EP3512504A1

EP3512504A1 - Process for the production of a solid formulation of abiraterone acetate using the fluid granulation method

Info

Publication number: EP3512504A1
Application number: EP17771978.8A
Authority: EP
Inventors: Pawel STASIAK; Monika Kurkova; Jaroslava SVOBODOVA
Original assignee: Zentiva KS
Current assignee: Zentiva KS
Priority date: 2016-09-16
Filing date: 2017-08-30
Publication date: 2019-07-24
Also published as: CZ2016573A3; RU2019110098A3; RU2019110098A; WO2018050131A1

Abstract

The invention relates to solid formulations of abiraterone acetate, in particular granules, tablets and capsules prepared using the fluid granulation method. Good dissolution characteristics of such formulations have been proved using an in vitro method.

Description

PROCESS FOR THE PRODUCTION OF A SOLID FORMULATION OF ABIRATERONE ACETATE USING THE FLUID

GRANULATION METHOD

FIELD OF THE INVENTION

This invention relates to solid formulations of abiraterone acetate, in particular granules, tablets and capsules prepared using the fluid granulation method. Good dissolution characteristics of such formulations have been proved using an in vitro method.

BACKGROUND ART

Abiraterone ((3 )-17-(pyridin-3-yl) androsta-5,16-dien-3-ol; CAS: 154229-19-3; formula: C₂₄H₃₁NO; molar mass: 349.5 g/mol) is an inhibitor of CYP17. It prevents synthesis of androgens in the testicles, adrenal glands and tissue with a prostate tumor. Abiraterone acetate (17-(3-Pyridyl) androsta-5 acetate, CAS #154229-18-2), a prodrug of abiraterone, has been approved for the treatment of castration-resistant prostate carcinoma. Abiraterone acetate is considered to be a substance that is poorly soluble in water (US 20150246060 A). Zytiga® 250 mg tablets are approved in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate carcinoma. The package insert information for Zytiga® tablets recommends 1000 mg (tablets 4x250 mg) administered orally once a day in combination with prednisone (5 mg) administered orally twice a day (US 20150246060A). Granulation is a process wherein small particles are agglomerated to a bigger mass where the original particles still remain identifiable. Within wet granulation, particles are subjected to spraying to achieve agglomeration of the active substance and excipients during mixing of the binder, usually in a high-speed mixer or a fluid layer. Particles are agglomerated by a combination of capillary and viscose forces until more stable bonds are created after drying. Granulation prevents disintegration of the constituents of a powdery mixture, improves the flow characteristics of the mixture and improves compression into tablets (AAPS PharmSciTech, 15 (4), 2014, 1039-1048).

Within high-speed granulation, dry powder is stirred in a bowl comprising a stirrer rotating on a horizontal plane and a breaker rotating on a vertical or horizontal plane. Before spraying of liquid binder onto the top part of the powder layer, the powders are mixed. Granules are produced, liquid drops being dispersed in the powder and growing until the prescribed time has elapsed. Then, granules are removed to the next part of the plant where drying is carried out (AAPS PharmSciTech, 15 (4), 2014, 1039-1048).

Compared to high-speed mixers, fluid granulators feature a number of advantages. All the processes, including drying, are carried out in the same device. This saves labor costs, transfer costs and time (AAPS PharmSciTech, 15 (4), 2014, 1039-1048).

According to the reference literature, the original drug Zytiga® is produced with the use of high-speed granulation. It is well-known from the literature that granules produced with the use of the high-speed technology have different physical characteristics from granules produced in a fluid granulator. The differences comprise the bulk density, which is generally higher with the use of the high-speed granulation process, and porousness, which is higher with the use of the general fluid granulation process (Int J Pharm, 237, 2002, 1-14). This has an impact on the dissolution behavior of the resulting formulations (e.g. tablets, capsules), which is usually slower in the case of the high-speed granulation process. On the other hand, data from the reference literature indicate that both the technologies ( Int J Pharm, 237, 2002, 1-14) can achieve similar dissolution behavior by optimizing the process parameters. DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a solid formulation of abiraterone acetate, in particular granules, tablets and capsules prepared using the fluid granulation method. Since the product Zytiga (Janssen-Cilag), which is commercially available at present, is produced with the use of high-speed technology, another production device for drying of granules is required. Unlike the high number of publications that mention a higher dissolution rate of products made using the fluid granulation technology as compared to the standard granulation method we have found out that dissolution of abiraterone acetate remains on a similar level if fluid granulation and at the same time suitable process parameters are used. In addition, due to a low solubility and biological availability, abiraterone acetate must be used in a micronized form. The disadvantage of the fluid granulation method is that micronized materials usually tend to deposit on the device walls. This is manifested in unsatisfactory determination of the content of the active substance in the drug form. However, elaborate studies dealing with the process parameters of the method have led to generating a robust preparation method with the determination of 95.0 to 105.0% by weight of abiraterone acetate, wherein granules do not settle on the walls, with meets the product specification limits. Our observations have led to the development of a quick preparation method, maintaining the CQA (Critical Quality Attributes).

