Abiraterone acetate

Abstract

To provide compositions or drugs containing abiraterone acetate having an improved dissolution profile, where it is known that increasing the rate of dissolution of poorly soluble drugs will, in many cases, increase the rate and extent of oral absorption of such drugs.SOLUTION: Disclosed herein are pharmaceutical compositions, including unit dosage forms, comprising fine particle abiraterone acetate with or without an antioxidant and / or sequestering agent. Also disclosed are methods for producing and using such compositions.SELECTED DRAWING: None

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to a method for producing abiraterone acetate particles using a dry milling process, Compositions containing lateron acetate, compositions made using abiraterone acetate and a therapeutically effective amount of abiraterone acetate administered as said drug. This relates to treatment methods. [Background technology]

[0002] Background of the Invention Low oral bioavailability is a result of poor solubility in water for therapeutic compositions, especially at physiological pH. This is a significant problem encountered in the development of compositions containing active pharmaceutical ingredients. Availability is the degree to which a drug is absorbed into the bloodstream after oral administration. Various factors affect oral bioavailability, including dosage form, solubility, and dissolution rate. Make a sound.

[0003] In therapeutic applications, poorly water-soluble drugs are absorbed into the gastrointestinal tract before being completely absorbed into the blood circulation. Furthermore, such drugs tend to be excreted from the body due to their slow absorption rate. Furthermore, poorly water-soluble drugs tend to have slower therapeutic effects. It is disadvantageous for intravenous administration because of the risk of blocking blood flow within the body. It is often even dangerous.

[0004] Increasing the dissolution rate of poorly soluble drugs often improves the rate of oral absorption of such drugs. It is known that the dissolution rate of particulate drugs increases with increasing surface area. It is also known that the surface area can be increased by increasing the product. Therefore, the surface of the drug particles used in the pharmaceutical composition may be reduced. Micronized or finely sized drugs intended to increase volume and dissolution rate Methods for preparing the agent have been investigated.

[0005] Abiraterone ((3β)-17-(pyridin-3-yl)androsta-5,16-di En-3-ol; CAS number: 154229-19-3; Chemical formula: C 24 H 31 NO; Molecular weight: 349.5 g / mol) is an inhibitor of CYP17 and is involved in the testes, adrenal glands and It blocks androgen synthesis in prostate tumor tissue. It is a prodrug of abiraterone. Abiraterone acetate (17-(3-pyridyl)androsta-5, acetic acid; CA S No. 154229-18-2) is approved in the United States for the treatment of castration-resistant prostate cancer. Abiraterone acetate is considered to be poorly water-soluble.

[0006] Zytiga® tablets (250 mg) are used in combination with prednisone for the treatment of metastatic Approved in the US for the treatment of patients with castration-resistant prostate cancer. Zytiga® Tablets The prescribing information for is 1000 mg once daily (4 x 250 mg tablets) with prednisone twice daily ( In Europe, it is recommended to administer it in combination with oral prednisone. or prednisolone. (trademark) should be taken on an empty stomach and at least 2 hours before and at least 2 hours after taking the drug. The prescribing information also states that no food should be consumed for one hour after administration of the drug. Steady-state Cmax (average) in patients with resistant prostate cancer receiving 1000 mg once daily The steady-state AUC (mean ± standard deviation) was 226 ± 178 ng / mL. The blood pressure was 1173±690ng.hr / mL. In a crossover study in which Zytiga® was administered to healthy subjects, It was found that taking abiraterone with food increases systemic exposure. Abiraterone C max and AUC 0-∞ Zytiga® low fat When administered with a meal (7% fat, 300 calories), the doses were approximately 7 times and 7 times higher, respectively. 5 times higher when Zytiga® was administered with a high-fat meal (57% fat, 825 calories) When administered at 100 mg / kg, the effects were approximately 17-fold and 10-fold higher, respectively. Summary of the Invention [Problem to be solved by the invention]

[0007] Summary of the Invention The present disclosure relates to pharmaceutical compositions containing abiraterone acetate microparticles, unit dosage forms thereof, and Forms and methods of making and using such compositions are featured.

[0008] In various embodiments, the particle size of the abiraterone acetate particles in the pharmaceutical composition is The particle diameter is based on the particle volume ([D 50 ] or D

[50] or [D50]) are 1000nm, 900nm, 800nm, 700nm, 600nm, 500nm, 4 Particle sizes of 00 nm, 300 nm, 200 nm, and 100 nm or less are selected from the group consisting of In some embodiments, [D 50 ] is 25nm or more or 100nm or more In various embodiments, [D50] is 1000 nm to 25 nm, 1000 nm to 100nm, 800nm ​​to 100nm, 700nm to 100nm, 600n In various embodiments, the [D 4, 3) (Volume average particle size) is 1000nm to 25nm, 1000nm to 100nm, 8 00nm to 100nm, 700nm to 100nm, 600nm to 100nm, 50 0nm to 100nm, 1000nm to 200nm, 900nm to 200nm, 80 0 nm to 200 nm, 700 nm to 200 nm. 90]([D 90 ] or D

[90] ) is 1000nm to 300nm, 1000nm to 400nm, 1000nm to 500nm, 1000nm to 600nm, 1000 nm to 700 nm or 1000 nm to 800 nm.

[0009] In various examples described herein, [D90] is less than 1000 nm or less than 900 In some embodiments, [D 90 ] is 1000nm to 600nm, 900nm to 700nm or 900nm and 800nm.

[0010] In another embodiment, the crystallinity profile of abiraterone acetate is A small amount of abiraterone acetate, wherein at least 50% of the abiraterone acetate is crystalline. At least 60% crystalline, at least 70% crystalline abiraterone acetate At least 75% of the abiraterone acetate is crystalline. At least 85% of the abiraterone acetate is crystalline. 90% crystalline, at least 95% of the abiraterone acetate is crystalline; wherein at least 98% of the abiraterone acetate is crystalline. In some embodiments, the crystallinity profile of abiraterone acetate is The crystallinity profile of abiraterone acetate before the material was treated with the method described herein It is essentially equivalent to

[0011] In another embodiment, the amorphous content of abiraterone acetate is Less than 50% of the abiraterone acetate is amorphous, and less than 40% of the abiraterone acetate is amorphous. less than 30% of the abiraterone acetate is amorphous; Less than 25% of the ester is amorphous, and less than 15% of the abiraterone acetate is amorphous. Abiraterone acetate, wherein less than 10% of the abiraterone acetate is amorphous. Less than 5% of the abiraterone acetate is amorphous, less than 2% of the abiraterone acetate is amorphous, or In some embodiments, the material is dried using the methods described herein. There is no significant increase in the amorphous content of abiraterone acetate after milling.

[0012] In some embodiments, the nanoparticles of abiraterone acetate are It is made by dry grinding acetate esters with grindable grinding compounds and accelerators. Additional ingredients may be used in the milling, such as abiraterone acetate esters, which are used in dry milling. Collectively, these various components (excluding the terpolymer and grinding bodies) are referred to as the grinding matrix. The particle size of abiraterone acetate was significantly reduced by milling, and the particles were transferred to the milled matrix. All components in the grinding matrix are pharmaceutically acceptable. a mixture of abiraterone acetate and a grinding matrix generated by the grinding In some cases, additional drugs may be used to make pharmaceutical compositions. A physiologically acceptable ingredient is added to the mixture of abiraterone acetate and the grinding matrix. In some embodiments, dry milling is carried out in the presence of milling media.

[0013] In some cases, abiraterone acetate is added to lactose monohydrate or Lactose (such as anhydrous lactose), mannitol and sodium lauryl sulfate and povidone one or more pulverizable agents selected from one or more accelerators selected from In some cases, abiraterone acetate is milled with a milling compound. Milled with lactose (such as lactose monohydrate) and sodium lauryl sulfate In some cases, the percentage of abiraterone acetate in the dry mill is 20-60% (w / w), lactose content up to 80% (w / w), mannitol content up to 80% ( w / w), providone and sodium lauryl sulfate, respectively (or both) It may be 1-3% (w / w).

[0014] In some embodiments, abiraterone acetate is administered in at least one millable form. In addition to the grinding compound and at least one accelerator, one or more antioxidants may be added. and / or one or more sequestering agents (i.e., sequestering ions, such as metal ions). Therefore, butylated hydroxyanisole may be used. (BHA), butylated hydroxytoluene (BHT), ascorbic acid, fumaric acid, alcohol Tartaric acid and citric acid (such as anhydrous citric acid) or a mixture of these Dry milling may be carried out in the presence of more than one acid. In some cases, at least one acid Dry milling may be carried out in the presence of both an antioxidant and at least one sequestering agent. (e.g., 5%-0.1%, 1%-0.1%, or 0.2% respectively or in combination) Less than % (w / w) of ascorbic acid, fumaric acid, tartaric acid and citric acid (such as anhydrous citric acid) Enoic acid and (individually or in combination 0.5%-0.01%, 0.1%-0 Less than 0.5% BHT (such as 0.08%, 0.08%-0.04% or 0.05%) and Dry milling may be carried out in the presence of one or more additional antioxidants and BHA. and / or one or more additional sequestering agents are added to the milled material after milling is complete. Good too.

[0015] The pharmaceutical composition is 5, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 17 5, 200, 225, 250, 275, 300, 325, 350, 375 or 400m capsules or tablets containing 10-400 mg of abiraterone acetate (e.g., g) It may be in a unit dosage form such as:

[0016] (900, 850, 800, 750, 700, 650, 600, 550, 500, 45 0, 400, 350, 300, 250, 225, 200, 150, 100, 90, 80, 900 mg-50 mg per day of a pharmaceutical agent described herein (e.g., 70, 60, 50 mg) Abiraterone acetate in the form of a therapeutic composition (a composition containing abiraterone acetate) The dosage form may be administered in one or more doses (e.g., by administering one or more unit dosage forms as described herein). Also described herein are methods of treating a patient, comprising administering to the patient prednisone, prednisolone, or Treatment may include glucocorticoids such as zolon or dexamethasone. The patient may be treated with methylprednisolone (e.g., 100 mg per day).

[0017] In some cases, the dosage forms described herein may be administered in combination with a low-fat diet (7% fat, 3% AUC of the dosage forms described herein when administered as a single dose with 00 calories 0-∞ is fasting 4 times (e.g., less than 3 times, less than 2 times, or less than 1.5 times) greater than when administered in the normal state is less than.

[0018] In some cases, the dosage forms described herein may be administered in combination with a high fat meal (57% fat, AUC of the dosage forms described herein when administered as a single dose with 825 calories 0-∞ Is, absolutely Compared to when administered in a fed state, (less than 7 times, less than 5 times, less than 3 times, less than 2 times, or 1 Less than 8 times (e.g., less than 0.5 times).

[0019] In some cases, a single dose was administered with a low-fat meal (7% fat, 300 calories). The Cmax of the dosage forms described herein when administered in the fasted state is (5 less than 6 times (such as less than 1x, less than 4x, less than 3x, less than 2x or less than 1.5x).

[0020] In some cases, the dosage forms described herein may be administered in combination with a high fat meal (57% fat, The Cmax of the dosage forms described herein when administered as a single dose with 825 calories is measured in the fasted state. Compared with when administered in the normal state, the results were (less than 13 times, less than 11 times, less than 9 times, less than 7 times, less than 5 times) less than 15 times (full, less than 3 times, less than 2 times, or less than 1.5 times, etc.).

[0021] Tablets containing 100 mg of abiraterone acetate (or, for example, 200 mg Tablets containing more than 100 mg of abiraterone acetate, such as half a tablet containing The dissolution rate of abiraterone acetate (100 mg) was measured using USP Apparatus II at pH 7.5. When tested in 900 ml of phosphate buffer (0.1% SLS) at 75 rpm , at least 90% or at least 95% of the abiraterone acetate is Within 9 minutes, Within 18 minutes, Within 18 minutes, Within 17 minutes, Within 16 minutes, Within 15 minutes, Within 14 minutes The rate at which the tablet dissolves within 20 minutes (e.g., within 13 minutes, within 11 minutes, within 9 minutes, etc.). If the dose contains more or less than 0.00 mg of abiraterone acetate, Dissolution rate is determined by the dissolution rate of abiraterone acetate in larger tablets (or multiple smaller tablets). This is the dissolution rate for a portion containing 100 mg of ester.

[0022] In some cases, at 25°C and 60% RH (e.g., for 8 or 12 weeks) At least 90% of abiraterone acetate remains after storage for at least 4 weeks 95% is (for example, within 19 minutes, within 18 minutes, within 18 minutes, within 17 minutes, within 16 minutes, within 1 Dissolves within 20 minutes (e.g., within 5 minutes, within 14 minutes, within 13 minutes, within 11 minutes, within 9 minutes, etc.) In some cases, the temperature is kept at 40°C and 75% RH for 3 weeks (e.g., 6 or 9 weeks). At least 95% of abiraterone acetate remains stable after storage for more than a week (e.g., 13 min). It dissolves within 15 minutes (within 100 mg tablets, within 11 minutes, within 9 minutes, etc.). When the formulation contains more or less abiraterone acetate than the above dissolution rate Abiraterone acetate in a larger tablet (or multiple smaller tablets) This is the dissolution rate for a portion containing 100 mg of the compound.

[0023] In some examples, in a comparative pharmacokinetic study with Zytiga® The abiraterone acetate compositions of the present disclosure exhibit smaller fluctuations compared to conventional compositions. Therefore, in some examples, the pharmaceutical compositions herein are observed to One or more of Cmax, AUC(0-t) and AUC(0-∞) The coefficient of variation may be less than 50%, less than 40%, less than 30%, less than 25%, or less than 20%. In some embodiments, the pharmaceutical compositions described herein may be administered at a predetermined time. The mean plasma concentration fluctuations over time were greater compared to Zytiga® small.

[0024] In some cases, the hardness of the abiraterone tablets is between 110N and 160N. etc.) 100N to 170N.

