WO2011160798A1

WO2011160798A1 - Pharmaceutical compositions comprising imatinib or pharmaceutically acceptable salt thereof and processes for the manufacture thereof

Info

Publication number: WO2011160798A1
Application number: PCT/EP2011/003020
Authority: WO
Inventors: Sayisiva Prasad Ravula; Anand Kumar Mamidi
Original assignee: Zaklady Farmaceutyczne Polpharma Sa
Priority date: 2010-06-21
Filing date: 2011-06-17
Publication date: 2011-12-29
Also published as: PL402710A1; EA201300034A1; EP2582362A1; EA029416B1; PL234542B1

Abstract

The present invention relates to pharmaceutical compositions comprising imatinib or pharmaceutically acceptable salt thereof and to processes for manufacture thereof.

Description

Pharmaceutical compositions comprising imatinib or pharmaceutically acceptable salt thereof and processes for the manufacture thereof.

FIELD OF THE INVENTION

The invention relates to pharmaceutical compositions comprising imatinib or pharmaceutically acceptable salt thereof as active ingredient and processes for the manufacture thereof.

BACKGROUND OF THE INVENTION

4-((4-Methyl-l-piperazinyl)methyl)-N-(4-methyl-3-((4-(3-pyridinyl)-2- pyrimidinyl)amino)phenyl) benzamide, known under the INN of imatinib, pharmaceutically acceptable salt thereof and also processes for manufacture thereof were first disclosed in EP 0564409A. Imatinib in the form of methanesulfonate is marketed under trade name Glivec and is indicated for the treatment of chronic myeloid leukaemia, Philadelphia chromosome positive acute lymphoblastic leukaemia, myelodysplastic or myeloproliferative diseases, advanced hypereosinophilic syndrome or chronic eosinophilic leukaemia, gastrointestinal stromal tumours and dermatofibrosarcoma protuberans. Imatinib is administered orally to patients in daily doses of up to 800 mg depending on the condition of the patient. Imatinib was first launched in the doses of 50 mg and 100 mg in the form of capsules which were substantially disadvantageous to patients who had to be administered several capsules at the same time. EP 1501485A1 disclosed tablets with high load of imatinib and defined contents of excipients were described. The excipients comprise at least one binder, at least one disintegrant, at least one glidant and at least one lubricant. The process for obtaining the tablets disclosed in EP 1501485A1 employs the steps of wet granulation of imatinib blended with pharmaceutically acceptable excipients, including a binder, addition of further pharmaceutically acceptable excipients to the thus obtained granulate and compressing the mixture to tablet. EP 1762230A1 discloses the preparation of pharmaceutical compositions comprising imatinib or its salt by dry-granulation processes. All the examples disclose dry-granulation processes which employ the use of imatinib or pharmaceutically acceptable salt thereof with at least one binder. The most important disadvantage of dry-granulation method is cost of the equipment which renders the technology very expensive and uncommon.

SUMMARY OF THE INVENTION

The aim of the present invention is to develop a new oral tablet comprising imatinib or pharmaceutically acceptable salt thereof as active ingredient that can be produced in a simple manner without using expensive technology as disclosed in the prior art. Additionally, to afford patient compliance, the tablet according to the invention should preferably have the active ingredient present in a high amount in the tablet in order to obtain smaller tablets, more suitable especially for patients who have problems with swallowing.

Surprisingly, it was found that tablets comprising imatinib or pharmaceutically acceptable salt thereof as active ingredient in the core of the tablet can be obtained without using any binder in the core of the tablet. Furthermore, surprisingly, it was found that wet granulation of imatinib or pharmaceutically acceptable salt thereof without the use of any binder can afford granulates suitable for obtaining a tablet comprising imatinib or pharmaceutically acceptable salt thereof and such obtained tablets have better bioavailability by exhibiting shorter disintegration time. Additionally, according to the present invention, the active ingredient is preferably present in a high amount in the core of the tablet.

