PHARMACEUTICAL COMPOSITIONS COMPRISING NILOTINIB

Field of the invention

The present invention relates to pharmaceutical compositions comprising a tyrosine kinase inhibitor. More particularly, the present invention relates to a composition comprising Nilotinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients and process for preparing such compositions.

Background of the invention

Nilotinib, a synthetic aminopyrimidine, is an ATP-competitive inhibitor for BCR-ABL. The chemical name of nilotinib is 4-methyl-N-[3-(4-methyl-lH-imidazol- l-yl)-5-(trifhioromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrim idinyl]amino]benzamide.

Nilotinib is approved as a monohydrochloride monohydrate salt in the form of capsules and marketed by Novartis under the brand name TASIGNA®. The Capsules are approved in the strengths of 50mg, 150 mg and 200 mg.

Nilotinib is a kinase inhibitor indicated for the treatment of: Adult and pediatric patients greater than or equal to 1 year of age with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. Adult patients with chronic phase (CP) and accelerated phase (AP) Ph+ CML resistant to or intolerant to prior therapy that included imatinib. Pediatric patients greater than or equal to 1 year of age with Ph+ CML-CP resistant or intolerant to prior tyrosine-kinase inhibitor (TKI) therapy.

TASIGNA (nilotinib) capsules, for oral use, contain 50 mg, 150 mg or 200 mg nilotinib base, anhydrous (as hydrochloride, monohydrate) with the following inactive ingredients: colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate and polyoxamer 188. The capsules contain gelatin, iron oxide (red), iron oxide (yellow), iron oxide (black) and titanium dioxide.

US 8501760 discloses a pharmaceutical composition comprising nilotinib. Such a pharmaceutical composition may be prepared by a wet granulation process for preparing granules that are subsequently filled into a capsule.

US 8501760 further discloses that “The present invention provides for a novel pharmaceutical composition that comprises a therapeutic compound of formula I, for example, nilotinib or a salt thereof. The pharmaceutical compositions are in the form of solid oral dosage forms, especially capsules. The capsules are filled with granules of the therapeutic compound blended with an external phase comprising at least one pharmaceutically acceptable excipient. A particularly useful process for making the granules is a wet granulation process. The therapeutic compound and any pharmaceutically acceptable excipients, for example a surfactant, are wet massed with purified water (or organic solvents) and subsequently dried to form granules”.

TASIGNA (nilotinib) capsules were marketed in form of hard gelatin capsules. However, the EMEA scientific discussion of TASIGNA (Nilotinib) capsules disclosed that:

“Some gelatin shell cross linking was observed which was always reversible after addition of pepsin to the dissolution medium as recommended according to USP. At accelerated storage conditions gelatin shell cross linking was also observed. For some samples cross linking could not be reversed by addition of pepsin and thus did not comply with the specifications”.

Further, the EMEA assessment report for TASIGNA (nilotinib) capsules (Procedure No.: EMEA/H/C/000798/X/0028 dated December 20, 2010) further disclosed that:

“Stability results have been presented for up to 24 months in long-term and intermediate and up to six months in accelerated conditions. Supportive results for up to six months at -20 °C, up to 24 months at 5 °C and up to three months at 50°C were also provided. All test results stayed well within the proposed specifications with following exceptions. After 6 months storage at 40 C one batch failed to meet dissolution specification. This was explained as a result of a cross-linking phenomenon of the Gelatine shell (formation of water insoluble membrane during dissolution) occurring when hard gelatin capsules are stressed by high temperature and humidity. The reversibility of the cross-linking phenomenon can be demonstrated by adding pepsin to the dissolution medium. An investigation of this phenomenon has been performed at the 200 mg capsules (it has been concluded that the excipients Poloxamer, Lactose and probably Crospovidone are inducing the reaction). Relating to these points it has to be considered that gelatine capsules generally are not considered to be suitable at storage conditions above 30°C”.