[0025] In some embodiments, the dry milling device is an attritor mill (vertical and horizontal). , rocking mill, tower mill, pearl mill, planetary mill, vibration mill, eccentric vibration mill, gravity type A grinding device selected from the group consisting of a ball mill, a rod mill, a roller mill, and a grinding mill. In some embodiments, the grinding body in the grinding device is one, two or three. Preferably, the method comprises the step of: The grinding body is configured to continuously produce a material selected from ceramic, glass, steel, and polycarbonate. The material may be selected from the group consisting of polymers, ferromagnetic materials, metals and other suitable materials. In some embodiments, the grinding bodies may be sized from 1 to 20 mm, 2 to 1 A plurality of steel balls having a diameter selected from the group consisting of 5 mm and 3 to 10 mm. In various embodiments of the dry grinding method, the grinding bodies are sized from 1 to 20 mm, from 2 to 15 mm, zirconium oxide spheres having a diameter selected from the group consisting of 1000 rpm and 3 to 10 mm. In another embodiment, the grinding time is from 10 minutes to 2 hours, from 10 minutes to 90 minutes, from 10 minutes to 1 hour, minutes to 1 hour, 10 minutes to 45 minutes, 10 minutes to 30 minutes, 5 minutes to 30 minutes, 5 minutes to 20 minutes , 2 to 10 minutes, 2 to 5 minutes, 1 to 20 minutes, 1 to 10 minutes and 1 to 5 minutes The range is selected from the group consisting of:

[0026] Further grinding matrices and promoters In another embodiment, the grinding matrix is ​​a single material or any ratio of In some embodiments, the single material or two or more materials are blends of the above. A mixture of two or more ingredients, including mannitol, sorbitol, isomalt, xylitol, maize Lucititol, lactitol, erythritol, arabitol, ribitol, glucose, Fructose, mannose, galactose, anhydrous lactose, lactose monohydrate, sucrose maltose, trehalose and maltodextrin. In some embodiments, the single ingredient or mixture of two or more ingredients is dextrin. , inulin, dextrates, polydextrose, starch, wheat flour, corn flour, rice Flour, rice starch, tapioca flour, tapioca starch, potato flour, potato starch, other flours and starches , milk powder, skimmed milk powder, other milk solids and derivatives, soy flour, defatted soybeans or other large Soy products, cellulose, crystalline cellulose, mixed materials containing crystalline cellulose, gelatinized (or partially gelatinized) starch, HPMC, CMC, HPC, citric acid, tartaric acid, Malic acid, maleic acid, fumaric acid, ascorbic acid, succinic acid, sodium citrate, alcohol Sodium tartrate, sodium malate, sodium ascorbate, potassium citrate, Potassium tartrate, potassium malate, potassium acetate, potassium ascorbate, sodium carbonate Sodium, potassium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium carbonate Calcium, dibasic calcium phosphate, tribasic calcium phosphate, sodium sulfate, sodium chloride ammonium, sodium metabisulfite, sodium thiosulfate, ammonium chloride, sodium sulfate, ammonium carbonate ammonium, sodium bisulfate, magnesium sulfate, potassium alum, potassium chloride, sulfur Sodium hydrogen carbonate, sodium hydroxide, crystalline hydroxide, bicarbonate, ammonium chloride , methylamine hydrochloride, ammonium bromide, silica, thermal silica, alumina, titanium dioxide , talc, chalk, mica, kaolin, bentonite, hectorite, magnesium trioxide Silicates, clay materials or aluminum silicate, sodium lauryl sulfate, stearyl Sodium cetyl sulfate, sodium cetostearyl sulfate, docusate Sodium Lauroyl Sarcosine, Sodium Deoxycholate, N-Lauroyl Sarcosine Sodium Salt, Glyceryl monostearate, glycerol distearate, glyceryl palmitostearate Glyceryl behenate, glyceryl caprylate, glyceryl oleate, benzoyl chloride Zarkonium, CTAB, CTAC, Cetrimide, Cetylpyridinium chloride, Cetyl bromide Pyridinium, Benzethonium chloride, PEG-40 stearate, PEG- 100, Poloxamer 188, Poloxamer 338, Poloxamer 407 Polyoxyl 2 Stearyl Ether, Polyoxyl 100 Stearyl Ether, Polyoxyl 20 Stearyl Polyoxyl 10 Stearyl Ether, Polyoxyl 20 Cetyl Ether , Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 61 , Polysorbate 65, Polysorbate 80, Polyoxyl 35 Castor Oil, Polyoxyl 40 Castor Oil, Polyoxyl 60 Castor Oil, Polyoxyl 100 Castor Oil, Polyoxyl 200 Castor Oil, Polyoxyl 40 Hydrogenated Castor Oil, Polyoxyl 60 Hydrogenated Castor Oil, Poly Oxyl 100 hydrogenated castor oil, Polyoxyl 200 hydrogenated castor oil, Cetostearyl alcohol ethanol, macrogel 15 hydroxystearate, sorbitan monopalmitate, sorbitan Sucrose monostearate, sorbitan trioleate, sucrose palmitate, sucrose Sucrose stearate, sucrose distearate, sucrose laurate, glycocholate, glyco Sodium cholate (sodium glycholate), cholic acid, sodium cholate sodium, deoxycholate sodium, deoxycholic acid, sodium taurocholate, Taurocholic acid, sodium taurodeoxycholate, taurodeoxycholic acid, soybean Cysteine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine Phosphatidylinositol, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkylnaphthalenesulfonic acid condensate / lignos sulfonate mixture, calcium dodecylbenzenesulfonate, dodecylbenzenesulfone Sodium distearate, diisopropyl naphthalene sulfonate, erythritol distearate , naphthalenesulfonic acid formaldehyde condensate, nonylphenol ethoxylate (p oe-30), tristyrylphenol ethoxylate, polyoxyethylene (15) Fatty alkylamine, sodium alkylnaphthalene sulfonate, alkylnaphthalene sulfonate Sodium sulfonate condensate, sodium alkylbenzene sulfonate, isopropyl naphthate Sodium methylnaphthalene formaldehyde sulfonate, sodium methylnaphthalene formaldehyde sulfonate, Sodium n-butylnaphthalene sulfonate, tridecyl alcohol ethoxylate (p oe-18), triethanolamine isodecanol phosphate ester, triethanolamine Mint tristyryl phosphate ester, tristyrylphenol ethoxylate sulfate , bis(2-hydroxyethyl) tallow alkylamine.

[0027] In some embodiments, the concentration of the single (or first) grinding matrix is ​​5- 99%w / w, 10-95%w / w, 15-85%w / w, 20-80%w / w, 25- 75% w / w, 30-60% w / w, 40-50% w / w. In some embodiments, the concentration of the second or subsequent grinding matrix is ​​5-50% w / 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, 20-30%w / w or wherein said second or subsequent material is selected from the group consisting of a surfactant or In the case of a water-soluble polymer, the concentration is 0.1-10% w / w, 0.1-5% w / w, 0.1-2.5%w / w, 0.1-2%w / w, 0.1-1%, 0.5-5%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%, 1% w / w.

