Palbociclib solid dosage forms

Abstract

To provide an improved dosage form of palbociclib that indicates satisfactory storage stability, and advantageous dissolving and pharmacokinetic profile.SOLUTION: The present invention relates to a solid dosage form of palbociclib containing water-soluble acid. A dosage form described in this specification has desirable pharmacokinetic characteristics.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to solid dosage forms of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (hereinafter palbociclib) having desirable pharmacokinetic characteristics that exhibit advantageous storage stability and dissolution properties. [Background technology]

[0002] Palbociclib:

[0003] [ka] It is a potent and selective inhibitor of CDK4 and CDK6, having the structure:

[0004] Palbociclib is described in WHO Drug Information, Vol.27, No.2, page 172 (2013). Palbociclib and its pharma- ceutically acceptable salts are disclosed in WO 2003 / 062236 and U.S. Patent Nos. 6,936,612, 7,208,489 and 7,456,168; WO 2005 / 005426 and U.S. Patent Nos. 7,345,171 and 7,863,278; WO 2008 / 032157 and U.S. Patent No. 7,781,583; and WO 2014 / 128588. The contents of each of the foregoing references are incorporated herein by reference in their entirety.

[0005] Palbociclib is approved in the United States for the treatment of hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative advanced or metastatic breast cancer in combination with letrozole as initial endocrine therapy or in combination with fulvestrant after disease progression on endocrine therapy. The drug is marketed by Pfizer Inc. under the trade name IBRANCE® in an immediate release (IR) capsule dosage form containing palbociclib as the free base for oral administration.

[0006] Palbociclib is a dibasic compound, possessing two basic groups with pKa of approximately 7.3 (secondary piperazine nitrogen) and 4.1 (pyridine nitrogen). The solubility of palbociclib free base is pH dependent. Palbociclib is water soluble at low pH (2.1-4.5), but solubility decreases dramatically as pH increases above 4.5. Palbociclib is slightly soluble in water at pH 7.9 (9 μg / mL). Coadministration of agents that increase gastric pH can alter the solubility and absorption of palbociclib free base formulations.

[0007] The absorption and bioavailability of therapeutic agents, when administered orally, can be affected by many factors, including whether the subject is in a fed or fasted state, the use of certain medications such as proton pump inhibitors (PPIs) or H2 receptor antagonists, and certain medical conditions. Compounds with pH-dependent solubility, particularly basic compounds, can exhibit undesirable pharmacokinetic properties such as poor absorption and / or reduced bioavailability, which can result in significant inter- and intra-patient variability. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2003 / 062236 [Patent Document 2] U.S. Patent No. 6,936,612 [Patent Document 3] U.S. Patent No. 7,208,489

Patent document 4

Patent document 5

Patent document 6

Patent document 7

Patent document 8

Patent document 9

Patent document 10

Patent document 11

Non-licensed literature

[0009]

Non-licensed literature 1

Non-licensed Document 2

Non-licensed Document 4

Non-licensed Document 5

[0010] There remains a need to discover improved dosage forms of palbociclib with favorable dissolution and pharmacokinetic profiles that also exhibit good storage stability.The inventors have surprisingly discovered that solid dosage forms according to the present invention exhibit excellent storage stability and provide substantially pH-independent delivery of palbociclib without significant food effects or adverse interactions with PPIs. [Means for solving the problem]

[0011] In a first aspect, the present invention provides a solid dosage form comprising palbociclib, a water soluble acid, and a pharma- ceutically acceptable carrier.

[0012] In a second aspect, the invention provides a solid dosage form of any of the embodiments described herein, wherein the dosage form, when added to a test medium comprising 500 mL of 10 mM pH 5.5 acetate buffer at 37° C. with paddles rotating at 50 rpm in a standard USP2 rotating paddle apparatus: (a) greater than or equal to 35% palbociclib in 15 minutes; (b) greater than or equal to 45% palbociclib in 30 minutes; (c) greater than or equal to 55% in 60 minutes; or (d) two or more of (a), (b), and (c) dissolve.

