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

Background of the invention
Neratinib is a novel HER2-targeted tyrosine kinase inhibitor chemically known as (E)-N-{4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide.
Neratinib as a maleate salt is approved in the form of tablets and marketed by Puma Biotechnology Inc. under the brand name NERLYNX®. The tablets are approved in the strength of Eq. 40 mg base.
Neratinib is indicated for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab based therapy.
US 6288082 and US 7399865 discloses Neratinib and its pharmaceutically acceptable salts including the maleate salt.
US 7982043 discloses a method of treating or inhibiting the growth of breast cancer in a mammal in need thereof, which method comprises administering to said mammal an effective amount of Neratinib or a pharmaceutically acceptable salt thereof.
US 8518446 and US 8790708 discloses oral pharmaceutical formulations of Neratinib provided in the form of coated tablets prepared by fluid bed granulation or by wet granulation, and improved methods of making these coated tablets. The references further discloses that Neratinib is a weak base having low bioavailability and low solubility in both water and alcohol. Neratinib maleate particles exhibit very high surface free energy, (work of cohesion=45.62 mN/m). This property renders the primary particles very cohesive and prone to aggregation. As a consequence of cohesiveness, Neratinib maleate powder does not lend itself easily to pharmaceutical operations such as mixing, flow or fluidization especially when it constitutes a high proportion in a composition. Due to these limitations, it was not possible to develop a Neratinib maleate formulation comprising a capsule or tablet of higher strength employing a direct compression or roller compaction processes successfully. A formulation using a conventional wet granulation method led to chemical degradation and stability issues. It is desirable to provide a Neratinib maleate formulation, where the surface property of the active ingredient is modified by spraying or otherwise applying a substance, such as a polymer like povidone, of low surface energy (for instance about 38 mN/m) on the surface of Neratinib maleate particles.
The reference also discloses a pharmaceutically acceptable composition comprising: a granulation comprising intragranular components: (a) 10-70 weight percent Neratinib maleate; (b) 15-65 weight percent of one or more fillers; (c) 0-8 or 0.5-8 weight percent of one or more disintegrants; and (d) 0.2-8 weight percent, in certain embodiments 0.2-6 weight percent, of one or more glidants; and (e) 5-15 weight percent of one or more surface modifying agents. The granulation is combined with extragranular components (f) 1-25 or 4-25 weight percent of one or more fillers; (g) 1-8 or 0-8 weight percent of one or more disintegrants and (h) 0.1-3 or 0.5-3 weight percent of one or more lubricants, and then compressed into tablets or dry-filled into capsules.
The above prior art references discloses immediate release compositions comprising Neratinib prepared by fluid bed granulation. The references does not disclose a melt granulation process for preparation of Neratinib compositions. The references does not disclose composition comprising more than 70% w/w of Neratinib. The inventors of the present invention have surprisingly found that Neratinib tablets prepared by melt granulation showed comparable/better dissolution with respect to the marketed tablet dosage forms of Neratinib.

Objective of the invention
The main objective of the present invention relates to a pharmaceutical composition comprising Neratinib or a pharmaceutically acceptable salt thereof.
The present invention also relates to a tablet composition comprising Neratinib maleate and one or more pharmaceutically acceptable excipients.
The present invention also relates to a process for the preparation of tablet composition comprising Neratinib maleate and one or more pharmaceutically acceptable excipients having comparable dissolution properties, content uniformity, stability and equivalent bioavailability w.r.t commercialized Neratinib tablet dosage form.

Summary of the invention
Accordingly, the present invention provides a pharmaceutical composition comprising Neratinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
The present invention also relates to a pharmaceutical composition comprising Neratinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the composition is prepared by melt granulation.