[0028] In some embodiments, the abiraterone acetate is (a) Lactose monohydrate or xylitol; anhydrous lactose; microcrystalline cellulose; sucrose ;Glucose;Sodium chloride;Talc;Kaolin;Calcium carbonate;Malic acid;Citric acid Trisodium dihydrate; DL-Malic acid; Sodium pentane sulfate; Sodium octadecyl sulfate Sodium N-lauroylsarcosinate;Brij700;Brij76;Sodium N-lauroylsarcosinate;Resin Chin; Docusate sodium; Polyoxyl 40 stearate; Aerosil (registered) Trademark) R972 fumed silica; sodium lauryl sulfate or other chain lengths from C5 C18 alkyl sulfate surfactant; Polyvinylpyrrolidone; Sodium lauryl sulfate Sodium and Polyethylene Glycol 40 Stearate, Sodium Lauryl Sulfate and Polyethylene Glycol 100 Stearate, Sodium Lauryl Sulfate and PEG 30 00, Sodium Lauryl Sulfate and PEG6000, Sodium Lauryl Sulfate and P EG8000, sodium lauryl sulfate and PEG10000, sodium lauryl sulfate and Brij 76700, sodium lauryl sulfate and poloxamer 407, lauryl sulfate Sodium Lauryl Sulfate and Poloxamer 338, Sodium Lauryl Sulfate and Poloxamer Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, Alkyl Naphthalenesulfonic acid condensate / lignosulfonate mixture; dodecylbenzenesulfonic acid Calcium (branched); Diisopropyl naphthalene sulfonate; Erythritol distearate linear or branched dodecylbenzenesulfonic acid; naphthalenesulfonic acid, formaldehyde Dehyde condensation products; Nonylphenol ethoxylate, POE-30; Phosphate ester, Listyrylphenol ethoxylate, free acid; Polyoxyethylene (15) tallow alkyl Sodium alkylnaphthalenesulfonate;Sodium alkylnaphthalenesulfonate;Sodium alkylnaphthalenesulfonate Thorium condensate; Sodium alkylbenzene sulfonate; Isopropyl naphthalene sulfonate Sodium methylnaphthalene;Sodium formaldehyde sulfonate;n- Sodium salt of butylnaphthalene sulfonate; Tridecyl alcohol ethoxylate, POE-18; Triethanolamine Isodecanol Phosphate; Triethanolamine Mint tristyryl phosphate ester; Tristyrylphenol ethoxylate sulfate bis(2-hydroxyethyl) tallow alkylamine; Combination of another ingredient with lactose monohydrate (b) anhydrous lactose or lactose monohydrate; xylitol; microcrystalline cellulose; sucrose ;Glucose;Sodium chloride;Talc;Kaolin;Calcium carbonate;Malic acid;Citric acid Trisodium dihydrate; DL-Malic acid; Sodium pentane sulfate; Sodium octadecyl sulfate Sodium N-lauroylsarcosinate;Brij700;Brij76;Sodium N-lauroylsarcosinate;Resin Chin; Docusate sodium; Polyoxyl 40 stearate; Aerosil (registered) Trademark) R972 fumed silica; sodium lauryl sulfate or other chain lengths from C5 C18 alkyl sulfate surfactant; Polyvinylpyrrolidone; Sodium lauryl sulfate Sodium and Polyethylene Glycol 40 Stearate, Sodium Lauryl Sulfate and Polyethylene Glycol 100 Stearate, Sodium Lauryl Sulfate and PEG 30 00, Sodium Lauryl Sulfate and PEG6000, Sodium Lauryl Sulfate and P EG8000, sodium lauryl sulfate and PEG10000, sodium lauryl sulfate and Brij 700, sodium lauryl sulfate and poloxamer 407, lauryl Sodium Sulfate and Poloxamer 338, Sodium Lauryl Sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, Alkyl Naphtho Poly(thalene sulfonic acid) / lignosulfonate mixture; calcium dodecylbenzenesulfonate Sodium (branched);Diisopropyl naphthalene sulfonate;Erythritol distearate Linear or branched dodecylbenzenesulfonic acid; Naphthalenesulfonic acid formaldehyde Nonylphenol ethoxylate, POE-30; Phosphate ester, Tris(2-methyl-2-propanol) Polyoxyethylene (15) tallow alkyl amine Sodium alkylnaphthalene sulfonate;Sodium alkylnaphthalene sulfonate Sodium alkylbenzene sulfonate; Isopropyl naphthalene sulfonate Sodium;Methylnaphthalene sodium;Formaldehyde sulfonate;n-butyl Sodium salt of naphthalene sulfonate; Tridecyl alcohol ethoxylate, POE -18; Triethanolamine isodecanol phosphate ester; Triethanolamine Listyryl phosphate ester; Tristyrylphenol ethoxylate sulfate; Bis At least one selected from the group consisting of (2-hydroxyethyl) tallow alkylamines Combination of the above ingredients with anhydrous lactose (c) Mannitol or lactose monohydrate; xylitol; anhydrous lactose; microcrystalline cellulose Rosin; Sucrose; Glucose; Sodium chloride; Talc; Kaolin; Calcium carbonate; Phosphorus Malic acid; Trisodium citrate dihydrate; DL-Malic acid; Sodium pentane sulfate; Octyl Sodium tadecyl sulfate; Brij700; Brij76; N-lauroyl sarcosinate Sodium thorium; Lecithin; Sodium docusate; Polyoxyl 40 stearate; Aer osil® R972 fumed silica; sodium lauryl sulfate or Other alkyl sulfate surfactants polyvinylpyrrolidone with chain lengths from C5 to C18; Sodium lauryl sulfate and polyethylene glycol 40 stearate, lauryl sulfate Sodium and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG3000, sodium lauryl sulfate and PEG6000, sodium lauryl sulfate Sodium Lauryl Sulfate and PEG 8000, Sodium Lauryl Sulfate and PEG 10000, Lauryl Sulfate Sodium Lauryl Sulfate and Brij700, Sodium Lauryl Sulfate and Poloxamer 407, Sodium Lauryl Sulfate and Poloxamer 338, Sodium Lauryl Sulfate and and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 18 8. Alkylnaphthalenesulfonic acid condensate / lignosulfonate mixture; dodecylbenzene Calcium branched naphthalene sulfonate;Diisopropyl naphthalene sulfonate;Distearate Erythritol phosphate; Linear or branched dodecylbenzenesulfonic acid; Naphthalenesulfonic acid Acid formaldehyde condensate; Nonylphenol ethoxylate, POE-30; Phosphate ester Ester, tristyrylphenol ethoxylate, free acid; polyoxyethylene (15) Beef tallow alkylamine; Sodium alkylnaphthalene sulfonate; Alkylnaphthalene Sodium alkylbenzene sulfonate condensate; Sodium alkylbenzene sulfonate; Isopropyl naphthate Sodium thalene sulfonate; Sodium methylnaphthalene; Formaldehyde sulfonate Sodium salt of n-butylnaphthalene sulfonate; Tridecyl alcohol ethoxylate Silane, POE-18; Triethanolamine Isodecanol Phosphate; Triethanolamine Isodecanol Phosphate Tanolamine tristyryl phosphate ester; Tristyrylphenol ethoxylates sulfate; bis(2-hydroxyethyl) tallow alkylamines A combination of at least one material selected from the group consisting of mannitol and mannitol. (d) Sucrose or lactose monohydrate; anhydrous lactose; mannitol; microcrystalline cellulose ;Glucose;Sodium chloride;Talc;Kaolin;Calcium carbonate;Malic acid;Tartaric acid; Trisodium citrate dihydrate; DL-Malic acid; Sodium pentane sulfate; Octadecimalic acid Sodium lauroyl sulfate; Brij700; Brij76; Sodium N-lauroyl sarcosyl Lecithin; Docusate sodium; Polyoxyl 40 stearate; Aerosi l® R972 fumed silica; sodium lauryl sulfate or other chain length C5 to C18 alkyl sulfate surfactants; polyvinylpyrrolidone; lauryl Sodium sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and P EG3000, Sodium Lauryl Sulfate and PEG6000, Sodium Lauryl Sulfate and PEG 8000, sodium lauryl sulfate and PEG 10000, sodium lauryl sulfate Sodium and Brij700, Sodium Lauryl Sulfate and Poloxamer 407, Sodium Lauryl Sulfate and Poloxamer 338, Sodium Lauryl Sulfate and Poloxamer Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, Al Kilnaphthalene sulfonic acid condensate / lignosulfonate mixture; dodecylbenzene sulfonate Calcium phosphate (branched); Diisopropyl naphthalene sulfonate; Ethyl distearate Sulitol; Linear or branched dodecylbenzenesulfonic acid; Naphthalenesulfonic acid formaldehyde Aldehyde condensates; Nonylphenol ethoxylate, POE-30; Phosphate esters, Tristyrylphenol ethoxylate, free acid; Polyoxyethylene (15) tallow alcohol Alkylamine; Sodium alkylnaphthalenesulfonate; Alkylnaphthalenesulfonic acid Sodium condensate; Sodium alkylbenzene sulfonate; Isopropyl naphthalene Sodium sulfonate;Sodium methylnaphthalene;Formaldehyde sulfonate;n -Butylnaphthalenesulfonate sodium salt; Tridecyl alcohol ethoxylate , POE-18; Triethanolamine Isodecanol Phosphate; Triethanol Amine tristyryl phosphate ester; Tristyrylphenol ethoxylate sulfate at least one selected from the group consisting of bis(2-hydroxyethyl) tallow alkylamines; A combination of one ingredient and sucrose (e) Glucose or lactose monohydrate; anhydrous lactose; mannitol; microcrystalline cellulose Sucrose; Sodium chloride; Talc; Kaolin; Calcium carbonate; Malic acid; Tartaric acid; Trisodium citrate dihydrate; DL-Malic acid; Sodium pentane sulfate; Octadecimalic acid Sodium lauroyl sulfate; Brij700; Brij76; Sodium N-lauroyl sarcosinate Lecithin; Docusate sodium; Polyoxyl 40 stearate; Aerosil l(R) R972 fumed silica; sodium lauryl sulfate or other chain Long C5 to C18 alkyl sulfate surfactants; Polyvinylpyrrolidone; Lauryl Sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG3000, Sodium Lauryl Sulfate and PEG6000, Sodium Lauryl Sulfate Sodium Lauryl Sulfate and PEG 8000, Sodium Lauryl Sulfate and PEG 10000, Sodium Lauryl Sulfate Sodium Lauryl Sulfate and Brij 700, Sodium Lauryl Sulfate and Poloxamer 407 , Sodium Lauryl Sulfate and Poloxamer 338, Sodium Lauryl Sulfate and Poloxamer Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, A Alkylnaphthalenesulfonic acid condensate / lignosulfonate mixture; Dodecylbenzenesulfonate Calcium stearate (branched); Diisopropyl naphthalene sulfonate; Ethyl distearate Lithritol; Linear or branched dodecylbenzenesulfonic acid; Naphthalenesulfonic acid phosphate Aldehyde condensate; Nonylphenol ethoxylate, POE-30; Phosphate ester , Tristyrylphenol ethoxylate, Free acid; Polyoxyethylene (15) Beef tallow Sodium alkylnaphthalene sulfonate;Alkyl amine;Sodium alkylnaphthalene sulfonate;Alkyl naphthalene sulfone Sodium alkyl benzene sulfonate; Sodium alkyl benzene sulfonate; Isopropyl naphthalene Sodium sulfonate; Sodium methylnaphthalene; Formaldehyde sulfonate; Sodium salt of n-butylnaphthalene sulfonate; Tridecyl alcohol ethoxylate POE-18; Triethanolamine Isodecanol Phosphate; Triethanolamine Tristyrylamine tristyryl phosphate ester; Tristyrylphenol ethoxylate sulfonate bis(2-hydroxyethyl) tallow alkylamine; A combination of at least one ingredient and glucose (f) Sodium chloride or lactose monohydrate; anhydrous lactose; mannitol; microcrystalline cellulose cellulose; sucrose; glucose; talc; kaolin; calcium carbonate; malic acid; tartaric acid; Trisodium citrate dihydrate; DL-Malic acid; Sodium pentane sulfate; Octadecimalic acid Sodium lauroyl sulfate; Brij700; Brij76; Sodium N-lauroyl sarcosinate Lecithin; Docusate sodium; Polyoxyl 40 stearate; Aerosil l(R) R972 fumed silica; sodium lauryl sulfate or other chain C5 to C18 alkyl sulfate surfactants; polyvinylpyrrolidone; Sodium Lauryl Sulfate and Polyethylene Glycol 40 Stearate, Sodium Lauryl Sulfate Sodium and Polyethylene Glycol 100 Stearate, Sodium Lauryl Sulfate and and PEG3000, sodium lauryl sulfate and PEG6000, sodium lauryl sulfate Sodium Lauryl Sulfate and PEG 8000, Sodium Lauryl Sulfate and PEG 10000, Lauryl Sodium sulfate and Brij 700, sodium lauryl sulfate and poloxamer 40 7, Sodium Lauryl Sulfate and Poloxamer 338, Sodium Lauryl Sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, Alkylnaphthalenesulfonic acid condensate / lignosulfonate mixture; dodecylbenzenes Calcium sulfonate (branched);Diisopropyl naphthalene sulfonate;Distearic acid Erythritol; Linear or branched dodecylbenzenesulfonic acid; Naphthalenesulfonic acid Formaldehyde condensate; Nonylphenol ethoxylate, POE-30; Phosphate ester Tristyrylphenol ethoxylate, free acid; Polyoxyethylene (15) tallow Alkylamines;Sodium alkylnaphthalenesulfonates;Alkylnaphthalenesulfonates Sodium alkylbenzene sulfonate condensate; Sodium alkylbenzene sulfonate; Isopropyl naphthalene Sodium methylnaphthalene sulfonate;Sodium methylnaphthalene;Formaldehyde sulfonate ;Sodium salt of n-butylnaphthalene sulfonate;Tridecyl alcohol ethoxylate POE-18; Triethanolamine Isodecanol Phosphate; Triethanolamine Tristyrylphenol ethoxylate sulfonylamine tristyryl phosphate ester; ... esters; bis(2-hydroxyethyl) tallow alkylamines; A combination of at least one ingredient with sodium chloride (g) Xylitol or lactose monohydrate; anhydrous lactose; mannitol; microcrystalline cellulose Rosin; Sucrose; Glucose; Sodium chloride; Talc; Kaolin; Calcium carbonate; Phosphorus Malic acid; Tartaric acid; Trisodium citrate dihydrate; DL-Malic acid; Sodium pentane sulfate Sodium octadecyl sulfate; Brij700; Brij76; N-Lauroylsulfate Cocin sodium; lecithin; docusate sodium; polyoxyethylene 40 stearate Aerosil® R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with chain lengths of C5 to C18; polyvinylpyrrolidone lolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, la Sodium Lauryl Sulfate and Polyethylene Glycol 100 Stearate, Lauryl Sulfate Sodium and PEG 3000, Sodium Lauryl Sulfate and PEG 6000, Lauryl Sodium Lauryl Sulfate and PEG 8000, Sodium Lauryl Sulfate and PEG 100 00, Sodium Lauryl Sulfate and Brij700, Sodium Lauryl Sulfate and Poly Poloxamer 407, sodium lauryl sulfate and poloxamer 338, sodium lauryl sulfate Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer Summer 188, alkylnaphthalene sulfonic acid condensate / lignosulfonate mixture; dodecyl Calcium silbenzenesulfonate (branched);Diisopropyl naphthalene sulfonate; Erythritol distearate; Linear or branched dodecylbenzenesulfonic acid; Naphthalene Polyphenol sulfonic acid formaldehyde condensate; Nonylphenol ethoxylate, POE-30 ; Phosphate ester, Tristyrylphenol ethoxylate, Free acid; Polyoxyethylene (15) Beef tallow alkylamine; Sodium alkylnaphthalene sulfonate; Alkylnaphthalene Sodium phthalenesulfonate condensate; Sodium alkylbenzenesulfonate; Isopropyl Sodium propylnaphthalenesulfonate;Sodium methylnaphthalene;Formaldehyde Naphthalene sulfonate; sodium salt of n-butylnaphthalene sulfonate; tridecyl alcohol Ethoxylate, POE-18; Triethanolamine Isodecanol Phosphate Ester Triethanolamine tristyryl phosphate ester; Tristyrylphenol ethoxylate From the group consisting of silyl sulfates; bis(2-hydroxyethyl) tallow alkylamines A combination of xylitol and at least one material selected from the group consisting of: (h) Tartaric acid or lactose monohydrate; anhydrous lactose; mannitol; microcrystalline cellulose ;Sucrose;Glucose;Sodium chloride;Talc;Kaolin;Calcium carbonate;Malic acid; Trisodium citrate dihydrate; DL-Malic acid; Sodium pentane sulfate; Octadecimalic acid Sodium lauroyl sulfate; Brij700; Brij76; Sodium N-lauroyl sarcosinate Lecithin; Docusate sodium; Polyoxyl 40 stearate; Aerosil l(R) R972 fumed silica; sodium lauryl sulfate or other chain Long C5 to C18 alkyl sulfate surfactants; Polyvinylpyrrolidone; Lauryl Sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG3000, Sodium Lauryl Sulfate and PEG6000, Sodium Lauryl Sulfate Sodium Lauryl Sulfate and PEG 8000, Sodium Lauryl Sulfate and PEG 10000, Sodium Lauryl Sulfate Sodium Lauryl Sulfate and Brij 700, Sodium Lauryl Sulfate and Poloxamer 407 , Sodium Lauryl Sulfate and Poloxamer 338, Sodium Lauryl Sulfate and Poloxamer Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, A Alkylnaphthalenesulfonic acid condensate / lignosulfonate mixture; Dodecylbenzenesulfonate Calcium stearate (branched); Diisopropyl naphthalene sulfonate; Ethyl distearate Lithritol; Linear or branched dodecylbenzenesulfonic acid; Naphthalenesulfonic acid phosphate Aldehyde condensate; Nonylphenol ethoxylate, POE-30; Phosphate ester , Tristyrylphenol ethoxylate, Free acid; Polyoxyethylene (15) Beef tallow Sodium alkylnaphthalene sulfonate;Alkyl amine;Sodium alkylnaphthalene sulfonate;Alkyl naphthalene sulfone Sodium alkyl benzene sulfonate; Sodium alkyl benzene sulfonate; Isopropyl naphthalene Sodium sulfonate; Sodium methylnaphthalene; Formaldehyde sulfonate; Sodium salt of n-butylnaphthalene sulfonate; Tridecyl alcohol ethoxylate POE-18; Triethanolamine Isodecanol Phosphate; Triethanolamine Tristyrylamine tristyryl phosphate ester; Tristyrylphenol ethoxylate sulfonate bis(2-hydroxyethyl) tallow alkylamine; A combination of at least one ingredient with tartaric acid (i) Microcrystalline cellulose or lactose monohydrate; xylitol; anhydrous lactose; mannitol Thor; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; phosphorus Malic acid; Tartaric acid; Trisodium citrate dihydrate; DL-Malic acid; Sodium pentane sulfate Sodium octadecyl sulfate; Brij700; Brij76; N-Lauroylsulfate Cocin sodium; lecithin; docusate sodium; polyoxyethylene 40 stearate Aerosil® R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with chain lengths of C5 to C18; polyvinylpyrrolidone Lithium; Sodium Lauryl Sulfate and Polyethylene Glycol 40 Stearate, Lauryl Sulfate Sodium Lauryl Sulfate and Polyethylene Glycol 100 Stearate, Sodium Lauryl Sulfate Sodium Lauryl Sulfate and PEG 3000, Sodium Lauryl Sulfate and PEG 6000, Lauryl Sodium Lauryl Sulfate and PEG 8000, Sodium Lauryl Sulfate and PEG 1000 0, Sodium Lauryl Sulfate and Brij700, Sodium Lauryl Sulfate and Poly Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate poloxamer 188; poloxamer 407, poloxamer 338, poloxamer mer 188, alkylnaphthalene sulfonic acid condensate / lignosulfonate mixture; dodecyl Calcium diisopropyl naphthalene sulfonate (branched);Diisopropyl naphthalene sulfonate;Diisopropyl naphthalene sulfonate Erythritol stearate; Linear or branched dodecylbenzenesulfonic acid; Naphthalene Sulfonic acid formaldehyde condensate;Nonylphenol ethoxylate, POE-30; Phosphate ester, tristyrylphenol ethoxylate, free acid; polyoxyethylene (15) Beef tallow alkylamine; Sodium alkylnaphthalene sulfonate; Alkylnaphthalene Sodium talensulfonate condensate; Sodium alkylbenzenesulfonate; Isopropyl Sodium pyrnaphthalene sulfonate; Sodium methylnaphthalene; Formaldehyde Sulfonates; Sodium salt of n-butylnaphthalene sulfonate; Tridecyl alcohol Ethoxylate, POE-18; Triethanolamine Isodecanol Phosphate Ester ;Triethanolamine tristyryl phosphate ester;Tristyrylphenol ethoxy from the group consisting of bis(2-hydroxyethyl) tallow alkylamines; Combination of at least one selected material with microcrystalline cellulose (j) Lactose monohydrate; xylitol; anhydrous lactose; mannitol; microcrystalline cellulose ;Sucrose;Glucose;Sodium chloride;Talc;Kaolin;Calcium carbonate;Malic acid; Tartaric acid; Trisodium citrate dihydrate; DL-Malic acid; Sodium pentane sulfate; Sodium octadecyl sulfate; Brij700; Brij76; N-Lauroyl sarcosine Sodium; Lecithin; Docusate Sodium; Polyoxyl 40 Stearate; Ae Rosil® R972 fumed silica; sodium lauryl sulfate or Other alkyl sulfate surfactants with chain lengths of C5 to C18; polyvinylpyrrolidone ;Sodium lauryl sulfate and polyethylene glycol 40 stearate, lauryl sulfate Sodium Stearate and Polyethylene Glycol 100 Stearate, Sodium Lauryl Sulfate and PEG3000, sodium lauryl sulfate and PEG6000, sodium lauryl sulfate Sodium and PEG8000, Sodium Lauryl Sulfate and PEG10000, La Sodium lauryl sulfate and Brij700, sodium lauryl sulfate and poloxamer -407, Sodium Lauryl Sulfate and Poloxamer 338, Sodium Lauryl Sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 1 88, Alkylnaphthalenesulfonic acid condensate / lignosulfonate mixture; dodecylbene Calcium branched naphthalene sulfonate; Diisopropyl naphthalene sulfonate; Distearate Erythritol phosphate; Linear or branched dodecylbenzenesulfonic acid; Naphthalene sulfonate Phosphoric acid formaldehyde condensate; Nonylphenol ethoxylate, POE-30; Phosphoric acid Ester, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15 ) Beef tallow alkylamine; Sodium alkylnaphthalene sulfonate; Alkylnaphthalene Sodium sulfonate condensate; Sodium alkylbenzene sulfonate; Isopropyl sodium Sodium phthalenesulfonate; Sodium methylnaphthalene; Formaldehyde sulfonate naphthalenesulfonate;sodium salt of n-butylnaphthalenesulfonate;tridecylalcohol ethoxylate Xylate, POE-18; Triethanolamine Isodecanol Phosphate Ester; Tri Ethanolamine tristyryl phosphate ester; Tristyrylphenol ethoxylate sulfate; bis(2-hydroxyethyl) tallow alkylamine A combination of kaolin with at least one material (k) Lactose monohydrate; xylitol; anhydrous lactose; mannitol; microcrystalline cellulose ;Sucrose;Glucose;Sodium chloride;Kaolin;Calcium carbonate;Malic acid;Tartaric acid; Trisodium citrate dihydrate; DL-Malic acid; Sodium pentane sulfate; Octadecimalic acid Sodium lauroyl sulfate; Brij700; Brij76; Sodium N-lauroyl sarcosinate Lecithin; Docusate sodium; Polyoxyl 40 stearate; Aerosil l(R) R972 fumed silica; sodium lauryl sulfate or other chain Long C5 to C18 alkyl sulfate surfactants; Polyvinylpyrrolidone; Lauryl Sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG3000, Sodium Lauryl Sulfate and PEG6000, Sodium Lauryl Sulfate Sodium Lauryl Sulfate and PEG 8000, Sodium Lauryl Sulfate and PEG 10000, Sodium Lauryl Sulfate Sodium Lauryl Sulfate and Brij 700, Sodium Lauryl Sulfate and Poloxamer 407 , Sodium Lauryl Sulfate and Poloxamer 338, Sodium Lauryl Sulfate and Poloxamer Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, A Alkylnaphthalenesulfonic acid condensate / lignosulfonate mixture; Dodecylbenzenesulfonate Calcium stearate (branched); Diisopropyl naphthalene sulfonate; Ethyl distearate Lithritol; Linear or branched dodecylbenzenesulfonic acid; Naphthalenesulfonic acid phosphate Aldehyde condensate; Nonylphenol ethoxylate, POE-30; Phosphate ester , Tristyrylphenol ethoxylate, Free acid; Polyoxyethylene (15) Beef tallow Sodium alkylnaphthalene sulfonate;Alkyl amine;Sodium alkylnaphthalene sulfonate;Alkyl naphthalene sulfone Sodium alkyl benzene sulfonate; Sodium alkyl benzene sulfonate; Isopropyl naphthalene Sodium sulfonate; Sodium methylnaphthalene; Formaldehyde sulfonate; Sodium salt of n-butylnaphthalene sulfonate; Tridecyl alcohol ethoxylate POE-18; Triethanolamine Isodecanol Phosphate; Triethanolamine Tristyrylamine tristyryl phosphate ester; Tristyrylphenol ethoxylate sulfonate bis(2-hydroxyethyl) tallow alkylamine; A combination of at least one material with talc The mixture is ground in the presence of

[0029] In some embodiments, abiraterone acetate is considered "generally recognized as safe" for pharmaceutical use. one or more materials selected from the group consisting of materials considered to be generally accepted as approved by the Food and Drug Administration (GRAS) In some embodiments, abiraterone acetate ester is dry milled with additional ingredients. Dry milling of the cellulose is carried out in the presence of a single promoter or a combination of promoters. In some embodiments, the accelerator is a colloidal silica, a surfactant, a polymer, a stearic acid, or the like. In some embodiments, the phosphate group is selected from the group consisting of phosphoric acid and derivatives thereof. The accelerator may be polyoxyethylene alkyl ether, polyoxyethylene stearate, Polyethylene glycol (PEG), poloxamer, poloxamine, sarcosine-based surfactants Antioxidants, polysorbates, fatty alcohols, alkyl and aryl sulfates, alkane alkyl and aryl polyether sulfonates and other sulfate surfactants, trime ethylammonium surfactant, lecithin and other phospholipids, bile acids, polyoxyethylene Ethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, sucrose fatty acids Esters, alkyl glucoranosides, glycerol fatty acid esters, alkylbenzenes sulfonic acids, alkyl ether carboxylic acids, alkyl and aryl phosphate esters, Alkyl and aryl sulfates, alkyl and aryl sulfonic acids, alkyl fluorides Phenol phosphate esters, alkylphenol sulfate esters, alkyl and and aryl phosphates, alkyl polysaccharides, alkylamine ethoxylates , alkylnaphthalenesulfonate formaldehyde condensate, sulfosuccinate, Glycerol Sulfonate, Ceto Oleyl Alcohol Ethoxylate, Condensed Naphthalene Dialkyl and alkyl naphthalene sulfonates, dialkyl sulfonates Succinate, Ethoxylated Nonylphenol, Ethylene Glycol Ester, Fatty Alcohol Coal alkoxylate, hydrogenated tallow alkylamine, monoalkyl sulfosuccinate, Nonylphenol ethoxylate, oleyl N-taurate, tallow alkylamine, The alkyl group is selected from the group consisting of linear or branched dodecylbenzenesulfonic acids.