In view of this, there exists a need to develop alternate compositions of Nilotinib. The inventors have surprisingly found that, Nilotinib composition when filled into capsules made up of hydroxypropyl methylcellulose (HPMC capsules), the problem of cross linking was eliminated and the composition was found to have comparable dissolution properties, content uniformity, stability and equivalent bioavailability w.r.t commercialized Nilotinib capsule dosage form.

Objective of the invention

The main objective of the present invention relates to a pharmaceutical composition comprising Nilotinib or a pharmaceutically acceptable salt thereof.

The present invention also relates to a capsule composition comprising Nilotinib and one or more pharmaceutically acceptable excipients.

The present invention also relates to a process for the preparation of capsule composition comprising Nilotinib and one or more pharmaceutically acceptable excipients having comparable dissolution properties, content uniformity, stability and equivalent bioavailability w.r.t commercialized Nilotinib capsule dosage form.

Summary of the invention Accordingly, the present invention provides a pharmaceutical composition comprising Nilotinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

The present invention also relates to a capsule composition comprising Nilotinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

The present invention also relates to a capsule composition comprising Nilotinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the composition is not prepared by wet granulation process.

The present invention also relates to a capsule composition comprising Nilotinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the composition is filled into capsules made up of hydroxypropyl methylcellulose (HPMC capsules).

Detailed description of the invention

The present invention relates to a pharmaceutical composition comprising Nilotinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

The present invention also relates to a capsule composition comprising Nilotinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

The present invention also relates to a capsule composition comprising Nilotinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the composition is not prepared by wet granulation process.

The present invention further relates to a capsule composition comprising Nilotinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the composition is not filled into capsules made up of gelatin.

The present invention further relates to a capsule composition comprising Nilotinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the composition is filled into capsules made up of hydroxypropyl methylcellulose (HPMC capsules).

In an embodiment, “Nilotinib” according to the present invention includes but not limited to Nilotinib free base and its pharmaceutically acceptable salts, ethers, esters, prodrugs, polymorphs and derivatives thereof.

In another embodiment, “Nilotinib” according to the present invention is in the form of nilotinib hydrochloride salt.

In another embodiment, “Nilotinib” according to the present invention is in the form of nilotinib hydrochloride salt which may be in the form of anhydrous, monohydrate, dihydrate or trihydrate.

In another embodiment, “Nilotinib” according to the present invention is in the form of nilotinib hydrochloride monohydrate salt.

As used herein, the term “% w/w” refers to the weight of the component based on the total weight of a composition comprising the component.

In another embodiment of the present invention, the composition comprises nilotinib hydrochloride monohydrate in an amount of 30-90% w/w, preferably 40-70 %w/w and most preferably 50-60% w/w of the composition.

“Pharmaceutically acceptable excipient/s” are the components added to pharmaceutical formulation to facilitate manufacture, enhance stability, control release, enhance product characteristics, enhance bioavailability, enhance patient acceptability, etc.

In another embodiment, the composition according to the present invention further comprises one or more pharmaceutically acceptable excipients which include but not limited to diluents/fillers, binders, surfactants, polymers, glidants and lubricants. These excipients may be present intragranularly or extragranularly. Diluents/fillers according to the present invention include but not limited to microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate, lactose anhydrous, fructose, maltose, trehalose, dextrose, polydextrose, dextrates, dextrins, isomalt, mannitol, maltitol, xylitol, maltodextrin, lactitol, sorbitol, erythritol, inulin, starch, sucrose, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, sodium bicarbonate, sodium carbonate, sodium chloride, cellulose acetate, ethyl cellulose, cellulose powdered, kaolin and the like or combinations thereof. The diluent can be used in the range of about 5-90% w/w of the composition.

