 10000, lauryl sodium sulfate and the stearyl ether of polyoxyethylene 100, lauryl sodium sulfate and pool Lip river Husky nurse 407, lauryl sodium sulfate and Pluronic/Lutrol F 108, lauryl sodium sulfate and PLURONICS F87；Poloxamer188, Pluronic/Lutrol F 108, PLURONICS F87, alkyl naphthalene sulfonic acid ester condensates/lignosulphonates blend；Calcium dodecyl benzene sulfonate (side chain)；Diisopropyl napsylate；Erythrite distearate；Straight chain and branched dodecylbenzene sulfonic acid；Naphthalene sulfonic acids first Aldehyde condensate；Nonyl phenol ethoxylate, POE-30；Phosphate, tristyrylphenol ethoxylates, free acid；Polyoxy Ethene (15) tallow alkylamine；Negel；Negel condensation product；Sodium alkyl benzene sulfonate；Isopropyl naphthalene sulfonic acid Sodium；Methyl naphthalene sodium；Formaldehyde sulphonic acid ester；Normal-butyl naphthalene sulfonate salt；Tridecyl alcohol ethoxylate, POE-18；Triethanolamine Isodecanol phosphate；Triethanolamine triphenylethylene base phosphate；Tristyrylphenol ethoxylates sulfate；Two (2- hydroxyls Ethyl) tallow alkyl amine.

(f) sodium chloride or sodium chloride be selected from following at least one combinations of substances：Lactose monohydrate；Anhydrous lactitol Sugar；Mannitol；Microcrystalline cellulose；Sucrose；Glucose；Talcum；Kaolin；Calcium carbonate；Malic acid；Tartaric acid；Trisodium citrate Dihydrate；D, L MALIC ACID；Pentane sodium sulphate；Sodium stearyl sulfate；The stearyl ether of polyoxyethylene 100；Polyoxyethylene 10 is hard Fat ether；N- sodium N-lauroyl sarcosinates；Lecithin；Docusate sodium；Polyoxyethylene -40- stearic acid；Hydrophobic colloid silica； Lauryl sodium sulfate or other alkyl sulfate surfactants with the chain length between C5 to C18；Polyvinylpyrrolidine Ketone；Lauryl sodium sulfate and the stearate of polyethylene glycol 40, lauryl sodium sulfate and the stearate of polyethylene glycol 100, ten Sodium dialkyl sulfate and PEG 3000, lauryl sodium sulfate and PEG 6000, lauryl sodium sulfate and PEG 8000,12 Sodium alkyl sulfate and PEG 10000, lauryl sodium sulfate and the stearyl ether of polyoxyethylene 100, lauryl sodium sulfate and pool Lip river Husky nurse 407, lauryl sodium sulfate and Pluronic/Lutrol F 108, lauryl sodium sulfate and PLURONICS F87；Poloxamer188, Pluronic/Lutrol F 108, PLURONICS F87, alkyl naphthalene sulfonic acid ester condensates/lignosulphonates blend；Calcium dodecyl benzene sulfonate (side chain)；Diisopropyl napsylate；Erythrite distearate；Straight chain and branched dodecylbenzene sulfonic acid；Naphthalene sulfonic acids first Aldehyde condensate；Nonyl phenol ethoxylate, POE-30；Phosphate, tristyrylphenol ethoxylates, free acid；Polyoxy Ethene (15) tallow alkylamine；Negel；Negel condensation product；Sodium alkyl benzene sulfonate；Isopropyl naphthalene sulfonic acid Sodium；Methyl naphthalene sodium；Formaldehyde sulphonic acid ester；Normal-butyl naphthalene sulfonate salt；Tridecyl alcohol ethoxylate, POE-18；Triethanolamine Isodecanol phosphate；Triethanolamine triphenylethylene base phosphate；Tristyrylphenol ethoxylates sulfate；Two (2- hydroxyls Ethyl) tallow alkyl amine.

(g) xylitol or xylitol be selected from following at least one combinations of substances：Lactose monohydrate；Anhydrous lactitol Sugar；Mannitol；Microcrystalline cellulose；Sucrose；Glucose；Sodium chloride；Talcum；Kaolin；Calcium carbonate；Malic acid；Tartaric acid；Lemon Sour trisodium dihydrate；D, L MALIC ACID；Pentane sodium sulphate；Sodium stearyl sulfate；The stearyl ether of polyoxyethylene 100；Polyoxy second The stearyl ether of alkene 10；N- sodium N-lauroyl sarcosinates；Lecithin；Docusate sodium；Polyoxyethylene -40- stearic acid；Hydrophobic colloid dioxy SiClx；Lauryl sodium sulfate or other alkyl sulfate surfactants with the chain length between C5 to C18；Polyethylene pyrrole Pyrrolidone；Lauryl sodium sulfate and the stearate of polyethylene glycol 40, lauryl sodium sulfate and the stearic acid of polyethylene glycol 100 Ester, lauryl sodium sulfate and PEG 3000, lauryl sodium sulfate and PEG 6000, lauryl sodium sulfate and PEG 8000th, lauryl sodium sulfate and PEG 10000, lauryl sodium sulfate and the stearyl ether of polyoxyethylene 100, dodecyl sulphate Sodium and poloxamer188, lauryl sodium sulfate and Pluronic/Lutrol F 108, lauryl sodium sulfate and PLURONICS F87；Pool Lip river Husky nurse 407, Pluronic/Lutrol F 108, PLURONICS F87, alkyl naphthalene sulfonic acid ester condensates/lignosulphonates blend；Dodecyl Benzene sulfonic acid calcium (side chain)；Diisopropyl napsylate；Erythrite distearate；Straight chain and branched dodecylbenzene sulfonic acid； Naphthalene sulfonic acid-formaldehyde condensation product；Nonyl phenol ethoxylate, POE-30；It is phosphate, tristyrylphenol ethoxylates, free Acid；Polyoxyethylene (15) tallow alkylamine；Negel；Negel condensation product；Sodium alkyl benzene sulfonate；Isopropyl Sodium naphthalene sulfonate；Methyl naphthalene sodium；Formaldehyde sulphonic acid ester；Normal-butyl naphthalene sulfonate salt；Tridecyl alcohol ethoxylate, POE-18；Three Monoethanolamine isodecanol phosphate；Triethanolamine triphenylethylene base phosphate；Tristyrylphenol ethoxylates sulfate；Two (2- ethoxys) tallow alkyl amine.

(h) tartaric acid or tartaric acid be selected from following at least one combinations of substances：Lactose monohydrate；Anhydrous lactitol Sugar；Mannitol；Microcrystalline cellulose；Sucrose；Glucose；Sodium chloride；Talcum；Kaolin；Calcium carbonate；Malic acid；Trisodium citrate Dihydrate；D, L MALIC ACID；Pentane sodium sulphate；Sodium stearyl sulfate；The stearyl ether of polyoxyethylene 100；Polyoxyethylene 10 is hard Fat ether；N- sodium N-lauroyl sarcosinates；Lecithin；Docusate sodium；Polyoxyl-40-stearate；Hydrophobic colloid titanium dioxide Silicon；Lauryl sodium sulfate or other alkyl sulfate surfactants with the chain length between C5 to C18；Polyvinyl pyrrole Alkanone；Lauryl sodium sulfate and the stearate of polyethylene glycol 40, lauryl sodium sulfate and the stearate of polyethylene glycol 100, Lauryl sodium sulfate and PEG 3000, lauryl sodium sulfate and PEG 6000, lauryl sodium sulfate and PEG 8000, ten Sodium dialkyl sulfate and PEG 10000, lauryl sodium sulfate and the stearyl ether of polyoxyethylene 100, lauryl sodium sulfate and pool Luo Shamu 407, lauryl sodium sulfate and Pluronic/Lutrol F 108, lauryl sodium sulfate and PLURONICS F87；Poloxamer 407th, Pluronic/Lutrol F 108, PLURONICS F87, alkyl naphthalene sulfonic acid ester condensates/lignosulphonates blend；Detergent alkylate sulphur Sour calcium (side chain)；Diisopropyl napsylate；Erythrite distearate；Straight chain and branched dodecylbenzene sulfonic acid；Naphthalene sulphur Sour formaldehyde condensation products；Nonyl phenol ethoxylate, POE-30；Phosphate, tristyrylphenol ethoxylates, free acid； Polyoxyethylene (15) tallow alkylamine；Negel；Negel condensation product；Sodium alkyl benzene sulfonate；Isopropyl naphthalene Sodium sulfonate；Methyl naphthalene sodium；Formaldehyde sulphonic acid ester；Normal-butyl naphthalene sulfonate salt；Tridecyl alcohol ethoxylate, POE-18；Three second Hydramine isodecanol phosphate；Triethanolamine triphenylethylene base phosphate；Tristyrylphenol ethoxylates sulfate；Two (2- ethoxys) tallow alkyl amine.

(i) microcrystalline cellulose or microcrystalline cellulose be selected from following at least one combinations of substances：Lactose monohydrate； Xylitol；Lactis Anhydrous；Mannitol；Sucrose；Glucose；Sodium chloride；Talcum；Kaolin；Calcium carbonate；Malic acid；Tartaric acid；Lemon Lemon acid trisodium dihydrate；D, L MALIC ACID；Pentane sodium sulphate；Sodium stearyl sulfate；The stearyl ether of polyoxyethylene 100；Polyoxy The stearyl ether of ethene 10；N- sodium N-lauroyl sarcosinates；Lecithin；Docusate sodium；Polyoxyethylene -40- stearic acid；Hydrophobic colloid two Silica；Lauryl sodium sulfate or other alkyl sulfate surfactants with the chain length between C5 to C18；Polyethylene Pyrrolidones；Lauryl sodium sulfate and the stearate of polyethylene glycol 40, lauryl sodium sulfate and the stearic acid of polyethylene glycol 100 Ester, lauryl sodium sulfate and PEG 3000, lauryl sodium sulfate and PEG 6000, lauryl sodium sulfate and PEG 8000th, lauryl sodium sulfate and PEG 10000, lauryl sodium sulfate and the stearyl ether of polyoxyethylene 100, dodecyl sulphate Sodium and poloxamer188, lauryl sodium sulfate and Pluronic/Lutrol F 108, lauryl sodium sulfate and PLURONICS F87；Pool Lip river Husky nurse 407, Pluronic/Lutrol F 108, PLURONICS F87, alkyl naphthalene sulfonic acid ester condensates/lignosulphonates blend；Dodecyl Benzene sulfonic acid calcium (side chain)；Diisopropyl napsylate；Erythrite distearate；Straight chain and branched dodecylbenzene sulfonic acid； Naphthalene sulfonic acid-formaldehyde condensation product；Nonyl phenol ethoxylate, POE-30；It is phosphate, tristyrylphenol ethoxylates, free Acid；Polyoxyethylene (15) tallow alkylamine；Negel；Negel condensation product；Sodium alkyl benzene sulfonate；Isopropyl Sodium naphthalene sulfonate；Methyl naphthalene sodium；Formaldehyde sulphonic acid ester；Normal-butyl naphthalene sulfonate salt；Tridecyl alcohol ethoxylate, POE-18；Three Monoethanolamine isodecanol phosphate；Triethanolamine triphenylethylene base phosphate；Tristyrylphenol ethoxylates sulfate；Two (2- ethoxys) tallow alkyl amine.

