WO2021220295A1

WO2021220295A1 - Immediate release pharmaceutical compositions comprising palbociclib

Info

Publication number: WO2021220295A1
Application number: PCT/IN2021/050405
Authority: WO
Inventors: Krishna Murthy Bhavanasi; Rama Swamy Chowdary TRIPURANENI; Chaitanya Kumar SAGI; Pavan Bhat; Venkaiah Chowdary Nannapaneni
Original assignee: Natco Pharma Limited
Priority date: 2020-04-29
Filing date: 2021-04-24
Publication date: 2021-11-04

Abstract

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

Description

IMMEDIATE RELEASE PHARMACEUTICAL COMPOSITIONS COMPRISING PALBOCICLIB

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

Background of the invention

Palbociclib is a potent and selective inhibitor of CDK4 and CDK6 and is chemically known as 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-l-yl)pyridin- 2yl] amino } pyrido [2,3-d]pyrimidin-7(8H)-one. Palbociclib in the form of free base is approved in the form of capsules and tablets and marketed by Pfizer under the brand name IBRANCE^®. The capsules and tablets are approved in the strengths of 75 mg, 100 mg and 125 mg.

Palbociclib is indicated for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2) -negative advanced or metastatic breast cancer in combination with:

• an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women or in men; or

• fulvestrant in patients with disease progression following endocrine therapy. WO 2003/062236 A1 discloses Palbociclib or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. The reference discloses that this invention relates to substituted 2-amino pyridines that are potent inhibitors of cyclin-dependent kinase 4. The compounds of the invention are useful for the treatment of inflammation, and cell proliferative diseases such as cancer and restenosis. WO 2016/193860 A1 discloses a solid dosage form comprising palbociclib, a water-soluble acid, and a pharmaceutically acceptable carrier. This reference further discloses a solid dosage form comprises from about 10 wt% to about 35 wt% of palbociclib, from about 5 wt% to about 25 wt% of a water-soluble acid selected from the group consisting of succinic acid, malic acid and tartaric acid, and a pharmaceutically acceptable carrier. This publication further discloses that Palbociclib is a dibasic compound and has two basic groups with pKa's of approximately 7.3 (the secondary piperazine nitrogen) and 4.1 (the pyridine nitrogen). The solubility of palbociclib free base is pH dependent. Palbociclib is water soluble at low pH (2.1 -4.5), while the solubility dramatically decreases as pH rises above 4.5. Palbociclib has poor water solubility (9 pg/ml) at pH 7.9. Concomitant administration of agents which increase gastric pH can alter the solubility and absorption of palbociclib free base formulations.

WO 2016/030439 A1 discloses a composition comprising different percentages of Palbociclib, filler, disintegrant, lubricant, glidant, and surfactant.

WO 2016/070833 A1 discloses a composition comprising a solid dispersion prepared by Palbociclib, a disintegrant, a diluent, a binder, a lubricant, a glidant.

WO 2016/070834 A1 discloses a composition comprising Palbociclib or a salt thereof, and a pharmaceutically acceptable excipient as a carrier, wherein the salt is selected from the group consisting of hydrochloride and isethionate. This publication discloses composition comprising different percentages of Palbociclib, diluent, disintegrant, lubricant, binder and surfactant.

WO 2016/156070 A1 discloses a pharmaceutical composition comprising an effective amount of palbociclib and a pH modifier which is a weak acid, preferably an organic acid.

WO 2017/036390 A1 discloses a pharmaceutical composition containing a Palbociclib solid dispersion, comprising a solid dispersion formed by Palbociclib and an organic carrier and at least one pharmaceutical excipient, wherein Palbociclib is amorphous. The pharmaceutical composition of the present invention increases the dissolution rate of Palbociclib, and helps improve the bioavailability of medicine.

WO 2017/115315 A1 discloses an amorphous solid dispersion of palbociclib with a pharmaceutically acceptable excipient. WO 2017/130219 A1 discloses composition comprising a stable amorphous solid dispersion of Palbociclib with one or more pharmaceutically acceptable carrier, optionally with one or more pharmaceutically acceptable excipients and process for the preparation of the composition.