[0013] In a third aspect, the invention provides a solid dosage form of any of the embodiments described herein, wherein the dosage form, when added to a test medium comprising 500 mL of 50 mM pH 6.5 phosphate buffer and 0.1 M NaCl at 37° C. with paddles rotating at 50 rpm in a standard USP2 rotating paddle apparatus: (a) greater than or equal to 15% palbociclib in 15 minutes; (b) greater than or equal to 20% palbociclib in 30 minutes; (c) greater than or equal to 25% palbociclib in 60 minutes; or (d) two or more of (a), (b), and (c) dissolve.

[0014] In some embodiments, the invention provides a solid dosage form of any of the embodiments described herein, wherein the dosage form, when added to a test medium comprising 500 mL of 50 mM pH 6.5 phosphate buffer and 0.1 M NaCl at 37° C. with paddles rotating at 50 rpm in a standard USP2 rotating paddle apparatus: (a) greater than or equal to 20% palbociclib in 15 minutes; (b) greater than or equal to 30% palbociclib in 30 minutes; (c) greater than or equal to 25% palbociclib in 60 minutes; or (d) two or more of (a), (b), and (c) dissolve.

[0015] In other embodiments, the invention provides a solid dosage form of any of the embodiments described herein, wherein the dosage form, when added to a test medium comprising 500 mL of 50 mM pH 6.5 phosphate buffer and 0.1 M NaCl at 37° C. with paddles rotating at 50 rpm in a standard USP2 rotating paddle apparatus: (a) greater than or equal to 40% of palbociclib in 15 minutes; (b) greater than or equal to 35% of palbociclib in 30 minutes; (c) greater than or equal to 25% of palbociclib in 60 minutes; or (d) two or more of (a), (b), and (c) dissolve.

[0016] In a fourth aspect, the invention provides a solid dosage form of any of the embodiments described herein, wherein the dosage form has: (a) a mean fed / fasted ratio of the area under the plasma concentration versus time curve (AUC) following administration of a single oral dose to a subject of about 0.8 to about 1.25; (b) a maximum plasma concentration (C max(a) has an average fed / fasted ratio of about 0.8 to about 1.25; or (c) both (a) and (b).

[0017] In a fifth aspect, the invention provides a solid dosage form of any of the embodiments described herein, wherein the dosage form: (a) provides a mean fasted AUC that is in the range of 80% to 125% of the mean fasted AUC for a controlled immediate release (IR) oral capsule containing an equivalent amount of palbociclib after administration of a single oral dose to a subject; or (b) provides a mean fasted C of 100% to 125% of the mean fasted AUC for a controlled immediate release (IR) oral capsule containing an equivalent amount of palbociclib after administration of a single oral dose to a subject. max Average fasting C in the range of 80%~125% max or (c) resulting in both (a) and (b).

[0018] In a sixth aspect, the invention provides a solid dosage form of any of the embodiments described herein, wherein the dosage form: (a) provides a mean AUC in the presence of a proton pump inhibitor (PPI) that ranges from 80% to 125% of the mean AUC in the absence of a PPI after administration of a single oral dose to a subject; (b) provides a mean C in the absence of a proton pump inhibitor (PPI) that ranges from 80% to 125% of the mean AUC in the absence of a PPI after administration of a single oral dose to a subject. max Mean C in the presence of PPIs ranged from 80% to 125% of max or (c) both (a) and (b). In some such embodiments, the PPI is rabeprazole.

[0019] In a seventh aspect, the present invention provides a solid dosage form of any of the embodiments described herein, wherein the dosage form exhibits less than 0.3% by weight acid adduct after storage for 96 days at 30° C. and 75% relative humidity (RH).

[0020] In an eighth aspect, the present invention provides a solid dosage form of any of the embodiments described herein, wherein the dosage form exhibits less than 1.0% by weight acid adduct after storage for 2 years at 30° C. and 75% RH.

[0021] In a ninth aspect, the invention provides a solid dosage form of any of the embodiments described herein, wherein the dosage form exhibits less than 0.05% by weight acid adduct after 1 year of storage at 25° C. / 60% RH, In some such embodiments, the dosage form is packaged together with a desiccant canister in a bottle using a heat induction seal.

[0022] In some embodiments of each aspect of the invention, the active pharmaceutical ingredient (API), palbociclib, comprises about 10% to about 35% by weight of the dosage form. In certain embodiments, palbociclib comprises about 20% by weight of the dosage form.

