WO2023239336A1

WO2023239336A1 - A pharmaceutical composition comprising palbociclib

Info

Publication number: WO2023239336A1
Application number: PCT/TR2023/050539
Authority: WO
Inventors: Manas Ranjan Mund; Mesut GUNDAR; Emre Erol ALDENIZ; Udaya Kumar DUDE
Original assignee: Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority date: 2022-06-08
Filing date: 2023-06-08
Publication date: 2023-12-14

Abstract

The present invention relates to a pharmaceutical composition comprising a) Palbociclib or its pharmaceutically acceptable salts, b) adipic acid, c) ascorbic acid, and d) one or more pharmaceutically acceptable excipients. The pharmaceutical composition of the present invention has desirable pharmacokinetic characteristics which exhibit favorable storage stability and comparative dissolution properties. The invention further relates to a process for the preparation of said pharmaceutical composition and use thereof as medicament in the treatment of breast cancer.

Description

A PHARMACEUTICAL COMPOSITION COMPRISING PALBOCICLIB

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

Palbociclib is chemically known as 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1 - yl)pyridin-2yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one, having the following formula (I),

(I).

Palbociclib is a potent and selective inhibitor of cyclin-dependent kinase 4 and 6 (CDK4 and CDK6) and CDK4/6 are downstream of multiple signaling pathways which lead to cellular proliferation by blocking progression of the cell from G1 into S phase of the cell cycle. Compared with other CDK enzymes, CDK4 and CDK6 have a narrow substrate range, catalysing the phosphorylation of retinoblastoma (Rb) and two other Rb-like family proteins. Treatment with Palbociclib is expected to inhibit the proliferation of rapidly dividing cells containing Rb, such as those in tumours. In hormone-receptor (HR)-positive breast cancer cells, 17-[3-oestradiol binds to the nuclear ER-a, resulting in the expression of several genes, including the gene encoding cyclin D1 , thereby resulting in CDK4/6 activation. Therefore, the combination of Palbociclib and an anti-oestrogen may have greater anti-tumour efficacy in patients with HR-positive breast cancer than either agent alone.

Palbociclib in the form of free base is approved in the form of capsules and tablets and marketed 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.

In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinizing hormone-releasing hormone (LHRH) agonist.

The recommended dose of Ibrance® is a 125 mg tablet or capsule taken orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days.

The Palbociclib is a non-hygroscopic yellow to orange crystalline powder that is classified as BCS Class II compound based on the Biopharmaceutical Classification System. It means that solubility of Palbociclib compound is critical and rate limiting factor for getting the adequate bioavailability of the finished product.

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). 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. According to EPAR, the maximum dose of 125 mg does not fully dissolve in 250 mL of media over the range of pH 1 to pH 6.8 but can be fully dissolved at pH values below 4.3. The solubility of Palbociclib free base is pH dependent. Therefore, it is very sensitive to pH of gastrointestinal area while dissolving in the tract.

The absorption of orally administered drugs may be affected by changes in pH as the drug passes through the gastrointestinal (Gl) tract. Absorption may occur at different locations along the Gl tract, e.g., at the cheek lining, or in the stomach, duodenum, jejunum, ileum or colon. The pH differs at each site of absorption, with the pH of the stomach (pH 1 -3.5) differing significantly from the pH of the small intestine (pH 4.5- 8). Drugs having pH-dependent solubility such as Palbociclib may precipitate from solution as the drug passes through the Gl tract, resulting in inter- or intra- patient variability in the extent and/or rate of absorption between doses or patients.

The pH of the Gl tract may also vary based on whether a patient or subject is in a fed or fasted state. In general, the gastric residence time of a drug is longer in the presence of food than in the fasted state. If the bioavailability of a drug is significantly affected by the presence or absence of food in the Gl tract, the drug is said to exhibit a "food effect". The rate of gastric emptying may also influence the concentration of drug in solution available for absorption at different sites along the Gl tract.

