WO2015032873A1

WO2015032873A1 - High-load pharmaceutical compositions comprising abiraterone acetate

Info

Publication number: WO2015032873A1
Application number: PCT/EP2014/068869
Authority: WO
Inventors: Agnes FERNÁNDEZ PEÑA; Lisardo ÁLVAREZ FERNÁNDEZ; Deepak Murpani
Original assignee: Synthon B.V.
Priority date: 2013-09-06
Filing date: 2014-09-04
Publication date: 2015-03-12

Abstract

The present invention relates to a high-load pharmaceutical composition for oral administration of abiraterone acetate, particularly to pharmaceutical granulates and tablets giving immediate release of abiratetone acetate in the stomach, which are obtainable by a specific granulation process.

Description

HIGH-LOAD PHARMACEUTICAL COMPOSITIONS COMPRISING ABIRATERONE ACETATE

Abiraterone acetate (3P-acetoxy-17-(3-pyridyl)androsta-5,16-diene) of formula (1)

is a pharmaceutically active compound used for treatment of castration-resistant prostate cancer in adult men, together with a low dose of prednisone or prednisolone.

Abiraterone acetate itself is a prodrug. It is converted in vivo by hydrolysis of the 3- acetyl group to abiraterone, an androgen biosynthesis inhibitor. Specifically, abiraterone selectively inhibits the enzyme CYP 17, which is required for androgen biosynthesis in testicular, adrenal and prostatic tumour tissues.

Abiraterone acetate is marketed in a tablet form under the brand name Zytiga. One tablet comprises 250 mg of the active substance. Further, it comprises microcrystalline cellulose, sodium crosscarmellose, lactose monohydrate (corresponding to 189 mg of lactose), povidone (K29/K32), sodium lauryl sulfate, magnesium stearate and colloidal anhydrous silica. The total weight of a single tablet is about 715 mg, making the overall content of the abiraterone acetate in the tablet about 35 % w/w.

The approved method of administration is 1000 mg (four tablets) in a single daily dose that must not be taken with food (it should be taken at least two hours after eating and no food should be eaten for at least one hour after taking the tablets). Tablets must be swallowed whole, with water. Taking the tablet with food significantly and undesirably increases the absorption of abiraterone acetate. Following the oral administration in the fasting state, the time to reach maximum plasma concentration of abiraterone is approx. 2 hours.

Abiraterone acetate was first disclosed in WO 93/20097. It is a solid crystalline compound, which exhibits polymorphism. All polymorphs are highly insoluble in water (less than 0.1 mg/ml). As a result, abiraterone acetate is pharmacologically considered in the BCS System as a Class IV compound, i.e. a compound of low solubility and low permeability.

No specific patent application specifically deals with the commercially available abiraterone acetate tablet Zytiga. The available information published at the publication of the marketing authorization approval teaches that the tablet is made by a wet granulation, but no details were disclosed. CN 102743393 discloses tablet compositions having the same qualitative composition and the same concentration of abiraterone acetate in the tablet as in the Zytiga tablet. Little is known about the method how to make such tablet.

CN 102336801 discloses a tablet comprising a high load of abiraterone acetate, however this composition exhibits a slower dissolution profile when comparing to the approved Zytiga 250 mg tablet.

As the recommended dosage form is 1000 mg in a single daily dose, four 250 mg tablets have to be administered at the same time. It would be thus more convenient to have a tablet with higher load of abiraterone acetate, e.g. 500 mg or 1000 mg. However, at the presently used concentration of abiraterone acetate in the only approved tablet composition represented by that of Zytiga (35 % w/w) the tablets would be extremely large and unsuitable for swallowing the whole tablet as prescribed.

