EA047590B1 - PHARMACEUTICAL COMPOSITION CONTAINING APIXABAN - Google Patents

Description

Field of technology

The present invention relates to pharmaceutical compositions containing apixaban and to methods for producing such pharmaceutical compositions. Furthermore, the present invention relates to the use of pharmaceutical compositions containing apixaban as a medicine.

Prior art

Apixaban is a compound with the chemical name 1-(4-methoxyphenyl)-7oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide and the structure represented by formula (I) below \

(I)

Apixaban is a factor Xa inhibitor and can be used to treat or prevent thromboembolic complications. Apixaban is disclosed in US Patent Document No. 6,967,208. Apixaban has been described as a poorly soluble compound. Due to such low solubility of apixaban, there is a need in the art to create a pharmaceutical composition containing apixaban that would provide an acceptable dissolution rate.

In the art, pharmaceutical compositions are known that contain the poorly soluble active ingredient apixaban. In particular, some publications describe the preparation of pharmaceutical compositions that contain apixaban having a certain particle size.

For example, WO 2011/106478 A2 discloses compositions comprising crystalline particles of apixaban with an average particle size equal to or less than about 89 μm and a pharmaceutically acceptable diluent or carrier.

Patent document WO 2015/097090 A1 mentions solid particles of poorly soluble drugs having an average particle size of 100 μm or less, wherein a solubility enhancer is adsorbed on the surface of the poorly soluble drug.

Patent document WO 2017/182908 A1 describes compositions that use apixaban with a particle size d(0.9) of approximately 20 μm.

In addition, some publications have attempted to address the problem of low solubility of apixaban by preparing solid dispersions or adsorbates on carriers, as described, for example, in patent documents US 2015/0018386 and WO 2014/203275.

More recent strategies for preparing pharmaceutical compositions containing apixaban are disclosed in patent documents WO 2015/121472 A1, WO 2017/163170 A1, EP 3 243 505 A1 and WO 2017/221209 A1, WO2015/103230, Research Disclosure Database No. 605034 (www.researchdisclosure.com), patent documents WO2017/088841 and WO2017/125535.

Although various strategies for producing pharmaceutical compositions containing apixaban are known in the art, there remains a need for a pharmaceutical composition containing apixaban that provides favorable, in particular improved solubility, as well as favorable, in particular improved bioavailability of the active ingredient apixaban. In addition, such a pharmaceutical composition should use readily available excipients and/or should be capable of large-scale production. At the same time, the pharmaceutical composition should have adequate storage stability and/or show a low tendency for the active ingredient to decompose, for example, upon contact with moisture and/or atmospheric oxygen.

Brief description of the essence of the invention

The solution to the problem of the present invention is further facilitated by the aspects, advantageous features and preferred embodiments of the present invention summarized in the following paragraphs, respectively, individually or in combination.

1. A pharmaceutical composition containing apixaban, wherein the pharmaceutical composition contains or consists of one or more granules containing apixaban, wherein each of the granules containing apixaban contains or consists of:

(i) apixaban and (ii) hydroxyethylcellulose.

2. The pharmaceutical composition according to claim 1, wherein each of the granules containing apixaban has a weight ratio of apixaban: hydroxyethylcellulose in the range from 1:10 to 10:1, preferably in

- 1 047590 in the range from 1:5 to 5:1, more preferably in the range from 1:2 to 2:1, in particular in the range from 1:1.6 to 1.6:1.

3. A pharmaceutical composition according to any of the preceding claims, wherein each of the granules containing apixaban is obtained by wet granulation in the presence of a granulating liquid containing water or consisting of water.

4. A pharmaceutical composition according to any of the preceding claims, wherein each of the apixaban-containing granules comprises or consists of:

a) apixaban, hydroxyethylcellulose and diluent, or

b) apixaban, hydroxyethylcellulose and disintegrant, or

c) apixaban, hydroxyethylcellulose and a surfactant, or

d) apixaban, hydroxyethylcellulose, diluent and disintegrant, or

e) apixaban, hydroxyethylcellulose, diluent and surfactant.

5. A pharmaceutical composition according to any of the preceding claims, wherein each of the apixaban-containing granules comprises or consists of:

apixaban, hydroxyethylcellulose, diluent, disintegrant and surfactant.

6. A pharmaceutical composition according to any of the preceding claims, wherein each of the granules containing apixaban comprises or consists of: apixaban, hydroxyethylcellulose and a diluent and has a weight ratio of apixaban:diluent in the range of from 1:10 to 1:60, preferably from 1:20 to 1:50, more preferably from 1:30 to 1:40, in particular from 1:34 to 1:38.

7. A pharmaceutical composition according to any one of paragraphs 4 to 6, wherein the diluent is or comprises a diluent selected from the group consisting of: carbohydrates and derivatives thereof, sugar alcohols, celluloses, starch and derivatives thereof, magnesium aluminometasilicate, calcium salts of phosphoric acid, alkali metal carbonates, alkaline earth metal carbonates, alkali metal hydrogen carbonates, alkaline earth metal hydrogen carbonates and mixtures thereof, the diluent optionally is or comprises a diluent selected from the group consisting of lactose, cellulose and mixtures thereof, wherein the diluent is optionally a mixture comprising or consisting of lactose monohydrate and microcrystalline cellulose.

8. A pharmaceutical composition according to any of the preceding claims, wherein the pharmaceutical composition comprises:

(A) one or more apixaban-containing granules, wherein each of the apixaban-containing granules comprises or consists of:

(i) apixaban and (ii) hydroxyethylcellulose, and (B) one or more extragranular excipients, wherein preferably said one or more extragranular excipients comprise a disintegrant.

9. A pharmaceutical composition according to any of the preceding claims, wherein the pharmaceutical composition is a comprimate (briquetted product), in particular a tablet.

10. A pharmaceutical composition according to any of the preceding claims, wherein each of the apixaban-containing granules comprises:

apixaban in an amount of from 0.7 to 30 wt.%, preferably from 1 to 15 wt.%, more preferably from 1.5 to 9 wt.%, even more preferably from 2 to 5 wt.%, based on the total weight of the one or more granules containing apixaban, hydroxyethylcellulose in an amount of from 0.5 to 30 wt.%, preferably from 1 to 15 wt.%, more preferably from 1.5 to 9 wt.%, even more preferably from 2 to 5 wt.%, based on the total weight of the one or more granules containing apixaban, optionally a diluent in an amount of from 50 to 99 wt.%, preferably from 70 to 97 wt.%, more preferably from 85 to 95 wt.%, based on the total weight of the one or more granules containing apixaban, optionally a disintegrant in an amount of from 0.5 to 10 wt.%, preferably from 1 to 8 wt.%, more preferably from 1.5 up to 6 wt.%, even more preferably from 2 to 4 wt.% of the total weight of one or more granules containing apixaban, optionally a surfactant in an amount of from 0.1 to 5 wt.%, preferably from 0.5 to 2 wt.%, more preferably from 0.7 to 1.8 wt.% of the total weight of one or more granules containing apixaban, and optionally one or more additional excipients.

11. A pharmaceutical composition according to any one of the preceding claims, wherein each of the apixaban-containing granules comprises or consists of apixaban in an amount of from 0.7 to 30 wt.%, preferably from 1 to 15 wt.%, more preferably from 1.5 to 9 wt.%, even more preferably from 2 to 5 wt.% of the total weight of the one or more apixaban-containing granules, hydroxyethylcellulose in an amount of from 0.5 to 30 wt.%, preferably from 1 to 15 wt.%, more

- 2 047 590 preferably from 1.5 to 9% by weight, even more preferably from 2 to 5% by weight, based on the total weight of the one or more granules containing apixaban, lactose, in particular lactose monohydrate, in an amount of from 25 to 60% by weight, preferably from 38 to 55% by weight, more preferably from 44 to 51% by weight, based on the total weight of the one or more granules containing apixaban, microcrystalline cellulose in an amount of from 25 to 55% by weight, preferably from 38 to 49% by weight, more preferably from 40 to 48% by weight, based on the total weight of the one or more granules containing apixaban, croscarmellose sodium in an amount of from 0.5 to 10% by weight, preferably from 1 to 8% by weight, more preferably from 1.5 to 6% by weight, even more preferably from 2 to 4% by weight, based on the total weight of the one or more granules containing apixaban, sodium lauryl sulfate in an amount of from 0.1 to 5 wt.%, preferably from 0.5 to 2 wt.%, more preferably from 0.7 to 1.8 wt.% of the total weight of one or more granules containing apixaban, and optionally one or more additional excipients.

12. A pharmaceutical composition according to any one of paragraphs 8 to 11, wherein the pharmaceutical composition comprises:

one or more granules containing apixaban in an amount of from 30 to 99% by weight, preferably in an amount of from 70 to 98% by weight, more preferably in an amount of from 85 to 97% by weight, in particular in an amount of from 90 to 95% by weight, based on the total weight of the pharmaceutical composition, and one or more extragranular excipients, wherein the total weight of the extragranular excipients is from 1 to 70% by weight, preferably from 2 to 30% by weight, more preferably from 3 to 15% by weight, in particular from 5 to 10% by weight, based on the total weight of the pharmaceutical composition.

13. A method for producing a pharmaceutical composition containing apixaban, in particular a pharmaceutical composition for oral use, in particular a method for producing a pharmaceutical composition containing apixaban, wherein said pharmaceutical composition comprises or consists of one or more granules containing apixaban, wherein said method comprises:

(i) obtaining a granulate containing apixaban and hydroxyethylcellulose, preferably by wet granulation;

(ii) optionally drying the granulate obtained in step (i), (iii) optionally sieving and/or milling the granulate obtained in step (i) or the optionally dried granules obtained in step (ii), (iv) optionally combining the granulate obtained in step (i) or the optionally dried granules obtained in step (ii) or the optionally sieved and/or milled granules obtained in optional step (iii) with at least one auxiliary substance to obtain a compaction mixture;

(v) optionally compressing the pressing mixture to obtain a compressed product, in particular a tablet; and (vi) optionally coating the compressed product.

14. A method for producing a pharmaceutical composition containing apixaban according to claim 13, wherein step i) is:

i) obtaining a granulate containing apixaban and hydroxyethylcellulose by subjecting a mixture containing apixaban and hydroxyethylcellulose to wet granulation in the presence of a granulating liquid containing a solvent, wherein the solvent is or contains water.

15. A method for producing a pharmaceutical composition containing apixaban according to any one of claims 13 to 14, wherein step (i) of producing a granulate containing apixaban comprises:

(I) preparing a mixture containing apixaban, hydroxyethylcellulose and optionally one or more additional excipients;

(II) granulating the mixture obtained in step (i) in the presence of a granulating solution containing a solvent, said solvent preferably being or comprising water.

16. A method for producing a pharmaceutical composition containing apixaban according to any one of claims 13 to 15, wherein step (i) of producing a granulate containing apixaban is step (i) of producing a granulate containing or consisting of:

a) apixaban, hydroxyethylcellulose and diluent, or

b) apixaban, hydroxyethylcellulose and disintegrant, or

c) apixaban, hydroxyethylcellulose and a surfactant, or

d) apixaban, hydroxyethylcellulose, diluent and disintegrant, or

e) apixaban, hydroxyethylcellulose, diluent and surfactant, or

f) apixaban, hydroxyethylcellulose, diluent, disintegrant and surfactant,

- 3 047590 preferably by wet granulation.

17. A pharmaceutical composition according to any one of claims 1 to 12 for use in the treatment or prevention of thromboembolic complications or disease, in particular venous thrombotic complications or disease.

18. A pharmaceutical composition containing apixaban, wherein said pharmaceutical composition comprises or consists of an extrudate containing apixaban, in particular a hot melt extrudate containing apixaban, wherein the extrudate containing apixaban, in particular a hot melt extrudate containing apixaban, comprises or consists of:

(I) apixaban and (II) a polymer component which is or comprises a polymer selected from a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, copovidone, polyvinyl alcohol) and mixtures thereof, and wherein the apixaban-containing extrudate, in particular the apixaban-containing hot melt extrudate, has a weight ratio between apixaban and the polymer component (apixaban:polymer component) of 1:4 or less, in particular of 1:6 or less, in particular in the range from 1:6 to 1:9, wherein optionally the apixaban-containing extrudate, in particular the apixaban-containing hot melt extrudate, can be obtained by a process comprising extrusion, in particular hot melt extrusion, carried out at a temperature of at least 190°C, in particular at a temperature in the range from 190 to 230°С.

19. A pharmaceutical composition containing apixaban according to claim 18, wherein the extrudate containing apixaban can be obtained by a method comprising hot melt extrusion carried out at a temperature in the range from 190 to 230°C.

20. A pharmaceutical composition comprising apixaban according to any one of the preceding claims 18 to 19, wherein the polymer component is or comprises polyvinyl alcohol.

21. A pharmaceutical composition comprising apixaban according to any one of the preceding claims 18 to 19, wherein the polymer component is or comprises a graft copolymer of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol.

22. A pharmaceutical composition comprising apixaban according to any one of the preceding paragraphs 18 to 19, wherein the polymer component is or comprises copovidone.

23. A pharmaceutical composition comprising apixaban according to any one of the preceding claims 18 to 22, wherein the weight ratio between apixaban and the polymer component (apixaban:polymer component) is 1:6 or less, preferably 1:9 or less, in particular in the range from 1:6 to 1:11, also in particular in the range from 1:6 to 1:9.

24. A pharmaceutical composition comprising apixaban according to any one of the preceding claims 19 to 23, wherein the hot melt extrusion is carried out at a temperature of at least 190°C, or wherein the hot melt extrusion is carried out at a temperature of at least 190°C and the weight ratio of apixaban:polymer component is 1:9 or less, in particular in the range from 1:9 to 1:11.

25. A pharmaceutical composition comprising apixaban according to any one of the preceding claims 19 to 23, wherein the hot melt extrusion is carried out at a temperature of at least 210°C and the weight ratio of apixaban:polymer component is 1:6 or less, preferably 1:9 or less, in particular in the range from 1:6 to 1:11, also in particular in the range from 1:6 to 1:9.

26. A pharmaceutical composition according to any one of paragraphs 18 to 25, wherein the extrudate comprises an amorphous form of apixaban, optionally a mixture comprising an amorphous form of apixaban and form N-1 of apixaban.

27. A pharmaceutical composition according to any one of the preceding claims 18 to 26, wherein the extrudate containing apixaban, in particular the hot melt extrudate containing apixaban, is in the form of granules.