[0023] In some embodiments of each aspect of the invention, the water-soluble acid comprises about 5% to about 40% by weight of the dosage form. In particular embodiments, the water-soluble acid comprises about 5% to about 25% by weight of the dosage form. In other embodiments, the water-soluble acid comprises about 5% to about 15% by weight of the dosage form. In more particular embodiments, the water-soluble acid comprises about 10% by weight of the dosage form.

[0024] In some such embodiments, the water-soluble acid is selected from the group consisting of succinic acid, malic acid, and tartaric acid. In particular embodiments, the water-soluble acid is succinic acid. In other embodiments, the water-soluble acid is malic acid. In further embodiments, the water-soluble acid is tartaric acid.

[0025] In preferred embodiments of each aspect described herein, the solid dosage form comprises about 10 wt% to about 35 wt% palbociclib, 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 pharma- ceutically acceptable carrier. In certain embodiments, the water-soluble acid is succinic acid. In some such embodiments, the solid dosage form comprises about 20 wt% palbociclib, about 10 wt% succinic acid, and a pharma- ceutically acceptable carrier.

[0026] In some embodiments of each aspect described herein, the pharma- ceutically acceptable carrier comprises one or more of the following pharma- ceutically acceptable excipients: diluents, disintegrants, binders, glidants, lubricants, and surfactants. Such excipients can be incorporated into either intragranular or extragranular tablet forms, and tablets may contain the same or different excipients as intragranular or extragranular components. For example, tablet formulations may contain intragranular lubricants, extragranular lubricants, or both intragranular and extragranular lubricants, which may be the same or different.

[0027] In some embodiments of each of the aspects described herein, the pharma- ceutically acceptable carrier comprises at least one diluent, comprising about 50 wt% to about 75 wt% of the solid dosage form. In certain embodiments, the carrier comprises at least one diluent selected from the group consisting of microcrystalline cellulose, lactose monohydrate, mannitol, sorbitol, xylitol, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate. In certain embodiments, the diluent is microcrystalline cellulose. In some such embodiments, the diluent is microcrystalline cellulose.

[0028] In other embodiments of each of the aspects described herein, the pharma- ceutically acceptable carrier comprises a lubricant comprising about 0.5 wt% to about 10 wt% of the solid dosage form. In certain embodiments, the carrier comprises at least one lubricant selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, and sodium stearyl fumarate. In certain embodiments, the lubricant is magnesium stearate, which may be present intragranularly, extragranularly, or both. In other embodiments, the lubricant is sodium stearyl fumarate. Other embodiments comprise both magnesium stearate and sodium stearyl fumarate as lubricants, which may be present intragranularly, extragranularly, or both.

[0029] In further embodiments of each of the aspects described herein, the pharma- ceutically acceptable carrier comprises at least one disintegrant, comprising about 5 wt% to about 10 wt% of the solid dosage form. In certain embodiments, the carrier comprises at least one disintegrant selected from the group consisting of crospovidone, croscarmellose sodium, and sodium starch glycolate. In certain embodiments, the disintegrant is crospovidone.

[0030] In frequent embodiments of each aspect described herein, the solid dosage form of the invention is in the form of a tablet. In some embodiments, the tablet is film-coated. In some embodiments, the tablet is a monolayer tablet. In other embodiments, the tablet is a bilayer tablet. In certain embodiments, the tablet of the invention comprises palbociclib in an amount of 25 mg, 75 mg, 100 mg, or 125 mg. In certain embodiments, the tablet of the invention comprises palbociclib in an amount of 125 mg.

[0031] In frequent embodiments of each aspect of the invention, the solid dosage form is in the form of a tablet. In some embodiments, the tablet is a monolayer tablet. In other embodiments, the tablet is a bilayer tablet.

[0032] In some embodiments of the aspects and embodiments described herein, the amount of palbociclib in the dosage form is 25 mg, 75 mg, 100 mg, or 125 mg. In certain embodiments, the amount of palbociclib in the dosage form is 125 mg.