Concomitant administration of agents which increase gastric pH can alter the solubility and absorption of Palbociclib free base formulations. Co-administration of certain medications, as well as medical conditions such as achlorhydria, may also affect the pH of the Gl tract. The use of acid-reducing agents, such as proton pump inhibitors (PPIs) or H2 receptor antagonists, may result in a relatively high stomach pH, which can result in only partial dissolution of drugs having pH-dependent solubility in the stomach. Further dissolution of the undissolved drug may be inhibited by low solubility in the higher pH environment of the upper intestine. This can result in non-uniform dissolution of drugs having pH-dependent solubility, increasing the risk of drug-drug interactions, and potentially leading to decreased absorption and reduced therapeutic benefit. Hard gelatin capsule form of Ibrance® (Palbociclib) was approved in 2016 by EMA with some restriction about administration of the product i.e. , should be taken with food to reduce variability in drug absorption and to mitigate drug-drug-interactions with gastric acid reducing agents. To overcome the said limitation, innovator has developed the tablet form of Ibrance® with organic acid, which can be taken with or without food.

WO 2003/062236 A1 discloses Palbociclib or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. According to said PCT publication, the disclosed compounds 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 2005/005426 A1 describes the preparation of Palbociclib free base and various mono- and di-acid addition salts thereof including various polymorphic forms of the isethionate salt.

WO 2014/128588 A1 describes a crystalline free base of Palbociclib having a specific surface area of < 2 m²/g, and wherein the crystalline free base is a polymorph Form A of the free base having a powder X-ray diffraction pattern comprising a peak at diffraction angle (29) of 10.1 ± 0.2.

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.

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 crystalline palbociclib having a specific surface area in the range of from 2.1 to 6.0 m²/g as determined by BET-nitrogen adsorption analysis. The said publication discloses a pharmaceutical composition comprising an effective amount of Palbociclib and a pH modifier which is a weak acid, preferably an organic acid. The pH modifier is selected from the group consisting of succinic acid, tartaric acid, ascorbic acid, citric acid, lactic acid, malic acid, fumaric acid, aspartic acid, glutamic acid, and mixtures thereof. Most preferably the pH modifier is succinic acid or a mixture of succinic acid and tartaric 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. This publication further discloses that said solid dispersion increases the dissolution rate of Palbociclib and improves the bioavailability of medicine.

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, wherein the mass ratio of the acidic adjuvant to Palbociclib is from 0.2: 1 to 5: 1 .

WO 2018/191950 A1 discloses a Palbociclib composition comprising Palbociclib comilled 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. WO 2021/220295 A1 discloses 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.

WO 2022/029799 A1 discloses solid dosage forms of Palbociclib comprising at least one compound selected from the group consisting of sulphur-containing amino acid or peptide, and at least one vitamin having antioxidant properties.

From above mentioned one or more prior art, it is evident that Palbociclib is pH dependent compound, and hence its bioavailability could be varied based on the pH of Gl track. Also, Palbociclib being BCS Class II compound it is very challenging to develop composition showing similar dissolution profile and devoid of food effect like Ibrance® tablet because the use of acidic excipient to create a micro-acidic environment would lead to the formation of acid adduct during preparation and/or stability. Therefore, to minimize the formation of acid adduct and controlling the same during stability without compromising with dissolution profile for a compound like Palbociclib is challenging. Without binding to any theory, it is thought that compounds having pH-dependent solubility, particularly basic compounds, may exhibit undesirable pharmacokinetic properties, such as poor absorption and/or reduced bioavailability, which may result in significant inter-patient and intra-patient variability. Therefore, there remains a need to discover improved dosage forms of having favorable dissolution and pharmacokinetic profiles, which also demonstrate good storage stability.

The inventors of the present invention have surprisingly found that a pharmaceutical composition of Palbociclib containing particular combination of organic acids showed similar dissolution profile to the reference product Ibrance® tablet.

The inventors of the present invention have found that the alternative solid dosage forms of the present invention demonstrate excellent storage stability and provide substantially pH-independent delivery of Palbociclib with no significant food effects or adverse interactions with PPIs. The inventors of the present invention have observed that use of particular combination of organic acids not only helps to create a micro-acidic environment but also suppresses the formation of high amount of degradation product i.e. acid adduct during the preparation and/or stability.