DETAILED DESCRIPTION OF THE INVENTION

The tablet according to the present invention comprises imatinib or pharmaceutically acceptable salt thereof as active ingredient and does not comprise any binder in the core of the tablet. In a preferred embodiment of the invention, the tablet further comprises extragranularly at least one disintegrant. In a more preferred embodiment of the invention, the tablet further comprises extragranularly at least one glidant and/or lubricant.

The binder which is not used in the present invention is a substance used to impart cohesive qualities to the powdered material and impart a cohesiveness to the tablet formulation that ensures the tablet remaining intact after compression. According to the present invention the terms binder and binding agent means the same and can be used interchangeably. The following substances are examples of binding agents which are not used in the present invention: hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, povidone, starch. The tablet according to the present invention comprises imatinib or pharmaceutically acceptable salt thereof as active ingredient in the core of the tablet preferably in a high amount, preferably from 55% to 93% by weight based on the total mass of the core of the tablet, more preferably from 60% to 90%, most preferably from 65% to 85%. In one of the embodiments of the invention the tablet comprises from 50 to 75% by weight of imatinib base based on the total mass of the total tablet and comprises at least one pharmaceutically acceptable excipient without a binding agent. In another embodiment of the invention the core of the tablet consists of imatinib or pharmaceutically acceptable salt thereof, at least one disintegrant, at least one glidant and/or lubricant. The tablet according to the present invention preferably comprises extragranularly at least one disintegrant preferably selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate and mixtures thereof. The disintegrant is preferably present in the core of the tablet in an amount from 7% to 30% by weight based on the total mass of the core of the tablet, more preferably from 10% to 25%, most preferably from 12% to 20%.

The tablet according to the present invention preferably comprises extragranularly at least one glidant and/or lubricant. Some of the glidants and the lubricants can be used interchangeably as some of them can exhibit both properties.

The glidant is preferably selected from the group consisting of colloidal silicon dioxide, calcium silicate, magnesium trisilicate and mixtures thereof. The glidant might be preferably present in the core of the tablet in an amount from 0.1% to 10% by weight based on the total mass of the core of the tablet, more preferably from 0.5% to 8%, most preferably from 1% to 5%.

The lubricant is preferably selected from the group consisting of sodium stearyl fumarate, talc, magnesium stearate, calcium stearate and zinc stearate and mixtures thereof. The lubricant is preferably present in the core of the tablet in an amount from 0.1% to 5% by weight based on the total mass of the core of the tablet, more preferably from 0.5% to 4%, most preferably from 1% to 3%.

The tablet according to the present invention comprises imatinib or pharmaceutically acceptable salt thereof as the active ingredient, preferably imatinib methanesulfonate also known as imatinib mesylate.

The core of the tablet of the present invention is understood to mean an uncoated tablet. The core of the tablet of the present invention can be coated using pharmaceutically acceptable coating mixtures.

Additionally, the invention is directed to a process for preparation of a pharmaceutical composition comprising imatinib or pharmaceutically acceptable salt thereof as active ingredient not comprising any binder.

The process according to the present invention comprises the step of wet granulation of imatinib or pharmaceutically acceptable salt thereof without any binder, preferably without any pharmaceutically acceptable excipient. Further steps of the process preferably comprise blending the granules comprising imatinib or pharmaceutically acceptable salt thereof with pharmaceutically acceptable extragranular excipients.

The process according to the present invention preferably employs the active ingredient in an amount from 55% to 93% by weight based on the total mass of the pharmaceutical composition, more preferably from 60% to 90%, most preferably from 65% to 85%. Preferably, imatinib is employed in the form of imatinib methanesulfonate also known as imatinib mesylate. In one of the embodiments of the invention the process employs from 50 to 75% by weight of imatinib or pharmaceutically acceptable salt thereof where the range from 50 to 75% by weight corresponds to imatinib base based on the total mass of the pharmaceutical composition without a binding agent. The process according to the present invention preferably employs pharmaceutically acceptable extragranular excipients, preferably at least one disintegrant, more preferably also at least one glidant and/or lubricant. In one of the embodiments of the invention the process employs imatinib or pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients consisting of at least one disintegrant, at least one glidant and/or lubricant. The disintegrant is preferably selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate and mixtures thereof. Preferably, the disintegrant is employed in the process of the present invention in an amount from 7% to 30% by weight based on the total mass of the pharmaceutical composition, more preferably from 10% to 25%, most preferably from 12% to 20%.