(j) kaolin be selected from following at least one combinations of substances：Lactose monohydrate；Xylitol；Lactis Anhydrous； Mannitol；Microcrystalline cellulose；Sucrose；Glucose；Sodium chloride；Talcum；Kaolin；Calcium carbonate；Malic acid；Tartaric acid；Citric acid Trisodium dihydrate；D, L MALIC ACID；Pentane sodium sulphate；Sodium stearyl sulfate；The stearyl ether of polyoxyethylene 100；Polyoxyethylene 10 stearyl ethers；N- sodium N-lauroyl sarcosinates；Lecithin；Docusate sodium；Polyoxyl-40-stearate；Hydrophobic colloid dioxy SiClx；Lauryl sodium sulfate or other alkyl sulfate surfactants with the chain length between C5 to C18；Polyethylene pyrrole Pyrrolidone；Lauryl sodium sulfate and the stearate of polyethylene glycol 40, lauryl sodium sulfate and the stearic acid of polyethylene glycol 100 Ester, lauryl sodium sulfate and PEG 3000, lauryl sodium sulfate and PEG 6000, lauryl sodium sulfate and PEG 8000th, lauryl sodium sulfate and PEG 10000, lauryl sodium sulfate and the stearyl ether of polyoxyethylene 100, dodecyl sulphate Sodium and poloxamer188, lauryl sodium sulfate and Pluronic/Lutrol F 108, lauryl sodium sulfate and PLURONICS F87；Pool Lip river Husky nurse 407, Pluronic/Lutrol F 108, PLURONICS F87, alkyl naphthalene sulfonic acid ester condensates/lignosulphonates blend；Dodecyl Benzene sulfonic acid calcium (side chain)；Diisopropyl napsylate；Erythrite distearate；Straight chain and branched dodecylbenzene sulfonic acid； Naphthalene sulfonic acid-formaldehyde condensation product；Nonyl phenol ethoxylate, POE-30；It is phosphate, tristyrylphenol ethoxylates, free Acid；Polyoxyethylene (15) tallow alkylamine；Negel；Negel condensation product；Sodium alkyl benzene sulfonate；Isopropyl Sodium naphthalene sulfonate；Methyl naphthalene sodium；Formaldehyde sulphonic acid ester；Normal-butyl naphthalene sulfonate salt；Tridecyl alcohol ethoxylate, POE-18；Three Monoethanolamine isodecanol phosphate；Triethanolamine triphenylethylene base phosphate；Tristyrylphenol ethoxylates sulfate；Two (2- ethoxys) tallow alkyl amine.

(k) talcum be selected from following at least one combinations of substances：Lactose monohydrate；Xylitol；Lactis Anhydrous；It is sweet Dew alcohol；Microcrystalline cellulose；Sucrose；Glucose；Sodium chloride；Kaolin；Calcium carbonate；Malic acid；Tartaric acid；The water of trisodium citrate two Compound；D, L MALIC ACID；Pentane sodium sulphate；Sodium stearyl sulfate；The stearyl ether of polyoxyethylene 100；The stearyl ether of polyoxyethylene 10； N- sodium N-lauroyl sarcosinates；Lecithin；Docusate sodium；Polyoxyl-40-stearate；Hydrophobic colloid silica；12 Sodium alkyl sulfate or other alkyl sulfate surfactants with the chain length between C5 to C18；Polyvinylpyrrolidone；Ten Sodium dialkyl sulfate and the stearate of polyethylene glycol 40, lauryl sodium sulfate and the stearate of polyethylene glycol 100, dodecyl Sodium sulphate and PEG 3000, lauryl sodium sulfate and PEG 6000, lauryl sodium sulfate and PEG 8000, dodecyl sulphur Sour sodium and PEG 10000, lauryl sodium sulfate and the stearyl ether of polyoxyethylene 100, lauryl sodium sulfate and poloxamer 407th, lauryl sodium sulfate and Pluronic/Lutrol F 108, lauryl sodium sulfate and PLURONICS F87；Poloxamer188, pool Lip river Husky nurse 338, PLURONICS F87, alkyl naphthalene sulfonic acid ester condensates/lignosulphonates blend；Calcium dodecyl benzene sulfonate (side chain )；Diisopropyl napsylate；Erythrite distearate；Straight chain and branched dodecylbenzene sulfonic acid；Naphthalenesulfonateformaldehyde formaldehyde is condensed Thing；Nonyl phenol ethoxylate, POE-30；Phosphate, tristyrylphenol ethoxylates, free acid；Polyoxyethylene (15) tallow alkylamine；Negel；Negel condensation product；Sodium alkyl benzene sulfonate；Isopropyl naphthalene sulfonate；First Base naphthalene sodium；Formaldehyde sulphonic acid ester；Normal-butyl naphthalene sulfonate salt；Tridecyl alcohol ethoxylate, POE-18；Triethanolamine isodecanol Phosphate；Triethanolamine triphenylethylene base phosphate；Tristyrylphenol ethoxylates sulfate；Two (2- ethoxys) oxen Fat alkylamine.

In some embodiments, Abiraterone acetate is done together with one or more selected from following other material Mill：For drug products are considered as " generally recognized as safe " (GRAS) material.

In some embodiments, the dry of Abiraterone acetate is carried out in the presence of reagent or promotion agent combination is promoted Mill.In some embodiments, reagent is promoted to be selected from glidant, surfactant, polymer and/or lubricant.At some In embodiment, reagent is promoted to be selected from：Cataloid, odium stearate and talcum.In some embodiments, examination is promoted Agent is selected from：Benzethonium chloride, docusate sodium, polyethylene alkyl ether, lauryl sodium sulfate, tricaprylin, alpha-tocopherol, Glyceryl monooleate, myristyl alcohol, poloxamer, polyoxyethylene alkyl ether, Myrj 45, Emulsifier EL-60 Derivative, the hydroxy stearic acid ester of polyoxyethylene 15, polyoxyethylene glyceride, polysorbate, propandiol dilaurate, dehydration Sorbitol ester, sucrose palmitate, vitamin E polyethylene glycol succinic acid ester, polyethylene glycol (PEG), poloxamer, Bo Luosha Amine, methyl amimoacetic acid based surfactants, polysorbate, aliphatic alcohol, alkyl and aromatic yl acid ester, alkyl and aryl polyether sulfonate With other sulfate surfactants, trimethyl ammonium based surfactants, lecithin and other phosphatide, bile salt, polyoxyethylene Castor oil derivative, polyoxyethylene sorbitan fatty acid ester, fatty acid esters of sorbitan, sucrose fatty ester, alkyl Glucopyranoside, alkyl pyrans maltoside, fatty acid glyceride, alkyl benzene sulphonate, alkyl ether carboxylic acid, alkyl and aryl phosphoric acids Ester, alkyl and aromatic yl acid ester, alkyl and aryl sulfonic acid, alkyl phenol phosphate, alkyl phenol sulfate esters, alkyl and aryl phosphoric acids Salt, alkyl polysaccharide, alkylamine ethoxylate, alkylnaphthalene sulfonate formaldehyde condensation products, sulfosuccinate, lignin sulfonic acid Salt, spermaceti-oleyl alcohol ethoxylate, condensation napsylate, dialkyl group and alkyl naphthalene sulfonic acid ester, dialkyl sulfosuccinates, Ethoxylated nonylphenol, glycol ester, fatty alcohol alkoxy compound, hydrogenated tallow alkyl amine, monoalkyl sulfosuccinamic acid Ester, nonyl phenol ethoxylate, oil base N methyl taurine sodium, tallow alkyl amine, straight chain and branched dodecylbenzene sulfonic acid.

In some embodiments, promote reagent selected from stearoyl sodium sulphate, sodium stearyl fumarate, magnesium stearate, Talcum, myristic acid, sodium hexadecyl sulfate, sodium cetostearylsulphate, docusate sodium, NaTDC, N- lauroyl Sodium sarcosinate, glycerin monostearate, glycerol distearate, glyceryl palmitostearate, Compritol 888 ATO, octanoic acid Glyceride, olein, benzalkonium chloride, cetrimonium bromide, cetyltrimethylammonium chloride, bromine palm fibre front three Ammonium, cetylpyridinium chloride, brocide, benzethonium chloride, the stearate of polyethylene glycol 40, polyethylene glycol 100 Stearate, PLURONICS F87, Pluronic/Lutrol F 108, poloxamer188, the stearyl ether of polyoxyethylene 2, polyoxyethylene 100 are hard It is aliphatic radical ether, the stearyl ether of polyoxyethylene 20, the stearyl ether of polyoxyethylene 10, the cetyl ether of polyoxyethylene 20, polysorbate 20, poly- Sorb ester 40, polysorbate 60, polysorbate 61, polysorbate 65, polyoxyethylene sorbitan monoleate, Emulsifier EL-35, polyoxy second The castor oil of alkene 40, Emulsifier EL-60, Emulsifier EL-100, the castor oil of polyoxyethylene 200, the hydrogen of polyoxyethylene 40 Change castor oil, Cremophor RH60, the rilanit special of polyoxyethylene 100, the rilanit special of polyoxyethylene 200, whale Wax stearyl alcohol, Solutol HS15, Arlacel-40, Arlacel-60, go Water D-sorbite trioleate, sucrose palmitate, stearic acid sucrose ester, sucrose distearate, Surfhope SE Cosme C 1216, sweet ammonia Cholic acid, NaGC, cholic acid, sodium taurocholate, NaTDC, deoxycholic acid, natrium taurocholicum, taurocholate, ox sulphur deoxidation Sodium taurocholate, tauroursodeoxycholic acid, soybean lecithin, phosphatid ylcholine, phosphatidyl-ethanolamine, phosphatidylserine, phosphatidyl-4 Alcohol, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkyl naphthalene sulfonic acid ester condensates/lignosulfonates Blend, calcium dodecyl benzene sulfonate, neopelex, diisopropyl napsylate, antierythrite distearate, Naphthalenesulfonate formaldehyde condensation compound, nonyl phenol ethoxylate (POE-30), tristyrylphenol ethoxylates, polyoxyethylene (15) tallow alkylamine, Negel, Negel condensation product, sodium alkyl benzene sulfonate, isopropyl naphthalene sulfonate, first Base naphthalene formaldehyde sulfonate, normal-butyl sodium naphthalene sulfonate, tridecyl alcohol ethoxylate (poe-18), triethanolamine isodecanol phosphoric acid Ester, triethanolamine triphenylethylene base phosphate, tristyrylphenol ethoxylates sulfate, double (2- ethoxys) butter alkane Base amine.

In some embodiments, the promotion reagent is selected from polyvinylpyrrolidone (PVP), polyvinyl alcohol, acrylic acid Based polyalcohol and acrylic acid copolymer.