WO 2017/166451 A1 discloses a pharmaceutical formulation of palbociclib, comprising a palbociclib free base or a pharmaceutically acceptable salt thereof and an acidic auxiliary material, wherein the acidic auxiliary material is one or more selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid and malic acid. This reference further discloses a solid dispersion of pabutrazil comprising a paclitaxel free base or a pharmaceutically acceptable salt thereof, an acidic adjuvant, and a hydrophilic polymeric material.

WO 2018/191950 A1 discloses a Palbociclib composition comprising Palbociclib co-milled with at least one hydrophilic excipient.

WO 2019/020715 A1 discloses a pharmaceutical granulate composition comprising a therapeutically effective dose of crystalline Palbociclib and one or more pharmaceutically acceptable excipients, wherein the Palbociclib crystals are needles with a surface area between 6 and 15 m²/g, and a particle size distribution d(0.9) between 5 and 50 micrometers.

The above prior art references discloses different compositions comprising Palbociclib. Still, there exists a need for the development of formulations comprising Palbociclib. The inventors of the present invention have surprisingly found that a tablet composition comprising Palbociclib and water soluble acid in separate layers showed comparable/better dissolution with respect to the marketed tablet dosage forms of Palbociclib which contain a water soluble acid. Objective of the invention

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

The present invention also relates to immediate release tablet composition comprising Palbociclib and one or more pharmaceutically acceptable excipients.

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

Summary of the invention

The present invention also relates to an immediate release tablet composition comprising a core comprising Palbociclib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients coated with a composition comprising a water soluble acid.

The present invention also relates to an immediate release tablet composition comprising:

(i) a core comprising Palbociclib or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients; and

(ii) a coating composition comprising a water soluble acid and one or more pharmaceutically acceptable excipients.

(i) a core comprising Palbociclib or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients; and (ii) a coating composition comprising fumaric acid and one or more pharmaceutically acceptable excipients.

The present invention also relates to an immediate release bilayered tablet composition comprising a first layer comprising Palbociclib or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients and a second layer comprising a water soluble acid and one or more pharmaceutically acceptable excipients.

The present invention also relates to an immediate release bilayered tablet composition comprising a first layer comprising Palbociclib or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients and a second layer comprising fumaric acid and one or more pharmaceutically acceptable excipients.

Detailed description of the invention The present invention relates to an immediate release pharmaceutical composition comprising Palbociclib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

The present invention further relates to an immediate release pharmaceutical composition comprising Palbociclib or a pharmaceutically acceptable salt thereof, a water soluble acid and one or more pharmaceutically acceptable excipients, wherein the composition contains palbociclib and water soluble acid in separate layers.

The present invention also relates an immediate release tablet composition comprising Palbociclib or a pharmaceutically acceptable salt thereof, a water soluble acid and one or more pharmaceutically acceptable excipients, wherein the composition contains palbociclib and water soluble acid in separate layers.

The present invention also relates to an immediate release pharmaceutical composition comprising a core comprising Palbociclib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients coated with a composition comprising a water soluble acid. The present invention also relates to an immediate release tablet composition comprising a core comprising Palbociclib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients coated with a composition comprising a water soluble acid.

(ii) a coating composition comprising fumaric acid and one or more pharmaceutically acceptable excipients.

The present invention also relates to an immediate release bilayered tablet composition comprising (i) a first layer comprising Palbociclib or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients and

(ii) a second layer comprising a water soluble acid and one or more pharmaceutically acceptable excipients.

The present invention also relates to an immediate release bilayered tablet composition comprising

(i) a first layer comprising Palbociclib or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients and

(ii) a second layer comprising fumaric acid and one or more pharmaceutically acceptable excipients.

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

In another embodiment, the Palbociclib used is in the form of a free base.

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 comprises Palbociclib or a pharmaceutically acceptable salt thereof in an amount of 10-80% w/w, preferably 10-60% w/w and more preferably 10-50% w/w of the composition.