The process according to the present invention preferably employs at least one glidant and/or lubricant. Some of the glidants and the lubricants can be used interchangeably as some of them can exhibit both properties.

The glidant is preferably selected from the group consisting of colloidal silicon dioxide, calcium silicate, magnesium trisilicate and mixtures thereof. Preferably, the glidant is employed in the process in an amount from 0.1% to 10% by weight based on the total mass of the pharmaceutical composition, more preferably from 0.5% to 8%, most preferably from 1% to 5%.

The lubricant is preferably selected from the group consisting of sodium stearyl fumarate, talc, magnesium stearate, calcium stearate and zinc stearate and mixtures thereof. Preferably, the lubricant is employed in the process in an amount from 0.1% to 5% by weight based on the total mass of the pharmaceutical composition, more preferably from 0.5% to 4%, most preferably from 1% to 3%.

In a preferred embodiment of the invention, the process comprises the following steps: a) wet granulation of imatinib or pharmaceutically acceptable salt thereof without any binder, preferably without any pharmaceutically acceptable excipient using purified water; b) drying and preferably sieving the granules as obtained in step a); c) sieving and blending pharmaceutically acceptable extragranular excipients comprising at least one disintegrant and at least one glidant and/or lubricant; d) adding the extragranular mixture as obtained in step c) to granules as obtained in step b) and blending thus obtained mixture e) compressing the mixture as obtained in step d) to tablets. In another preferred embodiment of the invention, the process comprises the following steps: i) self granulating the imatinib methanesulfonate with the aid of a solvent to obtain the granules, the solvent preferably is purified water; ii) mixing the granules obtained in the step (i) with at least one disintegrant, at least one glidant and/or lubricant; iii) compressing the mixture obtained in step (ii) to form the tablets and iv) optionally coating the tablets with a film coating agent to form the film coated tablets.

The process according to the present invention preferably affords the pharmaceutical composition in the form of a core of a tablet. Particularly, the process of the present invention can afford the core of the tablet described above. As a further step the process according to the present invention preferably comprises the step of coating the pharmaceutical composition, preferably a core of the tablet, using conventional coating mixtures and standard equipment. The process according to the present invention preferably employs a fluid bed granulator or a high shear mixer, more preferably a high shear mixer for the granulation process as described in step a) or i), an oven tray dryer or a fluid bed granulator for the drying process as described in step b), a V-blender or a bin mixer for blending as mentioned in steps c) or ii) and d), and a single punch tableting machine or a rotary tableting machine for compressing to tablets as mentioned in step d) or iii).

The invention is illustrated by the following examples which in no way restrict its scope. EXAMPLES

Example 1

[%/tablet]

Granulate:

Imatinib mesylate 82.13

Purified water q.s.

Extragranular excipients:

Croscarmellose sodium 13.57

Colloidal silicon dioxide 1.72

Sodium stearyl fumarate 1.55

Talc 1.03

The weighed amount of imatinib mesylate is wet granulated in a high shear mixer using purified water. Thus obtained granules are dried in a tray dryer and sieved through 20 mesh sieve. The weighed amount of extragranular excipients (croscarmellose sodium, colloidal silicon dioxide, sodium stearyl fumarate and talc) are sieved through 30 mesh sieve and blended for 3 minutes using bicone blender. Next, the granules and the blended mixture are mixed for 5 minutes using bicone blender and compressed into tablets using oblong 16.5x7mm punches. The resulting tablets have the weight of 582 mg. Example 2

[%/tablet]

Granulate:

Imatinib mesylate 88.78

Purified water q.s.

Extragranular excipients:

Sodium starch glycolate 5.35

Crospovidone 2.23

Sodium stearyl fumarate 2.60

Colloidal silicon dioxide 1.04 Procedure identical to that in Example 1. The resulting tablets have the weight of 538.4 mg.