28. A pharmaceutical composition comprising apixaban, in particular a pharmaceutical composition according to any of the preceding paragraphs 18 to 27, wherein said pharmaceutical composition comprises or consists of one or more granules comprising apixaban, wherein each of the granules comprising apixaban comprises or consists of:

(a) an extrudate containing apixaban, in particular a hot melt extrudate containing apixaban, wherein the extrudate comprises or consists of:

(I) apixaban and (II) a polymer component that is or contains a polymer selected from a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, copovidone,

- 4 047590 vinyl alcohol) and mixtures thereof, wherein optionally the extrudate containing apixaban, in particular the hot melt extrudate containing apixaban, optionally has a weight ratio between apixaban and the polymer component (apixaban:polymer component) of 1:4 or less, in particular of 1:6 or less, in particular lying in the range from 1:6 to 1:9, and (β) optionally one or more intragranular excipients.

29. A pharmaceutical composition, in particular a pharmaceutical composition according to any of the preceding paragraphs 18 to 28, comprising:

(A') one or more apixaban-containing granules, wherein each of the apixaban-containing granules comprises or consists of:

(a) an extrudate containing apixaban, in particular an apixaban-containing hot melt extrudate, wherein the extrudate comprises or consists of:

(I.) apixaban and (II.) a polymer component which is or comprises a polymer selected from a graft copolymer of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol, copovidone, polyvinyl alcohol) and mixtures thereof, and (β) optionally one or more intragranular excipients, and (B) one or more extragranular excipients, where preferably said one or more extragranular excipients comprise a disintegrant.

30. A pharmaceutical composition according to any one of the preceding claims 18 to 29, wherein the pharmaceutical composition is a compress, in particular a tablet.

31. A pharmaceutical composition according to any one of claims 18 to 30, wherein the pharmaceutical composition comprises one or more granules containing apixaban in an amount of from 30 to 99% by weight, preferably in an amount of from 70 to 98% by weight, more preferably in an amount of from 85 to 97% by weight, in particular in an amount of from 90 to 97% by weight based on the total weight of the pharmaceutical composition, and one or more extragranular excipients, wherein the total weight of the extragranular excipients is from 1 to 70% by weight, preferably from 2 to 30% by weight, more preferably from 3 to 15% by weight, in particular in an amount of from 3 to 10% by weight based on the total weight of the pharmaceutical composition.

32. A pharmaceutical composition according to any of the preceding claims for use in the treatment or prevention of thromboembolic complications or disease, in particular venous thrombotic complications or disease.

33. A method for producing an extrudate containing apixaban and optionally producing a granulate or compress, wherein the extrudate containing apixaban comprises or consists of (i) apixaban and (ii) a polymer component which is or contains a polymer selected from a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, copovidone, polyvinyl alcohol and mixtures thereof, wherein the method comprises:

(A) preparing a mixture comprising (i) apixaban and (ii) a polymer component which is or comprises a polymer selected from a polyvinylcaprolactam-polyvinyl acetate-polyethyleneglycol graft copolymer, copovidone, polyvinyl alcohol and mixtures thereof, optionally wherein apixaban and the polymer component are present in said mixture in a weight ratio of apixaban:polymer component of 1:4 or less, in particular of 1:6 or less, in particular in the range from 1:6 to 1:9;

(B) subjecting the mixture obtained in step (A) to extrusion, in particular hot melt extrusion, optionally hot melt extrusion carried out at a temperature of at least 190°C, also optionally at a temperature in the range from 190 to 230°C;

(C) optionally milling the apixaban-containing extrudate obtained in step (B) to obtain a milled apixaban-containing extrudate;

(D) optionally converting the apixaban-containing extrudate obtained in step (B) or the milled apixaban-containing extrudate obtained in step (C) to form a granulate;

(E) optionally mixing the apixaban-containing extrudate obtained in step (B) or the milled apixaban-containing extrudate obtained in step (C) or the granulate obtained in step (D) with at least one excipient to obtain a compaction mixture;

(F) optionally compressing the pressing mixture to obtain a compressed product, in particular a tablet; and (G) optionally coating the compressed product.

34. A method for producing an extrudate containing apixaban according to claim 33, wherein said polymer component is a graft copolymer of polyvinylcaprolactam-polyvinyl acetate.

- 5 047590 polyethylene glycol.

35. A method for producing an extrudate containing apixaban according to claim 33, wherein said polymer component is copovidone.

36. A process for producing an extrudate comprising apixaban according to any one of the preceding claims 33 to 35, wherein the mixture obtained in step (A) has a weight ratio between apixaban and the polymer component (apixaban:polymer component) of 1:6 or less, preferably 1:9 or less, in particular lying in the range from 1:6 to 1:11, also in particular in the range from 1:6 to 1:9.

37. A method for producing an extrudate comprising apixaban according to any one of the preceding paragraphs 33 to 36, wherein the hot melt extrusion is carried out at a temperature of at least 190°C, and wherein the mixture obtained in step (A) has a weight ratio between apixaban and the polymer component (apixaban:polymer component) of 1:9 or less, in particular lying in the range from 1:9 to 1:11.

38. A process for producing an extrudate comprising apixaban according to any one of the preceding claims 33 to 37, wherein the hot melt extrusion is carried out at a temperature of at least 210°C, and wherein the mixture obtained in step (A) has a weight ratio between apixaban and the polymer component (apixaban:polymer component) of 1:6 or less, preferably 1:9 or less, in particular lying in the range from 1:6 to 1:11, also in particular in the range from 1:6 to 1:9.

39. A method for producing an extrudate containing apixaban according to any of the preceding paragraphs 33 to 38, wherein the apixaban present in the extrudate obtained in step (B) consists of amorphous form of apixaban or contains at least 80% by weight, preferably at least 95% by weight of amorphous form of apixaban based on the total weight of apixaban present in the extrudate.

40. A method for producing an extrudate containing apixaban according to any one of the preceding paragraphs 33 to 38, wherein the apixaban present in the extrudate obtained in step (C) consists of amorphous form of apixaban or contains at least 80% by weight, preferably at least 95% by weight of amorphous form of apixaban based on the total weight of apixaban present in the extrudate.

Detailed description of the invention

The present invention relates to a pharmaceutical composition containing apixaban, wherein the pharmaceutical composition comprises or consists of one or more granules containing apixaban, wherein each of the granules containing apixaban comprises or consists of:

(i) apixaban and (ii) hydroxyethylcellulose.

It has been unexpectedly found that a pharmaceutical composition comprising one or more apixaban-containing granules, wherein each of the apixaban-containing granules comprises or consists of (i) apixaban and (ii) hydroxyethylcellulose, provides good solubility and exhibits high bioavailability of apixaban. It has also been unexpectedly found that apixaban-containing granules comprising or consisting of (i) apixaban and (ii) hydroxyethylcellulose have very good solubility and bioavailability and provide a better dissolution profile than apixaban-containing granules comprising, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose and PVP (polyvinylpyrrolidone). In addition, the solubility of the pharmaceutical composition is not sensitive to the presence of different amounts of hydroxyethylcellulose in the pharmaceutical composition.

According to a first aspect, a pharmaceutical composition is provided comprising apixaban, wherein said pharmaceutical composition comprises or consists of one or more granules comprising apixaban, wherein each of the granules comprising apixaban comprises or consists of:

(i) apixaban (wherein apixaban need not be or contain crystalline apixaban) and (ii) hydroxyethylcellulose.

Crystalline apixaban may have an average particle size of 0.1 to 200 μm, preferably 1 to 80 μm, more preferably 1 to 40 μm, most preferably 1 to 20 μm. The average particle size is determined by laser measurement using a Malvern Mastersizer.

In particular, a pharmaceutical composition comprising apixaban is provided, wherein said pharmaceutical composition comprises or consists of one or more granules comprising apixaban, wherein each of the granules comprising apixaban comprises or consists of (i) apixaban and (ii) hydroxyethylcellulose (HEC), and wherein each of the granules comprising apixaban has a weight ratio of apixaban:hydroxyethylcellulose in the range of from 1:10 to 10:1, preferably in the range of from 1:5 to 5:1, more preferably in the range of from 1:2 to 2:1, in particular in the range of from 1:1.6 to 1.6:1. Optionally, the one or more apixaban-containing granules comprising HEC can be obtained by wet granulation.

In particular, a pharmaceutical composition comprising apixaban is provided, wherein the pharmaceutical composition comprises or consists of one or more granules comprising apixaban, wherein

- 6 047 590 each of the apixaban-containing granules comprises or consists of apixaban, hydroxyethylcellulose and a diluent, and wherein each of the apixaban-containing granules has a weight ratio of apixaban:hydroxyethylcellulose in the range of from 1:10 to 10:1, preferably in the range of from 1:5 to 5:1, more preferably in the range of from 1:2 to 2:1, in particular in the range of from 1:1.6 to 1.6:1, and a weight ratio of apixaban:diluent in the range of from 1:10 to 1:60, preferably from 1:20 to 1:50, more preferably from 1:30 to 1:40, in particular from 1:34 to 1:38. Optionally, one or more apixaban-containing granules containing HEC can be obtained by wet granulation.

According to another aspect, a pharmaceutical composition is provided comprising apixaban, wherein the pharmaceutical composition comprises or consists of one or more granules comprising apixaban, wherein each of the granules comprising apixaban comprises or consists of an extrudate comprising apixaban, wherein the extrudate comprising apixaban comprises or consists of apixaban and a polymer component selected from a graft copolymer of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol, copovidone, polyvinyl alcohol and mixtures thereof.

In particular, a pharmaceutical composition is proposed, comprising or consisting of one or more granules containing apixaban, wherein each of the granules containing apixaban comprises or consists of:

(a) an extrudate containing apixaban, in particular from a hot melt extrudate containing apixaban, wherein the extrudate comprises or consists of:

(I.) apixaban and (II.) a polymer component which is or comprises a polymer selected from a graft copolymer of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol, copovidone, polyvinyl alcohol and mixtures thereof, wherein optionally the extrudate comprising apixaban, in particular the hot melt extrudate comprising apixaban, optionally has a weight ratio between apixaban and the polymer component (apixaban:polymer component) of 1:4 or less, in particular of 1:6 or less, in particular in the range from 1:6 to 1:9, and (β) optionally one or more intragranular excipients.

Apixaban is a known active agent and can be prepared by any of the methods described in the prior art. For example, apixaban can be prepared as described in U.S. Patent Document No. 6,967,208. The term apixaban encompasses pharmaceutically acceptable salts, hydrates and solvates thereof.

Hydroxyethyl cellulose (HEC) is a known commercially available compound. Hydroxyethyl cellulose is a partially substituted polyhydroxyethyl ether of cellulose. HEC may be a non-ionic water-soluble polymer. HEC is described in detail in the United States Pharmacopoeia USP32-N27, as well as in the Handbook of Pharmaceutical Excipients, 6th ed., edited by R.C. Rowe et al., Pharmaceutical Press, ISBN 9780853697923, in particular on pages 311-314. Hydroxyethyl cellulose is available in various viscosities. Hydroxyethyl cellulose of any viscosity can be used to prepare the pharmaceutical compositions of the present invention.

A person skilled in the art can select the degree of substitution and the molecular weight of hydroxyethyl cellulose based on general knowledge in the art. The molecular weight of hydroxyethyl cellulose can be approximately 4,000 to 1,600,000 g/mol, in particular approximately 10,000 to 1,350,000 g/mol.

Hydroxyethylcellulose may have a viscosity of a 2% by weight aqueous solution at a temperature of 20°C (in particular at a temperature of 20°C and a pressure of 101325 Pa) in the range from 2 to 20000 mPa s, preferably from 7 to 15000 mPa s, most preferably from 60 to 5100 mPa s, in particular from 70 to 450 mPa s. The viscosity may be determined by conventional means, for example by measuring the viscosity of an aqueous solution of the polymers of the required concentration at the specified temperature using a viscosity determination device (e.g. Ubbelohde capillary viscometers). In particular, the viscosity may be determined in accordance with the European Pharmacopoeia 9.2, in particular in accordance with Chapter 2.2.9 Capillary viscosimetry method.

The weight average molecular weight of hydroxyethyl cellulose can be from 80,000 to 1,350,000 Da, in particular from 89,000 to 350,000 Da.

The term one or more granules containing apixaban may correspond preferably to two or more, 3 or more, 4 or more, 10 or more granules and may be, for example, from 1 to 100 or from 4 to 20 granules containing apixaban.

A pharmaceutical composition comprising or consisting of one or more apixaban-containing granules, wherein each of the apixaban-containing granules comprises or consists of (i) apixaban and (ii) hydroxyethylcellulose, may have a solubility such that more than 70% of apixaban is dissolved within 22 minutes, in particular within 20 minutes, in 900 ml of a buffer comprising 50 mM sodium phosphate buffer at pH 6.8 containing 0.05 wt.% SDS (sodium dodecyl sulfate). The dissolution test may be performed according to conventional methods, from

- 7 047590 known to the person skilled in the art, for example, at a temperature of 37°C. According to a preferred embodiment of the present invention, the dissolution test is carried out at a temperature of 37°C using a USP Apparatus 2 (with a paddle stirrer) at a rotation speed of 75 rpm.

The one or more apixaban-containing granules may be prepared by any method known to those skilled in the art, including but not limited to granulation, such as, for example, wet granulation, moisture-activated granulation, dry granulation, melt granulation, extrusion, especially hot melt extrusion, and combinations thereof. Optionally, the one or more apixaban-containing HEC granules may be prepared by wet granulation.

The one or more apixaban-containing granules comprising HEC may be granules that are not obtained by dry granulation. According to one embodiment, the one or more apixaban-containing granules comprising HEC may be granules that are not obtained by melt granulation.

In particular, each of the one or more apixaban-containing granules containing HEC and apixaban can be prepared by wet granulation. Wet granulation allows obtaining particularly preferred granules containing HEC and apixaban. In particular, the one or more apixaban-containing granules containing HEC and apixaban can be prepared by wet granulation in the presence of a granulating liquid containing water or consisting of water.

Furthermore, in particular, the apixaban-containing granules comprising an extrudate comprising an apixaban can be obtained, for example, by pressing a mixture comprising an extrudate comprising an apixaban, as will be described in more detail below. The extrudate comprising an apixaban can in particular be obtained by melt extrusion, in particular by hot melt extrusion. Melt extrusion, in particular hot melt extrusion, allows obtaining particularly preferred extrudates and granules. In particular, one or more granules comprising an apixaban can be obtained by melt extrusion. Melt extrusion can in particular be a process known in the art as hot melt extrusion.

In particular, in a pharmaceutical composition comprising one or more granules comprising apixaban, each of the granules comprising apixaban (comprising both HEC and apixaban) may have a weight ratio of apixaban:hydroxyethylcellulose in the range of 1:10 to 10:1, preferably in the range of 1:5 to 5:1, more preferably in the range of 1:2 to 2:1, in particular in the range of 1:1.6 to 1.6:1 or in particular in the range of 1:7 to 1:4, in particular in the range of 1:1.65 to 1:1.55.