In some embodiments, promote reagent to have during dry grinding and be selected from following concentration：0.1-10%w/w, 0.1-5%w/w, 0.1-2.5%w/w, 0.1-2%w/w, 0.1-1%, 0.5-5%w/w, 0.5-3%w/w, 0.5-2%w/w, 0.5-1.5%, 0.5-1%w/w, 0.75-1.25%w/w, 0.75-1% and 1%w/w.

In some embodiments, using the combination for promoting reagent or promotion reagent during dry grinding.In some embodiment party In formula, add during dry grinding and promote reagent.In some embodiments, selected from the following time reagent will promoted to add In dry grinding：1-5%, the 1-10% of remaining total milling time, the 1-20% of remaining total milling time when remaining total milling time, The 1-30% of remaining total milling time, the 2-5% of remaining total milling time, the 2-10% of remaining total milling time, residue are always ground During the 5-20% of the 5-20% of time consuming and remaining total milling time.

Comprising offer is included but is not limited to the reason for promoting reagent, preferably dispersiveness, control are assembled, are released from delivery matrices Put or retentive activity particle.The example for promoting reagent is included but is not limited to：Lauryl sodium sulfate, cross-linked pvp (Crospovidone), Ac-Di-Sol (cross-linked carboxymethyl cellulose sodium), primojel, PVP (PVP), 30 POVIDONE K 30 BP/USP 12, poly- dimension Ketone K17,30 POVIDONE K 30 BP/USP 25, PVPK29/32 and PVP K30, stearic acid, magnesium stearate, calcium stearate, stearoyl-fumarate Sodium, stearoyl lactate, zinc stearate, odium stearate or lithium stearate, other solid fatty acids such as oleic acid, laurate, palm Acid, erucic acid, behenic acids or derivative (such as ester and salt), amino acid such as leucine, isoleucine, lysine, valine, first sulphur ammonia Acid, phenylalanine, Aspartame or acesulfame-K.

On the other hand, the disclosure includes the method that treatment needs the people of this treatment, including administering to the human effective dose As described herein pharmaceutical composition is used for the step for the treatment of castration-resistant prostate cancer.Treatment can include administration daily 500mg Abiraterone acetate (for example, with 1 or 2 or 4 equal dose (for example a, UD containing 500mg, two Individual UD respectively containing 250mg Abiraterone acetates or four are respectively containing the UD of 125mg Abiraterone acetates). Glucocorticoid, such as metacortandracin, dexamethasone or prednisolone (for example, 5mg, twice daily) treatment patient can also be used. Or, patient can be treated with methylprednisolone (such as with 4mg, twice daily).With other chemotherapeutics or can also be used for Other pharmaceutical treatments patient for the treatment of cancer (such as prostate cancer).

The disclosure also includes using composition treatment breast cancer as herein described (such as metastatic breast cancer) and oophoroma The method of (such as ovarian epithelial carcinoma).

On the other hand, the disclosure includes that pharmaceutical composition as herein described is being prepared for this treatment for the treatment of needs Purposes in the medicine of people.

On the other hand, the disclosure includes the method for preparing pharmaceutical composition as described herein, and it includes step： By the composition containing the Abiraterone acetate prepared by methods described herein or composition as described herein and diluent, One of lubricant, excipient, disintegrant, wetting agent are combined together, to produce pharmaceutically acceptable formulation.

Disclosure described herein can include the scope (such as size, concentration etc.) of one or more values.The model of value Enclose and will be understood to comprise all values in the range of this, including the value for defining the scope, and the value adjacent with the scope, Its cause with the value on the border for defining the scope close to the identical or substantially the same result of value.

Herein cited all publications (including patent, patent application, journal of writings, laboratory manual, books or Other documents) complete disclosure be incorporated herein by.Recognize that any bibliography constitutes existing skill comprising not constituting Art or it relates to field in the part of the common knowledge of those people that works.

Throughout the specification, unless the context otherwise requires, otherwise word " including " or modification such as "comprising" or " contain Have " will be understood to refer to include stated integer or integer group, but it is not excluded for any other integer or integer group.Should also note Meaning, in the disclosure, particularly in claim and/or paragraph, the term such as " including ", "comprising", " containing " can be with With giving its implication in United States patent law；For example, they can represent " including ", " including ", " containing " etc..

Should mean to provide with regard to " therapeutically effective amount " as used herein for the treatment of method and particularly drug dose The dosage of the specific pharmacological reaction carried out by the medicine is application of in a large amount of experimenters for needing this treatment.It is emphasized that " therapeutically effective amount " for bestowing particular subject under specific circumstances is not always effective when disease as herein described is treated, Even if the dosage is considered " therapeutically effective amount " by those skilled in the art.It should further be appreciated that drug dose is specific In the case of as oral dose or relative to the levels of drugs for measuring in blood measuring.

Throughout the specification, unless the context otherwise requires, phrase " dry grinding " or modification such as " dry grinding " should be managed Solve and be ground in the case of a liquid at least substantially not depositing to be referred to.If there is liquid, they are so that grinder Content keeps the amount of the characteristic of dry powder to exist.

Term " triturable " refers to that under the conditions of the dry grinding of method of disclosure grinding matrix can be reduced size. In one embodiment of the disclosure, milled grinding matrix has the particle diameter suitable with Abiraterone acetate.In the disclosure Another embodiment in, the particle diameter of matrix is significantly reduced, but little not as Abiraterone acetate.

It will be understood by those skilled in the art that in addition to those for specifically describing, disclosure described herein can be carried out Change and modifications.It should be appreciated that the disclosure includes all such change and modifications.The disclosure is also included either individually or collectively All steps, feature, composition and the material for referring in the description or indicating, and the step or any and institute in feature Have combination or any two or more.

The disclosure is not limited to the scope of specific embodiment only for the purposes of illustration described herein.It is functionally equivalent Product, composition and method obviously in the range of disclosure described herein.

By reading subsequent description, other aspects and advantage of the disclosure for those skilled in the art will become it is aobvious and It is clear to.

Description of the drawings

Fig. 1 is the granularity of the Abiraterone acetate of the formula 1 of the Abiraterone acetate and embodiment 1 do not ground and formula 2 The figure of analysis result.

Fig. 2 is the figure of the dissolution rate measurement result of Abiraterone acetate tablet as described in example 3 above.

Fig. 3 A and 3B are the figures of the result for describing the stability study described in embodiment 6.

Specific embodiment

Granularity

For the measurement carried out using laser diffraction, term " median particle diameter " is defined as on equivalent spherical particle volume basis The median particle diameter of upper measure.In the case of using term intermediate value, it is thus understood that describe that colony is split into two halves so that The particle diameter of the size is more than or less than based on the 50% of volume colony.Median particle diameter is written as：[D₅₀] or D_[50]Or [D50], D50, D (0.50) or D [0.5] are similar.As used herein [D₅₀] or D_[50]Or [D50], D50, D (0.50) or D [0.5] or similar it is considered as referring to median particle diameter.

Term " Dx of size distribution " is referred to based on the xth percentile of the distribution of volume；Therefore, D90 refers to the 90th percentage Digit, D95 refers to the 95th percentile, etc..By taking D90 as an example, this can generally be write as [D₉₀] or D_[90]Or [D90], D (0.90) Or D [0.9] or similar.With regard to median particle diameter and Dx, capitalization D or small letter d is interchangeable and with identical implication.Description passes through Another usual way of laser diffraction or the size distribution of equivalent method known in the art measurement is how many % of description distribution It is below specified size or more than specified size.Term " percentage is less than ", is also written as " %<", it is defined as by volume The percentage of the size distribution under specified size, such as %<1000nm.Term " percentage is more than ", is also written as " %>", definition The percentage of the size distribution to exceed specified size by volume, such as %>1000nm.Term D (3,2) is referred to as area and adds Weight average size or Sauter diameters；Term D (4,3) is referred to as volume weighting average-size.How these values detailed is calculated Description is known in the art, and can be in such as ISO 9276-2:Find in 2014 (E).

For many materials of experience disclosed method, particle diameter is easily measured.When active material has the water of difference When dissolubility and its matrix ground wherein have good water-soluble, powder can be simply dispersed in aqueous solvent. In this case, stromatolysis and leave dispersion active material in a solvent.May then pass through such as PCS or laser to spread out The commercial measurement the penetrated suspension.

Survey in the case where the tangible water-soluble or matrix of active material tool has low solubility in aqueous dispersion agent The appropriate method for measuring accurate particle diameter is summarized as follows.

1. in the case that wherein insoluble matrix such as microcrystalline cellulose prevents the measurement of active material, it is possible to use such as The isolation technics for filtering or being centrifuged separates insoluble matrix with active material particle.Also need to other ancillary techniques to determine Whether any active material is eliminated by isolation technics, so as to take into account.

2. in the case where active material is excessively dissolved in water, other solvents can be evaluated to determine particle diameter.Can find Active material be insoluble in wherein but be matrix the solvent of good solvent in the case of, measurement will be relatively easy.If be difficult to Such solvent is found, another kind of method is measurement matrix and active material in both undissolved solvents (such as isooctane) In set.Then, wherein but active material is solvable measures powder in the insoluble another solvent of matrix.Therefore, By measuring matrix particle size and measuring the size of matrix and active material together, it is possible to obtain to active substance particle size Understanding.

3. in some cases, it is possible to use graphical analysis is obtaining the information of the size distribution with regard to active material.Close Suitable image measurement technology can include transmission electron microscope (TEM), SEM (SEM), light microscope and Laser Scanning Confocal Microscope.In addition to these standard techniques, in addition it is also necessary to be used in parallel some other technologies to distinguish active material And matrix granule.According to the chemical composition of involved material, possible technology can be elementary analysis, Raman spectrum, FTIR Spectrum or fluorescence spectrum.

Improve dissolution characteristic

The method causes Abiraterone acetate to have the dissolution characteristic for improving.The dissolution characteristic of improvement has significant excellent Point, including in some cases, improving Abiraterone acetate bioavilability in vivo.For determining the external molten of material The standard method for going out curve is obtainable in this area.Determining the appropriate method of the dissolution characteristic of improvement in vitro may include to survey Determine concentration of the specimen material within a period of time in solution, and will be compared from the result of specimen material and control sample. It was observed that realizing that the peak value solution concentration of specimen material shows that specimen material has within the shorter time compared to control sample The dissolution characteristic of improvement.Test sample can be containing the Abiraterone acetate for carrying out disclosed method as herein described And grind matrix and/or other additives and prepare the unit dosage forms of the excipient of final formulation.Herein, control sample can With the component identical physical property for being with measure in sample, and sample identical active material, matrix and/or add with measurement Plus the relative scale of agent.Control sample can also be commercially available formulation,Tablet, it cuts to show and test The Abiraterone acetate of sample equivalent.For determine material improvement in vivo dissolution characteristic standard method in the art It is obtainable.

Crystallization property

The method of the crystallization property for determining Abiraterone acetate is broadly available in this area.Suitable method May include X-ray diffraction, differential scanning calorimetry and Raman or IR spectrum.

Amorphous characteristic

The method for determining the content of amorphous of Abiraterone acetate is that this area is widely available.Suitable method may include X-ray diffraction, differential scanning calorimetry and Raman or IR spectrum.