OBJECT OF THE INVENTION

A main object of the present invention is to provide a pharmaceutical composition comprising Palbociclib or its pharmaceutically acceptable salts, which provide similar in-vitro and in-vivo profile to the reference product i.e. Ibrance® tablet.

Another object of the present invention is to provide a stable pharmaceutical composition of Palbociclib or its pharmaceutically acceptable salts.

Yet another object of the present invention is to provide a stable pharmaceutical composition of Palbociclib or its pharmaceutically acceptable salts in the form of a tablet.

Yet another object of the present invention is to provide a stable pharmaceutical composition of Palbociclib or its pharmaceutically acceptable salts in the form of a tablet, which is devoid of food effect i.e. food intake has no significant impact on the variability of palbociclib exposure following administration of said tablet.

Yet another object of the present invention is to provide a stable pharmaceutical composition of Palbociclib or its pharmaceutically acceptable salts, which overcomes the problems of the prior art.

Yet another object of the invention is to provide a commercially scalable, cost effective, environment friendly and robust process for the preparation of Palbociclib or its pharmaceutically acceptable salts composition. SUMMARY OF THE INVENTION

In one aspect, the present invention provides a pharmaceutical composition comprising: a) Palbociclib or its pharmaceutically acceptable salts, b) adipic acid, c) ascorbic acid, and d) one or more pharmaceutically acceptable excipients.

In another aspect, the present invention provides a pharmaceutical composition comprising: a) Palbociclib or its pharmaceutically acceptable salts in amount of 10 wt% to 40 wt%, b) adipic acid, c) ascorbic acid, and d) one or more pharmaceutically acceptable excipients.

In another aspect, the present invention provides a pharmaceutical composition comprising: a) Palbociclib or its pharmaceutically acceptable salts, b) adipic acid in amount of 1 wt% to 20 wt%, c) ascorbic acid, and d) one or more pharmaceutically acceptable excipients.

In another aspect, the present invention provides a pharmaceutical composition comprising: a) Palbociclib or its pharmaceutically acceptable salts, b) adipic acid, c) ascorbic acid in amount of 1 wt% to 15 wt%, and d) one or more pharmaceutically acceptable excipients.

In another aspect, the present invention provides a pharmaceutical composition comprising: a) Palbociclib or its pharmaceutically acceptable salts, b) adipic acid in amount of 1 wt% to 20 wt%, c) ascorbic acid in amount of 1 wt% to 15 wt%, and d) one or more pharmaceutically acceptable excipients.

In another aspect, the present invention provides a pharmaceutical composition comprising: a) Palbociclib or its pharmaceutically acceptable salts in amount of 10 wt% to 40 wt%, b) adipic acid, c) ascorbic acid in amount of 1 wt% to 15 wt%, and d) one or more pharmaceutically acceptable excipients.

In another aspect, the present invention provides a pharmaceutical composition comprising: a) Palbociclib or its pharmaceutically acceptable salts in amount of 10 wt% to 40 wt%, b) adipic acid in amount of 1 wt% to 20 wt%, c) ascorbic acid, and d) one or more pharmaceutically acceptable excipients.

In another aspect, the present invention provides a pharmaceutical composition comprising: a) Palbociclib or its pharmaceutically acceptable salts in amount of 10 wt% to 40 wt%, b) adipic acid in amount of 1 wt% to 20 wt%, c) ascorbic acid in amount of 1 wt% to 15 wt%, and d) one or more pharmaceutically acceptable excipients.

In another aspect, the present invention provides a tablet composition comprising: a) Palbociclib or its pharmaceutically acceptable salts in amount of 10 wt% to 40 wt%, b) adipic acid in amount of 1 wt% to 20 wt%, c) ascorbic acid in amount of 1 wt% to 15 wt%, and d) one or more pharmaceutically acceptable excipients. In another aspect, the present invention provides a tablet core comprising: a) intragranular phase comprising: i) Palbociclib or its pharmaceutically acceptable salts in amount of 10 wt% to 40 wt%, ii) one or more pharmaceutically acceptable excipients, b) extragranular phase comprising: i) adipic acid in amount of 1 wt% to 20 wt%, ii) ascorbic acid in amount of 1 wt% to 15 wt%, and iii) one or more pharmaceutically acceptable excipients.