The preparation method in accordance with the invention is well reproducible and provides solid drug forms of abiraterone acetate with the required physical parameters. The method is characterized by the following steps:

1. Abiraterone acetate is mixed with one or more of the following excipients:

- 2-20% by weight of binders such as, without limitation, povidone, water-soluble cellulose derivatives (preferably methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose), sugar alcohols (preferably mannitol, sorbitol), calcium sulphate, calcium phosphate, starch;

10-60% by weight of fillers such as e.g., without limitation, microcrystalline cellulose, lactose, calcium phosphate, glucose, cellulose and its derivatives, calcium carbonate, starch, mannitol or other sugar alcohols;

- optionally 1-10% by weight of disintegrants such as, without limitation, sodium croscarmellose, sodium starch glycolate, crospovidone, alginates;

- optionally 0.5-5% by weight of surfactants such as, without limitation, sodium lauryl sulphate, polyoxyethylene sorbitans.

2. The mixture containing abiraterone acetate and excipients is granulated, dried and ground. The granulation method is based on using a fluid granulator. The powdery material is granulated with water or an aqueous solution of suitable excipients as surfactants and binders to a fluid layer of a mixture of abiraterone acetate with the excipients, namely at a temperature of 20 - 60°C, preferably 25 - 50°C and most preferably 30 - 40°C. The granulated material is then dried at a temperature of 20 - 60°C, preferably 25 - 50°C and most preferably 30 - 40°C until the water content of 0.1-5%, preferably 0.5-3% and most preferably 1.0-2.0% by weight is achieved. The dry material is then crushed to granules with the use of sieves of 0.5-1.7 mm, preferably 0.6-1.5 mm and most preferably 0.8-1.25 mm. The crushing method is carried out in such a way for the resulting granules to meet the following parameters:

- Granule size measured and described in the European Pharmacopoeia: >500 μπι 5- 50%, <100 μιη 10-60%.

- Bulk density defined in the European Pharmacopoeia: 500-800 g/1.

- Compacted bulk density defined in the European Pharmacopoeia: 750-1200 g/1.

- Carr index 25-75.

The granules can be possibly mixed with one or more excipients from the following list:

1-10% by weight of disintegrants such as, without limitation, sodium croscarmellose, sodium starch glycolate, crospovidone, alginates;

- 0.1-5% by weight of glidants such as, without limitation, colloidal silicon dioxide, corn starch;

- 0.1-5% by weight of moisteners such as, without limitation, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, talc, polyethylene oxide;

- 0.5-5% by weight of surfactants such as, without limitation, sodium lauryl sulphate.

The tabletting matter is compressed with the use of a rotary tabletting press into cores, which may be coated with any type of coating material ensuring immediate releasing. The compression is carried out with the use of the pre-compression force of 0 - 20 kN and compression force of 5 - 40 kN.

The tablet cores can be possibly coated with:

- 40-98% by weight of a film-forming polymer such as, without limitation, hypromellose, polyvinyl alcohol, polyvinylpyrrolidone or their mixtures;

- optionally 1-10% by weight of plasticizers such as, without limitation, polyethylene glycol (Macrogol), triethyl citrate, dibutyl sebacate;

- optionally 1-5% by weight of anti-sintering agents such as, without limitation, talc, lactose;

- optionally 0.01-1% by weight of pharmaceutically acceptable colorants such as, without limitation, iron (III) oxide, titanium dioxide, erythrosin. The entire preparation method defined by the patent claims comprises the following steps: a) mixing of abiraterone acetate with excipients selected from the group comprising fillers, binders, disintegrants, surfactants;

b) fluid granulation of the mixture of abiraterone acetate and excipients with the use of a fluid granulator;

c) drying the granules in a fluid granulator;

d) crushing the granules;

e) optionally admixing more excipients selected from the group comprising disintegrants, glidants, surfactants and moisteners;

f) compressing the tabletting matter with a rotary tabletting press, or filling the mixture into capsules or stick packs;

g) optionally coating the tablets

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1. Dissolution profiles of selected batches (Examples 1-4), acetate buffer solution with pH 4.5, 0.2% by weight, sodium lauryl sulphate, paddle device (30 rpm, 45 min; 150 rpm, 15 min), PEAK beakers.