In addition to apixaban and hydroxyethylcellulose, the pharmaceutical composition may optionally contain one or more additional excipients. In addition to apixaban and hydroxyethylcellulose, the pharmaceutical composition may optionally contain one or more additional excipients, such as 1 or 2, or 3, or 4, or 5 additional excipients selected from the group of diluents, binders, disintegrants, lubricants, glidants, surfactants and anti-adhesives.

Furthermore, in addition to apixaban and hydroxyethylcellulose, one or more granules containing apixaban may optionally contain one or more additional excipients. In addition to apixaban and hydroxyethylcellulose, one or more granules containing apixaban may optionally contain one or more additional excipients, such as 1 or 2, or 3, or 4, or 5 additional excipients selected from the group of diluents, binders, disintegrants, lubricants, glidants, surfactants and anti-adhesive agents.

The excipients used to prepare the pharmaceutical compositions of the present invention may be pharmaceutically acceptable excipients, i.e. excipients having a quality suitable for use in mammals.

Excipients can perform several functions, i.e. one excipient can be used as a binder/diluent, etc.

In the pharmaceutical compositions of the present invention (in particular, in the granules containing apixaban), other additional excipients with various functions, such as polymers, pH modifiers, antioxidants, surfactants, etc., may be included, or one or more excipients with various functions may be excluded from the composition.

Each of the one or more apixaban-containing granules may comprise or consist of:

a) apixaban, hydroxyethylcellulose and diluent, or

b) apixaban, hydroxyethylcellulose and disintegrant, or

c) apixaban, hydroxyethylcellulose and a surfactant, or

d) apixaban, hydroxyethylcellulose, diluent and disintegrant, or

- 8 047590

e) apixaban, hydroxyethylcellulose, diluent and surfactant.

In particular, a pharmaceutical composition comprising one or more granules containing apixaban may be a pharmaceutical composition wherein each of the granules containing apixaban comprises or consists of apixaban, hydroxyethylcellulose, a diluent, a disintegrant and a surfactant.

The pharmaceutical composition comprising one or more granules containing apixaban may also comprise at least one additional granule. The at least one additional granule may comprise apixaban or may not comprise apixaban.

The pharmaceutical composition of the present invention may be a solid dosage form such as a tablet, especially a film-coated tablet.

The pharmaceutical composition of the present invention may be a unit dosage form. The term unit dosage form refers to physically discrete unit(s) suitable as single dosages for human subjects and other mammals, each unit containing a predetermined quantity of apixaban calculated to produce the desired therapeutic effect, in combination with at least one excipient. According to one embodiment, the unit dosage form composition is preferred to be immediate release.

A pharmaceutical composition comprising one or more granules containing apixaban may comprise:

(A) one or more apixaban-containing granules, wherein each of the apixaban-containing granules comprises or consists of:

(i) apixaban (wherein apixaban is optionally or comprises crystalline apixaban) and (ii) hydroxyethylcellulose, and (B) one or more extragranular excipients, wherein preferably said one or more extragranular excipients comprise a disintegrant.

Furthermore, the pharmaceutical composition comprising one or more granules containing apixaban may be a pharmaceutical composition in which each of the granules containing apixaban comprises or consists of apixaban, hydroxyethylcellulose and a diluent and has a weight ratio of apixaban:diluent in the range of from 1:10 to 1:60, preferably from 1:20 to 1:50, more preferably from 1:30 to 1:40, in particular from 1:34 to 1:38.

Furthermore, the pharmaceutical composition comprising one or more granules containing apixaban may be a pharmaceutical composition in which each of the granules containing apixaban comprises or consists of apixaban, hydroxyethylcellulose and a diluent and has a weight ratio of hydroxyethylcellulose:diluent in the range of from 1:10 to 1:60, preferably from 1:20 to 1:50, more preferably from 1:30 to 1:40, in particular from 1:34 to 1:38.

The pharmaceutical composition of the present invention may contain a diluent. In a pharmaceutical composition comprising one or more granules containing apixaban and one or more extragranular excipients, the granulate may contain a diluent, or one or more extragranular excipients may contain a diluent, or both the granulate and one or more extragranular excipients may contain a diluent.

The term diluent may refer to one or more diluents and thus covers both a single diluent and a mixture of diluents.

The diluent may be or comprise a diluent selected from the group consisting of carbohydrates or derivatives thereof, such as lactose, for example lactose monohydrate, anhydrous lactose, spray-dried and/or granulated lactose, sucrose, fructose, dextrates, sucrose, raffinose, trehalose, fructose and mixtures thereof, dextrin, sugar alcohols such as xylitol, mannitol, maltitol, isomalt, sorbitol, celluloses, in particular powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, starch and derivatives thereof, in particular low-moisture starch, starch such as corn starch, potato starch, rice starch, tapioca starch or wheat starch, pregelatinized starch, low-moisture pregelatinized starch, magnesium aluminometasilicate, calcium salts of phosphoric acid such as calcium hydrogen phosphate (in anhydrous or in hydrate form), alkali metal carbonates, alkaline earth metal carbonates, alkali metal hydrogen carbonates, alkaline earth metal hydrogen carbonates such as calcium carbonate, sodium carbonate, potassium carbonate or calcium hydrogen carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate and calcium lactate, as well as mixtures thereof.

In particular, the diluent may be or comprise a diluent selected from the group consisting of lactose, cellulose and mixtures thereof, optionally the diluent may be a mixture containing or consisting of lactose monohydrate and microcrystalline cellulose.

The pharmaceutical composition of the present invention may also contain a disintegrant. In a pharmaceutical composition comprising one or more granules containing apixaban and one

- 9 047 590 or more extragranular excipients, each of the one or more granules containing apixaban may contain a disintegrant, or one or more extragranular excipients may contain a disintegrant, or both one or more extragranular excipients and each of the one or more granules containing apixaban may contain a disintegrant. In this application, the term disintegrant may refer to one or more disintegrants and thus covers both a single disintegrant and a mixture of disintegrants. The disintegrant may be or comprise a disintegrant selected from crospovidone, a starch such as corn starch, potato starch, rice starch, tapioca starch or wheat starch, pregelatinized starch, sodium starch glycolate, hydroxypropyl starch, microcrystalline cellulose, sodium and/or calcium salts of carboxymethylcellulose, cross-linked carboxymethylcellulose (e.g. sodium croscarmellose and/or calcium croscarmellose), potassium polacrilin, hydroxypropylcellulose, in particular low-substituted hydroxypropylcellulose, sodium and/or calcium alginate, sodium docusate, methylcellulose, agar, guar gum, chitosan, alginic acid, and mixtures thereof. Preferably, the disintegrant may be selected from cross-linked carboxymethylcellulose, in particular croscarmellose sodium and/or croscarmellose calcium and mixtures thereof. More preferably, the granules containing apixaban contain croscarmellose sodium.

Croscarmellose sodium may in particular be the sodium salt of cross-linked, partially O-carboxymethylated cellulose and may also be known under the name cellulose, carboxymethyl ether, sodium salt, cross-linked. The terms croscarmellose sodium and sodium croscarmellose are used interchangeably in this context. In particular, sodium croscarmellose may be used for the preparation of the pharmaceutical composition of the present invention, which is croscarmellose sodium, such as defined in the European Pharmacopoeia 6.0, in the chapter Sodium croscarmellose.

The pharmaceutical composition of the present invention may also contain a lubricant. In particular, each of the one or more granules containing apixaban may also contain a lubricant. In a pharmaceutical composition comprising one or more granules containing apixaban and one or more extragranular excipients, each of the one or more granules containing apixaban may contain a lubricant and/or the one or more extragranular excipients may contain a lubricant. In the present application, the term lubricant may refer to one or more lubricants and, accordingly, covers both a single lubricant and a mixture of lubricants. The lubricant may be selected from the group of alkali metal alkyl sulfates containing from 10 to 20 carbon atoms, preferably from 12 to 16 carbon atoms, such as sodium lauryl sulfate, metal salts of fatty acids containing from 12 to 20 carbon atoms, such as magnesium stearate, calcium stearate, aluminum stearate or zinc stearate, magnesium palmitate and magnesium oleate, fatty acids containing from 12 to 20 carbon atoms, such as stearic acid, palmitic acid and oleic acid, hydrogenated vegetable oil, hydrogenated castor oil, talc, honey wax or spermaceti, boric acid, sodium stearyl fumarate, macrogol and mixtures thereof.

Preferably, the granules containing apixaban may contain at least one lubricant selected from alkali metal salts of fatty acids containing from 10 to 20 carbon atoms, preferably from 12 to 16 carbon atoms, and mixtures thereof. More preferably, the granules containing apixaban contain at least one lubricant selected from the group of alkali metal alkyl sulfates containing from 10 to 20 carbon atoms, preferably from 12 to 16 carbon atoms. The alkali metal alkyl sulfate may in particular be a compound of the formula H3C-( _CH2 )n- _SO4 ^- Na ⁺ , where n is from 10 to 20, preferably from 12 to 16.

The lubricant may be selected from the group of alkali metal alkyl sulfates containing from 10 to 20 carbon atoms, preferably from 12 to 16 carbon atoms, such as sodium lauryl sulfate, metal (alkali metal) salts of fatty acids containing from 12 to 20 carbon atoms, such as magnesium stearate, calcium stearate, aluminum stearate or zinc stearate, magnesium palmitate and magnesium oleate, fatty acids containing from 12 to 20 carbon atoms, such as stearic acid, palmitic acid and oleic acid, hydrogenated vegetable oil, hydrogenated castor oil, talc, honey wax or spermaceti, boric acid, sodium stearyl fumarate, macrogol and mixtures thereof.

The pharmaceutical composition of the present invention and/or each of the one or more granules containing apixaban may also contain one or more glidants selected from colloidal silicon dioxide, talc and magnesium trisilicate, preferably colloidal silicon dioxide.

The pharmaceutical composition of the present invention, in particular the apixaban-containing granules containing HEC, may also contain a binder other than hydroxyethylcellulose. According to a preferred embodiment, the apixaban-containing granules (in particular those granules containing apixaban and HEC), and in particular the pharmaceutical composition of the present invention, may not contain a binder other than hydroxyethylcellulose. According to

- 10 047590 According to one embodiment, the granules containing apixaban (especially the apixaban-containing granules containing apixaban and HEC), and in particular the pharmaceutical composition of the present invention, may not contain a binder selected from the group consisting of povidone (polyvinylpyrrolidone), copovidone (vinylpyrrolidone-vinyl copolymer), hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polymethacrylates and mixtures thereof, or may contain no more than 1 wt.% (preferably no more than 0.4 wt.%) of one of povidone (polyvinylpyrrolidone), copovidone (vinylpyrrolidone-vinyl copolymer), hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polymethacrylates, based on the total weight of the granules containing apixaban.

In a pharmaceutical composition comprising one or more granules containing apixaban and optionally at least one extragranular excipient, each of the one or more granules containing apixaban may contain a glidant and/or the one or more extragranular excipients may contain a glidant.

The pharmaceutical composition of the present invention may also contain one or more anti-caking agents selected from talc, glyceryl monostearate and stearic acid, preferably stearic acid. In a pharmaceutical composition comprising one or more granules containing apixaban and one or more extra-granular excipients, the one or more granules containing apixaban may contain an anti-caking agent, or the one or more extra-granular excipients may contain an anti-caking agent, or both the one or more extra-granular excipients and the one or more granules containing apixaban may contain an anti-caking agent.

According to one embodiment, a pharmaceutical composition comprising one or more granules containing apixaban may comprise:

(A) one or more apixaban-containing granules, wherein each of the apixaban-containing granules comprises or consists of:

(i) apixaban (wherein the apixaban is optionally or comprises crystalline apixaban) and (ii) hydroxyethylcellulose, and (B) one or more extragranular excipients, wherein said one or more extragranular excipients comprise a disintegrant and optionally a lubricant. In particular, the pharmaceutical composition may be a comprimate, in particular a tablet. The one or more extragranular excipients may comprise at least one of a disintegrant and a lubricant. Preferably, the one or more extragranular excipients may comprise a disintegrant and a lubricant.

According to one embodiment, the pharmaceutical composition of the present invention may be a pharmaceutical composition comprising:

(A') one or more apixaban-containing granules, wherein each of the apixaban-containing granules comprises or consists of:

(α) an extrudate containing apixaban, in particular from a hot melt extrudate containing apixaban, wherein the extrudate comprises or consists of:

(I.) apixaban and (II.) a polymer component which is or comprises a polymer selected from a graft copolymer of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol, copovidone, polyvinyl alcohol) and mixtures thereof, and (β) optionally one or more intragranular excipients, and (B) one or more extragranular excipients, where preferably the one or more extragranular excipients comprise a disintegrant.

In particular, the pharmaceutical composition may be a comprimate, in particular a tablet. An apixaban-containing extrudate comprising or consisting of apixaban and a polymer component comprising or containing a polymer selected from a graft copolymer of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol, copovidone, polyvinyl alcohol will be described in more detail below.

One or more intragranular excipients may comprise a lubricant. One or more extragranular excipients may comprise a lubricant. The lubricant may be selected from the group of alkali metal alkyl sulfates containing from 10 to 22 carbon atoms, preferably from 12 to 16 carbon atoms, such as sodium lauryl sulfate, metal salts (especially alkaline earth metal salts) of fatty acids containing from 12 to 20 carbon atoms, such as magnesium stearate, calcium stearate, aluminum stearate or zinc stearate, magnesium palmitate and magnesium oleate, fatty acids containing from 12 to 20 carbon atoms, such as stearic acid, palmitic acid and oleic acid, hydriro

- 11 047590 vegetable oil, hydrogenated castor oil, talc, honey wax or spermaceti, boric acid, sodium stearyl fumarate, macrogol and mixtures thereof. In particular, one or more extragranular excipients may contain a lubricant which may be selected from the group of metal salts (especially alkaline earth metal salts) of fatty acids containing from 12 to 20 carbon atoms, such as magnesium stearate, calcium stearate, aluminum stearate or zinc stearate, magnesium palmitate and magnesium oleate.