Binders according to the present invention include but not limited to hydroxypropyl methylcellulose (Hypromellose), hydroxypropyl cellulose, gelatin, ethyl cellulose, polyvinyl alcohol, pregelatinized starch, carboxymethyl cellulose, sodium alginate, polyvinyl pyrrolidones (povidone), copovidone, microcrystalline cellulose, gelatin, polymethacrylates, polyethylene glycols (PEG), Poly(vinyl caprolactam-co-vinyl acetate-ethylene glycol) graft polymer (SOLUPLUS®), poloxamers, polyethylene oxide, acrylate based copolymers and the like or combinations thereof. The binder can be used in the range of about 0-15% w/w of the composition.

Surfactants according to the present invention may be selected from anionic, cationic or non- ionic surface-active agents or surfactants. Suitable anionic surfactants include but not limited to carboxylate, sulfonate, and sulfate ions such as sodium lauryl sulfate (SLS), sodium laurate, dialkyl sodium sulfosuccinates particularly bis- (2-ethylhexyl) sodium sulfosuccinate, sodium stearate, potassium stearate, sodium oleate and the like. Suitable cationic surfactants include but not limited to those containing long chain cations, such as benzalkonium chloride, bis-2- hydroxyethyl oleyl amine or the like. Suitable non-ionic surfactants include but not limited to polyoxyethylene sorbitan fatty acid esters (polysorbates), fatty alcohols such as lauryl, cetyl and stearyl alcohols; glyceryl esters such as the naturally occurring mono-, di-, and tri-glycendes; fatty acid esters of fatty alcohols; polyglycolized glycerides such as gelucire; polyoxyethylene-poly oxypropylene block co-polymer such as Poloxamer and other alcohols such as propylene glycol, polyethylene glycol. The surfactant can be used in the range of about 0-20% w/w of the composition.

Polymers according to the present invention include but not limited to hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, propylene glycol alginate ester, sodium caseinate, a carboxyvinyl polymer, powdered agar, guar gum, copolyvidone, hydroxyethylmethyl cellulose, or polyvinyl alcohol, the gastric- soluble polymer is amino alkylmethacrylate copolymer E, or polyvinylacetal diethylaminoacetate, and the enteric-soluble polymer is methacrylic acid copolymer LD, purified shellac, carboxymethylethyl cellulose, cellulose acetate phthalate, hydroxypropylmethyl cellulose acetate succinate, methacrylic acid copolymer S, casein, zein and mixtures thereof. The polymer can be used in the range of about 0- 60% w/w of the composition.

Glidants according to the present invention include but not limited to silica, colloidal silicon dioxide, talc and magnesium silicate and mixtures thereof. The glidants can be used in the range of 0-10% w/w of the composition.

Lubricants according to the present invention include but not limited to stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, zinc stearate, talc, glyceryl mono fatty acid, glyceryl monostearate, glyceryl dibehenate, glyceryl palmito stearic ester, hydrogenated castor oil and mixtures thereof. The Lubricants can be used in the range of 0-10% w/w of the composition.

In another embodiment of the present invention, Nilotinib may be present in crystalline form or amorphous form.

In another embodiment of the present invention, Nilotinib may be present in the form of monohydrate, dihydrate or anhydrate form.

In another embodiment, the present invention relates to a process for the preparation of pharmaceutical composition, comprising the steps of: (i) blending Nilotinib or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients,

(ii) formulating the blend of step (i) into suitable dosage form.

In another embodiment, the present invention relates to a process for the preparation of pharmaceutical composition, comprising the steps of:

(i) blending Nilotinib or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients,

(ii) optionally, lubricating the blended material of step (i) with a lubricant, and

(iii) preparing the lubricated material of step (ii) into a suitable dosage form.

In another embodiment, the present invention relates to a process for the preparation of pharmaceutical composition, comprising the steps of:

(i) blending Nilotinib or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients,

(ii) optionally, lubricating the blended material of step (i) with a lubricant, and

(iii) filling the lubricated material of step (ii) into capsules.