[0030] In some embodiments, the enhancer is sodium lauryl sulfate, stearyl sulfate Sodium, Cetyl Sulfate, Cetostearyl Sulfate, Docusate Sodium, Deoxycholate Sodium, N-Lauroyl Sarcosine Sodium Salt, Mono Glyceryl stearate, glycerol distearate, glyceryl palmitostearate Glyceryl behenate, glyceryl caprylate, glyceryl oleate, benzal chloride Conium, CTAB, CTAC, cetrimide, cetylpyridinium chloride, cetylpyridinium bromide Zinium, Benzethonium chloride, PEG-40 stearate, PEG-10 stearate 0, Poloxamer 188, Poloxamer 338, Poloxamer 407 Polyoxyl 2 Sterate Allyl Ether, Polyoxyl 100 Stearyl Ether, Polyoxyl 20 Stearyl Ether, Polyoxyl 10 Stearyl Ether, Polyoxyl 20 Cetyl Ether, Poly Resorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 61, Polysorbate Resorbate 65, Polysorbate 80, Polyoxyl 35 Castor Oil, Polyoxyl 40 Castor Oil, Polyoxyl 60 Castor Oil, Polyoxyl 100 Castor Oil, Polyoxyl 20 0 Castor Oil, Polyoxyl 40 Hydrogenated Castor Oil, Polyoxyl 60 Hydrogenated Castor Oil, Polyoxyl Sil 100 hydrogenated castor oil, Polyoxyl 200 hydrogenated castor oil, Cetostearyl alcohol , Macrogel 15 Hydroxystearate, Sorbitan Monopalmitate, Sorbitan Mono Sucrose palmitate, sorbitan trioleate, sucrose palmitate, sucrose stearate Sucrose distearate, sucrose laurate, glycocholate, glyco Sodium glycholate, cholic acid, sodium cholate Sodium deoxycholate, deoxycholic acid, sodium taurocholate, tau Taurodeoxycholate, Sodium Taurodeoxycholate, Taurodeoxycholic Acid, Soy Lecithin Phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, Phosphatidylinositol, PEG4000, PEG6000, PEG8000, PE G10000, PEG20000, alkylnaphthalenesulfonic acid condensate / lignosulfonate sulphonate mixture, calcium dodecylbenzenesulphonate, sodium dodecylbenzenesulphonate Sodium, diisopropyl naphthalene sulfonate, erythritol distearate, sodium Phthalene sulfonic acid formaldehyde condensate, nonylphenol ethoxylate (POE -30), Tristyrylphenol ethoxylate, Polyoxyethylene (15) Beef tallow alkylamine, sodium alkylnaphthalene sulfonate, alkylnaphthalene sulfone Sodium alkyl benzene sulfonate, sodium alkyl benzene sulfonate, isopropyl naphthalene Sodium sulfonate, methylnaphthalene formaldehyde sodium sulfonate, n- Sodium butyl naphthalene sulfonate, tridecyl alcohol ethoxylate (POE) -18), triethanolamine isodecanol phosphate ester, triethanolamine Tristyryl phosphate ester, tristyrylphenol ethoxylate sulfate, bis(tristyryl phenol) (2-hydroxyethyl) tallow alkylamines.

[0031] In some embodiments, the enhancer is polyvinylpyrrolidone (PVP), polyvinyl and the like, selected from the list of vinyl alcohols, acrylic acid polymers and acrylic acid copolymers. do.

[0032] In some embodiments, the concentration of the promoter during dry milling is 0.1-10% w / w , 0.1-5%w / w, 0.1-2.5%w / w, 0.1-2%w / w, 0.1-1% , 0.5-5%w / w, 0.5-3%w / w, 0.5-2%w / w, 0.5-1.5%, From 0.5-1% w / w, 0.75-1.25% w / w, 0.75-1%, 1% w / w The compound is selected from the group consisting of:

[0033] In some embodiments, a single promoter or a combination of promoters is added during dry milling. In some embodiments, the promoter is added during dry milling. In some embodiments, the accelerator is added for the remaining 1-5% of the total grinding time, the remaining 1% of the total grinding time, -10%, 1-20% of total grinding time remaining, 1-30% of total grinding time remaining, 2-5% of total grinding time remaining 2-10% of total grinding time remaining 5-20% of total grinding time remaining The remaining 5-20% is added to the dry mill at a point selected from the group consisting of:

[0034] Reasons for adding enhancers include improving dispersion, reducing aggregation, and enhancing activity through the delivery matrix. Examples of enhancers include, but are not limited to, sodium lauryl sulfate, sodium lauryl sulfate, sodium phosphate ... , Cross-linked PVP (crospovidone), cross-linked sodium carboxymethylcellulose (cross Carmellose sodium), sodium starch glycolate, povidone (PVP), Povidone K12, Povidone K17, Povidone K25, Povidone K29 / 32 and Povidone K30, stearic acid, magnesium stearate, calcium stearate, fumaric acid Sodium stearyl, sodium stearyl lactylate, zinc stearate, sodium stearate Sodium or Lithium Stearate, Oleic Acid, Lauric Acid, Palmitic Acid, Eruca Acids, other solid fatty acids such as behenic acid or derivatives (such as esters and salts), Leucine, isoleucine, lysine, valine, methosin, phenylalanine, aspartame or acesulfame-K.

[0035] Another aspect of the invention is to administer to a human an effective amount of a compound described herein for treating castration-resistant prostate cancer. and administering to a human in need of such treatment a pharmaceutical composition for the treatment of the disease. The method includes treating the patient with prednisone (e.g., 5 mg twice daily), dexamethasone, or Alternatively, the patient may be treated with a glucocorticoid such as steroid or prednisolone. The patient may be treated with methylprednisolone. The patient may be treated with cancer (such as prostate cancer). The patient may also be treated with other chemotherapeutic or other agents for the treatment of rheumatoid arthritis.

[0036] The present invention relates to breast cancer (such as metastatic breast cancer) and ovarian cancer (such as epithelial ovarian cancer) as defined herein. This also includes treatment with the composition described in .

[0037] In another aspect, the present invention provides a pharmaceutical composition for the treatment of a human in need of such treatment. The present invention includes the use of a pharmaceutical composition described herein in the manufacture of a medicament for treating atopic dermatitis.

[0038] In another aspect, the present invention provides an abiraterone analog prepared by the methods described herein. A therapeutically effective amount of a composition containing an acid ester or a composition described herein is added to a diluent, Mixed with one of a lubricant, an excipient, a disintegrant, a wetting agent and a carrier, and pharmaceutically acceptable The present invention also includes a method for producing the pharmaceutical compositions described herein, comprising the step of forming a suitable dosage form.

[0039] The invention described herein may be susceptible to variations and modifications other than those specifically described. It will be understood by those skilled in the art that the present invention includes all such variations and modifications. It should be understood that the present invention further relates to the methods, features and processes mentioned or illustrated in the specification. This includes all of the methods, compositions and materials, individually or collectively, and includes any of these procedures or features. Any combination of two or more of the features is also included.

[0040] The present invention is not limited in scope by the specific embodiments described herein, which are intended for illustrative purposes only. Functionally equivalent products, compositions and methods are not intended to be limiting of the inventions described herein. It is clear that this falls within the scope of

[0041] The invention described herein may include one or more ranges of values ​​(e.g., size, concentration, etc.). A range of values ​​may include a plurality of values ​​defining the range and values ​​defining the boundaries of the range. The ranges immediately adjacent to the specified value lead to results equal to or approximately equal to the values ​​immediately adjacent to the specified value. It will be understood that the ranges include all values ​​within the ranges, including values ​​within the ranges.

[0042] The materials cited in this specification (including patents, patent applications, journal articles, laboratory manuals, books, etc.) The entire disclosures of all publications (such as the US Provisional Patent Application No. 2004 / 0100299 or other documents) are incorporated herein by reference. Such citation does not necessarily imply that any of these references constitute prior art. nor does it imply that the invention is part of the general technical knowledge of a person skilled in the art to which the invention pertains. stomach.

[0043] Throughout this specification, unless the context requires otherwise, the words "comprises" and "includes" are used interchangeably. The word "comprises" and its variants "comprises" and "contains" Words such as "Comprising" are Stated Integrity er) or a set of whole numbers (Group of Integers) but to the exclusion of any other definite perfect or set of perfects. Furthermore, in this disclosure, particularly in several claims and / or paragraphs, "Comprise", "Comprised", "Completed" and "comprising" have the meaning that U.S. patent law provides for these terms. , i.e. "includes", "included", "containing" It may also have a meaning such as "including."

[0044] As used herein with respect to treatment methods and particularly drug dosages, the term "therapeutically effective amount" refers to the The administration of such drugs to a significant number of patients in need of such treatment has been associated with specific pharmacological responses. It may also refer to a "therapeutically effective" dose administered to a particular patient in a particular case. "Effective amount" means that such dosage is recognized by those skilled in the art as a "therapeutically effective amount." It should be noted that even if a compound is effective, it may not necessarily be effective in treating the diseases described herein. Also, drug dosages may, in certain cases, be measured as oral doses. or should be understood as measured with reference to drug levels measured in blood. It is.

[0045] The term "inhibit" means to arrest, prevent, suppress, reduce, halt or It includes the commonly accepted meaning of reversal and such effect on disease symptoms. The present invention therefore includes both therapeutic and prophylactic administration, as appropriate.

[0046] The term "grinding matrix" refers to abiraterone acetate mixed with a biologically active material. Defined as any substance that is or can be ground with an ester. The terms "co-grinding matrix" and "matrix" refer to the "grinding matrix" This is interchangeable with the term "service."

[0047] Throughout this specification, unless the context requires otherwise, the term "dry milling" will be used. The phrase, and variations thereof, such as "dry grinding," refers to at least a liquid or fluid It should be understood to mean grinding in the substantial absence of liquid. If so, it is present in an amount such that the contents of the milled bodies maintain the properties of a dry powder.

[0048] The term "flowable" refers to typical equipment used in the manufacture of pharmaceutical compositions and formulations. It means that the powder has physical properties that are suitable for the further processing used.

[0049] Additional definitions of selected terms used herein are set forth in the Detailed Description of the Invention. and apply throughout. Unless otherwise specified, other terms used in this specification All scientific and technical terms are used according to the ordinary skill in the art to which this invention pertains. It has the same meaning as commonly understood by those who hold it.

[0050] The term "grindable" means that the grinding matrix can withstand the dry grinding conditions of the method of the present invention. In one embodiment of the present invention, the particles are crushed. The resulting grinding matrix has a particle size similar to that of abiraterone acetate. In one embodiment, the grain size of the matrix is ​​substantially refined, but not abirate. It is not as fine as thoronacetate.

[0051] Additional definitions of selected terms used herein are set forth in the Detailed Description of the Invention. and apply throughout. Unless otherwise specified, other terms used in this specification All scientific and technical terms are used according to the ordinary skill in the art to which this invention pertains. It has the same meaning as commonly understood by those who hold it.

[0052] Other aspects and advantages of the present invention will become apparent to those skilled in the art from the following detailed description. [Brief explanation of the drawings]

[0053] [Figure 1] FIG. 1 is a graph illustrating the particle size distribution of the abiraterone acetate composition in the milled abiraterone acetate of Example 1 and unmilled abiraterone acetate. [Figure 2] FIG. 2 is a graph illustrating the solubility of the abiraterone acetate composition in the milled abiraterone acetate of Example 1 and unmilled abiraterone acetate. [Figure 3] FIG. 3 is a graph illustrating the solubility of the abiraterone acetate composition in milled abiraterone acetate and unmilled abiraterone acetate of Example 3. [Figure 4] FIG. 4 is a graph illustrating the particle size distribution of the abiraterone acetate composition in the milled abiraterone acetate of Example 1 and unmilled abiraterone acetate. [Figure 5A] FIG. 5A is a graph illustrating impurities detected in milled DPI over time. [Figure 5B] FIG. 5B is a graph illustrating impurities detected over time in tablets containing crushed DPI. [Figure 6] FIG. 6 is a graph illustrating the dissolution rate for tablets containing micronized abiraterone acetate. [Figure 7] FIG. 7 is a graph illustrating the dissolution rates of tablets containing micronized abiraterone acetate and tablets containing conventional abiraterone acetate. DETAILED DESCRIPTION OF THE INVENTION

[0054] Detailed Description of the Invention particle size There are a wide variety of techniques available to characterize the grain size of a material. Among these various techniques, two measurement methods are most commonly used: dynamic light scattering Photon Correlation Spectroscopy (PCS), also known as DLS, is used to measure particles smaller than 10 microns in size. This measurement method is usually used to measure the average particle size of the number distribution. The other common method for measuring particle size is to measure the equivalent hydrodynamic radius, which is expressed as the particle size of 10 This is a laser diffraction method commonly used to measure wavelengths from 1000 nm to 2000 microns. is the particle size of an equivalent spherical particle, which can be expressed as a median particle size or a percentage of particles of a given size. Calculate the volume distribution.

[0055] For measurements using a photon correlation spectroscopy instrument or equivalent methods known in the art, the term "number average particle size" is used. The term "particle size" is defined as the average particle size determined on a number basis.

[0056] For measurements using laser diffraction, the term "median particle size" is used to refer to the equivalent spherical particle volume. The term "centre" is used to mean the diameter of a particle measured on a standard. In this case, the particle size that divides the population in half, such as 50% of the population by volume, is smaller than this particle size. The median particle size is understood to represent the size of the particle, either large or small. 50 ]or D

[50] or [D50], D50, D(0.50) or D[0.5] or these As used herein, [D 50 ] or D

[50] Ma or [D50], D50, D(0.50) or D[0.5] or similar notations The above should be understood to mean the median particle size.

[0057] The term "Dx of particle size distribution" refers to x percent of said distribution by volume. , D90 refers to 90 percent, and D95 ​​refers to 95 percent. Take D90 as an example. , which is often [D90] or D

[90] or [D90], D(0.90) or or D[0.9] or similar notations. For particle size and Dx, capital D or lower case d are interchangeable and have the same meaning. Another common example of particle size distribution is measured by laser diffraction or equivalent methods known in the art. The notation used in this paper is what percentage of a distribution is smaller or larger than a given particle size. For example, %<1000nm is also written as "%<" which means "less than" The term "particle size distribution" is defined as the percentage of particle size distribution that is smaller than a given particle size on a volume basis. The term "greater than" can also be written as "%>", for example %>1000nm. , is defined as the percentage of a particle size distribution, on a volume basis, that is larger than a given particle size.

