EP2603288A1

EP2603288A1 - Pharmaceutical granulate comprising imatinib mesylate

Info

Publication number: EP2603288A1
Application number: EP10747433.0A
Authority: EP
Inventors: Dennie Johan Marijn Van Den Heuvel
Original assignee: Synthon BV
Current assignee: Synthon BV
Priority date: 2010-08-11
Filing date: 2010-08-11
Publication date: 2013-06-19
Also published as: WO2012019633A1; MX2013001653A; ZA201300872B; RU2013110058A

Abstract

The invention relates to a granulate containing 95-99 % of imatinib mesylate and 1-5% of a volatile liquid to a process of making a granulate of imatinib mesylate, which process comprises wetting imatinib mesylate with a granulation liquid, and granulating the mixture in a granulator, followed by drying, and optionally sieving and/or milling of the produced population of granules, to a pharmaceutical composition for oral administration, and for use in medicine.

Description

005214

PHARMACEUTICAL GRANULATE COMPRISING IMATINIB MESYLATE

Background of the Invention

The compound imatinib, chemically N- {5- [4- (4- methyl-piperazino-methyl)- benzoylamido]-2-methylphenyl}-4- (3-pyridyl)-2-pyrimidine-amine of the formula (1)

(1)

is a pharmaceutically active compound acting as a selective inhibitor of the ABL protein tyrosine kinase. As a (mono)mesylate salt it has been used in a medicament for the treatment of various types of cancer diseases, and is available, e.g. under the brand name GLIVEC®, as 100 mg and 400 mg tablets for oral administration.

Imatinib and its salts have been disclosed in EP B 564409 (US 5521 184). Specifically, imatinib mesylate and its crystalline polymorphic Forms a and β are disclosed in WO 99/03854.

Furthermore, EP 564409 and WO 99/03854 disclose generically many possible formulations, which are prepared in a manner known per se, for example by means of conventional mixing, granulating, dissolving or lyophilizing processes, and comprise approximately from 1% to 100%, especially from approximately 1% to approximately 20%, active ingredient. In the examples, direct compression, gelatinizing and mixing techniques are disclosed.

Wet granulation process for making imatinib pharmaceutical compositions has been disclosed in patent application EP 1 01485. Imatinib mesylate (Form a and β disclosed) and binder are mixed together with water and the mixture is processed for granulation, e.g., using a high-shear granulator to form wet granulates containing 30% to 80% imatinib mesylate and binder.

WO 2006/040779 discloses wet granulation of imatinib mesylate (10% to 80%) with gelling agents, gas generating components and a binding solution to form a granulate.

WO 2006/121941 discloses a melt granulation process which comprises the steps of (a) forming a mixture of imatinib mesylate with at least one release retardant, e.g., a release retarding polymer, a plasticizer or a release modifier; (b) granulating the mixture using an extruder and (c) cooling the granules.

US 2007/0036850 discloses a dry granulation (by compaction) process for the preparation of imatinib Form a or β granules prior to the tabletting process. The imatinib granule cores contain between 25 and 80% of imatinib together with filler-binder additives , e.g. with microcrystalline cellulose and crospovidone.

Granulation processes of the prior art have been developed, in particular, because of bad tabletting properties of imatinib mesylate itself, in particular its crystalline Form a. While many such procedures are known in the art, an improvement in this field, in particular by finding a simple and easy scalable process of improving tabletting properties of imatinib mesylate, is still desirable.

Summary of the Invention

The present invention relates to pharmaceutical granules comprising imatinib mesylate. The granules are prepared by wet granulation process without the use of additional excipients, such as binders, except for the granulation liquid. The granules are useful in making pharmaceutical compositions, particularly tablets, preferably by direct compression with suitable excipients.

In the basic aspect, the present invention provides a granulate containing 95-99 % of imatinib mesylate, in particular crystalline imatinib mesylate and in more particular the polymorphic Form a of imatinib mesylate , and 1-5% of a volatile liquid, preferably water, ethanol, isopropanol and mixtures thereof.