Detailed description of the invention
The present invention relates to a pharmaceutical composition comprising Neratinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
The present invention relates to a pharmaceutical composition comprising 70-90% w/w of Neratinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
The present invention further relates to a pharmaceutical composition comprising Neratinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the composition is prepared by melt granulation.
The present invention further relates to a pharmaceutical composition comprising 70-90% w/w of Neratinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the composition is prepared by melt granulation.
The present invention further relates to a pharmaceutical composition comprising granules comprising Neratinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
The present invention further relates to a pharmaceutical composition comprising granules comprising Neratinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the composition is prepared by melt granulation.
The present invention further relates to a pharmaceutical composition comprising granules comprising 70-90% w/w of Neratinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the composition is prepared by melt granulation.
In an embodiment, “Neratinib” according to the present invention includes but not limited to Neratinib free base and its pharmaceutically acceptable salts, ethers, esters, prodrugs, polymorphs and derivatives thereof.
In another embodiment, the pharmaceutically acceptable salt of Neratinib is a maleate 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.
“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, disintegrants, binders, surfactants, polymers, glidants and lubricants. These excipients may be present intragranularly or extragranularly.
Diluents according to the present invention include but not limited to 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.
Disintegrants according to the present invention include but not limited to starches or modified starches such as pregelatinized starch, croscarmellose sodium, carmellose sodium, carmellose calcium, povidone (polyvinyl pyrrolidone), copovidone, crospovidone (Crosslinked polyvinyl pyrrolidone), sodium starch glycolate, low substituted hydroxypropyl cellulose, hydroxypropyl cellulose, alginic acid, and the like or combinations thereof. The disintegrant can be used in the range of about 0-20% 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-glycerides; fatty acid esters of fatty alcohols; polyglycolized glycerides such as gelucire; polyoxyethylene-polyoxypropylene 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.
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, glyceryl mono fatty acid, glyceryl monostearate, glyceryl dibehenate, glyceryl palmito stearic ester, hydrogenated castor oil and mixtures thereof. The lubricant can be used in the range of 0-10% w/w of the composition.
In another embodiment of the present invention, Neratinib may be present in crystalline form or amorphous form.
In another embodiment, the present invention provides a composition comprising Neratinib or a pharmaceutically acceptable salt thereof in crystalline form and one or more pharmaceutically acceptable excipients.
In another embodiment, the present invention relates to a process for the preparation of pharmaceutical composition, comprising the steps of:
(i) blending Neratinib 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 Neratinib 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 Neratinib 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) compressing the lubricated blend of step (iii) into tablet dosage form.
In another embodiment, the present invention relates to a process for the preparation of pharmaceutical composition, comprising the steps of:
(i) blending Neratinib or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients,
(ii) granulating the blend of step (i) by melt granulation,
(iii) blending the granules of step (ii) with one or more pharmaceutically acceptable excipients, and
(iv) compressing the lubricated blend of step (iii) into tablet dosage form.
In another embodiment, the present invention relates to a process for the preparation of pharmaceutical composition, comprising the steps of:
(i) blending Neratinib or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients,
(ii) granulating the blend of step (i) by melt granulation,
(iii) blending the granules of step (ii) with one or more pharmaceutically acceptable excipients,
(iv) compressing the lubricated blend of step (iii) into tablets, and
(v) optionally coating the tablets obtained in step (iv) with a coating composition.
In another embodiment, the present invention relates to a process for the preparation of pharmaceutical composition, comprising the steps of:
(i) blending Neratinib 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
(iii) filling the blend of step (i) into capsules.
In another embodiment, the present invention relates to a process for the preparation of pharmaceutical composition, comprising the steps of:
(i) blending Neratinib or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients,
(ii) granulating the blend of step (i) by melt granulation,
(iii) blending the granules of step (ii) with one or more pharmaceutically acceptable excipients, and
(iv) filling the lubricated blend of step (iii) into 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, solid dispersion, encapsulation and direct compression.
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 tablets.
In another embodiment, the present invention provides a tablet composition comprising Neratinib or a pharmaceutically acceptable salt thereof in the range of about 1mg to about 500 mg, preferably 10mg to 100mg.
In another embodiment of the present invention, the composition comprises Neratinib or a pharmaceutically acceptable salt thereof in an amount of 70-90% w/w, preferably 70-85% w/w, more preferably 70-80% w/w of the composition.
In one preferred embodiment of the present invention, the composition comprises Neratinib or a pharmaceutically acceptable salt thereof in an amount of 70-90% w/w of the composition.
In another embodiment, the present invention provides a tablet composition comprising Neratinib or a pharmaceutically acceptable salt thereof for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab based therapy.
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: Tablet compositions comprising Neratinib maleate
S. No Ingredients Quantity (mg/tab)
Intra-granular
1 Neratinib maleate 48.310
2 PEG 2000 14.493
3 Colloidal silicon dioxide 0.630
Extra-granular
4 Microcrystalline cellulose 42.367
5 Crospovidone 6.900
6 Colloidal silicon dioxide 1.150
7 Magnesium stearate 1.150
Total weight of Core tablet 115.000
Film Coating
8 Opadry® 3.450
Total weight of coated tablet 118.450

The processing steps involved in manufacturing the tablets were given below:
(i) Neratinib maleate, PEG 2000 and colloidal silicon dioxide were sifted separately and blended,
(ii) the blend of step (i) was passed through a twin screw extruder set at 140°C (at Mixing zone) for melt granulation
(iii) the granules obtained in step (ii) were blended with extra-granular microcrystalline cellulose, crospovidone and colloidal silicon dioxide,
(iv) the blend of step (iii) was lubricated with magnesium stearate,
(v) the lubricated granules of step (iv) were compressed into tablets, and
(vi) the tablets prepared in step (v) was coated with Opadry® film coating composition.