[0058] For many of the materials subject to the method of the present invention, particle size is readily measurable. the active ingredient has low water solubility and the matrix in which the active ingredient is ground has high water solubility. In this case, the powder can be easily dispersed in an aqueous solvent. The solubility of the active ingredient in the solvent is then reduced by 2000 Wt. Measurement may also be performed by methods such as CS or laser diffraction.

[0059] The active material has a fairly high water solubility or dissolution in the aqueous dispersion medium of the matrix A suitable method for accurate particle size measurement at low resolution is outlined below. 1. Filtration or centrifugation may be necessary if an insoluble matrix such as microcrystalline cellulose interferes with the measurement. Active material separation techniques such as centrifugation are used to separate the insoluble matrix from the active material particles. To be able to take this into consideration, the separation technique Other auxiliary techniques may also be required to determine whether the active material has been separated. 2. If the active material is too water soluble, other solvents may be considered for particle size determination. If a solvent is found that has low solubility for the active material but high solubility for the matrix, If it is difficult to find such a solvent, other methods may be used. As a method, the aggregate of the matrix and the active material is dissolved in a solvent in which both are insoluble (isooctane Then, the active material may be soluble in a solvent such as HCl, but the matrix is ​​not. The powder may be measured in a different solvent that is not soluble in water. and the measurement of particle size of both the matrix and the active material. It is possible to grasp the particle size. 3. In some cases, image analysis may be used to obtain information about the particle size distribution of the active material. Suitable image measurement methods include transmission electron microscope (TEM), scanning electron microscope (SEM), In addition to these standard methods, active materials may also be used for the detection of oxidative stress. It will be necessary to use some additional method to distinguish between the material and the matrix particles. Depending on the chemical structure of the materials involved, elemental analysis, Raman spectroscopy, FTIR spectroscopy and fluorescence Optical spectroscopy can be used.

[0060] Improved dissolution profile This method results in abiraterone acetate with an improved dissolution profile. The improved dissolution profile is consistent with the in vivo dissolution of abiraterone acetate. This has significant advantages, including improved bioavailability. The improved dissolution profile is observed in vitro. The improved dissolution profile leads to an improved bioavailability profile. The dissolution profile of the material is observed in vivo by Several standard methods are available in the art for measuring the dissolution profile. One preferred method for measuring the concentration of a sample material in solution is to measure the concentration of the sample material in vitro. Measurements are taken over a period of time and the results obtained from the sample material are compared with a control sample. When the peak solution concentration of the sample material is shorter than that of the control sample, The observation that the results obtained between the two samples (assuming they are statistically significant) The material has an improved dissolution profile. Abiraterone acetate and a grinding matrix and / or The control sample is defined as a mixture of the test sample and the control sample. The ingredients of the material are in the same phase as the active ingredient, matrix component and / or excipient component of the test sample. is defined as a physical mixture (not subjected to the process of the present invention) containing the compounds in the proportions For dissolution testing purposes, a sample preparation of the test sample may be used. In this case, the control sample are prepared in the same manner. The improved dissolution profile of the material is measured in vivo. Several standard methods for improving lysis processes in humans are available in the art. A preferred method for measuring plasma concentrations of a sample compound over a period of time after administration is to measure the plasma concentration of the sample compound over a period of time after administration. The active ingredient is determined by comparing the results of the test compound with those of the control. The absorption rate of a test compound may be measured by measuring the plasma concentration of the test compound relative to the control compound. The observation that the peak was reached in a shorter time than the control (assuming statistical significance) Assuming that the sample compound has improved bioavailability and improved dissolution properties, In some embodiments, the improved dissolution profile The effect is observed at the appropriate gastrointestinal pH when observed in vitro. In the examples, the improved dissolution profile was measured by comparing the test sample to the control sample. This is sometimes observed at a suitable pH to demonstrate improved solubility. A variety of suitable methods for quantifying the concentration of a compound in an in vivo sample are known in the art. Suitable methods may include spectroscopy or radiolabeling.

[0061] Crystallinity Profile Various methods for determining the crystallinity profile of abiraterone acetate are known to those skilled in the art. Suitable methods are X-ray diffraction, differential scanning calorimetry, Raman or IR. Spectroscopy may also be included.

[0062] Amorphous Profile Various methods are available in the art for measuring the amorphous content of abiraterone acetate. Suitable methods are X-ray diffraction, differential scanning calorimetry, Raman or IR spectroscopy. may include:

[0063] Grinding Matrix As described below, selecting an appropriate grinding matrix is ​​an important aspect of the method of the present invention. As will be described below, a particularly advantageous aspect of the present invention is that Some grinding matrices suitable for use in the disclosed methods are also suitable for use in medicine. The present invention is characterized by the combination of abiraterone acetate and a grinding matrix. or in some cases both abiraterone acetate and part of the grinding matrix. A method for producing a pharmaceutical containing the compound, a pharmaceutical produced in this manner, and a method for producing a pharmaceutical using the compound. The present invention encompasses a method of treating a patient in need thereof, comprising administering to said patient a dose of abiraterone acetate in a dose-dependent manner. It may contain only the milled matrix or, more preferably, milled Avila. The terone acetate and the milled milling matrix are and any desired excipients or mixtures thereof commonly used in the preparation of pharmaceuticals. It may be mixed with other similar agents.

[0064] In some cases, at least one component of the grinding matrix is ​​abiraterone acetate. esters, and therefore, the abiraterone acetate is easily crushed under the dry milling conditions of the present invention. Again, without wishing to be bound by theory, In view of these circumstances, the smaller the particles of the milled matrix produced under dry milling conditions, the better the The second reason is that it is highly interactive with abiraterone acetate, so the crushable powder It is believed that the matrix provides the advantages of the present invention.

[0065] The amount of grinding matrix relative to the amount of abiraterone acetate and the grinding matrix The degree of physical disintegration of the matrix is ​​sufficient to inhibit re-agglomeration of the particles of the active material. In the examples, the amount of grinding matrix relative to the amount of abiraterone acetate and The degree of size reduction of the grinding matrix is ​​sufficient to inhibit re-agglomeration of the particles of the active material. As detailed above, the grinding matrix may contain one or more antioxidants and / or or one or more sequestering agents.

[0066] In some embodiments, the grinding matrix has a low tendency to agglomerate during dry grinding. Although it is difficult to objectively quantify the tendency of particles to aggregate, the tendency of particles to aggregate on the surface of the ground material as dry grinding progresses is and the level of "solidification" of the grinding matrix on the grinding chamber surfaces of the media mill. By observing the results, it is possible to obtain subjective measurements.

[0067] The grinding matrix can be inorganic or organic.

[0068] crushing body In the method of the present invention, the grinding bodies are preferably chemically inert and hard. The term "chemically inert" as used herein means that the milled product is not abiraterone acetate or milled This means that it does not chemically react with the matrix.

[0069] As mentioned above, the grinding bodies are inherently resistant to breakage and corrosion during the grinding process.

[0070] The grinding bodies are preferably of various smooth and uniform shapes, either flat or curved surfaces. The object may have a shape that is free of sharp or raised edges. For example, suitable grinding bodies are bodies having an elliptical, oval, spherical or right cylindrical shape. In some embodiments, the grinding bodies may be one or more beads, balls, spheres, A rod, a right cylinder, a tube, or a cylinder with a radius end (i.e., a hemispherical base with the same radius as the cylinder) The axial direction of the shaft is defined by a right cylinder having a cylindrical section.

[0071] Due to the properties of abiraterone acetate and the grinding matrix, the grinding mass is approximately 0.1 to 1.5 mm. to 30 mm, more preferably about 1 to about 15 mm, and even more preferably about 3 to 10 mm. It is desirable to have an average particle size (or "particle size").

[0072] The grinding bodies may be made of a variety of materials such as particulate ceramic, glass, metal or polymeric compositions. Suitable metal grinding bodies are typically spherical and generally have good hardness. (i.e. RHC60-70), with good roundness, high wear resistance and narrow particle size distribution, e.g. ROM steel 52100, 304, 316 or stainless steel 440C or high carbon steel 1065 The ball may include a ball made from

[0073] For example, ceramics may be made to have sufficient hardness and resistance to not chip or shatter during grinding. The ceramic may be selected from a variety of ceramics that are desirable to have a sufficiently high density while still providing a high thermal conductivity. The preferred density of the ground body is about 1 to 15 g / cm 3 , preferably about 1 to 8 g / cm 3 Yes The ceramic may be steatite, aluminum oxide, zirconium oxide, zirconium Zirconia-silica, yttria-stabilized zirconium oxide, magnesia-stabilized zirconium oxide Silicon nitride, silicon carbide, cobalt-stabilized tungsten carbide, and mixtures thereof You may choose from the items.

[0074] Glass grinding bodies are spherical (e.g., beads), have a narrow particle size distribution, and are durable. Highly soluble polymers include, for example, lead-free soda-lime glass and borosilicate glass. , preferably substantially spherical and of sufficient hardness and abrasion to not chip or break during grinding. Highly abrasive, it is resistant to metals, solvents and residues, minimizing abrasion that can cause product contamination. It can be selected from a wide variety of polymer resins that do not contain impurities such as residual monomers.

[0075] The grinding bodies may be formed from a polymeric resin. For example, the polymeric resin may be a mixture of divinylbenzene and Cross-linked polystyrene, styrene copolymers, polymethylmethacrylate Polyacrylates such as acrylate, polycarbonate, polyacetal, vinyl chloride polymers Polymers and copolymers, polyurethanes, polyamides, high density polyurethanes, polypropylene To grind materials to very fine particle size (mechanochemical grinding), The use of polymeric grinding bodies (rather than composites) is described, for example, in U.S. Pat. No. 5,478,705 and and 5,500,331. The polymeric resins typically have a viscosity of about 0.8 to 3.0 g / cm 3 Higher density polymeric resins are generally preferred. Alternatively, The grinding body may be a composite comprising a high density core with a polymeric resin bonded thereon. The core particles may be, for example, glass, alumina, zirconia silica, zirconium oxide, stainless steel, The grinding body may be selected from several materials known to be useful as grinding bodies, such as stainless steel. The core material is approximately 2.5 g / cm 3 It has a density greater than

[0076] In one embodiment of the present invention, the grinding body is made of a ferromagnetic material. Contaminants generated by the wear of the grinding body can be easily removed using magnetic separation technology. be.

[0077] Each type of grinding body has its own advantages. For example, metals have the highest specific gravity and are the most impact-resistant. The impact energy is large, so the crushing efficiency is high. Metals range from cheap to expensive. Although glass is widely used, contamination of the final product by metals can be an issue. This has the advantage that the bead size can be reduced to about 0.004 mm. Because the specific gravity of the glass is lower than that of other materials, it requires significantly longer grinding times. The advantages of ramic are that it is less abrasive and less polluting, is easy to clean, and has high hardness. do.

[0078] Dry grinding In the dry milling process of the present invention, abiraterone acetate and a crystalline, powder, etc. and a grinding matrix in the form of a powder, are mechanically agitated (i.e., It is mixed with several grinding bodies in the appropriate ratio in a grinding chamber where it is stirred or not. Typically, the grinding device is used to perform various translational, rotational and reversal movements or External agitation, blades, propellers, etc., which add a combination of these to the grinding chamber and its contents. Internal agitation using a rotating shaft terminating in an impeller or paddle, or a combination of both The motion caused by the force is given to the grinding body.

[0079] The motion imparted to the grinding body during grinding creates multiple impacts of great intensity along with shear forces. Impact or collision occurs between the grinding body and the abiraterone acetate particles and grinding matrix. The grinding body adds abiraterone acetate to the grinding matrix. The nature and intensity of the forces exerted depend on the type of grinding equipment; the intensity of the forces exerted; the dynamic aspects of the process; Size, density, shape and composition of the ground particles; weight ratio of abiraterone acetate and milling matrix; milling time; physical properties of both the material and the environment; can be.

[0080] Advantageously, the media mill applies mechanical compression and shear stress to the abiraterone acetate and and can be applied repeatedly or continuously to the grinding matrix. The grinding is carried out using a high-energy ball mill, sand mill, bead mill or pa ball mill, basket mill, planetary mill, vibrating ball mill, multi-axis shaker / mixer, agitator These include agitated ball mills, horizontal small media mills, and multi-ring fine grinding mills. The grinding device may have one or more rotating shafts. .

[0081] In one embodiment of the present invention, the dry milling is carried out in a ball mill. Throughout this section, dry milling is referred to as being performed by a ball mill. Examples of mills are attritor mills, rocking mills, tower mills, planetary mills, vibratory mills and gravity mills. The dry grinding according to the method of the present invention can be carried out in any suitable manner other than a ball mill. It will be appreciated that dry milling may be carried out using various means. For example, dry milling may be carried out using a jet mill. The grinding may be carried out using a rod mill, a roller mill or a crusher mill.

[0082] In some cases, abiraterone prior to dry milling according to the methods described herein. The particle size of the acetate ester is less than about 1000 μm as determined by sieve analysis. If the particle size of abiraterone acetate exceeds approximately 1000 μm, The particles of the base material were milled to about 100°C using another standard milling method before the dry milling described in this invention. It is preferable to reduce the diameter to less than 00 μm.

[0083] Abiraterone acetate aggregates after treatment Abiraterone acetate particle aggregates having particle sizes within the ranges specified herein are Regardless of whether the aggregates exceed the aforementioned ranges, they are still within the scope of the present invention. It should be understood as

[0084] Processing time In some embodiments, the abiraterone acetate and the grinding matrix are To minimize expected contamination from the Diamill and / or multiple grinding bodies, The dry milling is carried out for the shortest time required. This time is The time required for the grinding varies greatly depending on the grinding matrix and the grinding time, and can range from approximately 1 minute to several hours. It's okay to have one.

[0085] The suitable stirring speed and total milling time depend on the type and size of the milling equipment, the milling media, the number of The weight ratio of abiraterone acetate and grinding matrix to the number of grinding bodies, Chemical and physical properties of terone acetate and milling matrix and other , adjusted for each parameter that can be empirically optimized.

[0086] In some embodiments, the grinding matrix (grinding with abiraterone acetate) The ingredients used in this study (biraterone acetate) are not separated from the abiraterone acetate, but are instead incorporated into the final product. In some embodiments, the matrix is ​​held together with the biraterone acetate. The drug is considered "Generally Recognized as Safe" (GRAS).

[0087] In another aspect, the grinding matrix is ​​separated from the abiraterone acetate. In one aspect where the milled matrix is ​​not completely milled, the unmilled milled matrix In yet another aspect, the powder is separated from the abiraterone acetate. At least a portion of the resulting grinding matrix is ​​separated from the abiraterone acetate.

[0088] Containing 10%, 25%, 50%, 75% or substantially all of the grinding matrix Any part may be removed, including but not limited to:

[0089] In some embodiments of the present invention, a substantial portion of the milled milling matrix is having a particle size equal to and / or smaller than that of particles containing biraterone acetate The milled particles separated from the particles containing abiraterone acetate may be The trix is ​​equivalent to and / or better than particles containing abiraterone acetate. If the particles have a very small particle size, separation techniques based on particle size distribution cannot be used. In these cases, the method of the present invention may be carried out by electrostatic separation, magnetic separation, centrifugation (density separation), hydrodynamic separation, etc. The crushed ground material is separated by techniques including, but not limited to, chemical separation and flotation. The method may further comprise separating the abiraterone acetate from the sorbitol. removing at least a portion of the grinding matrix from the abiraterone acetate, This may be advantageously carried out by means such as selective dissolution, washing or sublimation.