In another embodiment, the present invention relates to a process for the preparation of pharmaceutical composition, comprising the steps of:

(i) blending Nilotinib or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients,

(ii) lubricating the blended material of step (i) with a lubricant, and

(iii) filling the lubricated material of step (ii) into capsules.

In another embodiment, the present invention relates to a process for the preparation of pharmaceutical composition, comprising the steps of:

(i) blending Nilotinib or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients,

(ii) lubricating the blended material of step (i) with a lubricant, and

(iii) filling the lubricated material of step (ii) into capsules made up of hydroxypropyl methylcellulose. In another embodiment, the present invention relates to a process for preparing the capsule composition, wherein the process comprises the steps of:

(i) blending Nilotinib or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients,

(ii) lubricating the blended material of step (i) with a lubricant, and

(iii) filling the lubricated blend of step (ii) into capsules.

In another embodiment, the present invention relates to a process for preparing the capsule composition, wherein the process comprises the steps of:

(i) blending Nilotinib or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients,

(ii) lubricating the blended material of step (i) with a lubricant, and

(iii) filling the lubricated blend of step (ii) into capsules made up of hydroxypropyl methylcellulose.

In another embodiment, the present invention relates to a process for the preparation of pharmaceutical composition, comprising the steps of:

(i) blending Nilotinib or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients,

(ii) granulating the blend of step (i),

(iii) blending the granules of step (ii) with one or more pharmaceutically acceptable excipients, and

(iv) formulating the blend of step (iii) into a suitable dosage form.

In another embodiment, the present invention relates to a process for the preparation of pharmaceutical composition, comprising the steps of:

(i) blending Nilotinib or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients,

(ii) granulating the blend of step (i),

(iii) blending the granules of step (ii) with one or more pharmaceutically acceptable excipients, and

(iv) filling the blend of step (iii) into capsules. In another embodiment, the present invention relates to a process for the preparation of pharmaceutical composition, comprising the steps of:

(i) granulating Nilotinib or a pharmaceutically acceptable salt thereof,

(iii) blending the granules of step (i) with one or more pharmaceutically acceptable excipients, and

(iii) formulating the blend of step (ii) into a suitable dosage form.

In another embodiment, the present invention relates to a process for the preparation of pharmaceutical composition, comprising the steps of:

(i) granulating Nilotinib or a pharmaceutically acceptable salt thereof,

(iii) blending the granules of step (i) with one or more pharmaceutically acceptable excipients, and

(iii) filling the blend of step (ii) into capsules.

In another embodiment, the present invention relates to a capsule composition comprising:

(i) Nilotinib or a pharmaceutically acceptable salt thereof,

(ii) at least one diluent,

(iii) at least one disintegrant,

(iv) at least one surfactant,

(iv) at least one glidant and

(v) at least one lubricant.

In another embodiment, the present invention relates to a capsule composition comprising:

(i) 50-60% w/w of Nilotinib or a pharmaceutically acceptable salt thereof,

(ii) 20-80% w/w of at least one diluent,

(iii) 1-10% w/w of at least one disintegrant,

(iv) 0.5-5% w/w at least one surfactant,

(iv) 0.5-5% w/w of at least one glidant and

(v) 0.5-5% w/w of at least one lubricant. In another embodiment, the present invention relates to a capsule composition comprising:

(i) Nilotinib or a pharmaceutically acceptable salt thereof,

(ii) at least one diluent,

(iii) at least one disintegrant,

(iv) at least one surfactant,

(iv) at least one glidant and

(v) at least one lubricant, wherein the capsule is made up of hydroxypropyl methylcellulose (HPMC capsules).

In another embodiment, the present invention relates to a capsule composition comprising:

(i) 50-60% w/w of Nilotinib or a pharmaceutically acceptable salt thereof,

(ii) 20-80% w/w of at least one diluent,

(iii) 1-10% w/w of at least one disintegrant,

(iv) 0.5-5% w/w of at least one surfactant,

(iv) 0.5-5% w/w of at least one glidant and

(v) 0.5-5% w/w of at least one lubricant, wherein the capsule is made up of hydroxypropyl methylcellulose (HPMC capsules).