Grinding matrix

As will be described later, suitable grinding matrix is selected to provide particularly advantageous application for disclosed method. Again, as will be described later, the highly advantageous aspect of the disclosure is to be suitable for the grinding of some of disclosed method Matrix can be also suitably used in medicine.The disclosure is included for production containing both Abiraterone acetate and grinding matrix or at some In the case of the method for medicine of Abiraterone acetate and part grinding matrix, the medicine that so produces and using the medicine Treatment method.Medicine can only include the Abiraterone acetate of grinding and the grinding matrix of grinding, or it is highly preferred that grind The Abiraterone acetate of mill and the grinding matrix of hardness can be with one or more pharmaceutically acceptable carrier and any institutes The excipient for needing or other the similar agent combinations for being commonly used for preparing medicine.

In some cases, at least one component for grinding matrix is harder than Abiraterone acetate, and therefore, it is possible in this public affairs Reduce the particle diameter of Abiraterone acetate under the conditions of the dry grinding opened.Equally it is not wishing to be bound by theory, in these cases, it is believed that can The grinding matrix of grinding by the second approach provide the disclosure advantage, wherein under the conditions of dry grinding produce grinding matrix compared with Little particle can realize the bigger interaction with Abiraterone acetate.Grinding discrete phase is for the amount of Abiraterone acetate amount And the degree of the mechanical degradation of grinding matrix be enough to reassociating for the particle of inhibitory activity material.In some embodiments, grind Mill discrete phase be enough to inhibitory activity material grainses for the degree that the amount and grinding substrate size of Abiraterone acetate amount reduce Reassociate.As described above, grinding matrix can include one or more antioxidant and/or one or more chelating agent.

In some embodiments, there is low aggregation to be inclined to during dry grinding to grind matrix.Although being difficult to objectively measure Change the aggregation tendency during grinding, it is possible that by the observation grinding matrix when dry grinding is carried out in the grinding chamber of grinding machine " caking " level is obtaining subjective measurement.

Grinding matrix can be inorganic or organic substance.

Abrasive body

In disclosed method, when using abrasive body, abrasive body is preferably chemically inert and rigid.This paper institutes Term " chemical inertness " refers to that abrasive body does not occur chemical reaction with Abiraterone acetate or grinding matrix.

As described above, abrasive body substantially resistance to fracture and erosion in process of lapping.

Abrasive body preferably can have any one of various smooth, regular shapes, flat or curved surface, and The form of the body without sharp or raised edge is provided.For example, suitable abrasive body can be with it is oval, avette, The form of spherical or right cylindrical body.In some embodiments, abrasive body with one or more pearl, ball, ball, rod, Right cylinder, drum type or radius rectify cylinder (that is, with the right cylinder with the domed bottom of cylinder identical radius) Form provide.

According to Abiraterone acetate and the property of grinding matrix, abrasive body ideally has between about 0.1 and 30mm, more It is preferred that about 1 and about between 15mm, even more preferably from the effective average diameter between about 3 and 10mm.

Abrasive body can include the various materials of particle form, such as ceramics, glass, metal or polymer composition.Close Suitable metal grinding body be typically it is spherical and generally have good hardness (i.e. RHC 60-70), circularity, high-wearing feature and Narrow Size Distribution, and can include for example by 52100 type chromium steel, 304,316 or 440C types stainless steel or 1065 type high-carbon The ball of steel making.

For example, ceramics can be selected from ceramics miscellaneous, and they ideally have enough hardness and resistance to fracture, with Allow them to avoid in process of lapping fragmentation or crushing and also with sufficiently high density.For the suitable of abrasive body Density range can be from about 1 to 15g/cm³, preferably from about 1 to 8g/cm³.Ceramics can selected from saponite, aluminum oxide, zirconium oxide, Zirconia-coated silica, the zirconium oxide of stabilized with yttrium oxide, the zirconium oxide of stabilized magnesium hydroxide, silicon nitride, carborundum, cobalt are stable Tungsten carbide etc., and their mixture.

Glass grinding body is spherical (such as pearl), is durable with narrow Size Distribution, and including for example, nothing Lead soda-lime glass and borosilicate glass.The abrasive body of polymerization is preferably essentially spherical, and can be selected from wide scope Fluoropolymer resin, it there is enough hardness and fragility to enable them to avoid fragmentation or crushing during grinding, has Enough wearabilities cause the abrasion of product pollution, and the impurity without such as metal, solvent and residual monomer to minimize.

Abrasive body can be formed by fluoropolymer resin.Fluoropolymer resin can for example be selected from the polystyrene of crosslinking, for example With the polystyrene of divinyl benzene crosslinked, styrol copolymer, polyacrylate such as polymethyl methacrylate, poly- carbonic acid Ester, polyacetals, vinyl chloride-base polymer and copolymer, polyurethane, polyamide, high density polyethylene (HDPE), polypropylene etc..Using polymerization Material is ground to very little particle diameter (contrary with Mechano-chemical Synthesizing) and is disclosed such as United States Patent (USP) 5 by thing abrasive body, In 478,705 and 5,500,331.Fluoropolymer resin could generally have scope from about 0.8 to 3.0g/cm³Density.Generally preferably More highdensity fluoropolymer resin.Or, abrasive body can be included in answering for the densification core body that is stained with polymer resin thereon Fit (composite body).Slug particle can be selected from the known material that can be used as abrasive body, for example glass, aluminum oxide, Zirconia silica, zirconium oxide, stainless steel etc..Core material has greater than about 2.5g/cm³Density.

In an embodiment of the invention, abrasive body is formed by ferromagnetic material, so as to contribute to by using magnetic Property isolation technics come remove by abrasive body abrasion produce pollutant.

Each type of abrasive body has the advantages that oneself.For example, metal has highest proportion, and it is due to rushing for increasing Hit energy and improve grinding efficiency.From low to high, but the metallic pollution of final products is probably a problem to metal cost.From From the point of view of low cost and as little as the availability viewpoint of the bead size of 0.004mm, glass is favourable.However, the proportion of glass is low In other abrasive bodies, and need significantly more milling time.Finally, ceramics are from low abrasion and pollution, easy to clean and height It is favourable from the viewpoint of hardness.

Dry grinding

In the dry grind process of the disclosure, in the case of with or without multiple abrasive bodies, by shapes such as crystal, powder The Abiraterone acetate and grinding matrix of formula is combined with proper ratio in churned mechanically grinding chamber, wherein mechanical agitation c The predetermined stirring intensity persistently predetermined time.Generally, using milling apparatus by the outside stirring for applying, dry gas stream or Other power to the content of the grinding machine comprising any abrasive body gives motion, thus by various translations, rotation or return motion or Its combination application is in grinding chamber and its content；Or by via the rotation terminated in blade, screw, impeller or blade Axle inside applies stirring and gives motion；Or by the combination of two kinds of effects.

In process of lapping, give abrasive body motion or flow through grinding system gas can cause apply shearing force and There is obvious intensity between the particle of abrasive component, any abrasive body for being used and Abiraterone acetate and grinding matrix Various impacts or collision.The property and intensity for putting on the power of Abiraterone acetate and grinding matrix is subject to various machined parameters Affect, including：The type of milling apparatus；The intensity of the power of generation；The kinematics aspect of process；Any grinding for being used The size of body, density, shape and composition；The weight of Abiraterone acetate and grinding substrate mixture and any abrasive body for being used Amount ratio；The grinding duration；The physical property of both Abiraterone acetate and grinding matrix；The atmosphere existed during grinding； And other factors.

Advantageously, grinding machine can Dichlorodiphenyl Acetate abiraterone and grinding matrix repeat or it is continuous apply mechanical compression force and Shear stress.In the remainder of this specification, refer to be dry grinded by ball mill.The example of such grinding machine It is grater, nutating mill, tower grinding machine, planetary mill, vibromill, gravity dependent form ball mill, jet mill, rod mill, roller Grinding machine or disintegrating machine, jet mill and crushing mill.It should be appreciated that can also pass through any according to the dry grinding of disclosed method Suitable Ginding process or means are realized.

In some cases, the particle diameter of Abiraterone acetate is less than about before the dry grinding according to method described herein 1000 μm, as determined by sieve analysis.If the particle diameter of Abiraterone acetate is greater than about 1000 μm, preferably in basis Before the dry grinding of methods described herein, the particle diameter of Abiraterone acetate matrix is decreased to using another kind of method for reducing particle diameter Less than 1000 μm.

The aggregation of Abiraterone acetate after processing

Aggregation comprising the Abiraterone acetate particle with the particle diameter specified herein in scope is appreciated that Enter in the scope of the present disclosure, regardless of whether whether the aggregation exceedes the scope of above-mentioned regulation.

Process time

In some embodiments, the shortest time needed for Abiraterone acetate and grinding matrix dry grinding is come with minimizing Any possible pollution of self-grind process and/or any abrasive body for being used.The time is according to Abiraterone acetate and grinds Grind the different of matrix and change very big, and its scope may be as little to 1 minute to a few houres.

Type and size, any grinding medium that used of appropriate stir speed (S.S.) and total milling time for milling apparatus Weight ratio, the vinegar of the type and size of matter, Abiraterone acetate and grinding substrate mixture and the multiple abrasive bodies that may be used Sour abiraterone is adjusted with the chemical and physical features for grinding matrix and the other specification that can rule of thumb optimize.

In some embodiments, grind matrix (material ground together with Abiraterone acetate) not with acetic acid Ah's bit Dragon separates, but is retained in final product together with Abiraterone acetate.In some embodiments, grinding matrix is considered as For drug products are to be generally viewed as safe (GRAS).

At selectable aspect, grinding matrix is separated with Abiraterone acetate.In one aspect, when grinding matrix not by When being fully ground, the grinding matrix do not ground is separated with Abiraterone acetate.On the other hand, by the grinding matrix milled At least a portion is separated with Abiraterone acetate.

Can remove any part of grinding matrix, including but not limited to 10%, 25%, 50%, 75% or substantially institute Some grinding matrix.

In some embodiments of the disclosure, the grinding matrix that most of Jing mills can containing size similar to/ Or less than the particle of the particle containing Abiraterone acetate.When what Jing detached with the particle containing Abiraterone acetate was milled Grinding matrix part comprising size similar to and/or less than the particle containing Abiraterone acetate particle when, do not apply to base In the isolation technics of size distribution.In these cases, disclosed method can relate to by include but is not limited to electrostatic separation, The technology of Magnetic Isolation, centrifugation (Density Separation), hydrodynamics separation and froth flotation is ground milled at least partially Mill matrix is separated with Abiraterone acetate.Advantageously, the milled grinding base of at least a portion is removed from Abiraterone acetate The step of matter, can be carried out by such as selective dissolution, washing or the method for distilling.

In some cases, it is possible to use the grinding matrix with two or more components, wherein at least one component It is that water miscible and at least one component has low solubility in water.In which case it is possible to use washing to remove Water-soluble matrix components, and Abiraterone acetate is dispersed in remaining matrix components.In the highly advantageous of the disclosure Aspect, the matrix with low solubility is functional excipients.

