Field of the invention

The present invention relates to pharmaceutical compositions of kinase inhibitors. More particularly, the present invention relates to immediate release compositions of nilotinib or its pharmaceutically acceptable salts and process for preparing the same.
Back ground of the invention

Nilotinib belongs to pharmacologic class of drugs known as kinase inhibitors. Chemically Nilotinib is 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(Triflouro methyl) phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino]-Benzamide. Its molecular formula is C28H22F3N70HC1 • H20 with molecular weight of 565.98. The structural formula is:

Nilotinib is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase and accelerated phase by inhibition of tyrosine kinase (TK) activity of Bcr-Abl.
Nilotinib hydrochloride is marketed as 150 mg and 200 mg oral capsules in United States under the trade name of TASIGNA by Novartis.

US7169791 assigned to Novartis claims 4-Methyl-3-[[4-(3-pyridinyl)-2- pyrimidinyl] amino]-N-[5-(4-methyl-lH-imidazol-l-yl) -3-(trifluoromethyl) phenyl] benzamide and its use for treatment of leukemia by inhibition of protein kinase activity.

US2010087463 assigned to Novartis claims pharmaceutical compositions of nilotinib in the form of granules prepared by wet granulation process. Also describes composition of nilotinib comprising surfactant.

W02009100176 assigned to Abbott claims solid dispersion product of tyrosine kinase inhibitor using polymers and solubilizers.

US20080269269 assigned to Novartis claims different polymorphs such as substantially pure crystalline Form A, B, C, and D of nilotinib, nilotinib hydrochloride and substantially pure amorphous form of nilotinib hydrochloride.

US2010190812 assigned to Teva claims crystalline nilotinib hydrochloride.

Nilotinib hydrochloride is a therapeutically high dose drug having poor flow properties, which can be improved by preparation in to granules.

Wet granulations, however, require the formulation to be exposed to water and/or solvents. Such exposure increases the risk that the solid-state form of the nilotinib could change (e. g., crystallize or change polymorphic form or hydrated forms etc) or degrade chemically. Since liquid addition amount and rate will depend on such factors as the volume and surface area of the wet granulation vessels and on the exact particle sizes of the drug and excipients used in a specific manufacturing run, there can be difficulties in scaling-up wet granulation processes. Wet granulation is a process of using a liquid binder to lightly agglomerate the powder mixture. The amount of liquid has to be properly controlled, as over-wetting will cause the granules to be too hard and under- wetting will cause them to be too soft and friable. Solute migration during drying may be an issue, especially for soluble drug substances. The major disadvantage of wet granulation may be its complexity because it involves several steps and many parameters to be controlled and is expensive.

Therefore there remains a need to provide dry granulation formulations and processes for nilotinib such that flow of said composition is acceptable for commercial unit dosage formation, having good dissolution rates and bioavailability where in drug will not be exposed to a solvent.

Inventors of the present invention have surprisingly found that compositions of the present invention prepared by dry granulation process using nilotinib as the active ingredient, exhibited excellent dissolution characteristics that were also found to be comparable with respect to the marketed formulation. In addition dry granulation is a robust (scalable) process, therefore cost effective.

The effect of surfactant over the intestinal membrane is more complex. It has been shown that most surfactants interact with the absorbing membranes. Permeability enhancement and local damage are closely related to sequelae of the interaction of surfactants with intestinal wall. The surfactants can facilitate their own entry and that of other material into the body, which thus enters into the systemic circulation. Thus, there is a need to develop compositions of nilotinib which is free of surfactant.

It was further surprisingly found that nilotinib could be formulated without the use of surfactant without retarding the dissolution characteristics of the drug.

Summary of the Invention

A first aspect of the present invention is a dry-granulated pharmaceutical composition comprising nilotinib or a pharmaceutically acceptable salt thereof.

A second aspect of the present invention provides process for preparing compositions of nilotinib using dry granulation.

A third aspect of the present invention provides a process for preparing dry- granulated pharmaceutical composition of nilotinib comprises compacting nilotinib hydrochloride alone or mixed with one or more of pharmaceutically acceptable excipient(s) by roller compactor or slugging; sizing the compacts or slugs into granules by milling; optionally mixing the granules with one or more of pharmaceutically acceptable excipients to form the composition.

A fourth aspect of the present invention provides compositions comprising nilotinib and at least one excipient selected from diluent(s), binder(s), disintegrant (s), glidant(s), and lubricant(s), where in the composition is free of surfactant.

A fifth aspect of the present invention provides composition comprising: i) nilotinib or its pharmaceutically acceptable salts, ii) water soluble polymer, iii) optionally one or more excipients selected from diluent(s), binder(s), disintegrant (s), glidant(s), and lubricant(s); where in the composition is free of surfactant.

In another aspect, the present invention provides a process for preparing compositions comprising nilotinib and one or more pharmaceutically acceptable excipients by dry granulation where in the composition is free of surfactant.