The term "water-soluble" used herein in relation to the acid present in the composition refers to an acid that has a solubility of at least 0.2% by weight in water at 25 °C. The water- soluble acid may be an organic or inorganic acid, and preferably is an organic acid having at least one pKa value which is at least one (preferably at least two) pK unit lower than the highest pKa of the basic groups present in the drug. In the case of the palbociclib, which has pKa values of approximately 4.1 and 7.3, the acid preferably has a pKa of less than 6.3, and more preferably a pKa of less than 5.3. Water-soluble organic acids include, for example, C2-C8 or C2-C6 aliphatic mono or poly-carboxylic acids, and preferably C4-C6 aliphatic mono or poly- carboxylic acids. Particularly preferred are C4-C6 dicarboxylic acids, which may be saturated or unsaturated.

Solid dosage forms of the invention may comprise a single water-soluble acid, or may include a combination of two or more such acids.

Water soluble acids according to the present invention include but not limited to fumaric acid, benzoic acid, tosylic acid, formic acid, lactic acid, acetic acid, chloroacetic acid, Dichloroacetic acid, Trichloroacetic acid, Trifluoroacetic acid, citric acid, propionic acid, butyric acid, oxalic acid, uric acid, benzenesulfonic acid and the like or combinations thereof.

In one embodiments of the invention, the water soluble acid is not selected from the group consisting of succinic acid, malic acid and tartaric acid.

In another preferred embodiment, the water soluble acid is fumaric acid.

In another embodiment, the composition according to the present invention comprises water soluble acid in an amount of 1-20% w/w, preferably 1-10% w/w of the composition.

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, glidants and lubricants. These excipients may be present intragranularly or extragranularly. Diluents according to the present invention include but not limited to lactose monohydrate, lactose anhydrous, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, pregelatinized starch, 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, hydroxyethyl cellulose, ethyl cellulose, methyl cellulose, polyvinyl alcohol, pregelatinized starch, carboxymethyl cellulose, sodium alginate, povidone (polyvinyl pyrrolidone), copovidone, microcrystalline cellulose, gelatin, polymethacrylates and the like or combinations thereof. The binder can be used in the range of about 0-40% 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, pollacrillin potassium and the like or combinations thereof. The disintegrant can be used in the range of about 0-25% 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-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.

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, glyceyryl palmito stearic ester, hydrogenated castor oil and mixtures thereof. The Lubricants and/or glidants can be used in the range of 0-10% w/w of the composition.

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

In another embodiment, the present invention provides a pharmaceutical composition comprising Palbociclib or a pharmaceutically acceptable salt thereof in crystalline form and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention relates to an immediate release pharmaceutical composition comprising:

(i) about 10-50% w/w of Palbociclib or a pharmaceutically acceptable salt thereof;

(ii) about 40-80% w/w of one or more of diluents;

(iii) about 1-20% w/w of one or more disintegrants;

(iii) about 0-15% w/w of a binder; (iv) about 0-10% w/w of a glidant and

(v) about 0.1-10% w/w of a lubricant.

In another embodiment, the present invention relates to an immediate release pharmaceutical composition comprising: (i) about 10-50% w/w of Palbociclib or a pharmaceutically acceptable salt thereof;

(ii) about 40-80% w/w of one or more of diluents;

(iii) about 1-20% w/w of one or more disintegrants;

(iii) about 0-15% w/w of a binder;

(iv) about 0-10% w/w of a glidant and (v) about 0.1-10% w/w of a lubricant. wherein the composition is coated with a coating composition comprising a water soluble acid.

In another embodiment, the present invention relates to an immediate release tablet composition comprising: (i) about 10-50% w/w of Palbociclib or a pharmaceutically acceptable salt thereof;

(ii) about 40-80% w/w of one or more of diluents;

(iii) about 1-20% w/w of one or more disintegrants;

(iii) about 0-15% w/w of a binder;

(iv) about 0-10% w/w of a glidant and (v) about 0.1-10% w/w of a lubricant.

In another embodiment, the present invention relates to an immediate release tablet composition comprising:

(ii) about 40-80% w/w of one or more of diluents; (iii) about 1-20% w/w of one or more disintegrants;

(iii) about 0-15% w/w of a binder;

(iv) about 0-10% w/w of a glidant and

(v) about 0.1-10% w/w of a lubricant. wherein the tablet is coated with a coating composition comprising a water soluble acid.