In another embodiment, the present invention relates to a capsule composition comprising:

(i) Nilotinib or a pharmaceutically acceptable salt thereof,

(ii) at least one diluent selected from mannitol, microcrystalline cellulose and lactose,

(iii) at least one disintegrant selected from sodium starch glycolate, crospovidone and croscarmellose sodium,

(iv) at least one surfactant selected from sodium lauryl sulphate and Poloxamer,

(iv) at least one glidant selected from colloidal silicon dioxide and talc and

(v) at least one lubricant selected from magnesium stearate and sodium stearyl fumarate. In another embodiment, the present invention relates to a capsule composition comprising:

(i) Nilotinib or a pharmaceutically acceptable salt thereof,

(ii) at least one diluent selected from mannitol, microcrystalline cellulose and lactose,

(iii) at least one disintegrant selected from sodium starch glycolate, crospovidone and croscarmellose sodium,

(iv) at least one surfactant selected from sodium lauryl sulphate and poloxomer,

(iv) at least one glidant selected from colloidal silicon dioxide and talc and

(v) at least one lubricant selected from magnesium stearate and sodium stearyl fumarate, wherein the capsule is made up of hydroxypropyl methylcellulose (HPMC capsules).

In another embodiment, the present invention relates to a capsule composition comprising:

(i) 50-60% w/w of Nilotinib monohydrochloride monohydrate,

(ii) 20-80% w/w of at least one diluent selected from mannitol, microcrystalline cellulose and lactose,

(iii) 1-10% w/w of at least one disintegrant selected from sodium starch glycolate, crospovidone and croscarmellose sodium,

(iv) 0.5-5% w/w of at least one surfactant selected from sodium lauryl sulphate and poloxomer,

(iv) 0.5-5% w/w of at least one glidant selected from colloidal silicon dioxide and talc and

(v) 0.5-5% w/w of at least one lubricant selected from magnesium stearate and sodium stearyl fumarate.

In another embodiment, the present invention relates to a capsule composition comprising:

(i) 50-60% w/w of Nilotinib monohydrochloride monohydrate,

(ii) 20-80% w/w of at least one diluent selected from mannitol, microcrystalline cellulose and lactose, (in) 1-10% w/w of at least one disintegrant selected from sodium starch glycolate, crospovidone and croscarmellose sodium,

(iv) 0.5-5% w/w of at least one surfactant selected from sodium lauryl sulphate and poloxomer,

(iv) 0.5-5% w/w of at least one glidant selected from colloidal silicon dioxide and talc and

(v) 0.5-5% w/w of at least one lubricant selected from magnesium stearate and sodium stearyl fumarate, wherein the capsule is made up of hydroxypropyl methylcellulose (HPMC capsules).

In another embodiment, the present invention relates to a capsule composition comprising:

(i) 50-60% w/w of Nilotinib monohydrochloride monohydrate,

(ii) 20-80% w/w of mannitol,

(iii) 1-10% w/w of crospovidone,

(iv) 0.5-5% w/w of poloxomer,

(iv) 0.5-5% w/w of colloidal silicon dioxide and

(v) 0.5-5% w/w of sodium stearyl fumarate

In another embodiment, the present invention relates to a capsule composition comprising:

(i) 50-60% w/w of Nilotinib monohydrochloride monohydrate,

(ii) 20-80% w/w of mannitol,

(iii) 1-10% w/w of crospovidone,

(iv) 0.5-5% w/w of poloxomer,

(iv) 0.5-5% w/w of colloidal silicon dioxide and

(v) 0.5-5% w/w of sodium stearyl fumarate, wherein the capsule is made up of hydroxypropyl methylcellulose (HPMC capsules).