In some cases, the grinding matrix being suitable to used in disclosed method is also pharmaceutically acceptable, and Therefore it is suitable in medicine.When disclosed method is not related to be kept completely separate grinding matrix with Abiraterone acetate, this Disclosure include for method of the production comprising Abiraterone acetate and the medicine of the milled grinding matrix of at least a portion, The medicine that so produces and by the medicine treated using the Abiraterone acetate of therapeutically effective amount animal (including People) method.

Abiraterone acetate and composition

The disclosure include according to disclosed method produce pharmaceutically acceptable material, including the group of such material Compound, including the grinding matrix containing this material and with or without grinding aid, the composition of promotion reagent, has At least a portion grinding matrix is separated with grinding matrix.

Medicine

The medicine of the disclosure can contain pharmaceutically acceptable material, optionally grind with grinding matrix or at least a portion Mill matrix together, with or without grinding aid, promotes reagent, and it is with one or more pharmaceutically acceptable carrier and logical Other reagents for being usually used in preparing pharmaceutically acceptable composition combine.

As used herein " pharmaceutically acceptable carrier " includes that any and all solvent of physical compatibility, dispersion are situated between Matter, coating, antiseptic and antifungal agent, isotonic agent and absorption delaying agent etc..In some embodiments, carrier is suitable to parenteral Administration, intravenous, intraperitoneal, intramuscular, sublingual, lung, percutaneous or oral administration.Pharmaceutically acceptable carrier is included for facing When prepare the aseptic aqueous solution or dispersion and aseptic powdery of sterile injectable solution or dispersion.This medium and reagent are used for The purposes for preparing medicine is well known in the art.Unless any conventional media or reagent and pharmaceutically acceptable material not phase Hold, then consider its use in the pharmaceutical composition according to the disclosure is prepared.

One or more following Examples can be included according to the pharmaceutically acceptable carrier of the disclosure：

(1) surfactant and polymer, including but not limited to, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), Lauryl sodium sulfate, polyvinyl alcohol, Crospovidone, polyvinylpyrrolidone-polyethylene acrylate copolymer, cellulose spread out Biology, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethylethylcellulose, hydroxypropyl methyl cellulose O-phthalic Acid esters, polyacrylate and polymethacrylates, urea, sugar, polyalcohol and its polymer, emulsifying agent, carbohydrate gum, starch, have Machine acid and its salt, vinyl pyrrolidone and vinyl acetate；

(2) adhesive, such as various celluloses and PVPP, microcrystalline cellulose；And/or

(3) filler, such as lactose monohydrate, Lactis Anhydrous, microcrystalline cellulose and various starch；And/or

(4) lubricant, for example, act on the reagent of the mobility of powder to be compressed, including cataloid, talcum, hard Resin acid, magnesium stearate, calcium stearate, silica gel；And/or

(5) sweetener, such as any natural or artificial sweetener, including sucrose, xylitol, saccharin sodium, honey element, Aspartame and acesulfame potassium K；And/or

(6) flavor enhancement；And/or

(7) preservative, such as potassium sorbate, methyl p-hydroxybenzoate, propylparaben, benzoic acid and its salt, Other esters of P-hydroxybenzoic acid such as butyl p-hydroxybenzoate, alcohol such as ethanol or benzylalcohol, phenols chemicals such as phenol or season Ammonium compounds such as benzalkonium chloride；And/or

(8) buffer；And/or

(9) diluent, such as pharmaceutically acceptable inert filler, such as microcrystalline cellulose, lactose, calcium monohydrogen phosphate, Carbohydrate and/or any aforesaid mixture；And/or

(10) wetting agent, such as cereal starch, farina, cornstarch and modified starch and its mixture；And/or

(11) disintegrant；Such as Ac-Di-Sol, Crospovidone, primojel；And/or

(12) effervescent agent, such as effervesce agent companion (Effervescent Couple), such as organic acid (for example, lemon Acid, tartaric acid, malic acid, fumaric acid, adipic acid, butanedioic acid and alginic acid and acid anhydrides and acid salt), or carbonate (such as carbonic acid Sodium, potassium carbonate, magnesium carbonate, sodium glycine carbonate, 1B carbonate and arginine carbonate) or bicarbonate (such as carbon Sour hydrogen sodium or saleratus)；And/or

(13) other pharmaceutically acceptable excipient.

The actual dose level of disclosed Abiraterone acetate can according to the property of Abiraterone acetate and due to There is provided and apply Abiraterone acetate advantage and potential raising effect (for example, the solubility of increase, faster dissolution, Surface area of the Abiraterone acetate of increase etc.) and change.Therefore, as used herein " therapeutically effective amount " is referred in animal Realize the amount of the Abiraterone acetate needed for therapeutic response.To this application, effectively amount will be depended on：Required therapeutic effect； Method of administration；The effect of Abiraterone acetate；The required treatment duration；The stage of the disease treated and seriousness；Suffer from The body weight and general health of person；With the judgement of prescriber.

The pharmacokinetic property of Abiraterone acetate composition

What is absorbed quickly starts

In some embodiments, the Abiraterone acetate composition of the disclosure is rapidly absorbed.In an example, when When the Abiraterone acetate composition of the disclosure is administered into the adult male under fasted conditions, it has less than about 2.5 little When (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, it is less than about 1.25 little When and greater than about 1.0 hours, such as T between 1.5 and 2.0 hours_max。

The bioavilability of raising

With the existing conventional composition applied with same dose (for example,) compare, the acetic acid Ah ratio of the disclosure Special dragon composition shows the bioavilability (AUC) of raising and needs less dosage.In some cases, can thanRealize under lower dosage similar toAUC and/or Cmax.Therefore, in some cases, with thanThe pharmaceutical composition as herein described that low dosage is applied provides suitable system exposure.For example, 500mg dosage Can be with bioequivalence in 1,000mg dosageAny pharmaceutical composition can have unfavorable side effect.Therefore, wish What is hoped is the relatively low medicine agent of the identical or more preferable therapeutic effect that can be obtained be observed with the conventional composition of larger dose Amount.This relatively low-dose can be realized with the composition of the disclosure, because compared with traditional drug formulations, being observed with said composition To higher bioavilability be intended to less drug dose to obtain desired therapeutic effect.

The pharmacokinetic property of the composition of the disclosure can less be subject to taking food for the experimenter of intake composition Or the impact of fasted conditions

The disclosure includes Abiraterone acetate composition, wherein withCompare, absorb the experimenter of said composition Feed or fasted conditions little effect said composition Pharmacokinetic Characteristics.This means when said composition is relative to take food When fasted conditions are applied, there is smaller difference in the amount or composition absorption rate of said composition.Therefore, in some cases, WithCompare, the composition of the disclosure reduces impact of the food to the pharmacokinetics of composition.

The pharmacokinetic property of the composition of the disclosure can show the inter-patient variability of reduction

In some cases, for Abiraterone acetate formulation as herein described, wherein C_max、AUC_0-tAnd AUC_0-∞In The geometric average coefficient of variation of one or more can be less thanTherefore, C_max、AUC_0-tAnd AUC_0-∞In one Or multiple geometric average coefficient of variation can compareLow 10%-50% (low by least 10%, low 10%-30% or Low 10%-20%).(it is calculated as CV- CV (formulation of the present invention)/CV× 100%).

Pharmacokinetic scheme

Any standard pharmacokinetic scheme can be used for after said composition is applied determining the PC point in human body Cloth, and thereby determine that whether said composition meets pharmacokinetics standard as herein described.It is, for example possible to use one group health into Year people experimenter carries out random single dose crossing research.The quantity of experimenter should be enough to be provided in statistical analysis fill variation Sub-control system, and typically about 10 or more, although for some purposes, less group is probably enough.Each experimenter, The about 8 a.m. generally after overnight fast, in time point 0 by the Orally administered test for receiving single dose (such as 100mg) Composite preparation.Experimenter continues fasting, and the posture about 4 hours of being kept upright after composition is applied.(example before administration Such as, 15 minutes) and after application several time intervals from each experimenter's collect blood sample.It is little first for this purpose When it is interior take several samples, and afterwards with lower frequency sampling.Illustratively, can upon administration 15,30,45,60 and 90 minutes Collect, then 2 to 10 hours collect blood samples per hour upon administration.Other blood sample, example can also subsequently be gathered Such as, upon administration 12,24,36 and 48 hours.If being used for the research of the second test formulation with identical experimenter, applying Should be through the time period of at least 7 days before second preparation.By the way that the separated plasma from blood sample is centrifuged, and by checking The composition of the blood plasma of high performance liquid chromatography (HPLC) or liquid chromatography mass (LCMS) method Analyze ＆ separate.The combination being mentioned above The PC of thing means the total concentration for including free and combination composition.

The method of application of the medicine containing Abiraterone acetate

The medicine of the disclosure can in any pharmaceutically acceptable mode, for example orally, rectum, lung, intravaginal, local It is (powder, ointment or drops), percutaneous, parenteral, intravenous, intraperitoneal, intramuscular, sublingual or as oral cavity or nose spray, It is applied to animal, including people.

Solid dosage forms for being administered orally includes capsule, tablet, pill, pulvis, micropill preparation and granule.Additionally, mixing Enter any excipient being usually used, such as those listed above, and the generally bioactivator of 5-95%, and more preferably with The concentration of 10%-75%, will form pharmaceutically acceptable nontoxic Orally administered composition.

If however, Abiraterone acetate is used in liquid suspension, once solid carrier is substantially removed, contained The particle for having Abiraterone acetate may need further to stablize, to guarantee to eliminate particle aggregation or at least minimize it.

Embodiment

The preparation of the fine grained Abiraterone acetate powder blend of embodiment 1.

With the percentage shown in table 1 in the presence of lactose monohydrate and lauryl sodium sulfate by Abiraterone acetate Dry grind to produce the pharmaceutical product intermediate for preparing tablet.By the material of two batches with 0.5 gallon of chuck cooling tank Union Process 1S graters in grind.200g dispensings are ground 40 minutes with abrasive body.

Table 1：For preparing the pharmaceutical product intermediate of tablet

Embodiment 2：Mill and Abiraterone acetate that is not grinding grain size analysis

Using the granularities of MAZ3000 types Malvern Mastersizer 3000 for being furnished with the wet sample dispersion units of Hydro MV Analyzer, by the acetic acid Ah's bit in two kinds of pharmaceutical product intermediary material batches described in light scattering measurement embodiment 1 The size distribution of dragon.In addition, the non-grinding and mixing of measurement Abiraterone acetate, lactose monohydrate and lauryl sodium sulfate Thing.Make to measure all three sample with the following method：The dispersant for being used is the aqueous solution of 0.1% PVP K30.Will about 20mg sample powders and 5mL dispersants are added in plastic centrifuge tube.Then swivelling pipe was opened and 15 seconds with dispersion powders with 5 seconds The ultrasonic circulation of closing is with 1 point of 20% amplitude ultrasonically treated (Branson digital supersonics instrument 250 is furnished with 102C type sonic probes) Clock.Particle Size Analyzer sample dispersion unit is filled dispersant and sample is moved into reservoir, until reaching 5-15% by pipette Target masking (obscuration) and keep constant.Agitator is with 1500rpm operations, and collects data 10 seconds.Carry out three The secondary mean value for measuring and reporting each grain size parameter.Table 2 and Fig. 1 show size distribution；The data display particle diameter reduces 10 More than times.