Example 2:
S. No Ingredients Quantity (mg/tab)
Intra-granular
1 Neratinib maleate 48.310
2 PEG 2000 4.831
3 Hydroxy propyl cellulose 4.831
4 Colloidal silicon dioxide 0.580
Extra-granular
5 Microcrystalline cellulose 47.248
6 Crospovidone 6.900
7 Colloidal silicon dioxide 1.150
8 Magnesium stearate 1.150
Total weight of Core tablet 115.000
Film Coating
9 Opadry® 3.450
Total weight of coated tablet 118.450

Example 3:
S. No Ingredients Quantity (mg/tab)
Intra-granular
1 Neratinib maleate 48.310
2 PEG 2000 7.247
3 Colloidal silicon dioxide 0.575
Extra-granular
4 Colloidal silicon dioxide 0.575
5 Magnesium stearate 0.575
Total weight of Core tablet 57.282
Film Coating
6 Opadry® 1.718
Total weight of coated tablet 59.000

Example 4:
S. No Ingredients Quantity (mg/tab)
Intra-granular
1 Neratinib maleate 48.310
2 PEG 2000 7.247
3 Hydroxy propyl cellulose 7.247
4 Colloidal silicon dioxide 0.650
Extra-granular
5 Colloidal silicon dioxide 0.650
6 Magnesium stearate 0.650
Total weight of Core tablet 64.754
Film Coating
7 Opadry® 1.943
Total weight of coated tablet 66.697

Example 5:
S. No Ingredients Quantity (mg/tab)
Intra-granular
1 Neratinib maleate 48.330
2 Polyethylene glycol 4000 12.083
3 Colloidal silicon dioxide 0.630
Extra-granular
5 Crospovidone XL 10 1.327
6 Magnesium stearate 0.630
Total weight of Core tablet 63.000

The tablets compositions given in Examples 2-5 were prepared using similar process provided in Example-1.
,CLAIMS:We Claim:
1. A pharmaceutical composition comprising Neratinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the composition is prepared by melt granulation.

2. The composition as claimed in Claim 1, wherein the composition comprises Neratinib or a pharmaceutically acceptable salt thereof in an amount of 70-90% w/w of the composition.

3. The composition as claimed in Claim 1, wherein the composition is in the form of tablets, capsules, granules and sachets.

4. The composition as claimed in Claim 1, wherein one or more pharmaceutically acceptable excipients is selected from the group consisting of disintegrants, binders, surfactants, glidants and lubricants and combination thereof.

5. The composition as claimed in Claim 4, wherein the binder is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, Polyvinylpyrrolidone (povidone), polyethylene glycol, gelatin, ethyl cellulose, polyvinyl alcohol, pregelatinized starch, carboxymethyl cellulose, sodium alginate and combination thereof.

6. The composition as claimed in Claim 4, wherein the disintegrant is selected from the group consisting of starch, pregelatinized starch, croscarmellose sodium, crospovidone, sodium starch glycolate, low substituted hydroxypropyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose and combination thereof.

7. The composition as claimed in Claim 4, wherein the glidant is selected from the group consisting of silica, colloidal silicon dioxide, talc, magnesium silicate and combination thereof.
8. The composition as claimed in Claim 4, wherein the lubricant is selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, zinc stearate, glyceryl mono fatty acid, glyceryl monostearate, glyceryl dibehenate, glyceryl palmito stearic ester, hydrogenated castor oil and combination thereof.

9. The composition as claimed in Claim 1, wherein the Neratinib is present in crystalline form or amorphous form.

10. The composition as claimed in Claim 1, wherein the composition is prepared by a process comprising the steps of:
(i) blending Neratinib or a pharmaceutically acceptable salt thereof with one or
more pharmaceutically acceptable excipients,
(ii) granulating the blend of step (i) by melt granulation,
(iii) blending the granules of step (ii) with one or more pharmaceutically
acceptable excipients,
(iv) compressing the lubricated blend of step (iii) into tablets, and
(v) optionally coating the tablets obtained in step (iv) with a coating
composition.