EXAMPLES

Example 1

Tablets comprising 250 mg of abiraterone acetate, 200 mg of lactose monohydrate, 140 mg of microcrystalline cellulose, 43 mg of sodium croscarmellose, 36 mg of povidone, 29.0 mg of sodium lauryl sulphate, 7 mg of colloidal anhydrous silicon dioxide and 10 mg of magnesium stearate in the tablet core were produced by fluid granulation of abiraterone acetate with microcrystalline cellulose, lactose monohydrate, a part of sodium croscarmellose, povidone and sodium lauryl sulphate with the use of a Glatt GPCG2 fluid granulator with the following parameters:

- Inlet air temperature 60°C

- Air flow 40 m³/h

- Outlet air temperature 26°C

- Spraying atmospheric pressure 0.1 MPa Spraying rate 50 g/min

Water was used as the granulation fluid

The granules are dried at the following parameters:

- Inlet air temperature 50°C

- Air flow 40 m³/h

- Outlet air temperature 25°C

The granules are then sieved with the use of an oscillating sieving device 0.8 mm, being mixed with a part of sodium croscarmellose, colloidal anhydrous silicon dioxide and magnesium stearate. The tabletting matter is compressed into tablet cores 715 mg with a rotary tabletting press.

Compound Concentration Concentration

name [mg/tablet] [% by weight]

Abiraterone

250.0

acetate 35.0

Lactose

200.0

monohydrate 28.0

Microcrystalline

140.0

cellulose 19.6

Sodium

43.0

croscarmellose 6.0

povidone 36.0 5.0

Sodium lauryl

29.0

sulphate 4.1

Silicon dioxide,

colloidal 7.0

anhydrous 1.0

Magnesium

10.0

stearate 1.4 Example 2

Tablets comprising 250 mg of abiraterone acetate, 200 mg of lactose monohydrate, 140 mg of microcrystalline cellulose, 43 mg of sodium croscarmellose, 36 mg of povidone, 29.0 mg of sodium lauryl sulphate, 7 mg of colloidal anhydrous silicon dioxide and 10 mg of magnesium stearate in the tablet core were produced by fluid granulation of abiraterone acetate with microcrystalline cellulose, lactose monohydrate, a part of sodium croscarmellose and povidone with the use of a Glatt GPCG2 fluid granulator at the following parameters:

- Inlet air temperature 60°C

- Air flow 60 m³/h

- Outlet air temperature 26°C

- Spraying atmospheric pressure 0.1 MPa

- Spraying rate 50 g/min

An aqueous solution of sodium lauryl sulphate was used as the granulation fluid.

The granules were dried with the use of the following settings:

- Inlet air temperature 60°C

- Air flow 40 m³/h

- Outlet air temperature 28°C

The granules are then dried with the use of an oscillating sieving device 0.8 mm in a mixture with sodium croscarmellose, colloidal anhydrous silicon dioxide and magnesium stearate. The tabletting matter is compressed into tablet cores 715 mg with a rotary tabletting press.

Compound Concentration Concentration

name [mg/tablet] [% by weight]

Abiraterone

250.0

acetate 35.0

Lactose

200.0

monohydrate 28.0

Microcrystalline 140.0 19.6 cellulose

Sodium

43.0

croscarmellose 6.0

povidone 36.0 5.0

Sodium lauryl

29.0

sulphate 4.1

Silicon dioxide,

colloidal 7.0

anhydrous 1.0

Magnesium

10.0

stearate 1.4

Example 3

Tablets comprising 250 mg of abiraterone acetate, 200 mg of lactose monohydrate, 140 mg of microcrystalline cellulose, 43 mg of sodium croscarmellose, 36 mg of povidone, 29.0 mg of sodium lauryl sulphate, 7 mg of colloidal anhydrous silicon dioxide and 10 mg of magnesium stearate in the tablet core were produced by fluid granulation of abiraterone acetate with microcrystalline cellulose, lactose monohydrate and a part of sodium croscarmellose with the use of a Glatt GPCG2 fluid granulator with the following parameters:

- Inlet air temperature 60°C

- Air flow 60 m³/h

- Outlet air temperature 28°C

- Spraying atmospheric pressure 0.1 MPa

- Spraying rate 50 g/min

An aqueous solution of sodium lauryl sulphate and povidone was used as the granulation fluid.

The granules were dried at the following parameters:

- Inlet air temperature 50°C

- Air flow 60 m³/h

- Outlet air temperature 30°C The granules are then sieved with the use of an oscillating sieving device 0.8 mm, mixed with a part of sodium croscarmellose, colloidal anhydrous silicon dioxide and magnesium stearate. The tabletting matter is compressed into tablet cores 715 mg with a rotary tabletting press.

Example 4

To compare the behavior during dissolution of tablets produced using the fluid granulation method to the original high-speed granulation process technique, one tablet batch was produced with the use of high-speed granulation.