Table 2. does not grind and Abiraterone acetate that is milling size distribution

Embodiment 3：The preparation of tablet and compare dissolution study

The pharmaceutical product intermediate milled is combined with intra-granular excipient, and dry method system is carried out using roll-in and grinding Grain.Particle is mixed with extra-granular excipient, and suppresses to obtain with composition shown in table 3 in rotary tablet machine 100mg Abiraterone acetate pieces.

The Abiraterone acetate 100mg tablets of table 3. are constituted

Using listing on FDA websites for Abiraterone acetate tablet, the method for 250mg measures piece prepared as described above The dissolution rate of agent；USP apparatus IIs, 50rpm is buffered in the pH 4.5 of the 900mL with 0.25% lauryl sodium sulfate In liquid.Sample is analyzed under 270nm by UV.In addition, in order to omparison purpose, testing under identical leaching conditionTablet.The result of the analysis is shown in table 4 and Fig. 2.For two kinds of tablets containing the Abiraterone acetate milled Preparation, realize within 10-20 minutes complete dissolution (>85% dissolution), compared to dissolution complete in 60 minutes (>85% dissolution) 's

The dissolution of the Abiraterone acetate tablet of table 4.

Embodiment 4：For the Abiraterone acetate tablet that the initial I phases are studied

To measure Abiraterone acetate of dry grinding in the presence of lactose monohydrate and lauryl sodium sulfate shown in table 5, To produce the pharmaceutical product intermediate for preparing the tablet used in the I phases test.By material cold with 1.5 gallons of chucks But grind in the Union Process 1S graters of tank.The material is ground 40 minutes with abrasive body.

Table 5：For preparing the pharmaceutical product intermediate of the tablet tested for the I phases

Components Name and grade	Percentage by weight	Amount/crowd (g)
			Abiraterone acetate	30.00	300.0
Lactose monohydrate, USP	67.75	677.5
			Lauryl sodium sulfate, NF	2.25	22.5
It is total	100.00	1000.0

Using the Micromeritics Saturn DigiSizer II 5205 for being configured with AquaPrep II sample cells The size distribution of the Abiraterone acetate in the pharmaceutical product intermediate of degree analyzer measurement grinding.The sample reservoir filling of instrument There is dispersant solution (0.1% PVP K30).The glass of 30mL is added by the dispersant of the powder that grinds 100mg and 20mL Sample is prepared in glass bottle.By disperseing particle with pipette stirring, then the bottle added a cover is placed in into ultrasonic water bath (Branson Ultrasonic bathe, model 5510-MT, export 135W, 42KHz) in cause bath water the half for being positioned horizontally in bottle side Place.Then sample ultrasonic is processed 30 minutes.Scattered sample is added dropwise in the reservoir of fluid sample processing unit, until Reach about 7% shading values.Internal sonic probe is run 300 seconds with 100% intensity, and and then is followed in sample before Data Collection Ring 120 seconds.When shading values are between 5 and 10%, in the case where 65 ° of beam angles are arranged data are collected.Each is measured in triplicate, And report three times measurement mean value.The granularity data of the powder for carrying out self-grind is reported in table 6.

Table 6：The Abiraterone acetate granularity of grinding

Grain size parameter	As a result (micron)
		D₁₀	0.105
D₅₀	0.387
		D₉₀	1.308
D_4,3	0.588
		D_3,2	0.247

The pharmaceutical product intermediate of grinding is combined with intra-granular excipient, and dry method system is carried out using roll-in and grinding Grain.Particle is mixed with extra-granular excipient, and suppresses to obtain with composition shown in table 7 in rotary tablet machine 100mg Abiraterone acetate tablets.

Table 7：For the Abiraterone acetate 100mg tablets composition of test of initial 1 phase

Composition	%w/w	Mg/ pieces
			Abiraterone acetate	14.29	100.0
Lactose monohydrate, NF	32.26	225.8
			Lauryl sodium sulfate, NF	1.42	10.0
Microcrystalline cellulose, NF	44.53	311.7
			Ac-Di-Sol, NF	7.00	49.0
Sodium stearyl fumarate, NF	0.50	3.5
			It is total	100.00	700.0

In USP apparatus IIs in the buffer solutions of pH 4.5 of the 900mL with 0.1%SLS, measure in 75rpm as described above The dissolution rate of the tablet of preparation.Sample is analyzed by HPLC.In addition, in order to omparison purpose, surveying under identical leaching condition ExaminationTablet.BecauseTablet is 250mg, the solubility limit of its close dissolution medium, so by piece Agent cuts into the weight for being equal to 100mg Abiraterone acetates.Measured under 270nm using UVSample.The analysis Result be shown in Table 8；Realized in 5 minutes prepared tablet complete dissolution (>85% dissolution), andPiece Agent dissolution was realized in 20 minutes.

Table 8：The dissolution of 100mg Abiraterone acetate tablets

Embodiment 5：With 1000mg'sCompare the Abiraterone acetate preparation of 100,200 and 400mg dosage The I phases are studied

In healthy male patient in fasted condition test 100mg, 200mg and 400mg dosage (respectively 1,2 or 4 × 100mg tablets) the Abiraterone acetate 100mg tablet formulations for preparing as described in example 4 above.In identical research, survey Examination 1000mg dosage (4 × 250mg tablets)The result of the research is shown in Table 9.

Table 9：Abiraterone acetate piece 100mg pharmacokinetic datas (arithmetic mean of instantaneous value)

* it was observed that difference four kinds process in be highly significant (p<0.0001, ANOVA).

The difference that ^ is observed is significant (p<0.05, Wilcoxon symbol rank is checked), with 1,000mg'sCompare.

Embodiment 6：The stability of Abiraterone acetate powder blend and tablet

After with lactose monohydrate and lauryl sodium sulfate dry grinding Abiraterone acetate, 0.2- is detected by HPLC The total impurities of 0.6%AUC increases.When will grinding Abiraterone acetate powder blend (or pharmaceutical product intermediate；“DPI”) When being processed further piece agent, it is found that impurity level is higher, about 0.5-1.1%.Stability test show impurity 25 DEG C/ Increase under 60%RH and 40 DEG C/75%RH, but do not increase at 2-8 DEG C.Additionally, the impurity in tablet increases the DPI than grinding In impurity increase fast.Table 10 and Fig. 3 A and 3B (rhombus, 5 DEG C；Square, 25 DEG C/60%RH；And triangle, 40 DEG C/75%RH) There is provided the overview of impurity level in the DPI batches and tablet ground in accelerated stability test.The tablet tool of stored frozen There is acceptable low-level impurity, it is desirable to have the preparation that can be stored at ambient conditions.

The Abiraterone acetate stability (total impurities) of table 10.

Impurity growth in DPI and tablet containing fine grained Abiraterone acetate is the oxygen due to Abiraterone acetate Change degraded.Test ageingThe purity of (Abiraterone acetate) tablet, and it was found that impurity level ratio contains thin The tablet of the ageing of the Abiraterone acetate of grain is much lower.The faster degraded of the tablet containing fine grained Abiraterone acetate may Produced by many sources, including but not limited to：Bigger API table area, relative to the higher excipient ratios and excipient of API Difference.Further investigation revealed that, API degrades in the presence of excipient with some, but once mixture is ground, drop Solution will be greatly accelerated.Data are provided in table 11.

The Abiraterone acetate stability of table 11.

Embodiment 7：With antioxidant or chelating agent grinding abiraterone

Vinegar is carried out in the presence of lactose monohydrate and lauryl sodium sulfate and various antioxidants and/or chelating agent The dry grinding of sour abiraterone.In a research, dry grinding includes combination or the Butylated hydroxy benzene first of ascorbic acid and fumaric acid The combination of ether (BHA) and Yoshinox BHT (BHT)：Formula is shown in Table 12.Per batch in the chuck cooling tank for having 0.5 gallon Union Process 1S graters in grind.200g batch of materials are ground 40 minutes with abrasive body.When according to institute in embodiment 2 When the method stated passes through light scattering test, two kinds of DPI formulas all contain D₉₀Abiraterone acetate less than 1000nm.

Table 12：DPI preparations containing antioxidant or chelating agent

By adding the excipient specified, dry granulation and compressing tablet in DPI preparations, using two kinds of different DPI formulas To prepare two kinds of different respective tablets preparations as described in detail in table 13.

Table 13：Tablet formulation containing antioxidant or chelating agent

The stability of two kinds of tablet formulations is tested under acceleration conditions.The number that table 14 contains is it was demonstrated that anti-oxidant with not containing The preparation of agent is compared, with antioxidant two kinds of tablet formulations store 3 months under 40 DEG C/75%RH after have significantly improve Stability, the preparation with BHA/BHT almost stops all degradeds.This show during grinding add antioxidant and/or Chelating agent can significantly improve stability.

Table 14. contains and the tablet stability data without antioxidant

Piece is tested in the phosphate buffer of the pH 4.5 that 900ml contains 0.1%SLS with 75rpm using USP apparatus IIs The dissolution rate of Abiraterone acetate in agent formulation Vitamin C agent/fumaric acid and tablet formulation BHA/BHT.All three type Tablet in 10 minutes complete dissolution (>85% Abiraterone acetate dissolution).

Embodiment 8：For the Abiraterone acetate tablet that the other I phases are studied

By dry grinding, Abiraterone acetate, lactose monohydrate, lauryl sodium sulfate, BHA and BHT prepare other medicine Thing product midbody preparation.Grinding is shown in Table 15 with the composition for forming the material of the intermediate.By said preparation in the folder for customizing Grind in 62 gallons of graters of set cooling；Powder blend is ground 72 minutes together with abrasive body.

Table 15：For the pharmaceutical product intermediate of the grinding containing BHA and BHT of 1 phase clinical research

Composition	Percentage by weight	Amount/crowd (g)
			Abiraterone acetate	30.0	8.400
Lactose monohydrate, USP	63.8	17.886
			Lauryl sodium sulfate, NF	6.0	1.680
BHA	0.1	0.028
			BHT	0.1	0.028
It is total	100	28.000

Using the MAZ3000 types Malvern Mastersizer 3000 for being configured with the wet sample dispersion units of Hydro MV Degree analyzer, by the size distribution of Abiraterone acetate in the light scattering measurement pharmaceutical product intermediate.Using two kinds of differences Method measurement size distribution, it is as described below：

Method 1：The dispersant for being used is the 0.1% PVP K30 aqueous solution.About 20mg sample powders and 5mL are disperseed Agent is added in plastic centrifuge tube.By pipe rotation with dispersion powders, then opened with 5 seconds and sonication cycles that 15 seconds close with 20% amplitude ultrasonically treated (Branson digital supersonics instrument 250, with 102C type sonic probes) 1 minute.Particle Size Analyzer sample Dispersal unit is filled with dispersant, and sample is moved into reservoir, until the target for reaching 5-15% is covered and is protected with pipette Hold constant.Agitator collects data 10 seconds with 1500rpm operations.Carry out three times and measure and report each particle size parameters Mean value.