One or more intragranular excipients may comprise a disintegrant. One or more extragranular excipients may comprise a disintegrant. The disintegrant may be selected from crospovidone, starch such as corn starch, potato starch, rice starch, tapioca starch or wheat starch, pregelatinized starch, sodium starch glycolate, hydroxypropyl starch, microcrystalline cellulose, sodium and/or calcium salts of carboxymethylcellulose, cross-linked carboxymethylcellulose (e.g. sodium croscarmellose and/or calcium croscarmellose), potassium polacrilin, hydroxypropylcellulose, in particular low-substituted hydroxypropylcellulose, sodium and/or calcium alginate, sodium docusate, methylcellulose, agar, guar gum, chitosan, alginic acid and mixtures thereof. Preferably, one or more extragranular excipients may comprise a disintegrant which may be selected from cross-linked carboxymethylcellulose, in particular croscarmellose sodium and/or croscarmellose calcium, and mixtures thereof. More preferably, the apixaban-containing granules comprise croscarmellose sodium.

The pharmaceutical composition comprising one or more granules containing apixaban may be a pharmaceutical composition in which each of the granules containing apixaban comprises apixaban in an amount of from 0.7 to 30 wt.%, preferably from 1 to 15 wt.%, more preferably from 1.5 to 9 wt.%, even more preferably from 2 to 5 wt.%, based on the total weight of the one or more granules containing apixaban (wherein the apixaban is optionally or comprises crystalline apixaban), hydroxyethylcellulose in an amount of from 0.5 to 30 wt.%, preferably from 1 to 15 wt.%, more preferably from 1.5 to 9 wt.%, even more preferably from 2 to 5 wt.%, based on the total weight of the one or more granules containing apixaban, optionally a diluent in an amount of from 50 to 99 wt.%, preferably from 70 to 97 wt.%, more preferably from 85 to 95% by weight of the total weight of one or more granules containing apixaban, optionally a disintegrant in an amount of 0.5 to 10% by weight, preferably 1 to 8% by weight, more preferably 1.5 to 6% by weight, even more preferably 2 to 4% by weight, of the total weight of the one or more granules containing apixaban, optionally a surfactant in an amount of 0.1 to 5% by weight, preferably 0.5 to 2% by weight, more preferably 0.7 to 1.8% by weight of the total weight of the one or more granules containing apixaban, and optionally one or more additional excipients.

The total amount of the components of each of the apixaban-containing granules of the present invention may be 100%.

In particular, the pharmaceutical composition comprising one or more granules containing apixaban may be a pharmaceutical composition in which each of the granules containing apixaban comprises apixaban in an amount of from 0.7 to 30% by weight, preferably from 1 to 15% by weight, more preferably from 1.5 to 9% by weight, even more preferably from 2 to 5% by weight, based on the total weight of the one or more granules containing apixaban (wherein the apixaban is optionally or comprises crystalline apixaban), hydroxyethylcellulose in an amount of from 0.5 to 30% by weight, preferably from 1 to 15% by weight, more preferably from 1.5 to 9% by weight, even more preferably from 2 to 5% by weight, based on the total weight of the one or more granules containing apixaban, a diluent in an amount of from 50 to 99% by weight, preferably from 70 to 97% by weight, more preferably from 85 to 95% by weight of the total weight of one or more granules containing apixaban, optionally a disintegrant in an amount of from 0.5 to 10% by weight, preferably from 1 to 8% by weight, more preferably from 1.5 to 6% by weight, even more preferably from 2 to 4% by weight of the total weight of the one or more granules containing apixaban, optionally a surfactant in an amount of from 0.1 to 5% by weight, preferably from 0.5 to 2% by weight, more preferably from 0.7 to 1.8% by weight of the total weight of the one or more granules containing apixaban, and optionally one or more additional excipients.

The total amount of the components of each of the apixaban-containing granules of the present invention may be 100%.

- 12 047590

Furthermore, in particular, the pharmaceutical composition comprising one or more granules containing apixaban may be a pharmaceutical composition in which each of the granules containing apixaban contains apixaban in an amount of 0.7 to 30% by weight, preferably 1 to 15% by weight, more preferably 1.5 to 9% by weight, even more preferably 2 to 5% by weight, based on the total weight of the one or more granules containing apixaban (wherein the apixaban is optionally or comprises crystalline apixaban), hydroxyethylcellulose in an amount of 0.5 to 30% by weight, preferably 1 to 15% by weight, more preferably 1.5 to 9% by weight, even more preferably 2 to 5% by weight, based on the total weight of the one or more granules containing apixaban, a diluent in an amount of 50 to 99% by weight, preferably 70 to 97% by weight, more preferably 85 up to 95% by weight of the total weight of one or more granules containing apixaban, optionally a disintegrant in an amount of from 0.5 to 10% by weight, preferably from 1 to 8% by weight, more preferably from 1.5 to 6% by weight, even more preferably from 2 to 4% by weight of the total weight of the one or more granules containing apixaban, a surfactant in an amount of from 0.1 to 5% by weight, preferably from 0.5 to 2% by weight, more preferably from 0.7 to 1.8% by weight, of the total weight of the one or more granules containing apixaban, and optionally one or more additional excipients.

The total amount of the components of each of the apixaban-containing granules of the present invention may be 100%.

The pharmaceutical composition comprising one or more granules containing apixaban may be a pharmaceutical composition in which each of the granules containing apixaban comprises or consists of apixaban in an amount of from 0.7 to 30 wt.%, preferably from 1 to 15 wt.%, more preferably from 1.5 to 9 wt.%, even more preferably from 2 to 5 wt.%, based on the total weight of the one or more granules containing apixaban, hydroxyethylcellulose in an amount of from 0.5 to 30 wt.%, preferably from 1 to 15 wt.%, more preferably from 1.5 to 9 wt.%, even more preferably from 2 to 5 wt.%, based on the total weight of the one or more granules containing apixaban, lactose, in particular lactose monohydrate, in an amount of from 25 to 60 wt.%, preferably from 38 to 55 wt.%, more preferably from 44 to 51 wt.%, based on the total weight of the one or more granules containing apixaban, the total weight of the one or more granules containing apixaban, microcrystalline cellulose in an amount of from 25 to 55% by weight, preferably from 38 to 49% by weight, more preferably from 40 to 48% by weight of the total weight of the one or more granules containing apixaban, croscarmellose sodium in an amount of from 0.5 to 10% by weight, preferably from 1 to 8% by weight, more preferably from 1.5 to 6% by weight, even more preferably from 2 to 4% by weight of the total weight of the one or more granules containing apixaban, sodium lauryl sulfate in an amount of from 0.1 to 5% by weight, preferably from 0.5 to 2% by weight, more preferably from 0.7 to 1.8% by weight of the total weight of the one or more granules containing apixaban, and optionally one or more additional excipients.

The total amount of the components of each of the apixaban-containing granules of the present invention may be 100%.

A pharmaceutical composition comprising one or more granules containing apixaban may comprise one or more granules containing apixaban (wherein the one or more granules containing apixaban are apixaban-containing granules containing HEC, in particular as disclosed herein), in an amount of from 30 to 99% by weight, preferably in an amount of from 70 to 98% by weight, more preferably in an amount of from 85 to 97% by weight, in particular in an amount of from 90 to 95% by weight based on the total weight of the pharmaceutical composition, and one or more extragranular excipients, wherein the total weight of the extragranular excipients is from 1 to 70% by weight, preferably from 2 to 30% by weight, more preferably from 3 to 15% by weight, in particular from 5 to 10% by weight based on the total weight of the pharmaceutical composition.

The total amount of components of the composition of the present invention may be 100%.

In particular, the pharmaceutical composition comprising one or more granules containing apixaban may be a pharmaceutical composition comprising apixaban in an amount of 0.7 to 28% by weight, preferably 1 to 15% by weight, more preferably 1.5 to 9% by weight, even more preferably 2 to 5% by weight, (wherein the apixaban is optionally or comprises crystalline apixaban), hydroxyethylcellulose in an amount of 0.5 to 30% by weight, preferably 1 to 15% by weight, more

- 13 047590 preferably from 1.5 to 9 wt.%, even more preferably from 2 to 5 wt.%, a diluent in an amount of from 48 to 98 wt.%, preferably from 70 to 97 wt.%, more preferably from 85 to 95 wt.%, optionally a disintegrant in an amount of from 1 to 20 wt.%, preferably from 1.5 to 16 wt.%, more preferably from 2 to 12 wt.%, even more preferably from 3 to 8 wt.%, optionally a surfactant in an amount of from 0.1 to 5 wt.%, preferably from 0.5 to 2 wt.%, more preferably from 0.7 to 1.8 wt.%, each component - from the total weight of the pharmaceutical composition and optionally one or more additional excipients.

The total amount of components of the pharmaceutical composition of the present invention can be 100%.

The pharmaceutical composition comprising one or more granules containing apixaban may be a pharmaceutical composition comprising apixaban in an amount of 0.7 to 28% by weight, preferably 1 to 15% by weight, more preferably 1.5 to 9% by weight, even more preferably 2 to 5% by weight, hydroxyethylcellulose in an amount of 0.5 to 28% by weight, preferably 1 to 15% by weight, more preferably 1.5 to 9% by weight, even more preferably 2 to 5% by weight, lactose, in particular lactose monohydrate, in an amount of 23 to 56% by weight, preferably 38 to 55% by weight, more preferably 44 to 51% by weight, microcrystalline cellulose in an amount of 23 to 52% by weight, preferably 38 to 49% by weight, more preferably 40 to 48 wt.%, sodium croscarmellose in an amount of 1 to 20 wt.%, preferably 1.5 to 16 wt.%, more preferably 2 to 12 wt.%, even more preferably 3 to 8 wt.%, sodium lauryl sulfate in an amount of 0.1 to 5 wt.%, preferably 0.5 to 2 wt.%, more preferably 0.7 to 1.8 wt.%, each component - from the total weight of the pharmaceutical composition, optionally magnesium stearate and optionally one or more additional excipients.

The total amount of components of the composition of the present invention may be 100%.

According to another aspect, a method for producing a pharmaceutical composition containing apixaban, in particular a pharmaceutical composition containing one or more granules containing apixaban, is provided, wherein said method comprises:

(i) obtaining a granulate containing apixaban and hydroxyethylcellulose, preferably by wet granulation;

(ii) optionally drying the granulate obtained in step (i), (iii) optionally sieving and/or milling the granulate obtained in step (i) or the optionally dried granules obtained in step (ii), (iv) optionally combining the granulate obtained in step (i) or the optionally dried granules obtained in step (ii) or the optionally sieved and/or milled granules obtained in optional step (iii) with at least one auxiliary substance to obtain a compaction mixture;

(v) optionally compressing the pressing mixture to obtain a compressed product, in particular a tablet; and (vi) optionally coating the compressed product;

optionally, the pharmaceutical composition containing apixaban, in particular the pharmaceutical composition containing one or more granules containing apixaban, may be a pharmaceutical composition for oral use. Optionally, the apixaban used for the manufacture of the granulate is or contains crystalline apixaban.

In particular, step i) of the method for producing a pharmaceutical composition containing apixaban may be:

i) obtaining a granulate containing apixaban and hydroxyethylcellulose by subjecting a mixture containing apixaban and hydroxyethylcellulose to wet granulation in the presence of a granulating liquid containing a solvent, wherein the solvent is or contains water.

In addition, step (i) of obtaining a granulate containing apixaban may include:

(I) preparing a mixture containing apixaban, hydroxyethylcellulose and optionally one or more additional excipients;

(II) granulating the mixture obtained in step (I) in the presence of a granulating liquid containing a solvent, wherein the solvent is preferably or comprises water.

Granulating a mixture containing apixaban, hydroxyethylcellulose and optionally one or more additional excipients in the presence of a granulating liquid may in particular comprise contacting said mixture containing apixaban, hydroxyethylcellulose and optionally one or more additional excipients.

- 14 047590 cellulose and optionally one or more additional excipients, with a granulating liquid, in particular spraying the granulating liquid onto and optionally into a mixture containing apixaban, hydroxyethylcellulose and optionally one or more additional excipients.

Step (i) of obtaining a granulate containing apixaban may be step (i) of obtaining a granulate comprising or consisting of:

a) apixaban, hydroxyethylcellulose and diluent, or

b) apixaban, hydroxyethylcellulose and disintegrant, or

c) apixaban, hydroxyethylcellulose and a surfactant, or

d) apixaban, hydroxyethylcellulose, diluent and disintegrant, or

e) apixaban, hydroxyethylcellulose, diluent and surfactant, or

f) apixaban, hydroxyethylcellulose, diluent, disintegrant and surfactant, preferably by wet granulation or melt granulation, in particular by wet granulation.

According to one embodiment, a method for producing a pharmaceutical composition containing apixaban, in particular a pharmaceutical composition containing one or more granules containing apixaban, may include:

(i) obtaining a granulate containing apixaban and hydroxyethylcellulose by wet granulation;

(ii) drying the granulate obtained in step (i), (iii) optionally sifting and/or grinding the dried granules obtained in step (ii), (iv) combining the dried granules obtained in step (ii) or the optionally sifted and/or ground granules obtained in optional step (iii) with at least one auxiliary substance to obtain a pressing mixture;

(v) compressing the pressing mixture to obtain a compressed product, in particular a tablet; and (vi) optionally coating the compressed product.

According to another aspect, the present invention provides a pharmaceutical composition comprising one or more granules containing apixaban as defined herein for use as a medicament.

According to another aspect, the pharmaceutical composition of the present invention can be used as a medicine, in particular can be used for the treatment or prevention of thromboembolic complications or disease, in particular venous thrombotic complications or disease.

Wet granulation technologies are known to the person skilled in the art; in particular, wet granulation may be a granulation comprising contacting the compound or mixture to be granulated (during and/or after granulation) with a granulating liquid, in particular with a granulating liquid containing water or consisting of water. Preferably, the granulating liquid contains water as a main component, where the main component is considered to be the component present in the granulating liquid in the largest mass quantity compared to the mass quantities of all components present in the granulating liquid.

In particular, a method for producing a pharmaceutical composition comprising granules comprising apixaban may include mixing apixaban with hydroxyethylcellulose, sodium lauryl sulfate and a diluent (e.g., lactose). The mixture may optionally be sieved through a sieve, for example, with a mesh size of 30#. The resulting mixture (e.g., apixaban triturate) may be mixed with a diluent (e.g., microcrystalline cellulose and lactose) to obtain a mixture for granulation.

The granulation mixture thus obtained can then optionally be dry-blended. Water can then be sprayed onto the granulation mixture (e.g. at a rate in the range of 40 to 200 g/min), preferably until sufficient agglomeration is achieved. After optional homogenization of the granulate, it can be dried (e.g. in a fluidized bed at an inlet air temperature of at least 30°C), e.g. until a loss on drying of less than 3% is achieved (e.g. at a temperature of 105°C for 5 min). The dried granulate can then be sieved. To prepare the tabletting mixture, the granulate is first mixed with a disintegrant, preferably sodium croscarmellose, then a lubricant, e.g. magnesium stearate, is added. Tableting can be carried out, for example, on a rotary tablet press. The tablet core may then be coated, for example using standard coating technology, until the desired weight gain is achieved.