[0090] An advantageous aspect of the present invention is a composition comprising two or more components, at least one of which is By using a milling matrix that is water-soluble and at least one that is poorly soluble in water, In this case, water-soluble matrix components are removed by washing, and the remaining matrix Abiraterone acetate may be dispersed within the composition. In one aspect, a poorly water-soluble matrix is ​​the functional excipient.

[0091] One highly advantageous aspect of the present invention is that several grinding matrices suitable for use in the method of the present invention are that the compound is pharmaceutically acceptable and therefore suitable for use in medicine; The method of the present invention completely separates the grinding matrix from the abiraterone acetate. If not, the present invention provides a method for preparing a composition comprising abiraterone acetate and a milled grinding matrix. and a method for producing a medicament containing at least a portion of the medicament, the medicament thus produced, and and administering a therapeutically effective amount of the abiraterone acetate to an animal, including a human, by the medicament. The present invention also includes methods of treatment using the same.

[0092] Abiraterone acetate and compositions The present invention also relates to pharmaceutically acceptable materials produced according to the methods of the present invention, such materials Compositions containing such materials and compositions containing or containing grinding aids, accelerators, and a grinding matrix having no or a composition separated from said grinding matrix, The present invention also includes compositions containing such materials.

[0093] Pharmaceutically acceptable materials may be present in the compositions of the present invention at a concentration of about 0.1% to about 99.0% by weight. In some embodiments, the pharmaceutically acceptable material in the composition The concentration is from about 5% to about 80% by weight, for example from about 10% to about 50% by weight. The above composition before subsequent removal (if desired) of any portion of the grinding matrix. The concentration in the composition is preferably about 10 to 15% by weight, 15 to 20% by weight, 20 to 25 to 25% by weight, 25 to 30% by weight, 30 to 35% by weight, 35 to 40% by weight, 40 to 45 to 45% by weight, 45 to 50% by weight, 50 to 55% by weight, 55 to 60% by weight, 60 to 65 to 65 wt%, 65 to 70 wt%, 70 to 75 wt%, or 75 to 80 wt% The pharmaceutically acceptable salts in the composition after removing some or all of the grinding matrix are The relative concentrations of available materials are significantly higher than before removal due to the amount of milling matrix removed. For example, if all the grinding matrix is ​​removed, the particle concentration in the preparation may be The concentration may be nearly 100% by weight (assuming the presence of an accelerator).

[0094] Pharmaceuticals The medicament of the present invention is prepared by mixing pharmaceutically acceptable materials and, if necessary, grinding aids, accelerators, one or more and one or more pharmaceutically acceptable carriers and other components for preparing pharmaceutically acceptable compositions. A grinding matrix or small amount of material, with or without other commonly used materials. It may also contain at least a portion of the grinding matrix.

[0095] As used herein, a "pharmaceutically acceptable carrier" refers to any and all physiologically compatible carriers. All solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. In some embodiments, the carrier is suitable for parenteral, intravenous, or intraperitoneal administration. Suitable for intramuscular, sublingual, pulmonary, transdermal or oral administration. Acceptable carriers include sterile aqueous solutions or dispersions for the extemporaneous preparation of sterile injectable solutions or dispersions. The use of such media and substances in the preparation of pharmaceutical preparations includes liquid dispersions and sterile powders. It is well known in the art that if a conventional media or agent is incompatible with the pharmaceutically acceptable material, Except as otherwise provided herein, their use in preparing pharmaceutically acceptable compositions of the present invention is not contemplated. There are.

[0096] Pharmaceutically acceptable carriers according to the present invention may include one or more of the following examples: : (1) Polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), polyvinyl Alcohol, Crospovidone, Polyvinylpyrrolidone-Polyvinyl acrylate Copolymer Cellulose derivatives, hydroxypropyl methylcellulose, hydroxypropyl cellulose Roasted, carboxymethylethylcellulose, hydroxypropylmethylcellulose lid acrylates, polyacrylates and polymethyl acrylates, urea, sugars, polyols and and their polymers, emulsifiers, sugar-coated gums, starch, organic acids and their salts, vinyl surfactants and polymers, including but not limited to lolidone and vinyl acetate (2) Various cellulose and cross-linked polyvinylpyrrolidone, microcrystalline cellulose, etc. agents; and / or (3) Lactose monohydrate, anhydrous lactose, microcrystalline cellulose, and various starches fillers; and / or (4) Colloidal silicon dioxide, talc, stearic acid, magnesium stearate, Substances that affect the flowability of powders to be compressed, including calcium tearate and silica gel lubricants; and / or (5) Sucrose, xylitol, sodium saccharin, cyclamate, aspartame, Sweeteners, such as any natural or artificial sweetener, including acesulfame K; and / or or (6) fragrances; and / or (7) Potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts Other esters of parahydroxybenzoic acid such as butylparaben, ethyl or butylparaben Alcohols such as benzyl alcohol, phenolic chemicals such as phenol, or chlorinated benzyl alcohol Preservatives such as quaternary compounds such as benzocaine and / or (8) buffering agents; and / or (9) Microcrystalline cellulose, lactose, dibasic calcium phosphate, sugars and / or a diluent, such as a pharmaceutically acceptable inert filler, such as any mixture thereof; and / or (10) Corn starch, potato starch, maize starch, modified starch, and mixtures thereof; and / or (11) Croscarmellose sodium, crospovidone, sodium starch glycolate disintegrants, such as ammonium; and / or (12) (citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid and arginine Organic acids (such as carboxylic acids and anhydrides and acid salts), (sodium carbonate, potassium carbonate, Magnesium carbonate, sodium glycine carbonate nate) carbonates or (sodium bicarbonate, such as L-lysine carbonate and arginine carbonate) effervescent combinations such as sodium or potassium bicarbonate foaming agents such as t couples) and / or (13) Other pharmaceutically acceptable excipients

[0097] The actual dosage level of the abiraterone acetate of the present invention is properties and delivery and administration benefits of abiraterone acetate that may be improved as a result The drug has several beneficial effects (such as improved solubility, faster dissolution, and increased surface area of ​​abiraterone acetate). Therefore, as used herein, a "therapeutically effective amount" may vary based on the efficacy of the compound in an animal. This refers to the amount of abiraterone acetate required to produce a therapeutic response in An effective amount for such uses will depend on the desired therapeutic effect; the route of administration; and the abiraterone acetate ester. the efficacy of the drug; the desired duration of treatment; the stage and severity of the disease being treated; the patient's weight and overall general health condition; subject to the judgment of the prescribing physician.

[0098] Pharmacokinetic properties of abiraterone acetate compositions Rapid onset of action In some embodiments, the abiraterone acetate compositions of the present invention are rapidly absorbed. In one embodiment, the abiraterone of the present invention contains abiraterone acetate. T after administration of acetate ester composition max is less than about 2 hours, less than about 1.75 hours, and about 1. Less than 5 hours, Less than about 1.25 hours, Less than about 1.0 hour, Less than about 50 minutes, Less than about 40 minutes or is less than about 30 minutes.

[0099] Improved bioavailability The abiraterone acetate of the present invention exhibits excellent bioavailability (AUC). compared to conventional compositions (such as Zytiga®) administered at the same dose. Therefore, a lower dose is required. Any pharmaceutical composition can have side effects. The therapeutic effect observed with a lower dose of the drug is the same as or greater than that observed with a higher dose of the conventional composition. It is desirable to be able to achieve a better therapeutic effect. The observed superior bioavailability compared to the formulation is believed to contribute to the desired therapeutic effect. This means that a smaller dose of the drug is needed to achieve the desired effect. Low doses are achievable.

[0100] The fed or fasted state of a subject ingesting the composition of the present invention affects the pharmacokinetic profile of the composition. Significantly less impact on The present invention relates to a method for determining whether the pharmacokinetic profile of the composition is in a fed or fasted state of a subject who ingests the composition. Avila is significantly less affected by steroids than Zytiga®. The present invention relates to a method for administering a steroid ester composition to a patient in a fed or fasted state. This means that there is little substantial difference in the amount or rate of absorption of the composition when administered in a different state. Therefore, the compositions of the present invention can be used to assess the effect of food on the pharmacokinetics of the compositions using Zytig a (registered trademark) is significantly reduced.

[0101] Any standard pharmacokinetic protocol may be used to determine the pharmacokinetics in humans after administration of a composition. and measuring the plasma concentration profile of the composition, whereby the composition meets the pharmacokinetic criteria defined herein. Compliance with the criteria may be determined, for example, using a group of healthy adult human subjects. A randomized single-dose crossover study may be conducted. The number of subjects should be adjusted to adequately account for variability in statistical analysis. The value should be sufficient to control the A smaller number may also be sufficient. Each subject receives one dose of the test formulation of the composition (e.g., 10 A single dose (e.g., 0 mg) is usually given orally around 8:00 AM after an overnight fast. The elephants continued to fast and remained in a sedentary position for approximately 4 hours after administration of the composition. Blood samples were taken from each subject. Multiple samples should be taken before (e.g., 15 minutes before) and at intervals after administration. Samples are taken several times during the first hour and then at longer intervals. For example, blood samples are taken. Samples were collected 15, 30, 45, 60, and 90 minutes after administration, and then 2 hours after administration. Further blood samples may be taken every hour for 10 hours. Samples may be taken at mid- and 24-hour intervals. If the animals must be used, they should be kept at least 7 days before administration of the second test formulation. The plasma should be separated from the blood sample by centrifugation and the separated Plasma composition was analyzed by validated high performance liquid chromatography (HPLC) or liquid chromatography. The compositions referred to herein are analyzed by chromatography-mass spectrometry (LCMS). Plasma concentration refers to the total concentration, including both free and bound components. It is intended as.

[0102] Any formulation that results in the desired pharmacokinetic profile is suitable for administration according to the methods of the present invention. Examples of formulation types that result in such profiles are dispersions and and solid dosage forms. If the liquid dispersion medium is one in which the composition has very low solubility, , the particles are present as suspended particles.

[0103] Methods for administering medicines containing abiraterone acetate The pharmaceutical agent of the present invention can be administered to animals, including humans, by oral administration, rectal administration, pulmonary administration, vaginal administration, (powder administration), or the like. topical administration (e.g., ointment or eye drops), transdermal administration, parenteral administration, intravenous administration, intraperitoneal administration , intramuscular, sublingual, or buccal or nasal sprays. The compound may be administered in any pharmaceutically acceptable manner.

[0104] Solid dosage forms for oral administration include capsules, tablets, pills, powders, pellets and granules. In addition, commonly used excipients such as those listed above and generally 5-95 %, more preferably in a concentration of 10%-75% of a biologically active substance. , forming a pharmaceutically acceptable, non-toxic oral composition.

[0105] However, when abiraterone acetate is used in a suspension, the solid carrier is substantially Further stabilizing the abiraterone acetate-containing particles after they have been selectively removed. It is necessary to ensure discharge or at least minimize particle agglomeration. It is also possible.

[0106] Example 1. Preparation of abiraterone acetate particles Abiraterone acetate drug substance was purchased from Hangzhao Day Chemical Co., Ltd. in Hangzhou, People's Republic of China. Abiraterone acetate (10% w / w), lactose- Sodium lauryl sulfate (1%) and sodium lauryl sulfate (89%; DMV Fonterra) %; Sigma-Aldrich) mixture (3.0 g) was ground in a Spex vibratory mill. The mixture was then ground together for 10 minutes to produce 2.7 g of nanoparticulate abiraterone acetate. Unmilled abiraterone acetate and nanoparticulate abiraterone acetate were The particle size distribution of the particles was measured by light scattering (Malvern Mastersizer 2000). The average particle size of the unground material was approximately 40 μm (volume statistics; D 10 =16μm, D5 0 = 37 μm; D 90 = 70 μm), while nanoparticulate abiraterone acetate esophagus The average particle size of the ter is about 1000 nm (D 10 = 75 nm; D 50 = 177 nm; D 90 = The results are shown in Figure 1.

[0107] Example 2: Comparative solubility test Approximately 250 mg of the nanoparticulate acetate preparation prepared in Example 1 (25 mg of active ingredient) The uncrushed granules were manually filled into size 1 hard gelatin capsules. Abiraterone acetate 250 mg was manually filled into similar capsules. The files were placed in a Varian VK7025 dissolution apparatus equipped with six 1000 mL containers. Measurements were performed in triplicate using a Varian UV-Vis spectrophotometer at 270 nm. Each container contained 10 mmol of phosphate buffer solution (pH 6) containing 0.1% SDS. The samples contained 900 mL of dissolution medium. The experiments were carried out at 37°C. Before the start of the dissolution experiments, The hard gelatin capsule was placed inside a spiral sinker.

[0108] The results showed that under the experimental conditions, uncrushed abiraterone acetate (25 mg) was Only about 10% of the nanoparticulate abiraterone acetate was dissolved in the (25 mg) showed 100% dissolution within approximately 10 minutes (Figure 2).

[0109] Example 3: Preparation of Abiraterone Acetate Microparticles Abiraterone acetate is available from Chongquing Pharmaceuticals Lactose monohydrate was obtained from the Research Institute Co., Ltd. (China). NF was obtained from Meggle Pharma (CapsuLac® 6 0). Sodium lauryl sulfate NF was obtained from Cognis (Texapon ( Registered trademark) K12 P PH). 2.5 ml stainless steel grinding vial and and two 1 / 4-inch stainless steel grinding balls. Using a Sample Prep 5100 mixer mill (Metuchen, Jersey) Abiraterone acetate was prepared in nanoparticulate form. The premixed powder was added, the grinding vial was capped, and the mixer mill was run for 20 minutes. The powder used for particle size analysis consisted of abiraterone acetate (30 mg), lactose (20 mg), and lactic acid bacteria (20 mg). The ingredients were sodium lauryl sulfate (1.5 mg), sodium thiamin monohydrate (68.5 mg), and sodium lauryl sulfate (1.5 mg). The powder used in the dissolution test consisted of abiraterone acetate (20 mg), lactose The components were sodium lauryl sulfate (1.5 mg), sodium lauryl sulfate monohydrate (78.5 mg), and sodium lauryl sulfate (1.5 mg). To obtain sufficient material for dissolution testing, the ground powders from multiple experiments were mixed. did.

[0110] Example 4: Particle size analysis of milled and unmilled abiraterone acetate The milled powder sample obtained in Example 3 was added to 26 mg of milled material (abiraterone acetate). 6 mg) in a 0.1% w / w aqueous solution of polyvinylpyrrolidone (PVP; BASF Kolli 5 mg of acetone was added to 5 mg of acetone-containing acetone (DON® 30) and then subjected to an external ultrasonic horn (Branson Using a Digital Sonifier®, sonicate for 5 seconds at 20% amplitude. After processing, the sample was analyzed by pausing for 15 seconds. This cycle was used to calculate the total ultrasound volume. The washing time was repeated until 1 minute was reached. The suspension was then added to 125 ml of 0.1 Malvern Mastersizer 3000 particle size analyzer (M The sample was then dropped into the sample cell of the Alvern Hydro MV pump unit. The mixture was stirred for 5 minutes before measurement. The data from the final measurement are shown in Table 1 and the graph in Figure 3.

[0111] For comparison, the particle size distribution of unmilled abiraterone acetate (drug substance) was also measured. The conditions were as follows: unground abiraterone acetate was placed in 130 ml of 0.1% PVP. Same as above except added directly to the Malvern Hydro MV pump unit To obtain the same obscuration value as the milled material, 26 mg of unmilled The crushed abiraterone acetate should be added directly to the Malvern pump unit. Next, abiraterone acetate was treated in an ultrasonic bath at 100% amplitude for 1 minute. The samples were then stirred for 5 minutes before measurements. The data obtained from these measurements are shown in Table 1. The graph is shown in Figure 3. These results demonstrate that the milled abiraterone acetate material The drug substance contained fine particles, and the crushed abiraterone acetate material showed that the particle size of the drug substance was significantly smaller (>10 times) compared to the unmilled material. No fine particles of abiraterone acetate were measured in the unmilled drug sample. Ta.