(ii) about 40-80% w/w of one or more of diluents selected from microcrystalline cellulose, lactose monohydrate and combination thereof;

(iii) about 1-20% w/w of one or more disintegrants selected from sodium starch glycolate, crospovidone and combinations thereof ; (iii) about 0-15% w/w of a binder selected from hydroxypropyl methylcellulose, microcrystalline cellulose and combinations thereof;

(iv) about 0-10% w/w of a glidant selected from colloidal silicon dioxide,

(v) about 0.1-10% w/w of a lubricant selected from sodium stearyl fumarate, magnesium stearate and combinations thereof. In another embodiment, the present invention relates to an immediate release pharmaceutical composition comprising:

(ii) about 40-80% w/w of one or more of diluents selected from microcrystalline cellulose, lactose monohydrate and combination thereof; (iii) about 1-20% w/w of one or more disintegrants selected from sodium starch glycolate, crospovidone and combinations thereof ;

(iii) about 0-15% w/w of a binder selected from hydroxypropyl methylcellulose, microcrystalline cellulose and combinations thereof;

(iv) about 0-10% w/w of a glidant selected from colloidal silicon dioxide, (v) about 0.1-10% w/w of a lubricant selected from sodium stearyl fumarate, magnesium stearate and combinations thereof, wherein the composition is coated with a coating composition comprising a water soluble acid. In another embodiment, the present invention relates to an immediate release tablet composition comprising:

(iii) about 1-20% w/w of one or more disintegrants selected from sodium starch glycolate, crospovidone and combinations thereof ;

(iii) about 0-15% w/w of a binder selected from hydroxypropyl methylcellulose, microcrystalline cellulose and combinations thereof; (iv) about 0-10% w/w of a glidant selected from colloidal silicon dioxide,

(v) about 0.1-10% w/w of a lubricant selected from sodium stearyl fumarate, magnesium stearate and combinations thereof, wherein the composition is coated with a coating composition comprising a water soluble acid, and wherein the composition is prepared by dry granulation.

(v) about 0.1-10% w/w of a lubricant selected from sodium stearyl fumarate, magnesium stearate and combinations thereof, wherein the composition is coated with a coating composition comprising a water soluble acid, and wherein the composition is prepared by roller compaction.

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

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

(ii) compressing the blend of step (i) into tablets, and

(iii) coating the tablets obtained in step (ii) with a coating composition comprising a water soluble acid.

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

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

(iv) lubricating the blend of step (iii) with a lubricant,

(v) compressing the lubricated material of step (iv) into tablets, and

(vi) coating the tablets obtained in step (v) with a coating composition comprising a water soluble acid.

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

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

(iv) lubricating the blend of step (iii) with a lubricant, (v) compressing the lubricated material of step (iv) into tablets,

(vi) coating the tablets obtained in step (v) with a coating composition, and

(vii) coating the tablets obtained in step (vi) with a second layer of coating composition comprising a water soluble acid.

(i) blending Palbociclib or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients selected from diluent, disintegrant, glidant and lubricant,

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

(iii) blending the granules of step (ii) with one or more pharmaceutically acceptable excipients selected from diluent, disintegrant and glidant,

(iv) lubricating the blend of step (iii) with a lubricant,

(v) compressing the lubricated material of step (iv) into tablets, and

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

(iv) lubricating the blend of step (iii) with a lubricant,

(v) compressing the lubricated material of step (iv) into tablets,

(vi) coating the tablets obtained in step (v) with a coating composition, and

(vii) coating the tablets obtained in step (vi) with a second layer of coating composition comprising a water soluble acid. In another embodiment, the present invention relates to a process for the preparation of pharmaceutical composition, comprising the steps of:

(i) dissolving/dispersing Palbociclib or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients in suitable granulating solvents,

(ii) blending one or more pharmaceutically acceptable excipients

(iii) granulating the blend of step (ii) with the solution/dispersion formed in step (i),

(iv) blending the granules of step (iii) with one or more pharmaceutically acceptable excipients, and (v) lubricating the blend of step (iv) with a lubricant,

(vi) compressing the lubricated material of step (v) into a tablet dosage form, and

(vii) coating the tablets obtained in step (vi) with a coating composition comprising a water soluble acid.