Example 3

[%/tablet]

Granulate:

Imatinib mesylate 87.87

Purified water q.s.

Extragranular excipients:

Sodium starch glycolate 5.29

Crospovidone 2.21

Sodium stearyl fumarate 2.57

Colloidal silicon dioxide 1.03

Talc 1.03

Procedure identical to that in Example 1. The resulting tablets have the weight of 544 mg.

Example 4

[%/tablet]

Granulate:

Imatinib mesylate 86.19

Purified water q.s.

Extragranular excipients:

Sodium starch glycolate 8.12

Crospovidone 2.16

Sodium stearyl fumarate 2.52

Colloidal silicon dioxide 1.01

Procedure identical to that in Example 1. The resulting tablets have the weight of 544 mg. Example 5

[%/tablet]

Granulate:

Imatinib mesylate 82.13

Purified water q.s.

Extragranular excipients:

Crospovidone 13.57

Sodium stearyl fumarate 1.55

Colloidal silicon dioxide 1.72

Talc 1.03

Procedure identical to that in Example 1. The resulting tablets have the weight of 582 mg.

Example 6

[%/tablet]

Granulate:

Imatinib mesylate 82.13

Purified water q.s.

Extragranular excipients:

Crospovidone 13.57

Colloidal silicon dioxide 1.72

Talc 2.58

Procedure identical to that in Example 1. The resulting tablets have the weight of 582 mg. The tablets from examples 1 to 6 were tested to confirm their physical properties using standard methods. The following results were obtained:

Additionally, the tablets obtained in Example 6 were coated with coating mixture of hypromellose, macrogol, talc, iron oxide red and iron oxide yellow using a standard method. The tablet after coating weighs 593.5 mg. The obtained coated tablets of Example 6 and coated tablets marketed under trade name Glivec^® comprising imatinib mesylate in amount of 478 mg, the following pharmaceutical excipients cellulose microcrystalline, crospovidone, hypromellose, magnesium stearate and silica colloidal anhydrous and coating consisting of iron oxide red, iron oxide yellow, macrogol, talc and hypromellose were tested for disintegration time using a standard method. The results are shown in the table below.

Coated tablets of Example 6 Coated tablets Glivec^®

Disintegration time 5-6 minutes 7-8 minutes

Claims

1. A tablet comprising imatinib or pharmaceutically acceptable salt thereof as active ingredient in the core of the tablet, characterized in that the core of the tablet does not comprise any binder.

2. The tablet according to claim 1, wherein the core of the tablet further comprises at least one disintegrant.

3. The tablet according to any of the claims 1 to 2, wherein the core of the tablet further comprises at least one glidant and/or lubricant.

4. The tablet according to any of the claims 1 to 3, wherein the active ingredient is present in an amount from 55% to 93% by weight based on the total mass of the core of the tablet, preferably from 60% to 90%, more preferably from 65% to 85%.

5. The tablet according to any of the claims 2 to 4, wherein the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate and mixtures thereof.

6. The tablet according to any of the claims 2 to 5, wherein the disintegrant is present in the core of the tablet in an amount from 7% to 30% by weight based on the total mass of the core of the tablet, preferably from 10% to 25%, more preferably from 12% to 20%.

7. The tablet according to any of the claims 3 to 6, wherein the glidant is selected from the group consisting of colloidal silicon dioxide, calcium silicate, magnesium trisilicate and mixtures thereof.

8. The tablet according to any of the claims 3 to 7, wherein the glidant is present in the core of the tablet in an amount from 0.1% to 10% by weight based on the total mass of the core of the tablet, preferably from 0.5% to 8%, more preferably from 1% to 5%.

9. The tablet according to any of the claims 3 to 8, wherein the lubricant is selected from the group consisting of sodium stearyl fumarate, talc, magnesium stearate, calcium stearate and zinc stearate and mixtures thereof.