A therapeutically suitable tablet composition having high load of the abiraterone, e.g. 40 weight and higher, advantageously 50 weight and higher, would effectively diminish the tablet size allowing the administration of a higher drug dose in a single doses. Being "therapeutically suitable", as used for purposes of the present application, such alternate tablet should exhibit at least two important limiting characteristics: it should release the abiraterone acetate in the stomach at least as quickly as the approved Zytiga 250 mg (for to provide comparable therapeutic levels in blood plasma) and it should have sufficient hardness (to be handleable by the patient without any precaution). Due to inherently very limited solubility of abiraterone acetate in aqueous environment, particularly the first characteristic is crucial and the way to reach it is not straightforward: as the increase of the content of the active is logically associated with the corresponding decrease of the total amount of other excipients, the so caused decrease of their effect on the overall release rate must be balanced by their careful selection and suitable processing into the final form.

The present invention provides a therapeutically suitable tablet composition having high load of the abiraterone acetate.

BRIEF DESCRIPTION OF THE PRESENT INVENTION

The present invention relates to pharmaceutical compositions comprising a granulate comprising from about 50 to about 80 % w/w, preferably from about 55 to about 75 % w/w, and most preferably from about 60 to about 70 % w/w of abiraterone acetate calculated on the basis of the dry granulate an at least one wetting agent, obtainable by a wet granulation process wherein the granulation liquid comprises a solution of a wetting agent in a solvent comprising water.

These pharmaceutical compositions of abiraterone acetate are suitable for making dosage forms for oral administration of abiraterone acetate to humans (tablets and capsules) comprising up to 1000 mg of the active substance in a single dose.

In a first aspect, the invention relates to a high- loaded pharmaceutical granulate comprising abiraterone acetate, at least one hydrophilic binder, at least one wetting agent and at least one disintegrant. In an embodiment, the granulate comprises abiraterone acetate, one wetting agent, one hydrophilic binder and one hydrophilic disintegrant.

Most preferably, the wetting agent is sodium lauryl sulfate, the binder is povidone and the disintegrant is crosscarmellose sodium.

In one embodiment of the present invention, the granulate comprises from about 50 to about 80 % w/w, preferably from about 55 to about 75 % w/w, and most preferably from about 60 to about 70 % w/w of abiraterone acetate , calculated on the basis of the dry granulate.

In another embodiment, the particle size of the granules is less than 0.7 mm as determined by sieve analysis.

In another embodiment, the dried granulate comprises less than 2%, preferably less than 1.5%, of residual volatiles.

In a second aspect, the invention relates to a process for making said pharmaceutical granulate comprising the steps of

i) Preparing the granulation liquid comprising a solution of a wetting agent in a solvent comprising water;

ii) Charging granulation equipment with abiraterone acetate, at least one hydrophilic binder, at least one hydrophilic disintegrant and, optionally, with other excipients; iii) Granulating the mixture using the aqueous solution from the step i) as the

granulation liquid; and

iv) Drying the granulate.

In a third aspect, the invention relates to a pharmaceutical composition for oral administration of abiraterone acetate comprising the granulate disclosed above and at least one further pharmaceutically acceptable excipient, which preferably comprises at least one disintegrant. The composition preferably comprises from 75 to 95 % w/w, preferably from 80 to 90 % w/w of the granulate, based on the total weight of the composition.

In a specific aspect, the composition is formulated into a unit dose form. The unit dosage suitably comprises from 250 to 1000 mg, preferably 500 mg, of abiraterone acetate. In one embodiment of the present invention, the composition is compressed into an immediate release tablet. The immediate release tablet may be further coated by a film coat.

In particular, the unit dosage forms, particularly the tablets, in accordance with the present invention are characterized by a dissolution rate of more than 70%, of the dose of abiraterone acetate in 30 minutes when tested by USP dissolution test in phosphate buffer pH4.5 with 0.25% SDS, in 900 ml standard vessel, with paddle apparatus 2 of paddle speed 50 rpm.

In a fourth aspect, the invention relates to a process for making an immediate release tablet for oral administration of abiraterone acetate comprising the steps of

i) Preparing a pharmaceutical granulate comprising abiraterone acetate, at least one hydrophilic binder, at least one wetting agent and at least one disintegrant by granulating a mixture comprising abiraterone acetate, at least one hydrophilic binder and at least one disintegrant by a granulation liquid comprising an aqueous solution of a wetting agent, and drying the wet granulate;

ii) Mixing the optionally milled granulate with at least one further pharmaceutically acceptable excipient, which preferably comprises at least one disintegrant; and iii) Compressing the mixture into a tablet.