Typically, the population of granules has an average size of between 250-800 μπι, as determined by sieve analysis.

In a next aspect, the invention provides a process for making a granulate comprising imatinib mesylate, which process comprises wetting imatinib mesylate with a granulation liquid, which is preferably water, ethanol and/or isopropanol and most preferably in an amount of 5 - 50 weight %, in respect to the mass of imatinib mesylate, and granulating the mixture in a suitable granulator, e.g. high shear or fluid bed granulator, followed by drying, and optionally sieving and/or milling of the produced population of granules.

In yet another aspect, the invention provides a pharmaceutical composition for oral administration of imatinib mesylate, comprising the imatinib mesylate granulate of the preceded aspects, and ,optionally, at least one pharmaceutically acceptable excipient. It also provides a pharmaceutical tablet of imatinib mesylate comprising the above pharmaceutical composition in a compressed form.

In a further aspect, the invention provides a process for making pharmaceutical composition and/or pharmaceutical tablet comprising imatinib mesylate, wherein the process comprises steps of dry admixing the imatinib mesylate granulate of the present invention with excipients to provide a composition, and optionally, compressing the composition into tablets comprising the therapeutical dose of imatinib.

The last aspect deals with the use of the pharmaceutical imatinib mesylate granulate of the present invention and/or a composition comprising it for making a medicament.

Detailed Description of the Invention

Imatinib mesylate, as used herein, is a generic term for N- {5- [4- (4- methyl-piperazino- methyl)-benzoylamido]-2-methylphenyl}-4- (3-pyridyl)-2-pyrimidine-amine (mono)methane sulfonate.

The crystalline "form a" of imatinib mesylate and the crystalline "form β" of imatinib mesylate are polymorphic forms as prepared and characterized by methods disclosed in WO 99/03854. In particular, the form a is obtainable according to WO 99/03854 for example by precipitating out the crystalline imatinib mesylate Form a from a solution comprising imatinib mesylate, in a solvent other than methanol, for instance in ethanol, and without adding a seed crystal of the β-crystal form of imatinib mesylate. A typical process is shown in the Example 1 of WO 99/03854. As no single decisive parameter has been used therein for sufficient

characteristics and/or distinction of both forms, reference is made herein to the full document for further characterization of both crystalline forms of imatinib mesylate.

Imatinib mesylate (and particularly the form a) has, in general, bad tabletting properties for direct compression with excipients. Therefore any prior art process of making solid

pharmaceutical compositions comprising imatinib mesylate and useful for making compressed dosage forms, such as tablets, comprises the step of granulation of imatinib with filler-binders excipients to yield a "composite" granulate, i.e. a granulate comprising imatinib and at least one granulate-forming excipient.

The "wet granulation" as used herein is a process, which itself is well known in the art and comprises, within many technological variants, moistening a solid component or a mixture of solid components with a liquid, and vigorous mixing of the composition, whereby the wet particles of solids adhere together by cohesive forces to form larger, sometimes essentially spherical, agglomerates (a granulate). The excess of the granulation liquid may be removed from the raw granulate by drying and the suitable size range of particles is obtained by sieving and/or milling the population of granules.

Quite surprisingly, it was now found that imatinib mesylate can be wet granulated without using any granulate-forming excipient, such as a filler and/or binder , to form a free flowing solid granulate material comprising ,based on a solvent-free basis, only imatinib (small amounts of used granulation liquid may be present). Contacting solid particles ( a powder form) of imatinib mesylate with a granulation liquid, which is preferably water and/or an alcohol, e.g. ethanol or isopropanol, and processing the mixture in a suitable granulator results in a stable free flowing granulate form of imatinib mesylate with suitable characteristics for further processing.