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

(ii) blending one or more pharmaceutically acceptable excipients (iii) granulating the blend of step (ii) with the solution/dispersion formed in step (i),

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

(v) lubricating the blend of step (iv) with a lubricant,

(vi) compressing the lubricated material of step (v) into a tablet dosage form, and (vii) coating the tablets obtained in step (vi) with a coating composition,

(viii) coating the tablets obtained in step (vii) with a second layer of coating composition comprising a water soluble acid. In another embodiment, the present invention relates to a process for the preparation of immediate release bilayer tablet composition, comprising the steps of:

1. Preparation of granules for the first layer:

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

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

(iv) lubricating the blend of step (iii) with a lubricant, 2. Preparation of granules for the second layer:

(i) blending water soluble acid with one or more pharmaceutically acceptable excipients,

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

(iv) lubricating the blend of step (iii) with a lubricant,

3. compressing the lubricated material of steps 1 and 2 into bilayer tablets, and

4. optionally coating the bilayer tablets obtained in step (v) with a coating solution.

In another embodiment, the present invention relates to a process for the preparation of immediate release bilayer tablet composition, comprising the steps of:

1. Preparation of Active layer granules:

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

(iv) lubricating the blend of step (iii) with a lubricant,

2. Preparation of Acid layer granules: (i) blending water soluble acid with one or more pharmaceutically acceptable excipients,

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

(iv) lubricating the blend of step (iii) with a lubricant,

4. coating the bilayer tablets obtained in step (v) with a coating solution.

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 preferred embodiment, the pharmaceutical composition according to the present invention is in the form of tablets and bilayered tablets.

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, 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, dichloromethane 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 and melt granulation.

The pharmaceutical composition may be 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. The coating composition may be prepared in-house or can be selected from commercially available coating compositions like Opadry, Opadry AMB, Instacoat etc.. 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 another embodiment, the coating composition can be applied as one or more layers over the pharmaceutical composition.

In another embodiment, the coating composition further comprises the water soluble acid.

In another embodiment, the coating composition further comprises the water soluble acid which is preferably fumaric acid.

In another embodiment, the pharmaceutical composition is coated with a first layer of film coating composition followed by a second layer of coating composition which comprises a water soluble acid.

In another embodiment, the coating composition can be used in the range of 0.1-20% w/w of the pharmaceutical composition.

In one preferred embodiment, the pharmaceutical composition according to the present invention is in the form of tablets. In yet another embodiment, the present invention provides an immediate release tablet composition comprising Palbociclib or a pharmaceutically acceptable salt thereof in the range of about lmg to about 500 mg, preferably 50mg to 200mg.

In another embodiment, the present invention provides an immediate release tablet composition comprising Palbociclib or a pharmaceutically acceptable salt thereof for the treatment of adult patients with hormone receptor (HR) -positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.

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 Palbociclib

^#Does not contribute to the final mass, however present in traces; qs- Quantity sufficient

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

(i) Palbociclib, lactose monohydrate, microcrystalline cellulose (intra granular), sodium starch glycolate, colloidal silicon dioxide (intra granular) were sifted and blended,

(ii) the blend obtained in step (i) was lubricated with intra granular magnesium stearate,

(iii) The lubricated blend of step (ii) was roll compacted and milled to obtain granules,

(iv) the granules of step (iii) were sifted with extra granular microcrystalline cellulose, colloidal silicon dioxide and blended,

(v) the above blend of step (iv) was lubricated with magnesium stearate,

(vi) the lubricated blend of step (v) was compressed into tablets,

(vii) The compressed tablets of step (vi) were coated with Opadry yellow coating suspension which consists of hypromellose, triacetin, titanium dioxide, fumaric acid and iron oxide yellow.