In a fifth aspect, the invention relates to a pharmaceutical granulate or a pharmaceutical composition as described above for use as a medicament. DETAILED DESCRIPTION OF THE INVENTION

The invention relates to an oral pharmaceutical composition, advantageously a tablet composition, with immediate release of abiraterone acetate comprising an abiraterone acetate-comprising granulate. The term "immediate release" as used throughout the disclosure and claims means, in accordance with common understanding, that more than 70% of the dose of the active pharmaceutical ingredient is released in the stomach within less than 30 minutes after oral administration. The pharmaceutical composition comprises more than 45 weight % of abiraterone acetate, calculated on the total mass of the composition, i.e.

significantly higher loading of the active than in the commercially available tablets.

Abiraterone acetate of formula (1) above is a known compound, which is commercially available or may be produced by procedures known in the art. Abiraterone acetate, as used throughout the present invention, comprises any solid state form thereof, including any crystalline polymorphic form thereof. The potential differences in inherent solubility of the respective polymorphs do not have any influence on the dissolution rate of abiraterone acetate composition.

It was found by the present inventors that an abiraterone acetate comprising

pharmaceutical composition, particularly a tablet composition, exhibiting bioavailability comparable to the marketed tablets but comprising higher load of the active substance, typically higher than 45 weight %, can be prepared by a specific modification of granulation technology. Such specific granulation process effectively increases the final release of abiraterone acetate from the dosage form, typically from a compressed dosage form such as a tablet, in aqueous environment. As a result, the hydrophilic excipients, which must be present in the composition in order to reach the desired solubility of inherently poorly soluble abiraterone acetate, are utilized more effectively and their amount may thus be decreased allowing a higher drug load with a smaller tablet size. Accordingly, a therapeutically suitable final dosage form, e.g. tablet, comprising a single dose of 500 mg of abitaterone acetate and more, can be made from this composition and such dosage form may be administered by the patient without problems because of its acceptable size and hardness.

The essential part of the high-loaded immediate release pharmaceutical compositions for oral administration of abiraterone acetate according to the present invention is a pharmaceutical granulate comprising abiraterone acetate and a solid carrier, which comprises at least one hydrophilic binder, at least one wetting agent and at least one disintegrant.

Preferably, the granulate comprises from about 50 to about 80 % w/w, preferably from about 55 to about 75 % w/w, and most preferably from about 60 to about 70 % w/w of abiraterone acetate , calculated on the basis of the dry granulate, i.e. on the mass of the granulate after drying minus the mass of residual volatiles.

The excipient components of the granulate are preferably selected such that every one of them is fully soluble in the patient's stomach.

Preferably, the hydrophilic binder is povidone, hypromellose, hydro xypropyl cellulose, starch or copovidone, most preferably povidone.

The wetting agent is preferably sodium lauryl sulfate, polysorbate 80, poloxamer or a cyclodextrin, most preferably sodium lauryl sulfate. In an important aspect, the wetting agent is used as a solution or suspension in water.

The disintegrant is preferably croscarmellose sodium, crospovidone or sodium starch glycollate, most preferably croscarmellose sodium.

Further, the granulate composition may comprise at least one hydrophilic filler. Such filler is preferably a sugar-type compound, e.g. lactose, isomalt or maltodextrin.

The pharmaceutical granulate of the invention is made by agglomerating agitated powder mixture of abiraterone acetate and the excipients after wetting the mixture by a suitable granulation liquid. In particular, the granulation process of the present invention is characterized in that the granulation liquid comprises a solution or suspension of a suitable wetting agent in a solvent comprising water. In one embodiment, the granulation liquid also comprises a part of abiraterone acetate, suitably 10 - 40 % of the total charge of abiratetone acetate, dispersed therein. The solvent used for making the granulation liquid is typically water but it may be also a mixture of water with a pharmaceutically suitable alcohol, e.g. ethanol.

The pharmaceutical granulate of the present invention is typically prepared in a four- step process.