Tablets comprising 250 mg of abiraterone acetate, 200 mg of lactose monohydrate, 140 mg of microcrystalline cellulose, 43 mg of sodium croscarmellose, 36 mg of povidone, 29.0 mg of sodium lauryl sulphate, 7 mg of colloidal anhydrous silicon dioxide and 10 mg of magnesium stearate in the tablet core were produced by high-speed granulation of abiraterone acetate with macrocrystalline cellulose, lactose monohydrate, a part of sodium croscarmellose, povidone and sodium lauryl sulphate with the use of a Glatt VG50 high-speed granulator with the following parameters:

- Homogenization time 5 min

- Spraying rate 730 g/min

- Granulation time 5 min

The drying was conducted in a Glatt WSG CD- 15 fluid granulator with the following parameters:

- Inlet air temperature 50°C

- Air flow 650 m³/h

- Final product temperature 40°C.

The granules are then sieved with the use of an oscillating sieving device 0.8 mm, in a mixture with a part of sodium croscarmellose, colloidal anhydrous silicon dioxide and magnesium stearate. The tabletting matter is compressed into tablet cores 715 mg with a rotary tabletting press.

Compound Concentration Concentration

name [mg/tablet] [% by weight]

Abiraterone

250.0

acetate 35.0

Lactose

200.0

monohydrate 28.0

Microcrystalline

140.0

cellulose 19.6

Sodium

43.0

croscarmellose 6.0

povidone 36.0 5.0

Sodium lauryl

29.0

sulphate 4.1

Silicon dioxide,

7.0

colloidal 1.0 anhydrous

Magnesium

10.0

stearate 1.4

In the above mentioned batch example, the dissolution test was carried out with an acetate buffer solution with pH 4.5 containing 0.2% by weight of sodium lauryl sulphate with the use of a paddle device (30 rpm, 45 min; 150 rpm, 15 min, Fig. 1).

Claims

1. A method for preparing a solid drug formulation of abiraterone acetate, characterized in that it comprises fluid granulation of a mixture of abiraterone acetate and excipients with the use of a fluid granulator and compression of tablets, or filling the mixture into capsules or stick packs.

2. The method of preparing in accordance with claim 1, characterized in that comprises the following steps:

a) mixing of abiraterone acetate with excipients selected from the group comprising fillers, binders, disintegrants, surfactants;

c) drying the granules in a fluid granulator;

d) crushing the granules;

f) compressing the tabletting matter with a rotary tabletting press, or filling the mixture into capsules or stick packs and

g) optionally coating the tablets.

3. The method of preparing in accordance with claim 2, characterized in that the filler is selected from the group of microcrystalline cellulose, lactose, calcium phosphate, calcium carbonate, glucose, cellulose and its derivatives, starch, mannitol or other sugar alcohols.

4. The method of preparing in accordance with claim 2, characterized in that the binder is selected from the group of povidone, water-soluble cellulose derivatives, sugar alcohols, calcium sulphate, calcium phosphate and starch.

5. The method of preparing in accordance with claim 2, characterized in that the disintegrant is selected from the group of sodium croscarmellose, crospovidone, sodium starch glycolate and alginates.

6. The method of preparing in accordance with claim 2, characterized in that the surfactant is selected from the group of sodium lauryl sulphate and polyoxyethylene sorbitan.

7. The method of preparing in accordance with claim 1 to 6, characterized in that step b) of fluid granulation comprises spraying of the mixture of abiraterone acetate with the excipients from step a) with water or aqueous solutions of a binder or a surfactant, namely at a temperature of 20 - 60°C, preferably 25 - 50°C and most preferably 30 - 40°C.

8. The method of preparing in accordance with claim 1 to 7, characterized in that the granules prepared in step b) are dried in step c) at a temperature of 20 - 60°C, preferably 25 - 50°C, and most preferably 30 - 40°C, until the water content of 0.1-5%, preferably 0.5 -3%, and most preferably 1.0 - 2.0% by weight is achieved.

9. The method of preparing in accordance with claim 1 to 8, characterized in that the granules prepared in step c) are further crushed in step d) with the use of sieves of 0.5 - 1.7 mm, more preferably 0.6-1.5 mm and most preferably 0.8-1.25 mm.

10. The method of preparing in accordance with claim 1 to 9, characterized in that in step e), excipients from the group of disintegrants and fillers, glidants and moisteners are admixed to the granulate.

11. The method of preparing in accordance with claim 1 to 10, characterized in that the mixture from step e) is further compressed to tablet cores containing 250.0 - 500.0 g of abiraterone acetate, or are filled into capsules or stick packs containing 250.0 - 500.0 mg of abiraterone acetate.