Example 2: Bilayer Tablet compositions comprising Palbociclib

^#Does not contribute to the final mass, however present in traces; qs- Quantity sufficient The processing steps involved in manufacturing the bilayer tablets were given below:

1. Preparation of Active layer granules:

(i) Palbociclib, lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide were sifted and blended,

(ii) The blend obtained in step (i) was lubricated with magnesium stearate, (iii) The lubricated blend of step (ii) was roll compacted and milled to obtain granules,

2. Preparation of Acid layer granules: (i) Microcrystalline cellulose, fumaric acid, colloidal silicon dioxide were sifted and blended,

(ii) The blend obtained in step (i) was lubricated with magnesium stearate,

3. The active layer granules and acid layer granules were compressed into bilayer tablets

4. The tablets were coated with Opadry yellow coating suspension which consists of Hypromellose, triacetin, titanium dioxide and iron oxide yellow.

Example 3: Tablet compositions comprising Palbociclib

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

(v) the above blend of step (iv) was lubricated with magnesium stearate,

(vi) the lubricated blend of step (v) was compressed into tablets,

(vii) The compressed tablets of step (vi) were coated with Film Coating composition comprising fumaric acid. Dissolution Data: Table 1 given below provides the comparative dissolution profile of palbociclib tablets prepared according to Example 3 and IBRANCE^® tablets carried out in 900 ml of 0.1N HC1 as dissolution medium in USP II apparatus (paddle) at 75 rpm.

Table 1: Comparative dissolution profile of Palbociclib tablets prepared according to Example 3 and IBRANCE^® tablets

Claims

We Claim:

1. An immediate release tablet composition comprising Palbociclib or a pharmaceutically acceptable salt thereof, a water soluble acid and one or more pharmaceutically acceptable excipients, wherein the composition contains palbociclib and water soluble acid in separate layers.

2. The tablet composition as claimed in claim 1, wherein one or more pharmaceutically acceptable excipients are selected from diluents, disintegrants, binders, surfactants, glidants and lubricants.

3. The tablet composition as claimed in claim 2, wherein the diluent is selected from lactose monohydrate, lactose anhydrous, fructose, dextrose, dextrates, dextrins, mannitol, lactitol, sorbitol, starch, sucrose, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, sodium chloride, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, kaolin and combination thereof.

4. The tablet composition as claimed in claim 2, wherein the disintegrant is selected from starch, modified starches, pregelatinized starch, croscarmellose sodium, carmellose sodium, carmellose calcium, povidone, copovidone, crospovidone, sodium starch glycolate, low substituted hydroxypropyl cellulose, hydroxypropyl cellulose, alginic acid and combinations thereof.

5. The tablet composition as claimed in claim 1, wherein the water soluble acid is selected from fumaric acid, benzoic acid, tosylic acid, formic acid, lactic acid, acetic acid, chloroacetic acid, Dichloroacetic acid, Trichloroacetic acid, Trifluoroacetic acid, citric acid, propionic acid, butyric acid, oxalic acid, uric acid, benzenesulfonic acid and combinations thereof.

6. The tablet composition as claimed in claim 1, comprising

7. The tablet composition as claimed in claim 1, wherein the tablet composition is a bilayered tablet comprising

(i) a first layer comprising Palbociclib or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients; and

8. A process for the preparation of tablet composition as claimed in claim 1, comprising the steps of:

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

(iv) lubricating the blend of step (iii) with a lubricant,

(v) compressing the lubricated material of step (iv) into tablets, and

9. The process for the preparation of tablet composition as claimed in claim 7, wherein the process for preparation of the tablet composition is selected from wet granulation, dry granulation, roller compaction, fluidized bed granulation, high-shear granulation, low shear granulation, spray granulation and melt granulation.

10. An immediate release tablet composition comprising:

(ii) about 40-80% w/w of one or more of diluents selected from microcrystalline cellulose, lactose monohydrate and combination thereof; (iii) about 1-20% w/w of one or more disintegrants selected from sodium starch glycolate, crospovidone and combinations thereof;

(iv) about 0-15% w/w of a binder selected from hydroxypropyl methylcellulose, microcrystalline cellulose and combinations thereof;

(v) about 0-10% w/w of a glidant selected from colloidal silicon dioxide, (vi) about 0.1-10% w/w of a lubricant selected from sodium stearyl fumarate, magnesium stearate and combinations thereof, wherein the composition is coated with a coating composition comprising a water soluble acid, and wherein the composition is prepared by roller compaction.