[0033] Each embodiment of the invention described herein may be combined with one or more other embodiments of the invention described herein that are not inconsistent with the embodiment with which it is combined. [Brief description of the drawings]

[0034] [Figure 1]FIG. 1 shows in vitro dissolution data of prototype formulations containing eight tested water-soluble acids (malic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, tosylic acid, benzoic acid and benzenesulfonic acid) in 10 mM sodium acetate buffer solution, pH 5.5, at 37° C. with paddle rotation at 50 rpm in a USP2 apparatus. [Diagram 2] FIG. 1 shows in vitro dissolution data of prototype formulations containing succinic acid, malic acid and tartaric acid in 10 mM sodium acetate buffer, pH 5.5 at 37° C. with paddle rotation at 50 rpm in a USP2 apparatus. [Diagram 3] FIG. 1 shows non-sink in vitro dissolution data of prototype formulations containing succinic acid in 50 mM phosphate buffer solution, pH 6.5, containing +0.1 M NaCl at 37° C. in a USP2 apparatus with paddles rotating at 50 rpm. [Figure 4] FIG. 1 shows non-sinking in vitro dissolution data of formulations A1, A2 and B in 50 mM phosphate buffer solution, pH 6.5, containing +0.1 M NaCl at 37° C. in a USP2 apparatus with paddles rotating at 50 rpm. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] The present invention can be more readily understood by reference to the following detailed description of the preferred embodiments of the present invention and examples contained herein. It should be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not limiting. It should be further understood that unless specifically defined herein, the terminology used herein should be given its conventional meaning as known in the relevant art.

[0036] As used herein, the singular forms "a," "an," and "the" include plural references unless otherwise indicated. For example, "an" excipient includes one or more excipients.

[0037] The term "about" means that the value falls within the acceptable standard error of the mean as viewed by a person skilled in the art. Often, the term "about" means ±15%, preferably ±10%, more preferably ±5% of the value or range to which it refers. For example, "about 10wt%" means 10wt%±1.5wt%, preferably 10wt%±1wt%, more preferably 10wt%±0.5wt%.

[0038] Unless otherwise indicated herein, palbociclib refers to the free base form of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one and can exist in crystalline or amorphous form, or a mixture of amorphous and crystalline forms.

[0039] Absorption of orally administered drugs can be affected by changes in pH as the drug passes through the gastrointestinal (GI) tract. Absorption can occur at different locations along the GI tract, for example, the cheek lining, or the stomach, duodenum, jejunum, ileum, or colon. The pH is different at each site of absorption, with the pH of the stomach (pH 1-3.5) being significantly different from the pH of the small intestine (pH 4.5-8). Drugs with pH-dependent solubility can precipitate out of solution as the drug passes through the GI tract, resulting in inter- or intra-patient variability in the extent and / or rate of absorption between doses or patients.

[0040] The pH of the GI tract may also differ based on whether the 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 GI tract, the drug is said to exhibit a "food effect." The rate of gastric emptying may also affect the concentration of drug in solution available for absorption at different sites along the GI tract.

[0041] Concurrent administration of certain pharmaceuticals, as well as medical conditions such as achlorhydria, can also affect the pH of the GI tract. The use of acid-reducing agents, such as proton pump inhibitors (PPIs) or H2 receptor antagonists, can result in a relatively high gastric pH, which may result in only partial dissolution of drugs with pH-dependent solubility in the stomach. Further dissolution of undissolved drugs may be inhibited by their low solubility in the higher pH environment of the upper intestine. This can result in uneven dissolution of drugs with pH-dependent solubility, increasing the risk of drug-drug interactions and potentially leading to reduced absorption and reduced therapeutic benefit.

[0042] A study in healthy volunteers showed that exposure to palbociclib treatment (125 mg once daily as free base capsules) was slightly increased in fed (AUCinf, 23%-27%; Cmax, 21%-24%) vs. fasted (AUCinf, 39%; Cmax, 73%) subjects, with PK variability significantly reduced in the fed state. Ruiz-Garcia et al., Annals of Oncology (2014) 25(Suppl 4):iv146-iv164, 10, 1093 / annonc / mdu331. Due to the reduced interpatient variability observed in the fed state, the commercial palbociclib free base capsule formulation is recommended in the US package insert to be taken with food.