In another aspect, the present invention provides a tablet comprising Palbociclib or its pharmaceutically acceptable salts having SSA (specific surface area) more than 2 m²/g, adipic acid, ascorbic acid and at least one pharmaceutically acceptable excipient.

In another aspect, the present invention provides a tablet comprising: a) 10 wt% to 40 wt% of Palbociclib or pharmaceutically acceptable salt thereof, b) 1 wt% to 20 wt% of adipic acid, c) 1 wt% to 15 wt% of ascorbic acid, d) 30 wt% to 80 wt% of one or more of diluents, e) 1 wt% to 10 wt% of one or more of disintegrants, f) 0 wt% to 10 wt% of one or more binders, g) 0.1 wt% to 5 wt% of one or more lubricant, and h) 0.1 wt% to 5 wt% of one or more glidant.

In another aspect, the present invention provides a pharmaceutical composition of any of the above aspects, wherein the said composition contains not more than 0.2 % individual acid adduct by weight after storage of at least 3 months at 40°C and 75% relative humidity (RH).

In another aspect, the present invention provides a pharmaceutical composition of any of the above aspects, wherein the said composition contains not more than 1 % of total impurities by weight after storage of at least 3 months at 40°C and 75% relative humidity. In another aspect, the present invention provides a pharmaceutical composition as mentioned herein above, which is prepared by dry granulation.

In another aspect, the present invention discloses a use of such pharmaceutical composition as medicament in the treatment of breast cancer.

The details of one or more embodiments of the present invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a graph showing the simulated progressive dissolution of Palbociclib of Example 1 & Example 2 vis-a-vis reference drug Ibrance® tablet in simulating fasting condition.

Figure 2 is graph showing the simulated progressive dissolution of Palbociclib of Example 1 & Example 2 vis-a-vis reference drug Ibrance® tablet in simulating fasting condition with PPI (Proton Pump Inhibitor).

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The present invention will now be more specifically illustrated as hereunder.

The term % used in this specification means the percentage by weight unless otherwise stipulated.

The term "about" can indicate a difference of 10 percent of the value specified. Numerical ranges as used herein are meant to include every number and subset of numbers enclosed within that range, whether particularly disclosed or not. Further, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range. The term “composition” as used in the present invention means solid pharmaceutical composition includes, without limitation, capsules, tablets, caplets, powders, pellets, granules, liquid dispersions, beads, etc.

The term ' Palbociclib ' as used in the present invention includes, but is not limited to, Palbociclib per se, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs, and pharmaceutically acceptable prodrugs thereof, and also its various crystalline and amorphous forms.

The term "dry granulation" means the process of blending bulk active product with at least one excipient. The blend is then compressed, or compacted, to form a compressed material or "compact". This material may be broken apart to form granules by crushing, grinding or cutting into dry granulated particles. Optionally, the particles may be further processed. Crushing, grinding, or cutting processes involve an operation that reduces the size of the compressed material such as accomplished by milling or by other operations known to those skilled in the art.

The term "similarity factor" or f2 factor as used herein refers to one way of comparing dissolution profiles of two different products (Multisource Pharmaceutical Products: Guidelines on Registration Requirements to establish Interchangeability, Quality Assurance and Safety: Medicines, Essential Drugs and Medicines Policy, World Health Organization, 1211 Geneva 27, Switzerland). This model independent mathematical approach compares the dissolution profile of the two products: test and reference (or two strengths, or pre- and post-approved products from the same manufacturer). Tests are recommended to be performed under the same test conditions. The dissolution time points for both the profiles should be the same, for example for immediate release products e.g. 10, 15, 30, 45, 60 minutes and for extended release products, e.g., 1 , 2, 3, 5 and 8 hours. Only one time point should be considered after 85% dissolution of the reference product. An f2 value of 50 or greater (50-100) ensures sameness or equivalence of the two curves, and thus the performance of the two products. The similarity factor f2 should be computed using the equation: f2 =50 log {[l+(l/n) t=1 n (Rt - Tt )2 ]-0-5 100} where Rt and Tt are the cumulative percentage of the drug dissolved at each of the selected n time points of the comparator (reference) and (test) product respectively .