Method 2：The dispersant for using is the aqueous solution containing 0.1% Pluronic/Lutrol F 108 and 0.1% calcium chloride, and it makes Filtered by 0.2 μm of nylon filter with front.About 20mg sample powders and 5mL dispersant solutions are added in vial. Bottle is added a cover and turn is with dispersed powder particles.Then little bottle cap is unclamped, bottle is placed in into sound wave bath (Elma Elmsonic P30H ultra sonic baths) center.Bottle is immersed so that body lotion liquid level higher than dispersant in bottle level, it is but little Bottle does not contact bath tub bottom part.By sample in 37kHz, ultrasonically treated 10 minutes under 100% power.Particle Size Analyzer sample dispersion unit Filled with dispersant, and sample is moved into reservoir with pipette, until obtaining the masking of 5-15% and keeping constant.Agitator With 1500rpm operations, data are collected 10 seconds.Carry out the mean value for measuring and reporting each grain size parameter for three times.

Table 16 is presented using said method 1 and 2, before the grinding and afterwards the pharmaceutical product intermediate described in table 15 (DPI) comparison of the granularity of Abiraterone acetate in.

Table 16：The particle size distribution data of the Abiraterone acetate DPI containing BHA and BHT

The pharmaceutical product intermediate of grinding is combined with intra-granular excipient, and dry method system is carried out using roll-in and grinding Grain.Particle and extra-granular excipient are blended and the compacting in rotary tablet machine, are obtained with the 125mg constituted table 17 Suo Shi Abiraterone acetate tablet.

Table 17：The Abiraterone acetate tablet 125mg compositions of grinding

Component	%w/w	Mg/ pieces
			Abiraterone acetate	14.37	125.00
Lactose monohydrate, NF	30.56	265.83
			Lauryl sodium sulfate, NF	2.87	25.00
BHA (butylated hydroxyanisol), NF	0.05	0.42
			BHT (Yoshinox BHT), NF	0.05	0.42
Microcrystalline cellulose, NF	44.60	388.06
			Ac-Di-Sol, NF	7.00	60.90
Sodium stearyl fumarate, NF	0.50	4.38
			It is total	100.00	870.00

In USP apparatus IIs, in 75rpm, the dissolution of these tablets is measured in the buffer solutions of pH 4.5 with 0.12%SLS Speed.Sample is analyzed by HPLC.The result of the analysis is shown in Table 18；Reached in 10 minutes complete dissolution (>85% is molten Go out).

Table 18：The dissolution of Abiraterone acetate tablet

Time (minute)	The Abiraterone acetate of % dissolutions	%RSD
			5	53	6.6
10	86	3.4
			15	93	3.5
30	95	2.9
			45	95	3.1
60	95	3.0

Embodiment 11：The Abiraterone acetate preparation of 125mg, 500mg and 625mg dosage is compared to 1000mg'sThe I phases study

Test in fasted condition in healthy male patient 125mg, 500mg and 625mg dosage (respectively 1,4 or 5 × 125mg tablets) the Abiraterone acetate 125mg tablets for preparing as described in example 10 above.In identical research, test 1000mg dosage (4 × 250mg tablets)The result of the research is shown in Table 19.

Table 19：Abiraterone acetate piece 125mg pharmacokinetic datas (arithmetic mean of instantaneous value)

Embodiment 12：Other Abiraterone acetate powder and tablet

By dry grinding, Abiraterone acetate, lactose monohydrate, lauryl sodium sulfate, BHA and BHT prepare other medicine Produce product midbody preparation.It is ground the composition to form the material of the intermediate to be shown in Table 16.Two batch materials are with different Processing conditions grinds, and produces slightly different granularity.

Table 16：The pharmaceutical product intermediate of other grinding

Using the granularities of MAZ3000 types Malvern Mastersizer 3000 for being furnished with the wet sample dispersion units of Hydro MV Analyzer, by the size distribution of Abiraterone acetate in light scattering measurement two batches pharmaceutical product intermediate.Using in embodiment 8 Described method 1 obtains the size distribution shown in table 17.

Table 17：The other particle size distribution data of Abiraterone acetate DPI

To be combined with intra-granular excipient from the pharmaceutical product intermediate of the grinding of batch materials 1, and using roll-in and ground Mill carries out dry granulation.Particle and extra-granular excipient are blended, and are suppressed in rotary tablet machine, to obtain with table 18 Shown in constitute 100mg Abiraterone acetate tablets.

Table 18：The Abiraterone acetate tablet 100mg compositions of grinding

In USP apparatus IIs, in 75rpm, the dissolution of these tablets is measured in the buffer solutions of pH 4.5 with 0.1%SLS Speed.Sample is analyzed under 270nm by UV.The result of the analysis is shown in Table 19；Reached in 10 minutes complete dissolution (> 85% dissolution).

Table 19：Abiraterone acetate piece, the dissolution of 100mg

Embodiment 13：The stability of tablet

By dry grinding, Abiraterone acetate, lactose monohydrate, lauryl sodium sulfate, BHA and BHT prepare other medicine Thing product midbody preparation.It is ground the composition to form the material of the intermediate to be shown in Table 20.

Table 20：The pharmaceutical product intermediate of the grinding containing BHA and BHT

Composition	Percentage by weight	Amount/crowd (kg)
			Abiraterone acetate	30.00	7.44
Lactose monohydrate, USP	63.8	15.82
			Lauryl sodium sulfate, NF	6.0	1.49
Yoshinox BHT (BHT)	0.10	0.025
			Butylated hydroxyanisol (BHA)	0.10	0.025
It is total	100.00	24.80

Using the MAZ3000 types Malvern Mastersizer 3000 for being configured with the wet sample dispersion units of Hydro MV Degree analyzer, by the size distribution of Abiraterone acetate in the light scattering measurement pharmaceutical product intermediate.Using in embodiment 8 Described method 1 obtains the size distribution shown in table 21.

Table 21：The other particle size distribution data of the Abiraterone acetate DPI containing BHA and BHT

The pharmaceutical product intermediate of grinding is combined with intra-granular excipient, and dry method system is carried out using roll-in and grinding Grain.Particle and extra-granular excipient are blended, and are suppressed in rotary tablet machine, obtained with composition table 22 Suo Shi 125mg Abiraterone acetate tablets.

Table 22：The Abiraterone acetate tablet 125mg compositions of grinding

Composition	%w/w	Mg/ pieces
			Abiraterone acetate	14.34	125.00
Lactose monohydrate, USP	30.49	265.83
			Yoshinox BHT (BHT)	0.05	0.42
Butylated hydroxyanisol (BHA)	0.05	0.42
			Lauryl sodium sulfate, NF	2.87	25.00
Microcrystalline cellulose, NF	44.69	389.63
			Ac-Di-Sol, NF	7.02	61.25
Sodium stearyl fumarate, NF	0.50	4.38
			It is total	100.00	871.92

Install additional for accelerated stability by tablet packaging and under 40 DEG C and 75% relative humidity.Indicated by stability HPLC methods measure impurity.In USP apparatus IIs, in 75rpm, in the buffer solutions of pH 4.5 with 0.12%SLS these are measured The dissolution rate of tablet.As a result it is shown in Table 23.Jing is not observed impurity for 3 months and increases under 40 DEG C/75%RH, and Through 3 months under 40 DEG C/75%RH, dissolution keeps constant, in 10 minutes complete dissolution (>85% dissolution).

The stability of the Abiraterone acetate tablet 125mg of table 23.

Embodiment 14：Feed or the impact of fasted conditions

Comment in single centre, single dose, random, open-label, 2- stages, 2- treatment crossover pharmacokinetic researchs The impact of the oral administration biaavailability of the abiraterone tablet that valency high fat diet is ground to the 125mg of 500mg dosage.Give first Medicine is interim, after fasting 10 hours, test article is applied to about half experimenter with 240mL water.In the high fat breakfast of standard FDA of taking Give test article to remaining experimenter within about 30 minutes afterwards.After the removing phase of seven days, each experimenter is intersected carries out another controlling Treat.Before test article is applied immediately and 0.25 after test article is applied, 0.5,1.0,1.5,2.0,3.0,4.0,6.0, 8.0th, plasma sample is extracted within 12.0,18.0,24.0 and 48.0 hours.The abiraterone concentration of analysis sample, and result is used In the pharmacokinetic parameter (AUC for calculating each experimenter and treatment_0-∞、AUC_0-tAnd C_max).Survey when applying under fasting state During test product, AUC_0-∞、AUC_0-tAnd C_maxGeometrical mean be respectively 1444.1ngh/mL, 1393.4ngh/mL and 443.7ng/mL, and when being administered under fasted conditions, the geometrical mean of these identical parameters be 322.7ngh/mL, 301.0ngh/mL and 67.9ng/mL.AUC_0-∞、AUC_0-tAnd C_maxRatio (feed/on an empty stomach) be respectively 4.48,4.63 and 6.53。

Claims

1. a kind of unit dosage forms of Abiraterone acetate, the wherein unit dosage forms of 500mg dosage and 1000mg dosageThe bioequivalence in the healthy male subjects of fasted conditions.

2. unit dosage forms of Abiraterone acetate according to claim 1, wherein for the healthy male to fasted conditions Experimenter applies 500mg dosage and applies 1000mg dosage with the healthy male subjects to fasted conditionsCompare, AUC_(0-∞)The ratio of logarithm of geometric average be selected from：0.6 to 1.4,0.7 to 1.3,0.8 to 1.2 and 0.9 to 1.1.

3. unit dosage forms of Abiraterone acetate according to claim 1, wherein for the healthy male to fasted conditions Experimenter applies 500mg dosage and applies 1000mg dosage with the healthy male subjects to fasted conditionsCompare, C_(max)The ratio of logarithm of geometric average be selected from：0.6 to 1.4,0.7 to 1.3,0.8 to 1.2 and 0.9 to 1.1.

4. unit dosage forms of Abiraterone acetate according to claim 1, wherein [D90] of the Abiraterone acetate is big In 300nm and less than one below：7500nm、7000nm、6000nm、5000nm、4500nm、4000nm、3000nm、 2000nm, 900nm, 800nm and 700nm.

5. unit dosage forms of Abiraterone acetate according to claim 1, wherein [D50] of the Abiraterone acetate is big In 100nm and less than one below：3500nm、3000nm、2500nm、1600nm、1400nm、1200nm、1000nm、800nm、 500nm, 400nm and 300nm.

6. unit dosage forms of Abiraterone acetate according to claim 1, wherein [D4,3] of the Abiraterone acetate More than 300nm and less than one below：7000nm、6000nm、5000nm、4000nm、3000nm、2500nm、2400nm、 2200nm, 2000nm, 1900nm, 1700nm, 1500nm, 1300nm, 1100nm, 900nm and 800nm.