In another embodiment, the present invention relates to a capsule composition comprising: (i) 50-60% w/w of Nilotinib monohydrochloride monohydrate,

(ii) 20-80% w/w of lactose,

(iii) 1-10% w/w of sodium starch glucolate,

(iv) 0.5-5% w/w of sodium lauryl sulphate,

(iv) 0.5-5% w/w of colloidal silicon dioxide and

(v) 0.5-5% w/w of sodium stearyl fumarate, wherein the capsule is made up of hydroxypropyl methylcellulose (HPMC capsules).

In another embodiment, the present invention relates to a capsule composition comprising:

(i) 50-60% w/w of Nilotinib monohydrochloride monohydrate,

(ii) 20-80% w/w of mannitol,

(iii) 1-10% w/w of sodium starch glucolate,

(iv) 0.5-5% w/w of poloxamer,

(iv) 0.5-5% w/w of colloidal silicon dioxide and

(v) 0.5-5% w/w of sodium stearyl fumarate, wherein the capsule is made up of hydroxypropyl methylcellulose (HPMC capsules).

In another embodiment, the present invention relates to a capsule composition of Nilotinib prepared by a process comprising the steps of:

(i) blending Nilotinib or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients,

(ii) optionally, lubricating the blended material of step (i) with a lubricant, and

(iii) filling the lubricated blend of step (ii) into capsules.

In another embodiment, the present invention relates to a capsule composition of Nilotinib prepared by a process comprising the steps of:

(i) blending Nilotinib or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients,

(ii) lubricating the blended material of step (i) with a lubricant, and

(iii) filling the lubricated blend of step (ii) into capsules. In another embodiment, the present invention relates to a capsule composition of Nilotinib prepared by a process comprising the steps of:

(i) blending Nilotinib or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients,

(ii) lubricating the blended material of step (i) with a lubricant, and

(iii) filling the lubricated blend of step (ii) into capsules made up of hydroxypropyl methylcellulose (HPMC capsules).

In another embodiment, the present invention relates to a capsule composition of Nilotinib prepared by a process comprising the steps of:

(i) blending Nilotinib or a pharmaceutically acceptable salt thereof with a diluent, surfactant, disintegrant and a glidant,

(ii) lubricating the blended material of step (i) with a lubricant, and

(iii) filling the lubricated blend of step (ii) into capsules.

In another embodiment, the present invention relates to a capsule composition of Nilotinib prepared by a process comprising the steps of:

(i) blending Nilotinib or a pharmaceutically acceptable salt thereof with a diluent, surfactant, disintegrant and a glidant,

(ii) lubricating the blended material of step (i) with a lubricant, and

(iii) filling the lubricated blend of step (ii) into capsules made up of hydroxypropyl methylcellulose (HPMC capsules).

In another embodiment, the present invention relates to a capsule composition of Nilotinib prepared by a process comprising the steps of:

(i) blending Nilotinib hydrochloride monohydrate with a diluent, surfactant, disintegrant and a glidant,

(ii) lubricating the blended material of step (i) with a lubricant, and

(iii) filling the lubricated blend of step (ii) into capsules made up of hydroxypropyl methylcellulose (HPMC capsules).

In another embodiment, the present invention relates to a capsule composition of Nilotinib prepared by a process comprising the steps of: (i) blending Nilotinib hydrochloride monohydrate with Mannitol, Poloxamer, Crospovidone and Colloidal silicon dioxide,

(ii) lubricating the blended material of step (i) with a Sodium stearyl fumarate, and

(iii) filling the lubricated blend of step (ii) into capsules made up of hydroxypropyl methylcellulose (HPMC capsules).

In another embodiment, the pharmaceutical composition according to the present invention is in the form of tablets, capsules, granules, powder, pellets and sachets.

In another embodiment, the blend is formulated into a suitable dosage form like tablets or capsules using different techniques which are well known in the prior art.

In another embodiment, the compositions of the present invention may be prepared using any method known in the art, but are not limited to wet granulation, melt granulation, dry granulation, roller compaction, direct compression, solid dispersion, direct blending and encapsulation.