In the first step, a granulation liquid comprising a solution of a wetting agent in a solvent comprising water is prepared. A preferred wetting agent is sodium lauryl sulfate, polysorbate 80, poloxamer or a cyclodextrin. Preferably, the concentration of the wetting agent in the solvent may be from 10 to 50% w/w, most preferably from 15 to 35% w/w. It should be noted that it was observed that too low or high amounts of the wetting agent in the final composition can negatively affect the release rate of the active from the pharmaceutical composition comprising the granulate. Accordingly, it is advantageous that the amount of the wetting agent in the granulate, particularly in case of using sodium lauryl sulfate as the wetting agent, is between 3 and 6 % w/w, in respect to the mass of abiraterone acetate.

In a preferred embodiment, the granulation liquid is prepared by dissolving or suspending the wetting agent, preferably sodium lauryl sulfate, in water or in a water-alcohol mixture. Typically, the wetting agent is contacted with the solvent at the ambient temperature under stirring, preferably in an atmosphere of inert gas, such as nitrogen or argon. In a specific embodiment, a certain part of the active substance, suitably 10 - 40 % of the total charge of abiratetone acetate, may be also dispersed in the solvent under the same conditions.

In the second step, the granulation equipment (typically a high-shear mixer/granulator), is charged with abiraterone acetate, at least one hydrophilic binder, at least one hydrophilic disintegrant and, optionally, with other excipients. Such hydrophilic binder component is advantageously povidone, hypromellose, hydroxypropyl cellulose, starch or copovidone, preferably povidone. The hydrophilic disintegrant is advantageously croscarmellose sodium, crospovidone or sodium starch glycollate, preferably croscarmellose sodium. In further, the mixture in the granulation equipment may comprise at least one inert hydrophilic filler.

Preferred inert hydrophilic fillers are sugar-type compounds such as lactose, isomalt or maltodextrin. The mixture to be granulated may also comprise a glidant, e.g. colloidal silicon dioxide.

It is preferred that the abiraterone acetate to be charged is of low particle size, preferably of Dso less than 20 microns, more preferably between 3-10 microns. Granulates made from abiraterone acetate of higher particle size may negatively affect dissolution and or the hardness of final tablets. Accordingly, starting abiraterone acetate should be fist milled and screened to the desirable particle size, if necessary, prior to charging in the granulator.

In the third step, the solid mixture in the granulation equipment is granulated upon stirring and slow addition of the granulation liquid prepared in the first step, until a wet homogeneous material is obtained. In a typical but not limiting arrangement, the granulation proceeds at ambient temperature.

In the fourth step, the formed wet granulate is dried. The granulate may be dried directly in the granulator or may be removed from the granulator and dried in a suitable drier. Typically, the granulate is dried until the content of residual volatiles drops below 2 weight , in a preferred embodiment below 1.5 weight %. The drying process may be

advantageously performed under reduced pressure, preferably at a temperature not exceeding 60°C, preferably not exceeding 55 °C.

Optionally, the dried granulate is sieved and/or milled in order to reduce possible remaining lumps and to obtain a product with desired properties such as flowability, tapped density, and content uniformity. In a suitable arrangement, the granulate is sieved through a 0.69 mm sieve, yielding in a population of granules having the particle size less than 0.7 mm.

The pharmaceutical granulate according to the present invention is a free-flowing homogeneous particulate material having preferably the particle size less than 0.7 mm.

Typically, the granulate comprises less than 2 weight % of residual volatiles, as determined by Karl Fischer titration and/or by determination of the loss on drying.

The granulate of the present invention is used for making pharmaceutical compositions and pharmaceutical unit dosage forms for oral administration of abiraterone acetate, e.g. tablets, capsules or sachets, preferably pharmaceutical tablets. Such pharmaceutical composition comprises the dried and optionally milled granulate of the present invention mixed with at least one further pharmaceutically acceptable excipient.

In the tablet composition, the extragranular excipients comprise at least one

disintegrant. The disintegrant may be the same or different than that as used in the granulate composition. A suitable disintegrant is, without limitation, sodium croscarmellose, sodium starch glycollate, and crospovidone.