[0112] Malvern Mastersizer 3000 Settings: Optical properties of abiraterone acetate: Refractive index: 1.583 Absorption: 0.01 Dispersant Optical Properties: Refractive index: 1.33 Sample measurement time: 10 seconds Background measurement time: 10 seconds Number of cycles measured: 3 (reported results are the average of these) Intercycle Delay: 0 Stirrer setting: 2000rpm

[0113] Table 1: Comparison of particle size distribution data for milled and unmilled abiraterone acetate (volume statistics) ) [Table 1]

[0114] Example 5: Dissolution of Milled and Unmilled Abiraterone Acetate Powder Mixtures The dissolution behavior of the milled abiraterone acetate powder mixture prepared in Example 3 was measured using Thermo Scientific Ethylene Propylene Glycol (Tetrahydrofuran). Fisher Scientific UV-Visible Spectrophotometer (product number EV030 Using a Sotax AT7 Smart automatic dissolution test unit equipped with 0 PC The dissolution medium was a 0.01N HCl (pH = 2) solution. 000 ml of medium was added and equilibrated to 37°C. USP2 type with agitation speed of 100 rpm The dissolution settings were based on the device. Two in-line filters with pore sizes of 0.7 μm and 2.7 μm were used. The filters were used in series. The absorbance was measured at λ = 236 nm. A duplicate sample of the bilaterone acetate powder mixture was added directly to the dissolution medium. The composition of the unmilled powder mixture was the same as that of the unmilled powder mixture, except that it was not milled. The total powder weight of each crushed and uncrushed sample was 500 mg. The sample used was 100 mg of abiraterone acetate. 2, 4, 6, 8, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 6 The dissolution was performed for 0, 70, 80, 90, 100, 110 and 120 minutes. The results of this comparative study are shown in Table 2 and are plotted as the percentage of abiraterone acetate. A rough outline is shown in Figure 4. These results are based on the results of the milled nanoparticulate abiraterone acetate ester. The results show that the powder dissolved more rapidly and at a higher rate than the unmilled material. .

[0115] Table 2: Milled microparticulate abiraterone acetate vs. unmilled abiraterone acetate Comparison of dissolution rate with Teru (n=2) [Table 2]

[0116] Example 6: Stability of Abiraterone Acetate Powder Blends Abiraterone acetate powder with a diameter of more than a few microns was mixed with lactose monohydrate and After dry grinding with sodium lauryl sulfate, the impurities were examined. Impurities of 0.4-0.6% were detected (%AUC). When I) is further processed into tablets, the impurity level is higher, about 0.5-1.1%. Stability testing showed that impurities increased at 25°C / 60% RH and 40°C / 75% RH. However, it was shown that there was no increase at 2-8°C. In addition, the rate of increase of impurities in the tablets was , the rate of increase of impurities in the milled DPI was greater than that in the milled DPI. ; triangle, 25°C / 60%RH; cross, 40°C / 75%RH) and Figure 5B (diamond, 5 °C; square, 25°C / 60%RH; triangle, 40°C / 75%RH) are the acceleration and stability The impurity levels of multiple lots of crushed DPI and tablets in a safety study were summarized. Tablets packaged under nitrogen purging and refrigerated have acceptable impurity levels. It is desirable to have a formulation that can be stored under ambient air conditions, even though the temperature is low.

[0117] The observed increase in impurities compared to Zytiga® resulted in a fine powder of Abirater®. The increase in impurities observed in DPIs and tablets containing thrombin acetate was due to the presence of Zytig The increase in impurities was found to be greater than that observed with α®.

[0118] Impurity levels in tablets containing micronized abiraterone acetate were The higher surface area of ​​the API compared to α® is due to the higher surface area of ​​the excipients. Due to multiple factors including but not limited to higher ratios and different excipients There is a possibility that this will happen.

[0119] As part of the analysis of impurity growth, various excipients useful in tablet preparation were found to have impurity levels. The effect of DPI on the solubility of soluble fiber was investigated by mixing DPI with various excipients and heating them at 80°C for 4 hours. Microcrystalline cellulose (MCC), sodium lauryl sulfate (SLS), croscarmellose Sodium citrate (CCS), sodium stearyl fumarate (SSF), stearic acid Increased levels of magnesium and hydrogenated vegetable oil impurities were observed in pregelatinized starch, spray-dried Dried lactose, poloxamer 188, crospovidone, sodium starch glycolate However, the increase in impurities of MCC, SLS, CCS and Mixtures of SSFs may have more harmful effects than would be suggested by the individual effects of the components. It was observed that the effect on

[0120] Further experiments revealed that the observed impurities were degradants of abiraterone acetate. Analysis of the API before reduction showed that after 4 hours at 80°C No degradation was observed, and no increase in impurities was observed when the unmilled API was mixed with excipients and heated. Further experiments were carried out to determine whether the degradation was simply due to interactions with excipients or the grinding itself. It was concluded that the cause was not due to the effects of either of these factors, but rather the result of a combination of factors.

[0121] Example 5: Grinding with antioxidants or sequestering agents Abiraterone acetate was dry milled with lactose monohydrate and sodium lauryl sulfate. The reactions were carried out in the presence of sodium and various antioxidants and / or sequestering agents. In the experiments, a combination of ascorbic acid and fumaric acid or butyl hydrochloride was used for dry grinding. Also included is a combination of hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). In this study, a DPI formulation combining ascorbic acid and fumaric acid (Formu DPI formulations combining BHA and BHT were prepared as shown in Table 3. Both DPI formulations contained abiraterone acetate esters with a [D90] of less than 1000 nm. The formulation contained a sterol and therefore contained microparticulate abiraterone acetate.

[0122] Table 3: DPI formulations containing antioxidants or sequestrants [Table 3]

[0123] Stability testing of the two DPI formulations in Table 3 was performed under accelerated conditions (80°C for 4 hours). In ascorbic acid / fumaric acid DPI formulations, total impurities ranged only from 0.23 to 0.80. The BHA / BHT DPI formulation did not increase total impurities (80 In contrast, the abiraterone acetate was administered at 4°C for 0.38 hours. Dried with sodium lauryl sulfate monohydrate and sodium lauryl sulfate only (no antioxidants, no sequestering agents) In the formula-milled DPI formulation, the impurities decreased from an initial 1.63 to 3.0 after 4 hours at 80°C. It increased to 86.

[0124] These two different DPI formulations were used to produce two different corresponding tablets detailed in Table 4. The formulation was prepared by dry granulating and compressing the DPI formulation with the indicated excipients. , was produced.

[0125] Table 4: DPI tablets containing antioxidants or sequestrants [Table 4]

[0126] Stability testing of these two tablet formulations was performed under accelerated conditions (80°C for 4 hours). In the corbic acid / fumaric acid tablet formulation, total impurities increased only from 0.31 to 0.38. The BHA / BHT tablet formulation had a total impurity content of only 0.41 to 0.44. This indicates that the addition of antioxidants and / or sequestering agents during grinding did not increase the This shows that the stability can be dramatically improved.

[0127] The dissolution rates of the ascorbic acid / fumaric acid tablet formulation and the BHA / BHT tablet formulation were measured using U The test was carried out using an SP2 type device at 75 rpm (900 ml of pH 4.5 phosphate buffer solution). (0.1% SLS)). In addition, neither BHA / BHT nor fumaric acid / ascorbic acid was added during grinding. A similar formulation (tablet formulation 3) without the addition of hydroxybenzoates was also tested. Formulation 3; square, BHA / BHT tablet Formulation; diamond, ascorbic acid / fumaric acid tablet As shown in the formulations, all three tablets contained 80% abiraterone acetate. %-90% dissolved within 10 minutes.