According to European Public Assessment Report (EPAR), Palbociclib is a BCS Class II compound (low solubility and high permeability) and the maximum dose of 125 mg does not fully dissolve in 250 ml of media over the range of pH 1 to pH 6.8, but can be fully dissolved at pH values below 4.3, hence solubility of the active substance is rate limiting for bioavailability of the product. Therefore, it is very critical and challengeable to obtain bioequivalent product in line with Ibrance® tablet.

Use of acidic compound(s) in the composition to create micro-acidic environment could lead to the formation of acid adduct. Therefore, selection of specific acidic compound(s) and their amount while preparing the composition is critical to obtain a bioequivalent, and stabile composition, which is devoid of food effect.

It was surprisingly found that a pharmaceutical composition of the present invention has overcome the problems of prior art.

In addition to that, the obtained stable tablet composition is able to mimic the dissolution profile of the Ibrance® tablets.

In general embodiment, a present invention provides a pharmaceutical composition comprising: a) Palbociclib or its pharmaceutically acceptable salts, b) adipic acid, c) ascorbic acid, and d) one or more pharmaceutically acceptable excipients.

In one embodiment, a composition of the present invention comprises active ingredient Palbociclib in the amount from 10 wt% to 40 wt% by weight based on the total weight of the composition.

In one embodiment, a composition of the present invention comprises adipic acid in amount from 1 % to 20 % by weight based on the total weight of the composition. In one embodiment, a composition of the present invention comprises ascorbic acid in amount from 1 % to 15% by weight based on the total weight of the composition.

In embodiments, a pharmaceutical composition of the present invention further comprises one or more pharmaceutically acceptable excipients. The excipients to be used in accordance with the present invention are well known and are those excipients which are conventionally used by the person skilled in the art. Depending on the dosage form chosen for the pharmaceutical composition, the person skilled in the art will be able to select suitable pharmaceutically acceptable excipients. The pharmaceutical excipient can be selected from diluent, binder, disintegrant, lubricant and glidant.

Diluent includes, but are not limited to, lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, pregelatinized starch, dextrates, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamers, polyethylene oxide, hydroxypropyl methyl cellulose and mixtures thereof.

The amount of diluent is preferably from about 30 wt% to about 80 wt%, more preferably from about 50% to about 65% by weight based on the total weight of the pharmaceutical composition.

Disintegrant includes, but are not limited to, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, Crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate and mixtures thereof.

The amount of the disintegrant is preferably from 1 wt% to about 10 wt%, more preferably from 1 % to 8% by weight based on the total weight of the pharmaceutical composition. Binder includes, but are not limited to, carrageenan, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, carboxymethylcellulose sodium, dextrin, dextran, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, polyvinyl alcohol, pregelatinized starch, sodium alginate, macrogol, pullulan, gums, synthetic resins and the like.

The amount of the binder is preferably from about 0 wt% to 10 wt%, more preferably from about 0 wt% to about 5 wt% by weight based on the total weight of the pharmaceutical composition.

Lubricant includes, but are not limited to, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, com starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, waxes, DL-leucine, sodium lauryl sulfate, magnesium lauryl sulfate, macrogol and mixtures thereof.

The amount of one or more lubricant is preferably from about 0.1 wt% to 5 wt%, more preferably from about 0.2 wt% to about 3 wt% by weight based on the total weight of the pharmaceutical composition.

Glidant includes, but are not limited to, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, com starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, waxes, DL-leucine, sodium lauryl sulfate, silicon dioxide, magnesium lauryl sulfate, macrogol, light anhydrous silicic acid and mixtures thereof.