Other suitable extragranular pharmaceutical excipients in a tablet composition include, without limitation:

• One or more compressible fillers, preferably water soluble fillers; examples of fillers include starch, lactose, microcrystalline cellulose, mannitol, and maltodextrin;

• One or more lubricants; examples of lubricants include magnesium stearate and sodium stearyl fumarate;

• One or more glidants; examples of glidants include silicon dioxide.

The composition of the present invention comprises from 75 to 95 % w/w, preferably from 80 to 90 % w/w of the above pharmaceutical granulate of the present invention and 5 to 25 % w/w, preferably from 10 to 20 weight % of the extragranular pharmaceutically acceptable excipients.

Preferably, the composition of the present invention is used for making compressed tablets for oral administration. Such oral administration may be direct, i.e. by swallowing one or more tablets by the patient, or the tablets may be used as dispersible tablets, i.e. the tablet is first dispersed in a suitable liquid, e.g. in water or juice, and then the liquid is administered.

Accordingly, the present invention provides for pharmaceutical tablet for oral administration of abiraterone acetate consisting of a) a granulate comprising 50-80 % w/w, preferably between 55-75 % w/w and most preferably of between 60-70 % w/w of abiraterone acetate, at least one wetting agent, at least one binder and at least one disintegrant and b) at least one further tablet excipient, wherein the content of the granulate in the tablet is preferably from 75 to 95 % w/w, yet preferably from 80 to 90 % w/w, calculated on the mass of an uncoated tablet.

The tablets comprising the pharmaceutical granulate of the present invention are made by compression of the above-disclosed pharmaceutical composition.

Thus, a suitable process for making an immediate release tablet for oral administration of abiraterone acetate, particularly a high-loaded tablet, comprises the following steps:

ii) Mixing the optionally milled granulate with at least one further pharmaceutically acceptable excipient comprising at least one disintegrant ; and

iii) Compressing into a tablet. The tabletting conditions depend on the composition and equipment used and may be easily adjusted by a skilled person; as a result, the tabletting process should preferably produce tablets having a hardness of between 30 and 200 N and/or with a disintegration time of between 0.5 and 30 minutes (as determined by a disintegration tester).

The tablets may be coated, e.g., by a film coat, for better handling and cosmetic purposes. The film coating may contain pharmaceutically acceptable colourants or flavouring agents. This film coating should be rapidly dissolvable in the stomach environment (a non- enteric coating) to minimize the latent period prior to release and should not have any other influence on the release characteristics of the active pharmaceutical ingredient.

As noted above, an important aspect of the compositions of the present invention is that they exhibit an adequate bioavailability of abiraterone acetate in the blood circulation after ingestion. This ability may be predicted by performing in vitro dissolution tests in suitable media. Thus the tablets of the present invention advantageously exhibit a dissolution rate such that more than 70% of the dose of abiraterone acetate is released from the tablet in 30 minutes, when tested in an in vitro dissolution test, e.g. in USP dissolution test in phosphate buffer pH4.5 with 0.25% SDS (sodium dodecyl sulfate), in 900 ml standard vessel, with paddle apparatus 2 of paddle speed 50 rpm.

Each tablet of the present invention represents a unit dosage form, which preferably contains 250 to 1000 mg of the drug substance, most preferably 500 mg. The weight of the tablet is advantageously less than 1100 mg, which allows relatively ease swallowing of the entire tablet.

A plurality of tablets may be packed in a suitable package material, which

advantageously protects them against light and moisture; blisters or bottles made from aluminium and/or hard polymer (i.e. PVC/PE/PVDC or PVC/PVDC) are examples of such package materials. Mutatis mutandis, the pharmaceutical granulate of the present invention and at least one further suitable excipient may be used for making pharmaceutical capsules or sachets. Such dosage forms typically exhibit the same dissolution properties and may comprise the same dose amounts of the active substance as those of the above tablets.

The present invention also relates to the pharmaceutical granulate comprising abiraterone acetate , at least one hydrophilic binder, at least one wetting agent and at least one disintegrant, as well as to pharmaceutical compositions comprising such granulate, as described above, for use as a medicament.