7. unit dosage forms of Abiraterone acetate as claimed in claim 1, wherein Abiraterone acetate in the unit dosage forms Dissolution rate cause when use USP apparatus IIs with 75rpm 900ml the pH with 0.1% lauryl sodium sulfate When the sample containing 100mg Abiraterone acetates is tested in 4.5 phosphate buffer, at least 70% Abiraterone acetate exists Between 5 and 15 minutes or dissolution between 5 and 10 minutes.

8. unit dosage forms of Abiraterone acetate according to claim 1, wherein acetic acid Ah bit in the unit dosage forms Dragon dissolution rate cause when use USP apparatus IIs with 75rpm 900ml the pH containing 0.12% lauryl sodium sulfate When the sample of the Abiraterone acetate containing 125mg is tested in 4.5 phosphate buffer, at least 70% Abiraterone acetate Between 5 and 15 minutes or dissolution between 5 and 10 minutes.

9. unit dosage forms of Abiraterone acetate according to claim 1, it contains the Abiraterone acetate of 125mg.

10. unit dosage forms of Abiraterone acetate according to claim 1, wherein when to the health man in fasted conditions During the Orally administered 500mg dosage of the colony of property experimenter, there is provided the average blood plasma C of 50-120ng/ml_max。

11. unit dose formulations according to claim 10, wherein when to the healthy male subjects in fasted conditions Colony's Orally administered 500mg dosage when, there is provided the median plasma t of 1 to 2.5 hour_max。

The unit dosage forms of 12. Abiraterone acetates according to claim 1, wherein when to the health man in fasted conditions During the Orally administered 500mg dosage of the colony of property experimenter, there is provided the average blood plasma AUC of 240-650h*ng/ml_(0-∞)。

13. unit dose formulations according to claim 1, it contains 125mg Abiraterone acetates.

The unit dosage forms of 14. Abiraterone acetates according to claim 1, wherein when receiving to the healthy male of fasted conditions When examination person applies 500mg dosage, average blood plasma C_max90% confidential interval be 50-120ng/ml between value.

The unit dosage forms of 15. Abiraterone acetates according to claim 1, wherein when receiving to the healthy male of fasted conditions When examination person applies 500mg dosage, average blood plasma AUC_(0-∞)90% confidential interval be value between 240 to 650h*ng/ml.

16. unit dosage forms according to claim 14, it contains 125mg Abiraterone acetates.

Unit dosage forms described in 17. any one according to claim 1, it also contains antioxidant.

A kind of 18. unit dosage forms of the Abiraterone acetate containing 125mg Abiraterone acetates, wherein Abiraterone acetate is based on The median particle diameter of particle volume is between 2000nm and 100nm.

19. unit dosage forms according to claim 18, wherein in the unit dosage forms Abiraterone acetate dissolution rate So that when use USP apparatus IIs with 75rpm the pH 4.5 with 0.12% lauryl sodium sulfate of 900ml phosphate When the sample of the Abiraterone acetate containing 125mg is tested in buffer solution, at least 70% Abiraterone acetate was at 5 and 15 minutes Between or dissolution between 5 and 10 minutes.

20. unit dosage forms according to claim 18, wherein when to the healthy male subjects administration in fasted conditions During 500mg dosage, average blood plasma AUC_(0-∞)90% confidential interval be value between 240 to 650h*ng/ml.

21. unit dosage forms according to claim 18, wherein when to the healthy male subjects administration in fasted conditions During 500mg dosage, average blood plasma C_max90% confidential interval be value between 50 to 120ng/ml.

A kind of 22. methods for treating castration-resistant prostate cancer, it includes applying daily 500mg to patient in need The Abiraterone acetate formulation of dosage and glucocorticoid, wherein described in the healthy male subjects in fasted conditions 500mg dosage and 1000mg dosageBioequivalence.

23. methods according to claim 22, wherein the glucocorticoid sprinkles selected from metacortandracin, prednisolone and methyl Ni Songlong.

A kind of 24. methods for producing the composition of the nano particle containing Abiraterone acetate, methods described includes：

Containing multiple abrasive bodies grinder in will containing Abiraterone acetate, can grind polishing compounds, promotion reagent with And one or two the composition in antioxidant and chelating agent is dry grinded one section and be enough to produce containing the thin of Abiraterone acetate The time of the composition of particle,

Wherein reduce the particle diameter of the Abiraterone acetate by dry grinding.

25. methods according to claim 24, wherein containing in the fine grain composition of Abiraterone acetate acetic acid Ah [the D of bit dragon₉₀] more than 100nm and less than one below：3000nm、2000nm、900nm、800nm、700nm、600nm、 500nm, 400nm, 300nm and 200nm.

26. methods according to claim 24 or claim 25, wherein one kind in antioxidant and chelating agent or The grinding is carried out in the presence of two kinds.

27. methods according to claim 3, wherein the antioxidant is selected from ascorbic acid, BHA and BHT.

28. methods according to claim 26, wherein the chelating agent is selected from fumaric acid, tartaric acid and citric acid.

29. methods according to any one of claim 23-28, wherein containing the fine grain combination of Abiraterone acetate Fine grain [the D of Abiraterone acetate in thing₅₀] more than 100nm and less than 2000nm, less than 1600nm, less than 1400nm, be less than 1200nm, less than 1000nm, less than 800nm, less than 500nm, less than 400nm or less than 300nm.

30. methods according to any one of claim 23-29, wherein containing the fine grain combination of Abiraterone acetate Fine grain [the D of Abiraterone acetate in thing_4,3] more than 100nm and less than one below：2500nm、2400nm、2200nm、 2000nm、1900nm、1700nm、1500nm、1300nm、1100nm、1000nm、900nm、800nm、700nm、600nm、 500nm, 400nm and 300nm.

A kind of 31. methods for preparing units dosage composition, it includes：According to any one of the claims Method is prepared and includes the fine grain composition of Abiraterone acetate, will it is described comprising the fine grain composition of Abiraterone acetate and One or more pharmaceutically acceptable diluent, disintegrant, lubricant, glidant or dispersant package.

32. methods according to claim 31, wherein the units dosage composition is tablet or capsule.

33. methods according to claim 32, wherein the units dosage composition contain 90,95,100,105,110, 115th, 120,125,130,135,140,145,150,175,200,225,250,275,300,325,350,375 or 400mg Abiraterone acetate.

34. methods according to claim 33, wherein the dissolution of Abiraterone acetate is fast in the units dosage composition Rate is caused when using USP apparatus IIs, with 75rpm, the test in the phosphate buffers of the pH 4.5 (0.1%SLS) of 900ml contains During the sample of the Abiraterone acetate of 100mg, at least 70% Abiraterone acetate is between 5 and 15 minutes or at 5 and 10 points Dissolution between clock.

35. methods according to claim 33 or 34, wherein the units dosage composition is tablet, and the dissolution Speed causes to work as tests institute with 75rpm using USP apparatus IIs in the phosphate buffer (0.1%SLS) of the pH 4.5 of 900ml When stating tablet, at least 80% Abiraterone acetate is between 5 and 15 minutes or the dissolution between 5 and 10 minutes.

36. a kind of unit dose drug compositions containing Abiraterone acetate, wherein Abiraterone acetate in the composition [D₉₀] more than 100nm and less than one below：5,000nm、4500nm、4000nm、3000nm、2000nm、900nm、 800nm, 700nm, 600nm, 500nm, 400nm, 300nm and 200nm.

37. unit dose drug compositions according to claim 36 the, wherein [D of the Abiraterone acetate₅₀] be more than 100nm and less than 2000nm, less than 1600nm, less than 1400nm, less than 1200nm, less than 1000nm, less than 800nm, be less than 500nm, less than 400nm, less than 300nm.

The 38. unit dose drug compositions according to claim 36 or claim 37, wherein the acetic acid Ah bit [the D of dragon_4,3] more than 100nm and less than one below：2500nm、2400nm、2200nm、2000nm、1900nm、1700nm、 600nm, 500nm, 400nm and 300nm.

39. units dosage compositions according to any one of claim 36-38, wherein in the units dosage composition The dissolution rate of Abiraterone acetate cause when use USP apparatus IIs with 75rpm 900ml the phosphate buffers of pH 4.5 (0.1%SLS) in during sample of the test containing 100mg Abiraterone acetates, at least 70% Abiraterone acetate is at 5 and 15 points Between clock or the dissolution between 5 and 10 minutes.

40. units dosage compositions according to any one of claim 36-39, wherein when being administered to edible low fat diet During the adult male of (7% is fatty, 300 calories), the average AUC of the units dosage composition_0-∞Than applying under fasted conditions Used time is high 2 times or lower.

41. units dosage compositions according to any one of claim 36-40, wherein when being administered to edible high fat diet During the adult male of (57% is fatty, 825 calories), the average AUC of the units dosage composition_0-∞Than under fasted conditions High 2 times or lower during administration.

42. units dosage compositions according to any one of claim 36-41, wherein when being administered to edible low fat diet During the adult male of (7% is fatty, 300 calories), the average C of the units dosage composition_maxThan applying under fasted conditions When high 2 times or lower.

43. units dosage compositions according to any one of claim 36-42, wherein when being applied to edible high fat diet During the adult male of (57% is fatty, 825 calories), the average C of the units dosage composition_maxThan applying under fasted conditions Used time is high 5 times or lower.

44. units dosage compositions according to any one of claim 36-42, wherein when the administration under fasted conditions When, for the C in healthy male patient_maxAnd AUC_0-tOne or both of, the units dosage composition of 500mg dosage and 1, The Zytiga bioequivalences of 000mg dosage.

45. units dosage compositions according to any one of claim 36-44, wherein when the administration under fasted conditions When, for the C in healthy male patient_maxAnd AUC_0-tBoth, the units dosage composition and the 1000mg agent of 500mg dosage The Zytiga bioequivalences of amount.

46. units dosage compositions according to any one of claim 36-45, wherein the units dosage composition contains Have 90,95,100,105,110,115,120,125,130,135,140,145,150,175,200,225,250,275,300, 325th, 350,375 or 400mg Abiraterone acetate.

A kind of 47. methods for treating castration-resistant prostate cancer, it includes applying the acetic acid Ah ratio of daily dosage 100-700mg Special dragon the, wherein [D of the Abiraterone acetate_4,3] more than 100nm and less than one below：2500nm、2400nm、2200nm、 2000nm, 1900nm, 1700nm, 600nm, 500nm, 400nm and 300nm.

48. methods according to claim 47, it includes applying the Abiraterone acetate of 200-600mg.

49. methods according to claim 48, it includes applying the Abiraterone acetate of 300-600mg.

A kind of 50. methods for treating castration-resistant prostate cancer, it includes applying any one of claim 36-47 The Abiraterone acetate of daily dosage 100-700mg of unit dosage forms.

51. methods according to claim 50, wherein Abiraterone acetate of the daily dosage for 500mg.

52. methods according to any one of claim 48-51, it also includes applying glucocorticoid.

53. methods according to claim 52, wherein the glucocorticoid is metacortandracin.

54. methods according to claim 52, wherein the glucocorticoid is prednisolone.

55. methods according to claim 52, wherein the glucocorticoid is methylprednisolone.

Pharmaceutical composition prepared by a kind of 56. methods by including the method any one of claim 23-34.