The amount of the glidant is preferably from about 0.1 wt% to about 5 wt%, more preferably from about 0.2 wt% to about 2 wt% by weight based on the total weight of the pharmaceutical composition. The pharmaceutical composition is in the form of a tablet. Most preferably, the tablet has immediate release.

The tablet composition of the present invention can be obtained by using known conventional methods i.e. granulation or direct compression. The process to obtain granulate includes, but is not limited to, wet granulation, fluid bed granulation, spray drying, or dry granulation, slugging, roller compaction.

The pharmaceutical composition of the present invention is intended for oral use, and can be in the form of tablets, capsules, minitablets, granules, or pellets, wherein the composition can be further film coated.

The pharmaceutical composition of the present invention may further be coated with a film- forming polymer and one or more pharmaceutically acceptable excipients, using techniques well known in the art e.g., spray coating in a conventional coating pan, or a fluidized bed processor, or dip coating. Alternatively, coating can also be performed using a hot melt technique. The film coating may contain one or more film-forming polymers, and optionally one or more pharmaceutically acceptable excipients. A suitable film-forming polymer is selected from the group comprising hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose phthalate, cellulose acetate trimellitate, methacrylic acid copolymers e.g., Eudragit®, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, or mixtures thereof. A preferred film- forming polymer is hydroxypropyl methyl cellulose. Other suitable film- forming polymers which are known in the art may also be used. The film coating may also contain opacifiers like titanium dioxide, flow aids like talc and pigment like iron oxide yellow.

The pharmaceutical composition in accordance with the present invention may be used as a medicament. The pharmaceutical composition typically may be used in the treatment of breast cancer. Moreover, the pharmaceutical composition of the present invention is very suitable for production on commercial scale making use of equipment and techniques commonly used in industry.

The following examples are intended to illustrate the scope of the present invention but not to limit it thereto.

Examples:

Example 1 : A pharmaceutical composition comprising Palbociclib

Table-1

Process For The Preparation:

1. Palbociclib, microcrystalline cellulose, colloidal silicon dioxide, crospovidone and magnesium stearate were sieved through a suitable mesh size for deagglomeration and mixed in a suitable tumbling mixer. 2. Obtained blend of step 1 was granulated by roller compaction and were sieved through a suitable mesh size. 3. Obtained blend of step 2 were mixed with adipic acid, ascorbic acid, microcrystalline cellulose, crospovidone, colloidal silicon dioxide and magnesium stearate.

4. The powder obtained in step-3 was compressed into tablet.

Example 2: A pharmaceutical composition comprising Palbociclib

Table-2

Process For the Preparation: 1. Palbociclib, microcrystalline cellulose, colloidal silicon dioxide, crospovidone and magnesium stearate were sieved through a suitable mesh size for deagglomeration and mixed in a suitable tumbling mixer.

2. Obtained blend of step 1 was granulated by roller compaction and were sieved through a suitable mesh size.

3. Obtained blend at step 2 were mixed with adipic acid, ascorbic acid, microcrystalline cellulose, crospovidone, colloidal silicon dioxide and magnesium stearate.

4. The powder obtained in step-3 was compressed into tablet.

Example 3: Dissolution Data of Example 1 and Example 2 at pH 6.0 phosphate buffer 900 ml 50 rpm with USP apparatus II at 37°C

Table-3

Dissolution of test product of Example-1 , Example 2 and reference product Ibrance® were performed using standard USP apparatus II, paddles, at 50 rpm in 900 ml at pH=6.0. The drug release was determined by using an HPLC method. From the above dissolution data given in table-3, it is evident that f2 is more than 50, which establishes sameness or equivalence both products i.e. test products (of Example-1 & 2) and reference product in terms of its dissolution and performance. Example 4: Progressive dissolution data of Example-1 & Example 2 while simulating fasting conditions

Table-4

The dissolution data as given in table-4 are also plotted in Figure-1. From the given comparative dissolution profile depicted in Figure-1 , it can be said that Example-1 and Example-2 to mimic dissolution profile of the Ibrance® tablets.