The term intragranular may refer to an intragranular phase, such as granules, where apixaban is granulated with an excipient or mixture of excipients. The term

- 15 047590 extra-granular may refer to additives added to the granulate, which may be an excipient(s) containing apixaban or not containing apixaban, preferably not containing apixaban.

According to another embodiment, the pharmaceutical composition of the present invention may comprise apixaban having an average particle size of 0.1 to 200 μm, optionally 1 to 80 μm. The average particle size is determined by laser method using a Malvern Mastersizer.

The term average particle size, when used in this context, refers to the volume average diameter of the particles. The diameter and volume average diameter can be determined using laser light scattering, for example using a Malvern Matersizer. Particle sizes are determined by measuring the angular distribution of laser light scattered by a homogeneous suspension of particles. The particles to be sized are first suspended in a suitable non-polar dispersant and then sized using a Malvern Mastersizer.

A preferred pharmaceutical composition according to the present invention is a solid pharmaceutical composition. The composition can have a form selected from the group of tablets, granules, granulate, mini-tablets, microtablets, coated tablets, coated mini-tablets, coated microtablets, pills, powders, lozenges, sachets, soft and hard gelatin capsules, suppositories, etc., and mixtures thereof. Tablets, mini-tablets, microtablets, coated tablets, coated mini-tablets, coated microtablets, pills, granules, granulate, powders can be placed in sachets (one or more), capsules, such as soft or hard gelatin capsules. The pharmaceutical composition according to the present invention is preferably suitable for oral use. Thus, it is preferable that the pharmaceutical composition is a dosage form for oral use, such as a tablet or a coated tablet. The pharmaceutical composition may also be a tablet core, granules or granulate.

The pharmaceutical composition of the present invention is preferably formulated as a unit dosage form, each unit dosage form containing about 1 to 100 mg of apixaban, more preferably about 2 to 8 mg of apixaban, most preferably 2.5 or 5 mg. The term apixaban may refer to apixaban in crystalline form and in amorphous form. Apixaban may be selected from apixaban in crystalline form, preferably in form N-1 or form H2-2, and in amorphous form and mixtures thereof.

The pharmaceutical composition of the present invention may be a dosage form (especially a dosage form for oral use, optionally a solid dosage form for oral use), preferably a tablet, wherein the dosage form contains about 1 to 100 mg of apixaban, more preferably about 2 to 8 mg of apixaban, most preferably about 2.5 to 5 mg of apixaban.

In particular, the pharmaceutical composition of the present invention may be a dosage form (especially an oral dosage form, optionally a solid oral dosage form), preferably a tablet, wherein the dosage form comprises about 1 to 100 mg of apixaban, more preferably about 2 to 8 mg of apixaban, most preferably about 2.5 to 5 mg of apixaban, and about 1 to 100 mg of hydroxyethylcellulose, more preferably about 2 to 8 mg of hydroxyethylcellulose, most preferably about 2.5 to 5 mg of hydroxyethylcellulose.

In particular, the pharmaceutical composition of the present invention may be a dosage form (especially an oral dosage form, optionally a solid oral dosage form), preferably a tablet, wherein the oral dosage form comprises about 2 to 8 mg of apixaban, preferably about 2.5 to 5 mg of apixaban and about 2 to 8 mg of hydroxyethylcellulose, most preferably about 2.5 to 5 mg of hydroxyethylcellulose.

Form N-1 (pure) and form H2-2 (hydrate) of apixaban can be characterized by unit cell parameters essentially equivalent to those presented in the following Table A, published in patent document WO 2011/106478 A2:

- 16 047590

Table A

Form N-1 N2-2 Solvate Absent Dihydrate T +22 +22 a(A) 10,233(1) 6,193(1) Ь(А) 13,852(1) 30,523(1) s(A) 15,806(1) 13,046(1) a,° 90 90 β,° 92.98(1) 90.95 Υ,° 90 90 V(A ³ ) 2237.4(5) 2466,0(5) Z’ 1 1 Vm 559 617 SG R2Up R2Up □calculated. 1,364 1,335 R 0,05 0.09 Solvate sites Absent 2H ₂ O

Z' - number of molecules per asymmetric unit

T(°C) - temperature for crystallographic data

Vm = V(cell)/(ZZ')

In addition, patent documents WO 2011/106478 A2 and EP 2538925 B1 and Table B below provide the positions of the characteristic X-ray diffraction peaks (degrees 2Θ plus/minus 0.1) at room temperature based on the X-ray diffraction pattern (especially a high quality X-ray diffraction pattern) obtained on a CuKa diffractometer (with a rotating capillary with 2θ calibrated against the appropriate NIST (National Institute of Standards and Technology) standards) for Forms N-1 and H2-2, respectively. Thus, Form N-1 can be characterized by the X-ray diffraction pattern obtained on a CuKa diffractometer showing the positions of the characteristic X-ray diffraction peaks (degrees 2θ plus/minus 0.1) given in Table B below, and the H2-2 form can be characterized by an X-ray diffraction pattern obtained on a diffractometer (CuKa), showing the positions of the characteristic X-ray diffraction peaks (degrees 2Θ plus/minus 0.1) given in Table B below:

- 17 047590

12.9 20.2 18,5 23.5 27.1 25.2

According to another aspect, a pharmaceutical composition comprising apixaban is provided, wherein the pharmaceutical composition comprises or consists of an extrudate comprising apixaban, in particular an apixaban-containing hot melt extrudate, wherein the extrudate comprising apixaban comprises or consists of:

(I.) apixaban and (II.) a polymer component which is or comprises a polymer selected from a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, copovidone, polyvinyl alcohol) and mixtures thereof, and wherein the extrudate containing apixaban, in particular the hot melt extrudate containing apixaban, has a weight ratio between apixaban and the polymer component (apixaban:polymer component) of 1:4 or less, in particular of 1:6 or less, in particular in the range from 1:6 to 1:9, wherein optionally the extrudate containing apixaban, in particular the hot melt extrudate containing apixaban, can be obtained by a process comprising extrusion, in particular hot melt extrusion, carried out at a temperature of at least 190°C, in particular at a temperature in the range from 190 to 230°С.

In particular, an extrudate (especially a melt extrudate, in particular a hot melt extrudate) comprising or consisting of (i.) apixaban and (ii.) a polymer component which is or contains a polymer selected from a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, copovidone, polyvinyl alcohol) and mixtures thereof has advantageous properties, such as good solubility. Without wishing to be bound by theory, it is currently believed that the combination of apixaban, the polymer component which is or contains a polymer selected from a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, copovidone, polyvinyl alcohol and mixtures thereof, and the hot melt extrusion process promotes the formation of amorphous apixaban in the extrudate. In particular, forms of apixaban other than amorphous apixaban may be converted to amorphous apixaban during hot melt extrusion.

Furthermore, the extrudate containing apixaban, in addition to apixaban and a polymer component that is or contains a polymer selected from a graft copolymer of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol, copovidone, polyvinyl alcohol and mixtures thereof, may optionally contain one or more additional excipients. The extrudate containing apixaban, in addition to apixaban and a polymer component as defined above, may optionally contain one or more additional excipients, such as 1 or 2, or 3, or 4, or 5 additional excipients selected from the group of diluents, binders, disintegrants, lubricants, glidants, surfactants and anti-sticking agents.

In addition, the granule containing apixaban, in addition to apixaban and the polymer component, may optionally contain one or more additional excipients. The granule (or granulate) containing apixaban and the polymer component, as intragranular excipients, may optionally contain one or more additional excipients, such as 1 or 2, or 3, or 4, or 5 additional excipients selected from the group of diluents, binders, disintegrants, lubricants, glidants, surfactants and anti-adhesive agents.

In particular, the granule (or granulate) comprising apixaban and a polymer component may comprise, as one or more optionally present intragranular excipients, a diluent, for example a diluent which is or contains a diluent selected from the group consisting of lactose, in particular lactose monohydrate, cellulose, in particular microcrystalline cellulose, and mixtures thereof), a disintegrant, for example sodium croscarmellose, optionally a lubricant, optionally a surfactant and optionally one or more further excipients.

The pharmaceutical composition comprising apixaban and a polymer component may also optionally contain one or more additional excipients, such as 1 or 2, or 3, or 4, or 5 additional excipients selected from the group of diluents, binders, disintegrants, lubricants, glidants, surfactants,

- 18 047590 active substances and anti-caking agents as one or more extragranular auxiliary substances. In particular, a pharmaceutical composition comprising apixaban and a polymer component may optionally contain as extragranular auxiliary substances a diluent, for example a diluent that is or contains a diluent selected from the group consisting of lactose, in particular anhydrous lactose, cellulose, in particular microcrystalline cellulose, colloidal silicon dioxide and mixtures thereof, a disintegrant, for example sodium croscarmellose, optionally a lubricant, optionally a surfactant and optionally one or more further auxiliary substances.

In particular, the said polymer component may be a graft copolymer of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol.

The polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCA-PVAPEG) may be a polymer comprising at least one caprolactam block, at least one polyvinyl acetate block, and at least one polyethylene glycol block, wherein at least one block is branched from another type of block. For example, some PCA-PVA-PEG copolymers may be represented by the following structure:

In the above structure, p may be from about 10 to 10000, from about 100 to 900, from about 100 to 500, or from about 500 to 900.

In the above structure, q may be approximately 20 to 20,000, approximately 150 to 1,500, approximately 200 to 800, or approximately 800 to 1,500.

In the above structure, r may be approximately 30 to 30,000, approximately 300 to 3,000, approximately 300 to 1,000, approximately 1,000 to 2,000, or approximately 2,000 to 3,000.

In particular, the PCA-PVA-PEG copolymer may have an average molecular weight (in particular, a weight average molecular weight) of about 1,000 to 5,000,000 g/mol, about 10,000 to 500,000 g/mol, or about 90,000 to 140,000 g/mol. Methods for determining the average molecular weight are known in the art; for example, the average molecular weight can be determined using gel permeation chromatography.

For example, the PCA-PVA-PEG copolymer may be a polymer with CAS No. 402932-23-4. In particular, the PCA-PVA-PEG copolymer may be SOLUPLUS®, available from BASF.

In particular, the said polymer component may be copovidone.

Copovidone is a commercially available component known to those skilled in the art. Copovidone may be a synthetic linear random copolymer of N-vinyl-2-pyrrolidone (VP) and vinyl acetate (VA), wherein in particular the VA content may nominally be 40% (but may vary, for example, in the range from 35 to 41%). In particular, copovidone may be a copolymer of 1-ethenylpyrrolidin-2-one and ethenyl acetate, for example in a weight ratio of 3:2. In particular, copovidone may be a copovidone as defined in the European Pharmacopoeia, for example in the European Pharmacopoeia 6.0.

In particular, said polymer component may be poly(vinyl alcohol) (PVA). Poly(vinyl alcohol) (PVA) may be a synthetic polymer obtained by polymerizing vinyl acetate followed by partial hydrolysis of the resulting esterified polymer.

In particular, the polyvinyl alcohol may be polyvinyl alcohol as defined in the European Pharmacopoeia (in particular reference may be made to the chapter of the European Pharmacopoeia entitled Poly(vinyl alcohol); the European Pharmacopoeia may in particular be the European Pharmacopoeia in the version in force from 15.11.2018). PVA may have an ester number (e.g. as defined in the European Pharmacopoeia) characterising the degree of hydrolysis not exceeding 280. PVA may have an average relative molecular weight of from 20,000 to 150,000 (e.g. as defined in the European Pharmacopoeia). PVA may have the following formula:

- 19 047590

In particular, the indices m and n can be chosen such that m and n satisfy the inequality:

less than or equal to n/m less than or equal to 0.35.

Polyvinyl alcohol (PVA) may be extrudable, in particular melt extrudable, in particular may be hot melt extrudable PVA. Polyvinyl alcohol may be extrudable powdered polyvinyl alcohol (PVA). Polyvinyl alcohol may be powdered polyvinyl alcohol obtained by grinding, in particular cryo-milling, of polyvinyl alcohol.

The PVA may be a polymer having both a glass transition temperature and a melting temperature. The PVA may be a polymer having a melting temperature of 170°C or lower. The PVA may preferably be PVA 4-88. The PVA is commercially available and sold, for example, as Parteck® MXP by Merck KGaA.

In particular, the weight ratio of apixaban:polymer component may be 1:6 or less, preferably 1:9 or less, such as 1:7 or less, in particular in the range from 1:6 to 1:11, such as from 1:7 to 1:11, also in particular in the range from 1:6 to 1:9.

In particular, hot melt extrusion can be carried out at a temperature of at least 190°C.

In particular, the hot melt extrusion can be carried out at a temperature of at least 190°C, wherein the weight ratio of apixaban:polymer component can be 1:9 or less, in particular be in the range of 1:9 to 1:11.

Advantageously, the hot melt extrusion can be carried out at a temperature of at least 210°C, wherein the weight ratio of apixaban:polymer component is 1:6 or less, preferably 1:9 or less, such as 1:7 or less, in particular in the range from 1:6 to 1:11, such as from 1:7 to 1:11, also in particular in the range from 1:6 to 1:9.

Each of said granules (optionally containing a polymer component) may comprise an amorphous form of apixaban, optionally a mixture comprising an amorphous form of apixaban and form N-1 of apixaban. In addition, each of the apixaban-containing granules containing a polymer component may be obtained by a process comprising or consisting of hot melt extrusion.

According to one embodiment, the apixaban-containing extrudate may comprise or consist of (i.) apixaban and (ii.) a polymer component which is or comprises polyvinyl alcohol), wherein the apixaban-containing extrudate has a weight ratio of apixaban to polyvinyl alcohol (apixaban:polyvinyl alcohol) of 1:4 or less, in particular 1:6 or less, also in particular in the range of 1:4 to 1:9, also in particular in the range of 1:6 to 1:7, in particular about 1:6, where optionally the apixaban-containing extrudate may be obtained by a process comprising hot melt extrusion carried out at a temperature of at least 190°C, in particular at a temperature in the range of 200 to 220°C, in particular about 210°C.

Optionally, the extrudate containing apixaban may be present in a mixture (especially a compressed mixture, such as a tablet) containing one or more additional excipients, such as 1 or 2, or 3, or 4, or 5 additional excipients selected from the group of diluents, binders, disintegrants, lubricants, glidants, surfactants and anti-sticking agents.