10. The tablet according to any of the claims 3 to 9, wherein the lubricant is present in the core of the tablet in an amount from 0.1% to 5% by weight based on the total mass of the core of the tablet, preferably from 0.5% to 4%, more preferably from 1% to 3%.

11. The tablet according to any preceding claim, wherein the core of the tablet comprises imatinib methanesulfonate as the active ingredient.

12. The tablet according to any preceding claim, wherein the core of the tablet is coated.

13. The tablet according to any of claims 1 to 3, wherein the tablet comprises imatinib base in amount from 50 to 75% by weight based on the total mass of the total tablet and comprises at least one pharmaceutically acceptable excipient without a binding agent.

14. The tablet according to any of claims 1 to 13, wherein the core of the tablet consists of imatinib or pharmaceutically acceptable salt thereof, at least one disintegrant, at least one glidant and /or lubricant.

15. A process for preparation of a pharmaceutical composition comprising imatinib or pharmaceutically acceptable salt thereof as active ingredient, characterized in that the process comprises the step of wet granulation of imatinib or pharmaceutically acceptable salt thereof without any binder.

16. The process according to claim 15, wherein the process comprises the step of wet granulation of imatinib or pharmaceutically acceptable salt thereof without any pharmaceutically acceptable excipient.

17. The process according to any of the claims 15 to 16, wherein the process further comprises the step of blending of the granules comprising imatinib or pharmaceutically acceptable salt thereof with pharmaceutically acceptable extragranular excipients, preferably with at least one disintegrant and at least one glidant and/or lubricant.

18. The process according to any of the claims 15 to 17, wherein the active ingredient is used in an amount from 55% to 93% by weight based on the total mass of the pharmaceutical composition, preferably from 60% to 90%, more preferably from 65% to 85%.

19. The process according to any of the claims 17 to 18, wherein the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate and mixtures thereof.

20. The process according to any of the claims 17 to 19, wherein the disintegrant is used in an amount from 7% to 30% by weight based on the total mass of the pharmaceutical composition, preferably from 10% to 25%, more preferably from 12% to 20%.

21. The process according to any of the claims 17 to 20, wherein the glidant is selected from the group consisting of colloidal silicon dioxide, calcium silicate, magnesium trisilicate and mixtures thereof.

22. The process according to any of the claims 17 to 21, wherein the glidant is used in an amount from 0.1% to 10% by weight based on the total mass of the pharmaceutical composition, preferably from 0.5% to 8%, more preferably from 1% to 5%.

23. The process according to any of the claims 17 to 22, wherein the lubricant is selected from the group consisting of sodium stearyl fumarate, talc, magnesium stearate, calcium stearate and zinc stearate and mixtures thereof.

24. The process according to any of the claims 17 to 23, wherein the lubricant is used in an amount from 0.1% to 5% by weight based on the total mass of the pharmaceutical composition, preferably from 0.5% to 4%, more preferably from 1% to 3%.

25. The process according to any of the claims 15 to 24, wherein imatinib methanesulfonate is used as the active ingredient.

26. The process according to any of the claims 15 to 25, wherein the pharmaceutical composition is in the form of a core of a tablet.

27. The process according to any of the claims 15 to 26, wherein the process further comprises the step of coating the core of the tablet.

28. A process for the preparation of a pharmaceutical composition according to any of the claims 1 to 14, wherein the process comprises the step of wet granulation of imatinib or pharmaceutically acceptable salt thereof.

29. The process according to claim 28, wherein the process comprises the step of wet granulation of imatinib or pharmaceutically acceptable salt thereof without any pharmaceutically acceptable excipient.

30. A process for the preparation of the tablet according to any of the claims 1 to 14 wherein the process comprises i) self granulating the imatinib methanesulfonate with the aid of a solvent to obtain the granules ii) mixing the granules obtained in the step (i) with at least one disintegrant, at least one glidant and/or lubricant iii) compressing the mixture obtained in step (ii) to form the tablets and iv) optionally coating the tablets with a film coating agent to form the film coated tablets.

31. The process according to claim 30 wherein the solvent is purified water.