Example 5: Progressive dissolution data of Example-1 & Example 2 while simulating fasting with PPI (Proton Pump Inhibitor) conditions

Table-5

The dissolution data as given in table-5 are also plotted in Figure-2. From the given comparative dissolution profile depicted in Figure-2, it can be said that Example-1 and Example-2 to mimic dissolution profile of the Ibrance® tablets even when taken with PPI.

Example 6: In-vivo analysis

Palbociclib film coated tablets of Example-2 were compared with the reference product Ibrance® film coated tablet under fasting conditions and fasting conditions with co- administration of the proton pump inhibitor. In vivo analysis of Example -2 tablets and reference product Ibrance® tablets in fasting conditions were given in Table-6. In vivo analysis of Example -2 tablets and reference product Ibrance® tablets in fasting conditions with co-administration of the proton pump inhibitor were given in Table-7. Table-6

Table-7

From the in-vivo results given in table - 6 & 7, it can be seen that test product of Example - 2 shows similar in-vivo release profile as compared to Ibrance® tablet.

Example 7: Stability Result of Example 2

The tablets prepared in Example-2, were placed in a plastic bottle along with a desiccant and airtightly sealed, and then, stored for 3 months under conditions of 40°C/75% RH. N-formyl adduct of Compound (I) i.e. Palbociclib and total impurities formation in the tablet were measured before and after the storage using high- performance liquid chromatography. The results of performed stability testing is shown herein below Table-8.

Table-8

It can be seen from the above Table-8 that the produced amount of the N-formyl adduct is not more than 0.2% and the amount of total impurities formation is not more than 1 % in above mentioned stability conditions for Example-2.

Claims

Claims:

1. A pharmaceutical composition comprising: a) Palbociclib or its pharmaceutically acceptable salts, b) adipic acid, c) ascorbic acid, and d) one or more pharmaceutically acceptable excipients.

2. A pharmaceutical composition according to claim 1 , wherein Palbociclib is present in an amount from 10 % to 40 % by weight based on the total weight of the composition.

3. A pharmaceutical composition according to claim 1 , wherein adipic is present in an amount from 1 % to 20 % by weight based on the total weight of the composition

4. A pharmaceutical composition according to claim 1 , wherein ascorbic acid is present in an amount from 1 % to 15 % by weight based on the total weight of the composition.

5. A pharmaceutical composition according to claim 1 , wherein one or more pharmaceutically acceptable excipient is selected from the group comprising of diluent, disintegrant, lubricant and glidant.

6. A pharmaceutical composition according to claim 5, wherein diluent is selected from lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, pregelatinized starch, dextrates, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamers, polyethylene oxide, hydroxypropyl methyl cellulose or mixtures thereof.

7. A pharmaceutical composition according to claim 5 or claim 6, wherein diluent is microcrystalline cellulose.

8. A pharmaceutical composition according to claim 5, wherein disintegrant is selected from sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, Crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkylsubstituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate or mixtures thereof.

9. A pharmaceutical composition according to claim 5 or claim 8, wherein disintegrant is crospovidone.

10. A pharmaceutical composition according to claim 5, wherein lubricant is selected from magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, sodium lauryl sulfate or mixtures thereof.

11. A pharmaceutical composition according to claim 5, wherein glidant is selected from magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, sodium lauryl sulfate or mixtures thereof.

12. A pharmaceutical composition according to claim 1 , wherein the pharmaceutical composition is selected from tablet, capsule, granules, sachet, lozenge and powder.

13. A pharmaceutical composition according to claim 1 or claim 12, wherein pharmaceutical composition is tablet.

14. A pharmaceutical composition according to any one of claim 1 to 13, wherein the tablet core comprising:

(i) Palbociclib or its pharmaceutically acceptable salts and one or more pharmaceutical acceptable excipient are present in intragranular phase,

(ii) adipic acid, ascorbic acid and one or more pharmaceutically acceptable excipient are present in extragranular phase.

15. A pharmaceutical composition according to any of claim 1 to 14 is prepared by dry granulation.