Said pharmaceutical compositions may be used for any therapeutic or prophylactic treatment approved for abiraterone acetate-comprising medicaments. For instance, it may be used for treatment of castration-resistant prostate cancer in adult men, together with a low dose of prednisone or prednisolone.

The invention will be further illustrated by way of the following non-limiting examples.

EXAMPLES

Example 1

Composition

a) Granulate

weight per tbl

Abiraterone acetate 500.00 mg

Lactose monohydrate (Pharmatose 200M) 140.73 mg

Sodium crosscarmellose (Ac-Di-Sol) 36.00 mg

Povidone (Plasdone K29-K32) 45.00 mg

Sodium lauryl sulfate 24.03 mg

Purified water (140.00 mg) will be removed

TOTAL (calc. on dry basis) 745.76 mg b) Extragranular components

weight per tbl

Microcrystalline cellulose (Vivapur 102) 127.33 mg

Sodium crosscarmellose (Ac-Di-Sol) 9.00 mg

Magnesium stearate 13.23 mg

Colloidal silicon dioxide (Aerosil) 4.68 mg

TOTAL a) + b) (calc. on dry basis) 900.00 mg c) Film coating

Opadry II yellow 85F32004 22.50 mg

Purified water (127.50mg) will be removed

Process

Granulation

1) Dissolve the sodium lauryl sulfate in purified water under stirring.

2) Sieve by a 0.8 or 2.5mm sieve the weighed amount of abiraterone acetate, povidone, lactose monohydrate and sodium croscarmellose.

3) Mix the components from the step 2 In a High Shear Mixer (HSM) granulator and granulate the mixture by adding the solution from the step 1.

4) Sieve the granulated product from the step 3 through a 6x6mm square sieve by using a conical sieving machine.

5) Dry the wet granulate from step 4 in a fluid bed drier until a Loss on drying value <1.5 . Product temperature should be <55°C.

6) Mill the dried granulate from step 5 through a 0.69mm sieve by using a Fitz-Mill provided with knives.

Tabletting

7) Weight the microcrystalline cellulose, sodium croscarmellose and colloidal silicon dioxide and sieve the components through a 0.8mm sieve.

8) Mix the granulate from step 6 with components from step 7 in a free fall blender.

9) Weight the magnesium stearate, sieve it through a 0.8mm sieve and mix it with the product from step 8.

10) Compress the final blend from the step 9 in a tablet press into tablet hardness between 100-200N and target tablet weight of 900mg. Coating

11) Weight the Opadry II yellow 85F32004 and stir it for 45 minutes in purified water.

12) Warm-up tablets from step 10 up to a tablet temperature of 45°C in a coater.

13) Coat the tablets with the suspension from step 11 up to a weight gain of 2.5%. Tablets temperature should be between 38-43°C.

14) Dry the coated tablets up to tablets temperature of 46°C.

Example 2 Composition

a) Granulate

weight per tbl

Abiraterone acetate 500.00 mg

Lactose monohydrate (Pharmatose 200M) 167.73 mg

Sodium crosscarmellose (Ac-Di-Sol) 36.00 mg

Povidone (Plasdone K29-K32) 18.00 mg

Sodium lauryl sulfate 24.03 mg

Colloidal silicon dioxide (Aen 4.68 mg

Purified water (140.00 mg) will be removed

TOTAL (calc. on dry basis) 750.44 mg b) Extragranular components

weight per tbl

Microcrystalline cellulose (Vivapur 102) 127.33 mg

Sodium crosscarmellose(Ac-Di-Sol) 9.00 mg

Magnesium stearate 13.23 mg

TOTAL a) + b) (calc. on dry basis) 900.00 mg c) Film coating

Opadry II yellow 85F32004 22.50 mg

Purified water (127.50mg) will be removed

Process

Granulation 1) Dissolve sodium lauryl sulfate in purified water under stirring

2) Mix the weighed amount of abiraterone acetate, povidone, lactose monohydrate, sodium croscarmellose and colloidal silicon dioxide in a free fall blender and sieve the mixture by 0.25mm sieve.