[0128] To compare the dissolution rates with conventional abiraterone acetate formulations, 250 mg Zytiga® tablets divided into 100 mg equivalents were tested under the dissolution conditions described above along with tablet formulations that did not contain an antioxidant or sequestrant. As shown in Figure 7 (squares, Zytiga® 100 mg scored tablets; squares, tablet formulation 3), the tablet formulation containing microparticulate abiraterone acetate without an antioxidant or sequestrant dissolved much more rapidly than the Zytiga® 100 mg scored tablets. In one aspect, the present invention includes the following. [Item 1] 1. A method for making a composition containing nanoparticles of abiraterone acetate, comprising: dry-milling a composition containing abiraterone acetate, a millable grinding compound, an accelerant, and one or both of an antioxidant and a sequestering agent in a mill comprising a plurality of grinding bodies for a time sufficient to produce a composition containing nanoparticles of said abiraterone acetate; In this case, dry milling reduces the particle size of the milled compound and the particle size of the abiraterone acetate. method. [Item 2] 2. The method of claim 1, wherein the abiraterone acetate nanoparticles have a [D90] greater than 100 nm and less than or equal to one of 2500 nm, 2000 nm, 1900 nm, 1800 nm, 1700 nm, 1600 nm, 1500 nm, 1400 nm, 1300 nm, 1200 nm, 1100 nm, 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, or 200 nm. [Item 3] 3. The method according to claim 1 or 2, wherein the grinding is carried out in the presence of one or both of an antioxidant and a sequestering agent. [Item 4] 2. The method of claim 1, wherein the antioxidant is selected from the group consisting of ascorbic acid, BHA, and BHT. [Item 5] 2. The method of claim 1, wherein the sequestering agent is selected from the group consisting of fumaric acid, tartaric acid and citric acid. [Item 6] 6. The method of any of items 1 to 5, wherein the abiraterone acetate nanoparticles have a [D50] greater than 100 nm and less than or equal to one of 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, or 200 nm. [Item 7] 7. The method of any one of items 1 to 6, wherein the [D4,3] of the abiraterone acetate nanoparticles is greater than 100 nm and less than or equal to one of 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, or 200 nm. [Item 8] preparing a composition containing nanoparticles of abiraterone acetate according to the method described in any one of items 1 to 7; combining said composition with one or more pharmaceutically acceptable diluents, disintegrants, lubricants, enhancers or dispersants. [Item 9] 9. The method of claim 8, wherein the unit dosage composition is a tablet or capsule. [Item 10] 10. The method of claim 9, wherein the unit dosage composition contains 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, or 400 mg of abiraterone acetate. [Item 11] Item 11. The method according to Item 10, wherein the dissolution rate of the nanoparticles of abiraterone acetate in the unit dosage composition is such that, when a sample containing 100 mg of abiraterone acetate is tested in 900 ml of pH 4.5 phosphate buffer (0.1% SLS) using a USP Type 2 apparatus at 75 rpm, at least 90% of the abiraterone acetate dissolves within 25 minutes. [Item 12] Item 12. The method of item 11, wherein the unit dosage composition is a tablet, and the tablet has a dissolution rate such that at least 90% of the abiraterone acetate dissolves within 15 minutes when tested in 900 ml of pH 4.5 phosphate buffer (0.1% SLS) using a USP Type 2 apparatus at 75 rpm. [Item 13] 13. The method according to any one of items 1 to 12, wherein the mill comprises a plurality of grinding bodies. [Item 14] 14. The method of any one of items 1 to 13, wherein the nanoparticles of abiraterone acetate have a [D90] of 657 nm or less. [Item 15] 15. The method of any one of items 1 to 14, wherein the [D50] of the abiraterone acetate nanoparticles is equal to or less than 215 nm or 177 nm. [Item 16] 16. The method of any one of items 1 to 15, wherein the [D4,3] of the abiraterone acetate nanoparticles is equal to or less than 490 nm or 177 nm. [Item 17] 17. The method of any one of items 1 to 16, wherein the nanoparticles of abiraterone acetate are dispersed in a milled compound. [Item 18] The grinding compound may be selected from the group consisting of mannitol, sorbitol, isomalt, xylitol, maltitol, lactitol, erythritol, arabitol, ribitol, glucose, fructose, mannose, galactose, anhydrous lactose, lactose monohydrate, sucrose, maltose, trehalose, and maltodextrin, dextrin, inulin, dextrates, polydextrose, starch, wheat flour, corn flour, rice flour, tapioca flour, potato flour, potato starch, and other flours and starches. , milk powder, skim milk powder, other milk solids and derivatives, soy flour, skim soy or other soy products, cellulose, crystalline cellulose, blends containing crystalline cellulose, pregelatinized (or partially gelatinized) starch, HPMC, CMC, HPC, citric acid, tartaric acid, malic acid, maleic acid, fumaric acid, ascorbic acid, succinic acid, sodium citrate, sodium tartrate, sodium malate, sodium ascorbate, potassium citrate, potassium tartrate, potassium malate, potassium acetate, potassium ascorbate, sodium carbonate, potassium carbonate, magnesium carbonate, Sodium bicarbonate, potassium bicarbonate, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, sodium sulfate, sodium chloride, sodium metabisulfite, sodium thiosulfate, ammonium chloride, sodium salt of mirabilite, ammonium carbonate, sodium bisulfate, magnesium sulfate, potassium alum, potassium chloride, sodium hydrogen sulfate, sodium hydroxide, crystalline hydroxide, bicarbonate, ammonium chloride, methylamine hydrochloride, ammonium bromide, silica, thermal silica, alumina, titanium dioxide, talc, chalk, mica, kaolin, bentonite, hectorite, magnesium trisilicate, clay or aluminum silicate, sodium lauryl sulfate, sodium stearyl sulfate, sodium cetyl sulfate, sodium cetostearyl sulfate, docusate sodium, sodium deoxycholate, sodium N-lauroyl sarcosinate, glyceryl monostearate, glycerol distearate, glyceryl palmitostearateLauryl Ether, Glyceryl Behenate, Glyceryl Caprylate, Glyceryl Oleate, Benzalkonium Chloride, CTAB, CTAC, Cetrimide, Cetylpyridinium Chloride, Cetylpyridinium Bromide, Benzethonium Chloride, PEG-40 Stearate, PEG-100 Stearate, Poloxamer 188, Poloxamer 338, Poloxamer 407, Polyoxyl 2 Stearyl Ether, Polyoxyl 100 Stearyl Ether, Polyoxyl 20 Stearyl Ether, Polyoxyl 10 Stearyl Ether, Polyoxyl 20 Cetyl Ether, Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 61, Polysorbate 65, Polysorbate 80, Polyoxyl 35 Castor Oil, Polyoxyl 40 Castor Oil, Polyoxyl 60 Castor Oil, Polyoxyl 100 Castor Oil, Polyoxyl 200 Castor Oil, Polyoxyl 40 Hydrogenated Castor Oil, Polyoxyl 60 Hydrogenated Castor Oil, Polyoxyl 100 Hydrogenated Castor Oil, Polyoxyl 200 Hydrogenated Castor Oil, Cetostearyl Alcohol, Macrogel 15 Hydroxystearate, Sorbitan Monopalmitate, Sorbitan Monostearate, Sorbitan Trioleate, Sucrose Palmitate, Sucrose Stearate, Sucrose Distearate, Sucrose Laurate, Glycocholate, Sodium Glycolateglycholate), cholic acid, sodium cholate, sodium deoxycholate, deoxycholic acid, sodium taurocholate, taurocholic acid, sodium taurodeoxycholate, taurodeoxycholic acid, soy lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkylnaphthalenesulfonic acid condensate / lignosulfonate mixture, calcium dodecylbenzenesulfonate, sodium dodecylbenzenesulfonate, diisopropylnaphthalenesulfonate, erythritol distearate, naphthalenesulfonic acid formaldehyde condensate, nonylphenol ethoxylate ( 18. The method of any one of items 1 to 17, wherein the alkyl group is selected from the group consisting of POE-30, tristyrylphenol ethoxylate, polyoxyethylene (15) tallow alkylamine, sodium alkylnaphthalene sulfonate, sodium alkylnaphthalene sulfonate condensate, sodium alkylbenzene sulfonate, sodium isopropyl naphthalene sulfonate, sodium methylnaphthalene formaldehyde sulfonate, sodium n-butyl naphthalene sulfonate, tridecyl alcohol ethoxylate (POE-18), triethanolamine isodecanol phosphate ester, triethanolamine tristyryl phosphate ester, tristyrylphenol ethoxylate sulfate, and bis(2-hydroxyethyl) tallow alkylamine. [Item 19] 19. The method according to any one of items 1 to 18, wherein the grinding compound is selected from the group consisting of lactose monohydrate, anhydrous lactose and mannitol. [Item 20] 20. The method according to any one of items 1 to 19, wherein the accelerator is selected from the group consisting of colloidal silica, surfactants, polymers, stearic acid and derivatives thereof. [Item 21] 21. The method according to any one of items 1 to 20, wherein the accelerator is at least one selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinyl alcohol, acrylic acid-based polymers, and acrylic acid copolymers. [Item 22] The enhancer may be polyoxyethylene alkyl ether, polyoxyethylene stearate, polyethylene glycol (PEG), poloxamer, poloxamine, sarcosine surfactant, polysorbate, fatty alcohol, alkyl and aryl sulfate, alkyl and aryl polyether sulfonate and other sulfate surfactant, trimethylammonium surfactant, lecithin and other phospholipid, bile acid, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, sucrose fatty acid 22. The method of any one of items 1 to 21, wherein the alkyl ester is at least one selected from the group consisting of alkyl esters, alkyl glucoranosides, glycerol fatty acid esters, alkyl benzene sulfonic acids, alkyl ether carboxylic acids, alkyl and aryl phosphate esters, alkyl and aryl sulfate esters, alkyl and aryl sulfonic acids, alkyl phenol phosphate esters, alkyl phenol sulfate esters, alkyl and aryl phosphates, alkyl polysaccharides, alkylamine ethoxylates, alkyl naphthalene sulfonate formaldehyde condensates, sulfosuccinates, lignosulfonates, ceto oleyl alcohol ethoxylates, condensed naphthalene sulfonates, dialkyl and alkyl naphthalene sulfonates, dialkyl sulfosuccinates, ethoxylated nonylphenols, ethylene glycol esters, fatty alcohol alkoxylates, hydrogenated tallow alkylamines, monoalkyl sulfosuccinates, nonylphenol ethoxylates, oleyl N-taurate, tallow alkylamines, and linear or branched dodecylbenzene sulfonic acids. [Item 23] 23. The method according to any one of items 1 to 22, wherein the enhancer is selected from the group consisting of sodium lauryl sulfate, cross-linked PVP (crospovidone), cross-linked sodium carboxymethylcellulose (croscarmellose sodium), sodium starch glycolate, povidone (PVP), povidone K12, povidone K17, povidone K25, povidone K29 / 32 and povidone K30, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, sodium stearyl lactylate, zinc stearate, sodium stearate or lithium stearate, other solid fatty acids such as oleic acid, lauric acid, palmitic acid, erucic acid, behenic acid or derivatives (such as esters and salts), amino acids such as leucine, isoleucine, lysine, valine, methicone, phenylalanine, aspartame or acesulfame-K. [Item 24] 24. The method of claim 23, wherein the enhancer is at least one of sodium lauryl sulfate or povidone (PVP). [Item 25] 1. A pharmaceutical composition in unit dosage form containing nanoparticles of abiraterone acetate, a millable grinding compound, an enhancer, and one or both of an antioxidant and a sequestering agent, wherein the [D90] of the abiraterone acetate in said unit dosage pharmaceutical composition is greater than 100 nm and less than or equal to one of 2500 nm, 2000 nm, 1900 nm, 1800 nm, 1700 nm, 1600 nm, 1500 nm, 1400 nm, 1300 nm, 1200 nm, 1100 nm, 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, or 200 nm. [Item 26] 26. The pharmaceutical composition in unit dosage form according to item 25, wherein the nanoparticles of abiraterone acetate in the pharmaceutical composition in unit dosage form have a [D50] of greater than 100 nm and less than or equal to one of 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, or 200 nm. [Item 27] 27. The pharmaceutical composition in unit dosage form according to item 25 or 26, wherein the [D4,3] of the nanoparticles of abiraterone acetate in the pharmaceutical composition in unit dosage form is greater than 100 nm and less than or equal to one of 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, or 200 nm. [Item 28] 28. The pharmaceutical composition in unit dosage form according to any one of items 25 to 27, wherein the dissolution rate of the nanoparticles of abiraterone acetate in the pharmaceutical composition in unit dosage form is such that, when a sample containing 100 mg of abiraterone acetate is tested in 900 ml of pH 4.5 phosphate buffer (0.1% SLS) using a USP Type 2 apparatus at 75 rpm, at least 90% of the abiraterone acetate dissolves within 15 minutes. [Item 29] 29. The pharmaceutical composition in unit dosage form according to any one of items 25 to 28, wherein the mean AUC of the pharmaceutical composition in unit dosage form when administered to adult males with a low-fat meal (7% fat, 300 calories) is no more than two-fold higher than when administered in the fasted state. [Item 30] 30. The pharmaceutical composition in unit dosage form according to any one of items 25 to 29, wherein the mean AUC of the pharmaceutical composition in unit dosage form when administered to adult males with a high-fat meal (57% fat, 825 calories) is no more than two-fold higher than when administered in the fasted state. [Item 31] 31. The pharmaceutical composition in unit dosage form according to any one of items 25 to 30, wherein the mean Cmax of the pharmaceutical composition in unit dosage form when administered to adult males with a low-fat meal (7% fat, 300 calories) is no more than 2-fold higher than when administered in the fasted state. [Item 32] 31. The pharmaceutical composition in unit dosage form according to any one of items 25 to 30, wherein the mean Cmax of the pharmaceutical composition in unit dosage form when administered to adult males with a high-fat meal (57% fat, 825 calories) is no more than 5-fold higher compared to when administered in the fasted state. [Item 33] 33. The pharmaceutical composition in unit dosage form according to any one of items 25 to 32, wherein the nanoparticles of abiraterone acetate have a [D90] of 657 nm or less. [Item 34] 34. The pharmaceutical composition in unit dosage form according to any one of items 25 to 33, wherein the [D50] of the nanoparticles of abiraterone acetate is 215 nm or less. [Item 35] 35. The pharmaceutical composition in unit dosage form according to any one of items 25 to 34, wherein the [D4,3] of the nanoparticles of abiraterone acetate is 490 nm or less. [Item 36] 1. Use of nanoparticles of abiraterone acetate in the preparation of a medicament for the treatment of castration-resistant prostate cancer, comprising: the medicament further comprises a composition containing 100-900 mg of abiraterone acetate, a millable grinding compound, an accelerant, and one or both of an antioxidant and a sequestering agent; and The use wherein the [D50] of the abiraterone acetate nanoparticles is greater than 100 nm and less than or equal to one of 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm or 200 nm. [Item 37] 37. The use according to item 36, wherein the medicament is administered so that the daily dose of abiraterone acetate is 100 to 900 mg. [Item 38] 38. The use according to item 37, wherein the medicament is administered so that the daily dose of abiraterone acetate is 200 to 500 mg. [Item 39] 39. The use according to item 38, wherein the medicament is administered so that the daily dose of abiraterone acetate is 300 to 500 mg. [Item 40] 40. The use according to any one of items 36 to 39, wherein the medicament comprises at least one glucocorticoid. [Item 41] 41. The use of item 40, wherein the at least one glucocorticoid comprises prednisone, prednisolone, methylprednisolone, or any combination thereof. [Item 42] 42. The use according to item 41, wherein the glucocorticoid is prednisone. [Item 43] 42. The use according to item 41, wherein the glucocorticoid is prednisolone. [Item 44] The use according to Item 41, wherein the glucocorticoid is methylprednisolone. 45. The use according to any one of items 36 to 44, wherein the nanoparticles of abiraterone acetate have a [D90] of 657 nm or less. [Item 46] 46. ​​The use according to any one of items 36 to 45, wherein the [D50] of the abiraterone acetate nanoparticles is 215 nm or less or 177 nm or less. [Item 47] 47. The use according to any one of items 36 to 46, wherein the [D4,3] of the nanoparticles of abiraterone acetate is 490 nm or less. [Item 48] 1. A pharmaceutical composition comprising nanoparticles of abiraterone acetate, a millable grinding compound, an enhancer, and one or both of an antioxidant and a sequestering agent, wherein the [D90] of the abiraterone acetate in the composition is greater than 100 nm and less than or equal to one of 2500 nm, 2000 nm, 1500 nm, 1400 nm, 1300 nm, 1200 nm, 1100 nm, 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, or 200 nm. [Item 49] 49. The pharmaceutical composition of item 48, wherein the nanoparticles of abiraterone acetate in the pharmaceutical composition have a [D50] greater than 100 nm and less than or equal to one of 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, or 200 nm. [Item 50] 50. The pharmaceutical composition of claim 48 or 49, wherein the [D4,3] of the abiraterone acetate nanoparticles in the pharmaceutical composition is greater than 100 nm and less than or equal to one of 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, or 200 nm. [Item 51] 51. The pharmaceutical composition of any one of items 48 to 50, wherein the nanoparticles of abiraterone acetate have a [D90] of 657 nm or less. [Item 52] 52. The pharmaceutical composition of any one of items 48 to 51, wherein the [D50] of the abiraterone acetate nanoparticles is 215 nm or less or 177 nm or less. [Item 53] 53. The pharmaceutical composition of any one of items 48 to 52, wherein the [D4,3] of the abiraterone acetate nanoparticles is 490 nm or less. [Item 54] 54. The pharmaceutical composition according to any one of items 48 to 53, wherein the medicament comprises a glucocorticoid. [Item 55] 55. The pharmaceutical composition of item 54, wherein the glucocorticoid is selected from prednisone, prednisolone, methylprednisolone, or any combination thereof. [Item 56] 56. The pharmaceutical composition of item 55, wherein the glucocorticoid is prednisone. [Item 57] 56. The pharmaceutical composition of item 55, wherein the glucocorticoid is prednisolone. [Item 58] 56. The pharmaceutical composition of item 55, wherein the glucocorticoid is methylprednisolone. [Item 59] 59. A pharmaceutical composition according to any one of items 48 to 58 for use in the treatment of castration-resistant prostate cancer. [Item 60] 60. The pharmaceutical composition according to any one of items 48 to 59, which is administered to a patient in combination with a glucocorticoid. [Item 61] Item 61. The pharmaceutical composition according to item 60, wherein the glucocorticoid is at least one selected from prednisone, prednisolone, and methylprednisolone. [Item 62] Item 63. The pharmaceutical composition according to Item 61, wherein the glucocorticoid is prednisone. 62. The pharmaceutical composition of item 61, wherein the glucocorticoid is prednisolone. [Item 64] 62. The pharmaceutical composition of item 61, wherein the glucocorticoid is methylprednisolone.

Claims

1. 1. A method for making a composition containing nanoparticles of abiraterone acetate, comprising: (i) abiraterone acetate, (ii) one or more millable grinding compounds selected from the group consisting of lactose monohydrate, anhydrous lactose, and mannitol; (iii) sodium lauryl sulfate; and (iv) a combination of butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT), or a combination of ascorbic acid and fumaric acid in a mill comprising a plurality of milling bodies for a time sufficient to produce a composition containing nanoparticles of said abiraterone acetate; Determined based on the particle volume of abiraterone acetate in the composition [D ４，３ ] is greater than 100 nm and less than one of 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, and 300 nm.

2. 2. The method of claim 1, wherein (iv) comprises a combination of BHA and BHT.

3. 3. The method of claim 1 or 2, further comprising combining the composition containing nanoparticles of abiraterone acetate with one or more diluents, disintegrants, lubricants, enhancers, dispersants, or combinations thereof to produce a unit dosage composition.

4. 4. The method of claim 3, wherein the unit dosage composition contains 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, or 400 mg of abiraterone acetate.

5. 5. The method of claim 3, wherein the dissolution rate of abiraterone acetate in the unit-dosage composition is such that, when a sample containing 100 mg of abiraterone acetate in the composition is tested in 900 ml of pH 4.5 phosphate buffer containing 0.1% sodium lauryl sulfate (SLS) using a USP Type 2 apparatus at 75 rpm, at least 80% of the abiraterone acetate dissolves within 15 minutes or within 10 minutes.

6. (i) abiraterone acetate, (ii) one or more millable grinding compounds selected from the group consisting of lactose monohydrate, anhydrous lactose, and mannitol; (iii) sodium lauryl sulfate; and (iv) a combination of butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT), or a combination of ascorbic acid and fumaric acid A pharmaceutical composition comprising: Determined based on the particle volume of abiraterone acetate in the composition [D ４，３ ] is greater than 100 nm and less than one of 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, and 300 nm.

7. 7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition contains 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, or 400 mg of abiraterone acetate.

8. 8. The pharmaceutical composition of claim 6, wherein the dissolution rate of abiraterone acetate in the composition is such that, when a sample containing 100 mg of abiraterone acetate in the composition is tested in 900 ml of pH 4.5 phosphate buffer containing 0.1% sodium lauryl sulfate (SLS) using a USP Type 2 apparatus at 75 rpm, at least 80% of the abiraterone acetate dissolves within 15 minutes or within 10 minutes.

9. Mean AUC when administered with a low-fat meal (7% fat, 300 calories) to adult males ０－∞ is up to two times higher than when administered in the fasting state, Mean AUC when administered with a high-fat meal (57% fat, 825 calories) to adult males ０－∞ is up to 5 times higher than when administered in the fasting state. When administered to adult males with a low-fat meal (7% fat, 300 calories), the mean Cmax was up to 2-fold higher compared to when administered in the fasting state. and / or When administered to adult males with a high-fat meal (57% fat, 825 calories), the mean Cmax was up to 7-fold higher compared to when administered in the fasting state. The pharmaceutical composition according to any one of claims 6 to 8.

10. The pharmaceutical composition according to any one of claims 6 to 9, wherein (iv) comprises a combination of BHA and BHT.

11. A pharmaceutical composition according to any one of claims 6 to 10 for use in the treatment of castration-resistant prostate cancer.

12. 1. A pharmaceutical composition for the treatment of castration-resistant prostate cancer in a subject in need thereof, comprising: (i) abiraterone acetate, (ii) one or more millable grinding compounds selected from the group consisting of lactose monohydrate, anhydrous lactose, and mannitol; (iii) sodium lauryl sulfate; and (iv) a combination of butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT), or a combination of ascorbic acid and fumaric acid Contains Determined based on the particle volume of abiraterone acetate in the composition [D ４，３ ] is greater than 100 nm and less than one of 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, and 300 nm.

13. 13. The pharmaceutical composition of claim 12, comprising a daily dose of 100 to 900 mg of abiraterone acetate.

14. 14. The pharmaceutical composition of claim 12 or 13, comprising a daily dose of 400 to 600 mg of abiraterone acetate.

15. The pharmaceutical composition of any one of claims 12 to 14, further comprising the use of a glucocorticoid for the treatment of castration-resistant prostate cancer in said subject.

16. 16. The pharmaceutical composition of claim 15, wherein the glucocorticoid is prednisone, prednisolone, methylprednisolone, or a combination thereof.

17. 17. The pharmaceutical composition of claim 16, wherein the glucocorticoid is methylprednisolone.

18. The pharmaceutical composition of any one of claims 12 to 17, wherein (iv) comprises a combination of BHA and BHT.

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