In another embodiment, the granulation can be done using one pharmaceutically acceptable excipient, a binder, which can be added to the drug substance in a dissolved state (e.g. in an aqueous/non-aqueous solution) or in a powder form and then granulated by adding a granulation liquid. A combination of more than one binder can be used.

In another embodiment, the solvents used for granulation process may be selected from water, isopropyl alcohol, methanol, ethanol, methylene chloride or combination thereof.

In another embodiment, the granulation can be done using any method known in the art, but are not limited to fluidized bed granulation, high-shear granulation, low shear granulation, spray granulation, melt granulation and hot melt extrusion.

The pharmaceutical composition may be further film coated with functional or non functional layer. The coating may be selected from amongst one or more of those suitable coating materials known in the art. For example, the coating material can be Opadry or Opadry AMB. Coating may be performed by applying one or more film forming polymers, with or without other pharmaceutically inert excipients, as a solution/suspension using any conventional coating technique known in the art, such as spray coating in a conventional coating pan or fluidized bed processor; or dip coating.

Coloring agent may be selected from FDA approved colorants such as Iron Oxide, Lake of Tartrazine, Allura Red, Lake of Quinoline Yellow, Lake of Erythrosine, Titanium Dioxide and the like.

In one preferred embodiment, the pharmaceutical composition according to the present invention is in the form of capsules.

In another preferred embodiment, the pharmaceutical composition according to the present invention is not prepared by wet granulation.

In one preferred embodiment, the pharmaceutical composition according to the present invention is filled into capsules made up of hydroxypropyl methyl cellulose (HPMC capsules).

In yet another embodiment, the present invention provides a capsule composition comprising Nilotinib or a pharmaceutically acceptable salt thereof in the range of about Img to about 500 mg, preferably 50mg to 200mg.

In another embodiment, the present invention provides a capsule composition comprising Nilotinib or a pharmaceutically acceptable salt thereof for the treatment of patients with chronic myeloid leukemia.

The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. Example 1: Capsule composition comprising Nilotinib

The processing steps involved in manufacturing the capsules were given below:

(i) Nilotinib hydrochloride monohydrate, Mannitol, Poloxamer 188, Croscarmellose sodium and Colloidal silicon dioxide were sifted separately and blended,

(ii) the blend of step (i) was lubricated with Sodium stearyl fumarate,

(v) the lubricated blend of step (ii) was filled into HPMC capsules.

Example 2:

Example 3:

The process involved in manufacturing the capsules of Examples 2-3 is similar to the process provided in Example 1.

Example 4:

The processing steps involved in manufacturing the capsules were given below:

(i) Nilotinib Hydrochloride Monohydrate, Mannitol, Poloxamer 188, Crospovidone and Colloidal silicon dioxide were sifted separately and blended, (ii) the blend of step (i) was lubricated with Sodium stearyl fumarate,

(v) the lubricated blend of step (ii) was filled into HPMC capsules.

Dissolution Data: Table 1 given below provides the comparative dissolution profile of Nilotinib hydrochloride capsules 200 mg prepared according to Example 4 with TASIGNA® (Nilotinib) capsules 200 mg in 1000 ml of 0.1N HC1 as dissolution medium in USP I apparatus (basket) at 100 rpm.

Table 1: Comparative dissolution profile of Nilotinib hydrochloride capsules 200mg prepared according to Example 4 with TASIGNA® (Nilotinib) capsules 200mg

Based on the above data more than 85% release was observed within 15 minutes in both Nilotinib hydrochloride capsules 200 mg prepared according to Example 4 and TASIGNA® (Nilotinib) capsules 200 mg. Hence, it was concluded that the dissolution profile of Nilotinib hydrochloride capsules 200 mg prepared according to

Example 4 was comparable with TASIGNA® (Nilotinib) capsules 200 mg.