In particular, this finding is very advantageous in respect to the Form a of imatinib mesylate, as this form has been described as hygroscopic, needle-shaped, and of low density. All these properties result in poor processing possibilities thereof in a direct tabletting process. Imatinib mesylate Form a has also been described as being metastable at room temperature. Thus, there implicitly exists a possibility that it could be converted into the Form β during wet granulation processes, thus affecting overall pharmacological properties of the composition. Wet granulation is thus not a method of the first choice for this form of imatinib mesylate. The process of the present invention now provides, i.a., a suitable and advantageous way of formulating the Form a of imatinib mesylate into pharmaceutical compositions.

By converting the imatinib mesylate into the granulate form of the present invention, processing properties of the compound are significantly improved. Imatinib mesylate is thereby obtained in a free-flowing form, which is well compatible with pharmaceutical excipients and is suitable for direct tabletting. Also the tap density of the compound is enhanced, thus minimizing the danger of segregation during dry mixing with excipients. The granulate is compatible with broader spectrum of useful excipients, as it now can be mixed with the excipients, which were currently not suitable in the techniques used so far.

The present invention thus provides a granulate form of imatinib mesylate, characterized in that smaller particles (crystals) of imatinib mesylate are agglomerated into granules. The granulate is free from granulation-aiding excipients such as binders or fillers, consisting only from imatinib mesylate (typically 95-99 weight% ) and rests of volatile liquid (typically 1 -5 weight %) from the granulation process, which liquid is preferably water, ethanol, isopropanol and mixtures thereof. The amount of the residual volatiles may be determined by standard analytical techniques, e.g. by a determination of a loss on drying according to a process of European Pharmacopoeia.

The advantageous granulate population is generally comprised of granules having an average size of between 250-800 μπι. The particle size of the population of granules may be adjusted by optional milling and/or sieving of the raw granules. Typically, two sieves of different mesh size are applied, and a population of granules passing the higher mesh and not passing the lower mesh size is used for further processing. Sieve analysis, i.e. measuring and calculating the relative proportions of particles that pass sieves of different mesh sizes, may be also used for determining the average particle size of the population of granules.

The granulate may be made from any solid form of imatinib mesylate. The "solid form" may comprise crystalline or amorphous form. The "crystalline form" may comprise Form a or Form β, as defined above. Preferably the granulate comprises the Form a of crystalline imatinib mesylate. It is important to note that, quite surprisingly, it was found that making a granulate from the Form a under conditions disclosed below does not result in any polymorphic transformation of imatinib, albeit the Form a has been reported metastable at ambient conditions. Thus, the present invention allows to formulate the metastable Form a of imatinib mesylate in pharmaceutical compositions, with a minimal risk that such form shall be transformed in Form β. Analytical processes allow to determine the relative amounts of both forms.

The granulate of the present invention is produced by a wet granulation process. The process typically comprises adding solid imatinib mesylate to a granulator and mixing there with a granulation liquid to form a population of granules. Typically, a high shear or a fluid bed granulator may be used.

The granulation liquid is advantageously water, an alcohol such as ethanol or isopropanol, and mixtures thereof. The suitable amount of the granulation liquid is about 5 - 50 weight %, relatively to the amount of imatinib mesylate. Typically, the amount of water may be from 5 to 20%, the amount of ethanol from 20 to 40%, that of isopropanol from 30 to 50%.

After granules are formed by wet granulation, a drying step is generally performed to remove essentially all amount of the granulation liquid. The drying step may include using a vacuum, microwave radiation, heating air, heating double-jacket, and/or gas flow (N₂ or air). The advantageous limit for the content of residual volatiles is from 1 to 5 %. The resulting dried granulate may be milled and/or sieved to obtain a free flowing granulate population of the desired particle size. The granules produced according to the present invention are, in essence, well cohesive so that they may be subjected to a gentle milling, which is useful in order to minimize the percentage of higher agglomerates.