According to one embodiment, the pharmaceutical composition may be or comprise a mixture (especially a compressed mixture, such as a tablet) comprising (A.) an extrudate comprising apixaban, especially a hot melt extrudate comprising apixaban (especially as disclosed herein), and (B.) one or more further components of the mixture. Such one or more further components of the mixture may be or comprise one or more further excipients, such as 1 or 2, or 3, or 4, or 5 further excipients selected from the group of diluents, binders, disintegrants, lubricants, glidants, surfactants and anti-sticking agents. In particular, (B.) one or more additional components of the mixture may comprise a diluent, for example a diluent which is or contains a diluent selected from the group consisting of lactose, in particular anhydrous lactose, cellulose, in particular microcrystalline cellulose and mixtures thereof, a disintegrant, in particular croscarmellose sodium, optionally a lubricant, in particular magnesium stearate and optionally one or more additional excipients. Optionally, said pharmaceutical composition, in particular a compressed mixture, for example a tablet, may be coated with a tablet coating.

According to one embodiment, the extrudate comprising apixaban may comprise or consist of (I.) apixaban and (II.) a polymer component comprising or consisting of

- 20 047590 a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCA-PVA-PEG), wherein the extrudate containing apixaban has a weight ratio between apixaban and the PCA-PVA-PEG copolymer (apixaban:PCA-PVA-PEG) of 1:4 or less, in particular 1:6 or less, also in particular in the range from 1:6 to 1:9, also in particular in the range from 1:6 to 1:7, in particular about 1:6, where optionally the extrudate containing apixaban can be obtained by a process comprising hot melt extrusion carried out at a temperature in the range from 222 to 232°C, in particular at a temperature in the range from 227 to 231°C, in particular about 230°C.

According to one embodiment, the apixaban-containing extrudate may comprise or consist of (I.) apixaban and (II.) a polymer component which is or contains copovidone, wherein the apixaban-containing extrudate has a weight ratio of apixaban to copovidone (apixaban:copovidone) of 1:4 or less, in particular 1:6 or less, also in particular in the range of 1:6 to 1:9, also in particular in the range of 1:5.5 to 1:7, in particular about 1.6, wherein optionally the apixaban-containing extrudate may be obtained by a process comprising hot melt extrusion carried out at a temperature in the range of 200 to 210°C.

According to one embodiment, the extrudate comprising apixaban may comprise or consist of (I.) apixaban and (II.) a polymer component comprising or containing copovidone, wherein the extrudate comprising apixaban has a weight ratio of apixaban to copovidone (apixaban:copovidone) of 1:9 or less, in particular in the range of 1:9 to 1:11, in particular in the range of 1:9 to 1:10, wherein optionally the extrudate comprising apixaban may be obtained by a process comprising hot melt extrusion carried out at a temperature of at least 190°C, preferably in the range of 190 to 210°C.

Optionally, the extrudate containing apixaban or one or more granules containing apixaban may contain apixaban in amorphous form, preferably containing at least 80 wt.%, in particular at least 95 wt.%, in particular at least 99 wt.% of apixaban in amorphous form.

The said pharmaceutical composition may be, for example, a compress, in particular a tablet, or may be placed in capsules or sachets, for example in the form of a powder.

The pharmaceutical composition (in particular a composition comprising a polymer component, in particular a composition comprising an extrudate comprising apixaban) may comprise: one or more apixaban-containing granules (comprising a polymer component, in particular one or more apixaban-containing granules comprising or consisting of an apixaban-containing extrudate comprising a polymer component, in particular as disclosed herein), optionally in an amount of from 30 to 99% by weight, preferably in an amount of from 70 to 98% by weight, more preferably in an amount of from 85 to 97% by weight, in particular in an amount of from 90 to 97% by weight, based on the total weight of the pharmaceutical composition, and one or more extragranular excipients, wherein the total weight of the extragranular excipients is optionally from 1 to 70% by weight, preferably from 2 to 30% by weight, more preferably from 3 to 15% by weight, in particular from 3 to 10% by weight of the total weight of the pharmaceutical composition. Said one or more extragranular excipients may, in particular, include a disintegrant (e.g. sodium croscarmellose) and, optionally, one or more additional excipients.

Moreover, according to one embodiment, the composition containing the extrudate containing apixaban does not require additional granulation.

According to another aspect, a method is provided for producing an extrudate containing apixaban and optionally producing a granulate or compressate, wherein the extrudate containing apixaban comprises or consists of (I) apixaban and (II) a polymer component which is or contains a polymer selected from a graft copolymer of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol, copovidone, polyvinyl alcohol and mixtures thereof, wherein the method comprises:

(A) preparing a mixture comprising (I) apixaban and (II) a polymer component which is or comprises a polymer selected from a polyvinylcaprolactam-polyvinyl acetate-polyethyleneglycol graft copolymer, copovidone, polyvinyl alcohol and mixtures thereof, wherein apixaban and the polymer component are optionally present in said mixture in a weight ratio of apixaban:polymer component of 1:4 or less, in particular of 1:6 or less, in particular in the range from 1:6 to 1:9;

(B) subjecting the mixture obtained in step (A) to extrusion, in particular hot melt extrusion, wherein the hot melt extrusion is optionally carried out at a temperature of at least 190°C, also optionally at a temperature in the range from 190 to 230°C;

(C) optionally milling the apixaban-containing extrudate obtained in step (B) to obtain a milled apixaban-containing extrudate;

- 21 047590 (D) optionally converting the extrudate containing apixaban obtained in step (B) or the milled extrudate containing apixaban obtained in step (C) to form a granulate;

(E) optionally mixing the apixaban-containing extrudate obtained in step (B) or the milled apixaban-containing extrudate obtained in step (C) or the granulate obtained in step (D) with at least one excipient to obtain a compaction mixture;

(F) optionally compressing the pressing mixture to obtain a compressed product, in particular a tablet; and (G) optionally coating the compressed product.

The step of converting the extrudate containing apixaban obtained in step (B) or the ground extrudate containing apixaban obtained in step (C) to obtain a granulate may be or include combining the extrudate containing apixaban obtained in step (B) or the ground extrudate containing apixaban obtained in step (C) with at least one auxiliary substance to obtain a mixture containing the extrudate, and pressing the mixture containing the extrudate to obtain a pressed mixture containing the extrudate, in particular a granulate, for example in the form of a tape. Optionally, the pressed mixture containing the extrudate, in particular a granulate, may be further ground.

The step of converting the extrudate containing apixaban obtained in step (B) or the ground extrudate containing apixaban obtained in step (C) to form a granulate may be or include combining the extrudate containing apixaban obtained in step (B) or the ground extrudate containing apixaban obtained in step (C) with at least one excipient to form a mixture containing the extrudate, and subjecting the mixture containing the extrudate to wet granulation, for example using a granulating liquid containing or consisting of a solvent selected from methanol, ethanol, propanol, water and mixtures thereof.

In the stage of grinding the extrudate or grinding the pressed mixture containing the extrudate, especially the granulate, conventional grinding or micronization methods can be used. For example, grinding can be milling or grinding and sieving. Grinding can be carried out, for example, with an air-jet mill, a hammer mill and a sieve mill, a fine impact mill, a ball mill or a vibratory mill or combinations thereof. Micronization can be carried out by known methods using an ultrasonic disintegrator, for example of the BRANSON Sonifier type, or by stirring the suspension with a high-speed mixer, for example a mixer of the HOMOREX type.

In pressing, impact compaction or roller compaction technology can be used. Rolling can be a preferred method for dry granulation. Rolling technology is known in the art. In rolling, two rollers are (essentially) used, which roll towards each other. A hydraulic plunger presses one of the rollers against the other, creating a compaction force with respect to the crushed particles fed into the roller press via a screw conveyor system. A compaction force of at least 10 kN can be used. The compressive material can be in the form of a belt, for example, in segments, depending on the surface of the rollers. The compressive material can be crushed and/or sieved to obtain granulate.

The apixaban present in the extrudate obtained in step (B) may consist of an amorphous form of apixaban or may contain at least 80 wt.%, preferably at least 95 wt.%, of an amorphous form of apixaban, based on the total weight of apixaban present in the extrudate.

The apixaban present in the extrudate obtained in step (C) may consist of an amorphous form of apixaban or may contain at least 80 wt.%, preferably at least 95 wt.%, of an amorphous form of apixaban, based on the total weight of apixaban present in the extrudate.

It has surprisingly been found that extrudates containing apixaban obtained by processes comprising hot melt extrusion as disclosed herein, in particular extrudates containing apixaban obtained by the method for producing an extrudate containing apixaban according to the present invention, provide very good solubility.

According to one embodiment of the method for producing an extrudate containing apixaban, the polymer component may be a graft copolymer of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol. According to one embodiment, the polymer component is copovidone. According to one embodiment, the polymer component is poly(vinyl alcohol).

The mixture comprising apixaban and a polymer component may be a mixture having a weight ratio of apixaban:polymer component of 1:4 or less, 1:6 or less, preferably 1:9 or less, in particular in the range of 1:6 to 1:11, such as in the range of 1:7 to 1:11, also in particular in the range of 1:6 to 1:9.

In the method for producing an extrudate containing apixaban, hot melt extrusion can be performed

- 22 047590 to be carried out at a temperature of at least 190°C, wherein the weight ratio of apixaban:polymer component may be 1:9 or less, in particular may be in the range from 1:9 to 1:11.

In particular, the hot melt extrusion can be carried out at a temperature of at least 210°C, wherein the weight ratio of apixaban:polymer component can be 1:6 or less, such as 1:7 or less, preferably 1:9 or less, in particular can be in the range of 1:6 to 1:11, such as in the range of 1:7 to 1:11, also in particular in the range of 1:6 to 1:9.

The starting material may be apixaban in any form; for example, apixaban that is or contains form N-1 of apixaban (or apixaban that is or contains an amorphous form and optionally form N-1) may be used to prepare the mixture in step (A).

Hot melt extrusion to obtain an extrudate containing apixaban may be carried out at a temperature of at least 190°C, such as at a temperature in the range of 190 to 230°C, optionally at a temperature in the range of 200 to 228°C, also optionally in the range of 190 to 228°C.

Furthermore, an extrudate containing apixaban is provided (and optionally a comprimate or granulate containing an extrudate containing apixaban), which can be obtained by the method for producing an extrudate containing apixaban or the method for producing a comprimate or granulate containing apixaban disclosed herein, in particular by a method such as defined in the appended claims.

The pharmaceutical compositions of the present invention, especially the pharmaceutical compositions of the present invention which are solid dosage forms such as, for example, tablets, may optionally be coated with a water-soluble film coating having an average thickness of at least 1 μm, measured by scanning electron microscopy (SEM) of a cross-section of the coated solid dosage form. The optional film coating may comprise a water-soluble polymer selected from cellulose ethers such as hydroxypropyl methylcellulose (hypromellose), having a viscosity of a 2 wt.% aqueous solution at 20°C of less than 60 mPa-s, preferably less than 40 mPa-s and most preferably less than 20 mPa-s. Other polymers that can be used for coating are selected from polyvinyl alcohol, povidone, sodium carboxymethylcellulose, waxy substances, acrylic polymers, block polymer of polyvinyl alcohol and polyethyleneglycol, commercially available under the trade names Kollicoat® IR and Kollicoat® Protect. Optionally, other auxiliary substances selected from lubricants, anti-adhesive agents, pigments, dyes and/or plasticizers can be used.

Typical cellulose ethers used in film coatings (which may be used to coat the pharmaceutical compositions of the present invention) are hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose and methylcellulose. Acrylic polymers include a group of synthetic polymers with various functional groups. Some of them can be further modified to improve swelling and permeability by including materials such as water-soluble cellulose ethers and starches, which allows for complete destruction/dissolution of the film.

Commonly used plasticizers (which can be used to coat the pharmaceutical compositions of the present invention) can be divided into three groups: polyhydric alcohols (glycerol, propylene glycol, macrogols), organic esters (phthalic acid esters, dibutyl sebacate, citric acid esters, triacetin), oils/glycerides (castor oil, acetylated monoglycerides, fractionated coconut oil).

Commonly used lubricants and/or anti-caking agents (which can be used to coat the pharmaceutical compositions of the present invention) can be selected from the group of metal salts of fatty acids containing from 12 to 20 carbon atoms, such as magnesium stearate, calcium stearate, aluminum stearate or zinc stearate, magnesium palmitate and magnesium oleate, fatty acids containing from 12 to 20 carbon atoms, such as stearic acid, palmitic acid and oleic acid, hydrogenated vegetable oil, hydrogenated castor oil, talc, honey wax or spermaceti, boric acid, sodium stearyl fumarate and mixtures thereof.

Dyes/opacity agents (which can be used to coat the pharmaceutical compositions of the present invention) can be divided into several groups: organic dyes and lakes based on them, inorganic dyes, natural dyes. Pigments can be selected from metal oxides, such as iron or titanium oxides.

Different materials from each group can be combined, in particular in certain proportions.

Film coating suspensions can be used in the form of ready-to-use compositions,

- 23 047590 commercially available. The film coating dispersion can be prepared using various solvents (water, alcohols, ketones, esters, chlorinated hydrocarbons), preferably water.

Particularly preferred is a coating suspension composition comprising (in terms of dry material):

from 1 to 99% by weight of polymer, preferably from 1 to 95% of polymer, from 1 to 50% by weight of plasticizer, preferably from 1 to 40% of plasticizer, from 0.1 to 20% by weight of lubricant, preferably from 1 to 10% of lubricant, from 0.1 to 20% by weight of colorant/opacifier and/or pigment, preferably from 0.1 to 10% of colorant/opacifier and/or pigment.

The coating layer composition of the pharmaceutical composition of the present invention preferably comprises at least one auxiliary substance selected from auxiliary substances having the function, as defined, of a polymer and a plasticizer. According to another embodiment of the present invention, the coating layer composition of the present invention preferably comprises at least one auxiliary substance selected from auxiliary substances having the function, as defined, of a polymer, a plasticizer, a lubricant and a colorant/opacifier.

Unless otherwise specified, all percentages (%) used in this context are percentages by weight (wt %). The excipients mentioned in this context, in particular the pH modifier, the polymer, may be pharmaceutically acceptable excipients. The term pharmaceutically acceptable when used in this context may, inter alia, indicate that the pharmaceutically acceptable compound or composition is suitable for administration to a subject to achieve treatment and/or prevention of a disease, disorder or condition without causing unduly deleterious side effects in light of the need for treatment. The term therapeutically effective amount when used in this context may, inter alia, mean an amount sufficient to reduce, arrest, stabilize, slow down and/or arrest the progression of the disease, disorder or condition.