3) Mix the components from the step 2 in a High Shear Mixer (HSM) granulator and granulate the mixture by adding the solution from the step 1

5) Dry the wet granulate from step 4 in a fluid bed drier until a LOD <1.5%. Product temperature should be <55°C.

Tabletting

7) Weight the microcrystalline cellulose, and sodium croscarmellose and sieve the components through a 0.8mm sieve.

9) Weight magnesium stearate, sieve it through a 0.8mm sieve and mix it with the product from step 8.

10) Compress the final blend from the step 9 in a tablet press into a tablet hardness between 100-200N and target tablet weight of 900mg.

Coating

11) Weight the Opadry II yellow 85F32004 and stir it for 45 minutes in purified water. 12) Warm-up tablets from step 10 up to a tablet temperature of 45°C in a coater.

14) Dry the coated tablets up to tablets temperature of 46°C. Example 3

Composition

The same as in Example 1

Process Granulation

1) Dissolve sodium lauryl sulfate and 30% of the total amount of abiraterone acetate in purified water under stirring

2) Sieve by a 0.8 or 2.5mm sieve the weighed amount of abiraterone acetate (70% of the total amount), povidone, lactose monohydrate and sodium croscarmellose.

6) Mill the dried granulate from step 5 through a 0.69mm sieve by using a Fitz-Mill provided with knives. Tabletting

See Example 1

Coating

See Example 1

Claims

1. A pharmaceutical composition comprising a granulate comprising from about 50 to about 80 % w/w of abiraterone acetate calculated on the basis of the dry granulate and at least one wetting agent, obtainable by a wet granulation process wherein the granulation liquid comprises a solution of the wetting agent in a solvent comprising water.

2. The pharmaceutical composition of claim 1 wherein the granulate comprises from

about 55 to about 75 w/w of abiraterone acetate calculated on the basis of the dry granulate.

3. The pharmaceutical composition of claim 1 wherein the granulate comprises from

about 60 to about 70 w/w of abiraterone acetate calculated on the basis of the dry granulate.

4. The pharmaceutical composition according to claim 1 to 3 wherein the granulate

comprises one wetting agent, one hydrophilic binder and one hydrophilic disintegrant.

5. The pharmaceutical composition according to claim 1 to 4, wherein the wetting agent is sodium lauryl sulfate.

6. The pharmaceutical composition according to claim 5, wherein the amount of sodium lauryl sulfate in respect to abiraterone acetate is between 3 and 6 % w/w in respect to the mass of abiraterone acetate.

7. The pharmaceutical composition according to any one of claims 1 to 6, further

comprising at least one hydrophilic filler.

8. The pharmaceutical composition according to any one of claims 1 to 7 comprising a granulate with a particle size less than 0.7 mm as determined by sieve analysis.

9. The pharmaceutical composition according to claims 1 to 8, wherein the concentration of the wetting agent in the solvent is from 10 to 50% w/w.

10. The pharmaceutical composition according to claims 1 to 8 wherein the concentration of the wetting agent in the solvent is from 15 to 35% w/w.

11. The pharmaceutical composition according to claim 1 to 10 wherein the particle size of abiraterone acetate used for the granulation is D50 less than 20 microns.

12. The pharmaceutical composition for oral administration of abiraterone according to claims 1 to 11 comprising at least one further pharmaceutically acceptable excipient.

13. The composition according to claim 12 wherein the excipient is at least one

disintegrant.

14. The composition according to any one of claims 1 to 13 comprising 250 to 1000 mg of abiraterone acetate of abiraterone acetate.

15. The composition according to any one of claims 1 to 14 comprising 500 mg of

abiraterone acetate of abiraterone acetate.

16. The composition according to any one of claims 1 to 15, which is in the form of a compressed tablet.

17. The composition according to claim 16 wherein the tablet is a film-coated tablet.

18. The composition according to claims 1 to 17 having a dissolution rate of more than 70% of the dose of abiraterone acetate in 30 minutes when tested by USP dissolution test in phosphate buffer pH4.5 with 0.25% SDS, in 900 ml standard vessel, with paddle apparatus 2 of paddle speed 50 rpm.