The imatinib mesylate granulate of the present invention may be used in making medicaments, particularly medicaments for oral administration of imatinib to a patient in need thereof. For this purpose, the granulate may be formulated advantageously with at least one suitable excipient, into pharmaceutical compositions and further processed into various pharmaceutical dosage forms comprising the pharmaceutical dose of imatinib. It is important to note that the final dosage form (e.g. a capsule or a sachet) may also comprise solely the imatinib mesylate granulate, thus it may contain 100 % of the imatinib mesylate ( when excluding the residual volatiles) , which was not possible in any prior art formulation.

Accordingly, the imatinib mesylate granulate of the present invention may be mixed in a suitable mixer, e.g., a free fall blender, with auxiliary excipients, such as filler(s), binder (s) disintegrant(s), lubricant(s), glidant(s), to provide an homogeneous mixture of desired properties and concentration of the active substance. Advantageously, all components are admixed in a dry state. Examples of the filler binder include microcrystalline cellulose and cellulose derivatives, polyvinylpyrrolidone, lactose monohydrate and pregelatinized starch. An example of the disintegrant is crospovidone or sodium starch glycolate. An example of the lubricant is magnesium stearate. An example of the glidant is silicon dioxide. The amounts and type of the auxiliary excipients depend on the desired physical properties of the final composition and desired concentration of imatinib mesylate. Typically, the granulate-comprising pharmaceutical composition of the present invention may be used in making solid dosage forms for oral administration, typically capsules or tablets. In the latter case, the pharmaceutical composition is compressed into tablets in a suitable tablet press. The tablets may be round, oval, biconvex or of other suitable shape. If desirable, the tablets may be coated, for instance by a water soluble film-coat, to improve the handling properties. Examples of coating material are an HPMC based coating, a polyvinylalcohol based coating or a polyethylene glycol-polyvinylalcohol based coating. Relative amount of the coating is typically from 2 to 6 %.

Alternatively, the granulate is suitable for making a composition for direct filling into capsules or sachets, optionally even without adding any auxiliary excipient.

Preferably the relative amount of the granulated form of imatinib mesylate in the pharmaceutical composition is at least 50 weight %, more preferably at least 60 weight %.

Compositions comprising 100% of imatinib mesylate are included. In unit doses such as a single tablet or capsule the absolute amount of imatinib is preferably within the range from 50mg to 800mg, especially of 1 OOmg, and of 400 mg, calculated as free base.

The invention is further illustrated by the following examples but is not limited thereto.

Example 1

Granulate of imatinib mesylate

Transfer 1 kg .Imatinib mesylate (Form a) into the 10 L high shear mixer, add 410 g isopropanol over 10 minutes and granulate in total for 20 minutes . Sieve the wet granulate over the oscillating sieve equipped with a 3 mm sieve. Transfer the sieved wet granulate into an oven and dry until a product temperature of 40°C is reached. Sieve the granulate over the oscillating sieve equipped with a 1.0mm sieve. Example 2

Granulate of imatinib mesylate

Transfer 1 kg .Imatinib mesylate (Form a) into the 10 L high shear mixer, add 373 g ethanol over 8 minutes and granulate in total for 20 minutes. Sieve the wet granulate over the oscillating sieve equipped with a 3 mm sieve. Transfer the sieved wet granulate into an oven and dry until a product temperature of 40°C is reached. Sieve the granulate over the oscillating sieve equipped with a 1.0mm sieve. Example 3

Granulate of imatinib mesylate

Transfer 2.4 kg Imatinib mesylate (Form a) into the 10 L high shear mixer, add 280 g water over 16 minutes and granulate in total for 16 minutes. Transfer the sieved wet granulate into a fluid bed drier and dry until a LOD < 2% is reached. Sieve the granulate over the oscillating sieve equipped with a 3 mm sieve and and then over the oscillating sieve equipped with a 1.0 mm sieve.