According to one embodiment, the pharmaceutical composition of the present invention is a coated comprimate comprising a comprimate and a coating applied to the comprimate (e.g. a film-coated tablet comprising a tablet core and a coating applied to the tablet core), wherein the comprimate comprises one or more granules containing apixaban in an amount of from 30 to 99% by weight, preferably in an amount of from 70 to 98% by weight, more preferably in an amount of from 85 to 97% by weight, in particular in an amount of from 90 to 97% by weight based on the total weight of the pharmaceutical composition, and one or more extragranular excipients, wherein the total weight of the extragranular excipients is from 1 to 70% by weight, preferably from 2 to 30% by weight, more preferably from 3 to 15% by weight, in particular from 3 to 10% by weight based on the total weight of the pharmaceutical composition. According to one embodiment, the pharmaceutical composition of the present invention is a coated comprimate comprising a comprimate and a coating applied to the comprimate (e.g. a coated tablet comprising a tablet core and a coating applied to the tablet core), wherein the comprimate comprises one or more granules comprising apixaban, wherein the one or more granules comprising apixaban are granules comprising hydroxyethylcellulose (especially as disclosed herein) in an amount of from 30 to 99% by weight, preferably in an amount of from 70 to 98% by weight, more preferably in an amount of from 85 to 97% by weight, in particular in an amount of from 90 to 95% by weight, based on the total weight of the pharmaceutical composition, and one or more extragranular excipients, wherein the total weight of the extragranular excipients is from 1 to 70% by weight, preferably from 2 to 30% by weight, more preferably from 3 to 15% by weight, in particular from 5 to 10% by weight of the total weight of the pharmaceutical composition.

In particular, the composition of the present invention can be obtained by technological processes including wet granulation or melt granulation.

Wet granulation (in particular for the production of granules containing HEC) can be carried out with a granulating liquid containing water. Wet granulation can be carried out with a granulating liquid in the absence of organic solvents, in particular in the absence of alcohols. The granulating liquid (used for wet granulation) preferably contains water and may optionally be free of organic solvent or contain no more than 10% by weight, preferably no more than 5% by weight of organic solvent based on the total weight of the granulating liquid. In particular, the granulating liquid (used for wet granulation) may optionally be free of organic solvent or contain no more than 10% by weight, preferably no more than 5% by weight of organic solvent based on the total weight of the granulating liquid. In the context of the present application, the organic solvent may in particular be a compound containing a carbon atom, wherein this compound is liquid at a temperature of 20°C, in

- 24 047590 features at pressure of 101325 Pa.

In particular, the granulating liquid (especially for the production of granules containing HEC) containing water may not contain one or more components selected from the group R ^a -OH, R ^b OR ^c , R ^d -C(O)-OR ^e , hydrocarbons and mixtures thereof, where each of R ^a , R ^b , R ^c , R ^d , R ^e may be independently selected from alkyls, for example C1-C10 alkyls (such as, for example, methanol, ethanol, diethyl ether, ethyl acetate, etc.), dimethyl sulfoxide, dimethylformamide, or may contain no more than 10 wt.%, preferably no more than 5 wt.% of said one or more components selected from the group R ^a OH, R ^b -OR ^c , R ^d -C(O)-OR ^e , hydrocarbons, dimethyl sulfoxide, dimethylformamide and mixtures thereof, based on the total weight of the granulating liquid. In particular, the granulating liquid may consist of water or may contain at least 60 wt.%, optionally at least 70 wt.%, also optionally at least 75 wt.% of water based on the total weight of the granulating liquid.

Wet granulation with a granulating liquid may include contacting the mixture or compound being granulated with the granulating liquid, for example the contacting may be or include spraying the granulating liquid onto the mixture or compound being granulated.

One or more auxiliary substances selected from pH modifiers, diluents, binders, disintegrants, lubricants, glidants, anti-sticking agents may optionally be dissolved, suspended, emulsified or dispersed in a granulating liquid which is sprayed onto a mixture, in particular a powder mixture containing apixaban and at least one auxiliary substance or mixture of auxiliary substances.

According to one embodiment of the present invention, the granulation can be performed using a granulator(s) (especially a granulator(s) of the state of the art), such as a high shear granulator, a low shear granulator or a fluid bed granulator.

Mixing of apixaban and at least one excipient or mixture of excipients can be carried out in conventional devices used for mixing powder or powders, such as stationary (passive) mixers, fluidized bed mixers, diffusion mixers, biconical diffusion mixers, single or biconical mixers, tubular mixers, cubic mixers, planetary mixers, Y-mixers, V-mixers or high shear mixers. The same equipment can also be used to prepare the compaction mixture from a previous stage of obtaining granulate by wet granulation.

Conventional drying devices such as fluidized bed dryers or drying chambers can be used to dry the garnulate obtained by wet granulation.

Conventional equipment such as a Wurster coating system or conventional perforated or non-perforated coating drums designed for pharmaceutical applications can be used for film coating.

Any possible combination of apixaban and polymer inclusions can be used in the wet granulation process.

It is particularly preferred that the composition according to the present invention comprises a granulate (i.e. an intra-granular phase) and an extra-granular phase. The intra- and extra-granular phases together constitute a pressing mixture. The pressing mixture may comprise or consist of an intra-granular phase and an extra-granular phase.

According to one embodiment, it is advantageous that the granulate, which can be, for example, a granulate containing HEC or a granulate containing a polymer component, can be produced by wet granulation. It is particularly advantageous that the wet granulation is carried out in a fluidized bed granulator/fluidized bed dryer.

A pharmaceutical composition comprising or consisting of one or more granules containing apixaban, in particular a pharmaceutical composition consisting of one or more granules containing apixaban, may be placed in a capsule(s) or a sachet (one or more) or may be compressed into one or more comprimate(s), preferably into one or more tablets or microtablets, or may be prepared as one or more pellets, wherein the comprimate(s) or pellet(s) may optionally be coated and/or optionally placed in a capsule(s) or a sachet (one or more).

According to another aspect, there is provided a pharmaceutical composition comprising apixaban, wherein the pharmaceutical composition comprises one or more granules comprising apixaban, wherein each of the granules comprising apixaban comprises or consists of (i) apixaban and (ii) hydroxyethylcellulose, wherein the composition can be obtained by the method for producing a pharmaceutical composition disclosed herein, in particular by the method as defined in the appended claims.

The terms melt extrudate and melt extrudate and the terms ext

- 25 047590 hot melt data and hot melt extrudate may be used interchangeably in this context.

The melt extrusion may be, in particular, hot melt extrusion (HME). Melt extrusion, in particular HME, is a technique well known to the person skilled in the art. Hot melt extrusion involves conveying material at a temperature of preferably at least 110°C, in particular at least 190°C, in particular at least 210°C, through a nozzle. The melt extrusion (in particular HME) may be carried out in an extruder, which may comprise a casting device and a shaft ensuring the advancement of the extruded material through a heated section and an extruding device (e.g. an extruder head). The period of time during which the extruded material remains in the extruder may be, for example, less than 9 minutes, in particular from 6 to 8 minutes. In particular, the NME may comprise pumping the mixture subjected to the NME at an elevated temperature, in particular at least 190°C, in particular at least 210°C, through a heated chamber to form an extrudate. The extruder may consist of one or two rotating screws within a chamber (usually cylindrical in shape).

The granules may be granules of any shape, in particular particles of any shape, including, but not limited to, the form of granules obtained by wet granulation, dry granulation, melt granulation, in particular hot melt extrusion, optionally in combination with a grinding and/or screening operation.

The one or more granules containing apixaban may be, in particular, an apixaban-containing extrudate obtained in step (B) or a sieved and/or ground apixaban-containing extrudate obtained in step (C) of the process for producing an extrudate containing apixaban described in this context. The term milling, when used in this context, includes any operation leading to a reduction in the size of the starting material subjected to milling. According to one embodiment, the milling may be carried out in one or more milling devices; milling devices, in particular milling devices used in the pharmaceutical field, are known to the person skilled in the art.

The term pharmaceutical composition comprising includes, among other things, the meaning of a pharmaceutical composition consisting of.

The following examples illustrate the invention and are not intended to limit the scope of the invention in any way.

Description of examples of implementation of the invention

Example 1 and reference examples 1-4.

Method for producing pharmaceutical compositions according to example 1 and reference examples 1-4

The volume of laboratory tests was 5000 tablets.

Apixaban was mixed with hydroxyethylcellulose (or other binder according to Reference Examples 1-4 as shown in Table 1), sodium lauryl sulfate and part of the lactose. The mixture was sieved through a 30# sieve. The apixaban triturate was then mixed with microcrystalline cellulose and the remaining lactose.

The granulation mixture was placed in a 10 L high shear mixer where it was first dry mixed for 2 min. Water was then sprayed onto the mixture at a rate of 40 to 200 g/min until sufficient agglomeration was achieved. After homogenization for 1 min, the granulation was dried in a fluid bed at an inlet air temperature of at least 30°C until less than 3% loss on drying was achieved (105°C, 5 min). The dried granulation was then sieved through a 18# sieve.

In the preparation of the mixture for tableting, the granulate was first mixed with sodium croscarmellose and then magnesium stearate was added.

Tableting was performed on a rotary tablet press. The tablet cores were then coated using standard technology until the required weight gain was achieved.

Table 1 presents the ingredients used in the manufacture of pharmaceutical compositions according to Example 1 (containing hydroxyethylcellulose as a binder) and according to Reference Examples 1-4, respectively.

- 26 047590

Table 1

Phase Material Example R 1 Reference example 1 Reference example 2 Reference example 3 Reference example 4 Extragranular Intragranular Apixaban 5 mg 5 mg 5 mg 5 mg 5 mg Lactose monohydrate 200 mesh 95.5 mg 95.5 mg 95.5 mg 95.5 mg 95.5 mg Microcrystalline cellulose type 102 82 mg 82 mg 82 mg 82 mg 82 mg Croscarmellose sodium 4 mg 4 mg 4 mg 4 mg 4 mg Sodium Lauryl Sulfate 2 mg 2 mg 2 mg 2 mg 2 mg Hydroxyethylcellulose a (Natrosol 250 L) 5 mg / / / / Hydroxypropylcellulose ose (klucel If) / 5 mg / / / Polyvinylpyrrolidone K90 / / 5 mg / / Polyvinylpyrrolidone KZO / / / 5 mg / Hydroxypropyl methylcellulose (Pharmacoat 603) Croscarmellose sodium Magnesium stearate / 4 mg 2.5 mg / 4 mg 2.5 mg / 4 mg 2.5 mg / 4 mg 2.5 mg 5 mg 4 mg 2.5 mg Coverage Ready-to-use coating mixture based on HRMS 7.84 mg 7.84 mg 7.84 mg 7.84 mg 7.84 mg Iron oxide yellow 0.16 mg 0.16 mg 0.16 mg 0.16 mg 0.16 mg Total 208 mg 208 mg 208 mg 208 mg 208 mg

Examples 2-9.

Examples 2-9 below were prepared in the same manner as described above for Example 1.

Examples 2-9 show that the beneficial properties of the pharmaceutical composition remain essentially unchanged even when using hydroxyethyl cellulose in the form of various commercially available products (especially hydroxyethyl cellulose with different degrees of viscosity).

Phase K

go m

Table 2. Resistance to go

Material Example P2 Example RZ Example p4 Example p5 Example rb Example P7 Example p8 Example p9 Apixaban 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg Lactose monohydrate 200 mesh 95.5 mg / 95.5 mg 95.5 mg / / 95.5 mg 89.5 mg Isomalt / 100 mg / / 85 mg 98 mg / / Microcrystalline cellulose type 102 82 mg 78.5 mg 82 mg 79.5 mg 93 mg 75.5 mg 77 mg 82 mg Croscarmellose sodium 4 mg / 4 mg 4 mg 3.5 mg / 4 mg / Crospovidone / 3 mg / / / 5.5 mg / 5 mg

- 27 047590

Sodium Lauryl Sulfate 2 mg 2 mg 2 mg 2 mg 2 mg 2 mg 2 mg 2 mg Hydroxyethyl cellulose (Natrosol 250 L) 5 mg 5 mg / 7.5 mg / 7.5 mg 10 mg 10 mg Hydroxyethyl cellulose (Natrosol 250 G) / / 5 mg / 5 mg / / / Croscarmellose sodium 4 mg 4 mg 4 mg 4 mg 4.5 mg 4 mg 4 mg 4 mg Magnesium stearate 2.5 mg 2.5 mg 2.5 mg 2.5 mg 2.0 mg 2.5 mg 2.5 mg 2.5 mg “Opadry” white 7.84 mg 7.84 mg 7.84 mg 7.84 mg 7.84 mg 7.84 mg 7.84 mg 7.84 mg Iron oxide yellow 0.16 mg 0.16 mg 0.16 mg 0.16 mg 0.16 mg 0.16 mg 0.16 mg 0.16 mg Total 208 mg 208 mg 208 mg 208 mg 208 mg 208 mg 208 mg 208 mg

Example 10.

Dissolution rates of the composition according to Example 1 and the compositions according to Reference Examples 1-4.

Table 3 below shows the dissolution rates of the composition according to Example 1 and the compositions according to the reference examples presented in Table 1.

Table 3

Apixaban dissolved [%] Time [min] Example 1 Reference example 1 Reference example 2 Reference example 3 Reference example 4 0 0 0 0 0 0 5 47 17 15 27 13 10 62 42 37 49 37 15 70 57 48 57 53 20 75 64 56 64 60 30 82 72 65 72 69

The accompanying Fig. 1 illustrates the dissolution rates for Example 1 and Reference Examples 1-4, respectively, and shows the improved solubility of the present invention.

Table 4 below shows the dissolution rates for Examples 2, 4, 5 and 8 (for the composition shown in Table 2) and confirms the stability of the solubility characteristics even when using binder in different amounts and with different degrees of viscosity.

Table 4. Dissolution rates for examples 2, 4, 5 and 8 (according to Table 2), demonstrating the stability of solubility characteristics for different amounts and degrees of viscosity of the binder

Apixaban dissolved [%] Time [min] Example 2 Example 4 Example 5 Example 8 0 0 0 0 0 5 63 62 68 71 10 78 80 82 84 15 85 87 88 89 20 88 91 91 92 30 92 94 94 94

The accompanying Fig. 2 shows the dissolution rates for Examples 2, 4, 5 and 8, which show comparable dissolution for the examples according to the present invention regardless of the change in the amount and quality of the binder.

The dissolution test illustrated in the accompanying Figs. 1 and 2 was carried out in 900 ml of dissolution medium (50 mM sodium phosphate buffer pH 6.8 containing 0.05 wt.% SDS). The dissolution test was carried out for 30 min at a rotation speed of 75 rpm. The dissolution test was carried out at a temperature of the dissolution medium of 37°C plus/minus 0.5°C (especially 37°C). A USP II (paddle) apparatus was used to carry out the dissolution test.

- 28 047590

Example 11.