The present invention also provides composition comprising nilotinib, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate and optionally hydroxypropyl methylcellulose, where in the composition is free of surfactant.

Detailed description of the invention

"Salts" or "pharmaceutically acceptable salt(s)", as used herein, include but not limited to inorganic or organic salts, hydrates, and solvates of nilotinib known to person skilled in the art.

The compositions of the present invention can be in the form of a capsule, tablet, bead, granule or pill, all of the above being collectively referred to as pharmaceutical compositions or formulations and contains medicament namely nilotinib or its salts and one or more pharmaceutically acceptable excipients.

The present invention provides dry-granulated pharmaceutical composition comprising nilotinib or a pharmaceutically acceptable salt thereof.

The present invention also provides compositions comprising nilotinib and at least one excipient selected from diluent(s), binder(s), disintegrant (s), glidant(s), and lubricant(s), where in the composition is free of surfactant.

Diluents, fillers, or bulking agents in addition to the particulate product of the present invention may be added in order to increase the bulk weight of the material to be tabletted or filled into capsules in order to make a practical size. Suitable fillers for this purpose include, but are not limited to lactose, microcrystalline cellulose, dibasic calcium phosphate, calcium phosphate, powdered cellulose, dextrates, isomalt, calcium carbonate, magnesium carbonate, starch, pre-gelatinized starch, and mixtures thereof.

A binder also sometimes called adhesive, can be added to a drug-filler mixture to increase the mechanical strength of the granules and tablets during formation. Suitable binders include starch, microcrystalline cellulose, gelatin, polyvinylpyrrolidone, and sugars such as sucrose, glucose, dextrose, lactose, polyvinyl alcohol and mixtures thereof.
One or more disintegrants are included in the compositions to ensure that the formulation has an acceptable dissolution rate in an environment of use such as the gastrointestinal tract. Efficacy of a drug mixture can be dependant on the rate at which the tablet or capsule disintegrates in the patient's gastrointestinal tract. Typically, disintegrants expand, swell, and dissolve when wet, causing the tablet or granule to break apart in the digestive tract, releasing the active ingredients and excipients for absorption. Examples of disintegrants suitable for use herein include, but are not limited to croscarmellose sodium, crospovidone, starch, potato starch, pregelatinized starch, corn starch, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose and other known disintegrants.

One or more glidants may be used in compositions to improve flow. Because of the shape and size of the particles, glidants improve flow in low concentrations. They may be mixed in the final compositions in dry form. Suitable glidants for example include but are not limited to silicon dioxide, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc, and other forms of silicon dioxide, such as aggregated silicates and hydrated silica.

Lubricants can be added to pharmaceutical compositions to decrease any friction that occurs between the solid and the die wall during manufacturing of formulations. Suitable lubricants include but not limited to fatty acids, fatty acid salts, and fatty acid esters such as magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil and the like.

Water soluble polymer as per the instant invention will increase the rate of drug release from its dosage form. Water soluble polymers as per the present invention include but not limited to polyethylene glycol, polyvinyl pyrrolidone, polyethylene oxides, alkyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose or mixtures thereof.
The present invention further provides process for preparing compositions of nilotinib using dry granulation.

Dry granulation process according to the present invention involves either slugging or roller compaction.

Slugging is a double compression process. The material to be processed is compressed to a large compressed mass, or "slug," which is milled to form granules which are filled into capsules or compressed into tablets. The process includes (i) sifting and blending of dry mix ingredients; (ii) slugging the blend of step (i) to obtain slugs; (iii) milling and sifting the step of (ii) to obtain granules; (iv) lubricating and blending the granules of step (iii) and finally filled into capsules or compressed into tablets.

The term "roller compaction" as used herein refers to a process by which two or more solid materials are compacted between two rotating rolls, desirably, counter- rotating rolls to form solid ribbons/ compacts. Sizing the compacts into granules by milling to modify the desired particle size; optionally mixing the granules with one or more of pharmaceutically acceptable excipients to form the composition.

A process for preparing dry-granulated pharmaceutical composition of nilotinib comprises compacting nilotinib hydrochloride alone or mixed with one or more of pharmaceutically acceptable excipient(s) by roller compactor or slugging; sizing the compacts or slugs into granules by milling; optionally mixing the granules with one or more of pharmaceutically acceptable excipients to form the composition.

The present invention also provides composition comprising: i) nilotinib or its pharmaceutically acceptable salts, ii) water soluble polymer iii) optionally one or more excipients selected from diluent(s), binder(s), disintegrant(s), glidant(s), and lubricant(s); where in the composition is free of surfactant.

In another aspect, the present invention provides a process for preparing compositions comprising nilotinib and one or more pharmaceutically acceptable excipients by dry granulation where in the composition is free of surfactant.

Another embodiment provides composition comprising nilotinib, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate and optionally hydroxypropyl methylcellulose, where in the composition is free of surfactant.