Example 4

Imatinib 100 and 400 mg tablet formulation

Composition :

% 100 mg tablet (rr ig) 400 mg tablet

Imatinib mesylate Form a granulate 63.7 1 19.5 478

Cellulose,microcrystalline 18.59 34.85 139.4

Crospovidone 14.93 28.0 1 12

Hypromellose 1.33 2.5 10

Silica, colloidal anhydrous 0.67 1.25 5

Magnesium stearate 0.75 1.4 5.6

Weight core: 100 187.5 750 Process ;

Transfer Silica colloidal anhydrous and microcrystalline cellulose into the 100 L mixing drum and mix for 10 minutes at 6 rpm using the free fall blender. Sieve this pre-mix over the oscillating sieve equipped with a 1.0mm sieve.

Transfer the imatinib mesylate granulate (Ex 1) , the pre-mix, crospovidone and hypromellose into 200 L mixing container and mix for 30 minutes at 6 rpm using the free fall blender.

Sieve magnesium stearate over the 1.0 mm hand sieve. Add magnesium stearate into the 200 L mixing container and mix for 5 minutes at 6 rpm using the free fall blender.

Compress the tablet cores using a rotary tablet press.

Optional Coating :

Transfer the Purified water into a stainless steel container, add an HPMC based coating

(Opadry), a polyvinylalcohol based coating (Opadry II) or an polyethylene glycol- polyvinylalcohol based coating (Kollicoat) Opadry II brown and mix for 45 minutes using a high speed mixer. Perform film-coating of the tablet cores using a 25 kg drum-coater .

The invention having been described it will be obvious that the same may be varied in many ways and all such modifications are contemplated as being within the scope of the invention as defined by the following claims.

Claims

1. A granulate containing 95-99 % of imatinib mesylate and 1-5% of a volatile liquid.

2. The granulate according to the claim 1 , wherein the imatinib mesylate is a crystalline imatinib mesylate, preferably the crystalline Form a of imatinib mesylate, obtainable by precipitating out the crystalline imatinib mesylate Form a from a solution of imatinib mesylate in a solvent other than methanol, such as in ethanol, and without adding a seed crystal of the β- crystal form of imatinib mesylate.

3. The granulate according to claims 1 or 2, wherein the volatile liquid is water, ethanol, isopropanol and mixtures thereof.

4. The granulate according to claims 1 - 3 comprised of granules having an average size of between 250-800 μπι.

5. A process of making a granulate of imatinib mesylate, which process comprises wetting imatinib mesylate with a granulation liquid, and granulating the mixture in a granulator, followed by drying, and optionally sieving and/or milling of the produced population of granules.

6. The process according to claim 5, wherein the granulation liquid is water, ethanol and/or isopropanol.

7. The process according to claim 5 or 6, wherein the amount of the granulation liquid is 5 - 50 weight %, in respect to the mass of imatinib mesylate.

8. The process according to claims 5 - 7, wherein the granulator is a high shear or fluid bed granulator.

9. A pharmaceutical composition for oral administration of imatinib mesylate, comprising the imatinib mesylate granulate according to the claims 1-4 and/or made according to claims 5-8, and ,optionally, at least one pharmaceutically acceptable excipient.

10. The composition according to claim 9 in a tablet form.

1 1. The composition according to claims 9 or 10 comprising at least 50 weight %, more preferably at least 60 weight % of the granulate.

12. The composition according to claims 9 - 1 1, comprising 50mg to 800mg, especially lOOmg and 400 mg of imatinib, calculated as free base.

13. A process for making the pharmaceutical composition for oral administration of imatinib mesylate according to claims 9 - 12, comprising a step of dry admixing the imatinib mesylate granulate with excipients.

14. A process according to claim 13, further comprising a step of compressing the composition into tablets.

15. The granulate according to the claims 1 - 4 and/or made according to claims 5 - 8, and/or the composition according to claims 9 - 12 and/or made according to claims 13 - 14 for use in medicine, such as the treatment of various types of cancer diseases.