Method for producing hot melt extrudate

The volume of laboratory studies was 0.5 kg of extrudate.

In a suitable mixer, apixaban was mixed with the polymer at the test ratio. The mixture was extruded using a twin-screw extruder at the required temperature and feed rate. Standard screw configurations were used, with a rotation speed of 70-110 rpm. The hot melt extrudate was extruded through a 2 mm diameter extruder die, cooled on a cooling conveyor belt, and ground to a smaller size. The ground extrudate was then sieved and subjected to stability testing under controlled conditions at a temperature of 40 to 50 °C and a relative humidity (RH) of 75%.

Table 5

Examples Apixaban Copovidon Maximum set extrusion T [°C] Apixaban extrudate form Stability test Example 11-1 1:4 190 didn't determine / Example 11-2 1:6 190 didn't determine / Example 11-3 1:6 200 Pure amorphous form didn't determine Example 11-4 1:6 210 Pure amorphous form 37 d / 50°C-75% RH / Pure amorphous form Example 11-5 1:9 190 Pure amorphous form 1 m/ 40°С-75% RH / Pure amorphous form Example 11-6 1:9 210 Pure amorphous form 1 m/ 40°С-75% RH / Pure amorphous form Example Apixaban: PCA-PVAPEG (Soluplus®) Maximum set extrusion T [°C] Apixaban extrudate form Stability test Example 11-7 1:6 230 Pure amorphous form / did not determine Example Apixaban : Parteck Maximum installed Apixaban form in Testing on MHR Extrusion T [°C] extrudate stability Example 11-8 1:6 210 Pure amorphous form didn't determine

d - days, m - months

Examples 12-17. Method for producing pharmaceutical compositions according to examples 12 to 17

The volume of laboratory tests was 5000 tablets.

In preparing the tabletting mixture, the sieved extrudate (obtained in accordance with Example 7) was first mixed with sodium lauryl sulfate, anhydrous lactose, microcrystalline cellulose type 102 and sodium croscarmellose, and then magnesium stearate was added.

Tableting was performed on a rotary tablet press. The tablet cores were then coated using standard technology until the required weight gain was achieved.

Table 6 presents the ingredients used in the manufacture of pharmaceutical compositions in accordance with Examples 12-17.

- 29 047590

Table 6

Phase Material Example 12 Example 13 Example 14 Example 15 Example 16 Example 17 Intragranular Apixaban 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg Copovidone 20 mg / 30 mg / / 45 mg PCA-PVA-PEG (Soluplus®) / / / 30 mg / / Parteck MHR 20 mg 45 mg Extragranular Lactose anhydrous 90 mg 94 mg 84 mg 84 mg 76 mg 84 mg Microcrystalline cellulose type 102 72.5 mg 68.5 mg 68.5 mg 68.5 mg 61.5 mg 53.5 mg Croscarmellose sodium 8 mg 8 mg 8 mg 8 mg 8 mg 8 mg Sodium Lauryl Sulfate 2 mg 2 mg 2 mg 2 mg 2 mg 2 mg Magnesium stearate 2.5 mg 2.5 mg 2.5 mg 2.5 mg 2.5 mg 2,5 Coverage “Opadry” white 7.84 mg 7.84 mg 7.84 mg 7.84 mg 7.84 mg 7.84 mg Iron oxide yellow 0.16 mg 0.16 mg 0.16 mg 0.16 mg 0.16 mg 0.16 mg Total 208 mg 208 mg 208 mg 208 mg 208 mg 208 mg

Examples 18, 19. Method for obtaining pharmaceutical compositions in accordance with examples 18 and 19

The volume of laboratory tests was 5000 tablets.

The granulating liquid was prepared by dissolving hydroxypropyl cellulose in a sufficient amount of 96% ethanol.

A granulation mixture was prepared by mixing the sieved extrudate (prepared according to Example 7) with lactose monohydrate, microcrystalline cellulose type 101 and croscarmellose sodium. The granulation mixture was then placed in a 10 L high shear mixer where it was first dry mixed for 2 min. The granulation liquid was then sprayed onto the mixture until sufficient agglomeration was achieved. After mixing for 1 min, the granulation was dried in a fluid bed at an air inlet temperature of at least 30°C until less than 3% loss on drying was achieved (105°C, 5 min). The dried granulation was then sieved through a sieve with a mesh size of 18#.

In the preparation of the mixture for tableting, the granulate was first mixed with anhydrous lactose, sodium croscarmellose, microcrystalline cellulose type 102, sodium lauryl sulfate, and then magnesium stearate was added.

Tableting was performed on a rotary tablet press. The tablet cores were then coated using standard technology until the required weight gain was achieved.

Table 7 presents the ingredients used in the preparation of the pharmaceutical compositions in accordance with Examples 18 and 19, respectively.

- 30 047590

Table 7

Phase Material Example 18 Example 19 Intragranular Extrudate 35 mg 50 mg Lactose monohydrate 56 mg 45 mg Microcrystalline cellulose type 101 45.7 mg 42 mg Croscarmellose sodium 2.7 mg 4 mg Hydroxypropyl cellulose 7 mg 7 mg Ethanol 96% q.s. q.s. Extragranular Lactose anhydrous 21 mg 20 mg Microcrystalline cellulose type 102 22.8 mg 23.5 mg Croscarmellose sodium 5.3 mg 4 mg Sodium Lauryl Sulfate 2 mg 2 mg Magnesium stearate 2.5 mg 2.5 mg Coverage “Opadry” white 7.84 mg 7.84 mg Iron oxide yellow 0.16 mg 0.16 mg Total 208 mg 208 mg

q.s. - in sufficient quantity

Examples 20, 21. Method for obtaining pharmaceutical compositions in accordance with examples 20 and 21

The volume of laboratory tests was 5000 tablets.

In the preparation of the triturate, the sieved extrudate (obtained in accordance with Example 7) was first mixed with sodium lauryl sulfate and microcrystalline cellulose type 101. Mannitol, polyethylene glycol and macrogol were then added and the mixture was sieved through a sieve with a mesh size of 0.6 mm.

The granulation mixture was then placed in a 10L high shear mixer with temperature control. During mixing, the mixture was heated until sufficient agglomeration was achieved. The granulate was cooled on a tray and sieved through a 21C sieve.

In preparing the mixture for tableting, the granulate was first mixed with sodium croscarmellose and colloidal silicon dioxide, and then magnesium stearate was added.

Tableting was performed on a rotary tablet press. The tablet cores were then coated using standard technology until the required weight gain was achieved.

Table 8 presents the ingredients used in the preparation of the pharmaceutical compositions according to Examples 20 and 21, respectively.

Table 8

Phase Material Example 20 Example 21 Intragranular Extrudate 35 mg 50 mg Mannitol 115 mg 105 mg Microcrystalline cellulose type 101 20 mg 15 mg Polyethylene glycol 11.3 mg 11.3 mg Poloxamer 11.2 mg 11.2 mg Sodium Lauryl Sulfate 1 mg 1 mg Extragranular Croscarmellose sodium 5 mg 5 mg Colloidal silicon dioxide 1 mg 1 mg Sodium stearyl fumarate 0.5 mg 0.5 mg Coverage “Opadry” white 7.84 mg 7.84 mg Iron oxide yellow 0.16 mg 0.16 mg Total 208 mg 208 mg

-

Claims (10)

Examples 22, 23. Method for obtaining pharmaceutical compositions in accordance with examples 22 and 23 The volume of laboratory tests was 5000 tablets. The pressing mixture was prepared by mixing the sieved extrudate (obtained according to Example 7) with lactose monohydrate, microcrystalline cellulose type 802, sodium croscarmellose and sodium lauryl sulfate, followed by the addition of magnesium stearate. The pressing mixture was pressed on a roller press with a pressure sufficient to obtain tapes of the appropriate density. The tapes were then crushed through a sieve with a mesh size of 18#. In preparing the mixture for tableting, the granulate was first mixed with sodium croscarmellose and then magnesium stearate was added. Tableting was performed on a rotary tablet press. The tablet cores were then coated using standard technology until the required weight gain was achieved. Table 9 presents the ingredients used in the preparation of the pharmaceutical compositions according to Examples 22 and 23, respectively. Table 9 Phase Material Example 22 Example 23 k £ t Extrudate 35 mg 50 mg rigra ry Lactose monohydrate 84 mg 75 mg m Microcrystalline cellulose type 802 68.5 mg 62.5 mg Croscarmellose sodium 4 mg 4 mg Sodium Lauryl Sulfate 2 mg 2 mg Magnesium stearate 1 mg 1 mg Croscarmellose sodium 4 mg 4 mg Magnesium stearate 1.5 mg 1.5 mg f S n -O “Opadry” white 7.84 mg 7.84 mg Coated Iron oxide yellow 0.16 mg 0.16 mg Total 208 mg 208 mg CLAUSE OF THE INVENTION 1. A pharmaceutical composition comprising apixaban, wherein said pharmaceutical composition comprises or consists of one or more granules comprising apixaban, wherein each of said granules comprising apixaban comprises or consists of apixaban, hydroxyethylcellulose and a diluent, wherein each of said granules comprising apixaban has a weight ratio of apixaban:hydroxyethylcellulose in the range of 1:10 to 10:1 and wherein each of said granules comprising apixaban has a weight ratio of apixaban:diluent in the range of 1:10 to 1:60. 2. The pharmaceutical composition according to claim 1, wherein each of said granules containing apixaban has a weight ratio of apixaban:hydroxyethylcellulose in the range of 1:5 to 5:1, more preferably in the range of 1:2 to 2:1, in particular in the range of 1:1.6 to 1.6:1. 3. The pharmaceutical composition according to claim 1 or 2, wherein each of said granules containing apixaban is obtained by wet granulation in the presence of a granulating liquid containing water or consisting of water. 4. A pharmaceutical composition according to any one of claims 1 to 3, wherein each of said granules containing apixaban contains or consists of: a) apixaban, hydroxyethylcellulose, diluent and disintegrant, or b) apixaban, hydroxyethylcellulose, diluent and surfactant, or c) apixaban, hydroxyethylcellulose, diluent, disintegrant and surfactant. 5. A pharmaceutical composition according to any one of claims 1 to 4, wherein each of said granules containing apixaban contains or consists of apixaban, hydroxyethylcellulose and a diluent and has - 32 047590 a weight ratio of apixaban:diluent in the range of from 1:20 to 1:50, more preferably from 1:30 to 1:40, in particular from 1:34 to 1:38, or where the diluent is or contains a diluent selected from the group consisting of carbohydrates and derivatives thereof, sugar alcohols, celluloses, starch and derivatives thereof, magnesium aluminometasilicate, calcium salts of phosphoric acid, alkali metal carbonates, alkaline earth metal carbonates, alkali metal hydrogencarbonates, alkaline earth metal hydrogencarbonates and mixtures thereof, optionally where the diluent is or contains a diluent selected from the group consisting of lactose, cellulose and mixtures thereof, optionally where the diluent is a mixture comprising or consisting of lactose monohydrate and microcrystalline cellulose. 6. A pharmaceutical composition according to any one of claims 1 to 5, wherein the pharmaceutical composition is a pharmaceutical composition comprising: (A) one or more granules containing apixaban, wherein each of said granules containing apixaban comprises or consists of apixaban, hydroxyethylcellulose and a diluent, wherein each of said granules containing apixaban has a weight ratio of apixaban:hydroxyethylcellulose in the range of from 1:10 to 10:1, and wherein each of said granules containing apixaban has a weight ratio of apixaban:diluent in the range of from 1:10 to 1:60, and (B) one or more extragranular excipients, wherein preferably said one or more extragranular excipients comprise a disintegrant. 7. A pharmaceutical composition according to any one of claims 1 to 6, wherein said pharmaceutical composition is a comprimate, in particular a tablet. 8. The pharmaceutical composition according to any one of claims 1 to 7, wherein each of said apixaban-containing granules comprises apixaban in an amount of from 0.7 to 30 wt.%, preferably from 1 to 15 wt.%, more preferably from 1.5 to 9 wt.%, even more preferably from 2 to 5 wt.% of the total weight of the one or more apixaban-containing granules, hydroxyethylcellulose in an amount of from 0.5 to 30 wt.%, preferably from 1 to 15 wt.%, more preferably from 1.5 to 9 wt.%, even more preferably from 2 to 5 wt.% of the total weight of the one or more apixaban-containing granules, a diluent optionally in an amount of from 50 to 99 wt.%, preferably from 70 to 97 wt.%, more preferably from 85 to 95 wt.% of the total weight of the one or more apixaban-containing granules, optionally a disintegrant in an amount of from 0.5 to 10 wt.%, preferably from 1 to 8 wt.%, more preferably from 1.5 to 6 wt.%, even more preferably from 2 to 4 wt.% of the total weight of one or more granules containing apixaban, optionally a surfactant in an amount of from 0.1 to 5 wt.%, preferably from 0.5 to 2 wt.%, more preferably from 0.7 to 1.8 wt.% of the total weight of one or more granules containing apixaban, and optionally one or more additional excipients. 9. The pharmaceutical composition according to any one of claims 1 to 8, wherein each of said apixaban-containing granules comprises or consists of apixaban in an amount of from 0.7 to 30% by weight, preferably from 1 to 15% by weight, more preferably from 1.5 to 9% by weight, even more preferably from 2 to 5% by weight, based on the total weight of the one or more apixaban-containing granules, hydroxyethylcellulose in an amount of from 0.5 to 30% by weight, preferably from 1 to 15% by weight, more preferably from 1.5 to 9% by weight, even more preferably from 2 to 5% by weight, based on the total weight of the one or more apixaban-containing granules, lactose, in particular lactose monohydrate, in an amount of from 25 to 60% by weight, preferably from 38 to 55% by weight, more preferably from 44 to 51% by weight, based on the total weight of the one or more apixaban-containing granules apixaban, microcrystalline cellulose in an amount of from 25 to 55 wt.%, preferably from 38 to 49 wt.%, more preferably from 40 to 48 wt.%, based on the total weight of the one or more granules containing apixaban, croscarmellose sodium in an amount of from 0.5 to 10 wt.%, preferably from 1 to 8 wt.%, more preferably from 1.5 to 6 wt.%, even more preferably from 2 to 4 wt.%, based on the total weight of the one or more granules containing apixaban, sodium lauryl sulfate in an amount of from 0.1 to 5 wt.%, preferably from 0.5 to 2 wt.%, more preferably from 0.7 to 1.8 wt.%, based on the total weight of the one or more granules containing apixaban, and optionally one or more additional excipients. 10. A pharmaceutical composition according to any one of claims 6 to 9, wherein the pharmaceutical composition is a pharmaceutical composition comprising: -