Nilotinib according to the present invention is in the form of amorphous nilotinib hydrochloride, anhydrous crystalline nilotinib hydrochloride, crystalline nilotinib hydrochloride monohydrate, crystalline nilotinib hydrochloride dihydrate or combinations thereof.

The following non-limiting examples illustrate the inventors preferred methods for preparing and using the pharmaceutical compositions of the present invention.

EXAMPLES 1-5

Compositions of nilotinib prepared by dry granulation using slugging method.

Manufacturing process

i) Intragranular materials were blended and sifted together through # 40 mesh.

ii) magnesium stearate was sifted separately through # 60 mesh.

iii) colloidal silicon dioxide was sifted separately through # 40 mesh.

iv) the material of step (i) was slugged and the resulted slugs were milled using multimill or cone mill with 2mm screen.

v) milled granules of step (iv) were sifted through # 30 mesh completely.

vi) granules obtained in step (v) were sifted through #60 mesh; retentions and passed were collected separately.

vii) steps of (iv) to (vi) were repeated with #60 mesh passed granules until 50%w/w of granules were passed through #30/60mesh.

viii) obtained granules of step (vii) were lubricated and blended with magnesium stearate of step (ii) and colloidal silicon dioxide of step (iii).

ix) the obtained blend is compressed into tablets or filled in to capsules.

EXAMPLES 6-7:

Compositions of nilotinib prepared by dry granulation using Roller compaction method.

Manufacturing process:

i) Intragranular materials were blended and sifted together through # 40 mesh.

ii) magnesium stearate was sifted separately through # 60 mesh.

iii) colloidal silicon dioxide was sifted separately through # 40 mesh.

iv) the material of step (i) was roller compacted and the resulted compacts were milled using multimill or cone mill with 2mm screen.

v) milled granules of step (iv) were sifted through #30 mesh completely.

vi) granules obtained in step (v) were sifted through #60 mesh; retentions and passed were collected separately.

vii) steps of (iv) to (vi) were repeated with #60 mesh passed granules until 50%w/w of granules were passed through #30/60mesh.

viii) obtained granules of step (vii) were lubricated and blended with magnesium stearate of step (ii) and colloidal silicon dioxide of step (iii).

ix) the obtained blend is compressed into tablets or filled in to capsules.

EXAMPLE – 8

Compositions of nilotinib prepared by dry granulation using slugging method.


Manufacturing process is same as given for examples 1-5.

The dissolution of capsules prepared according to the Example-8 is presented in Table 1.

Table 1

EXAMPLE - 9:

Compositions of nilotinib prepared by dry granulation using slugging method.

Manufacturing process is same as given for examples 1-5.

The dissolution of capsules prepared according to the Example-9 is presented in Table 2.

Table 2

The reference, i.e., Tasigna.RTM. is the nilotinib hydrochloride capsule from the innovator, Novartis. The dissolution rate of the capsule prepared in the present invention were found to be more than 75% in 45 minutes. Thus, the dissolution of the capsules prepared according to the present invention is acceptable.

Thus, by using the above simple and less expensive method, dissolution achieved is at least 75% in 45 minutes without the use of surfactants as shown in the relevant examples.

We claim:

1. A dry-granulated pharmaceutical composition comprising nilotinib or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising nilotinib and at least one excipient selected from diluent(s), binder(s), disintegrant (s), glidant(s), and lubricant(s), where in the composition does not contain any surfactant.

3. The pharmaceutical composition comprising: i) nilotinib or its pharmaceutically acceptable salts, ii) water soluble polymer, iii) optionally one or more excipients selected from diluent(s), binder(s), disintegrant(s), glidant(s), and lubricant(s); where in the composition is free of surfactant.

4. Water soluble polymer according to claim 3, is selected from polyethylene glycol, polyvinyl pyrrolidone, polyethylene oxides, alkyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose or mixtures thereof.

5. A process for preparing dry-granulated pharmaceutical composition of nilotinib comprises compacting nilotinib hydrochloride alone or mixed with one or more of pharmaceutically acceptable excipient(s) by roller compactor or slugging; sizing the compacts or slugs into granules by milling; optionally mixing the granules with one or more of pharmaceutically acceptable excipients to form the composition.

6. Process for preparing compositions comprising nilotinib and one or more pharmaceutically acceptable excipients by dry granulation where in the composition is free of surfactant.

7. Dry-granulated capsule composition comprising nilotinib hydrochloride, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate and optionally hydroxypropyl methylcellulose, where in the composition is free of surfactant.

8. The method of treating Philadelphia chromosome positive chronic myeloid leukemia comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 1, 2, 3 or 7.

9. Nilotinib according to any of the preceding claims is in the form of amorphous nilotinib hydrochloride, anhydrous crystalline nilotinib hydrochloride, crystalline
nilotinib hydrochloride monohydrate, crystalline nilotinib hydrochloride dihydrate or combinations thereof.

10. Pharmaceutical composition according to any of the preceding claims is in the form of capsules, tablets, MUPS, granules, pellets, solid dispersions, beads, particles, mini- tablets, and the like.