[0043] When formulating a compound into a tablet or other solid dosage form, it is desirable to develop a formulation that is storage stable at higher temperatures and relative humidity levels than those normally encountered. Other desirable properties of the formulation may also be sought, such as fast dissolution, so that the tablet dissolves quickly and the drug can be absorbed. Thus, good storage stability and fast dissolution are among the attributes sought as desirable features for the present invention.

[0044] Drug dissolution represents an important factor influencing the rate of systemic absorption. Various in vitro methods have been developed to evaluate the dissolution characteristics of pharmaceutical formulations, and dissolution tests are sometimes used as a surrogate for the direct assessment of drug bioavailability. See, for example, Emmanuel et al., Pharmaceutics (2010), 2:351-363, and references cited therein. Dissolution tests measure the percentage of API released from a drug product (i.e., tablet or capsule) and dissolved in a dissolution medium under controlled test conditions over a defined period of time. To maintain sinking conditions, the saturation solubility of the drug in the dissolution medium should be at least three times the drug concentration. For low solubility compounds, dissolution can sometimes be determined under non-sinking conditions. Dissolution is influenced by the characteristics of the API (e.g., particle size, crystal form, bulk density), the composition of the drug product (e.g., drug additives, excipients), the manufacturing process (e.g., compression force) and stability under storage conditions (e.g., temperature, humidity).

[0045] Methods for evaluating the chemical storage stability of solid dosage forms under accelerated aging conditions have been described in the literature. See, for example, ST Colgan, TJ Watson, RD Whipple, R. Nosal, JV Beaman, D. De Antonis, "The Application of Science and Risk Based Concepts to Drug Substance Stability Strategies," J. Pharm. Innov. 7:205-2013 (2012); Waterman KC, Carella AJ, Gumkowski MJ, et al., Improved protocol and data analysis for accelerated shelf-life estimation of solid dosage forms. Pharm Res 2007;24(4):780-90; and ST Colgan, RJ Timpano, D. Diaz, M. Roberts, R. Weaver, K. Ryan, K. Fields, G. Scrivens, "Opportunities for Lean Stability Strategies," J. Pharm. Innov. 9:259-271 (2014).

[0046] In the solid dosage forms of the present invention, the formation of an acid adduct of the piperazinyl moiety of palbociclib with a water-soluble acid is an important degradant to monitor to assess storage stability.

[0047] As further described herein, the present invention provides solid dosage forms comprising palbociclib, a water soluble acid, and a pharma- ceutically acceptable carrier, and methods for their production and use.

[0048] Solid dosage forms include, but are not limited to, immediate release tablets and capsules, controlled release (CR) tablets and capsules, fast dissolving dosage forms, chewable dosage forms, sachets, etc. The dosage forms of the present invention are preferably in the form of tablets, including single layer or bilayer tablets.

[0049] A "solid dosage form" of the present invention is a pharma- ceutically acceptable solid dosage form that is safe for oral administration to humans, where all excipients in the dosage form are pharma- ceutically acceptable for use in oral formulations, in other words, safe for human consumption. In frequent embodiments, the solid dosage form is a tablet.

[0050] As used herein, the term "unit dose" or "unit dosage" refers to a physically discrete unit containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect. A unit dose or unit dosage may be in the form of a tablet, capsule, sachet, etc., referred to herein as a "unit dosage form."

[0051] As used herein, the term "fasted" is defined as follows: a dosing state defined after at least 10 hours (i.e., ≧10 hours) of overnight fasting (where 0 calorie intake occurs). Subjects may administer the dosage form with 240 mL of water. No food should be allowed for at least 4 hours after administration. Water may be allowed as desired, except for 1 hour before and after drug administration.

[0052] In this specification, the term "fed" is defined as follows: after at least 10 hours of overnight fasting (where 0 calorie intake occurs), the subject then begins the recommended meal. The subject must eat this meal within 30 minutes; however, the drug product should be administered 30 minutes after the meal begins. The drug product can be administered with 240 mL of water. No food should be allowed for at least 4 hours after administration. Water can be allowed as desired, except for 1 hour before and after drug administration.

[0053] To assess fed / fasted ratios, a single oral dose of palbociclib can be administered: 30 minutes after a high-fat, high-calorie meal (approximately 800-1000 calories with 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively); 30 minutes after a low-fat, low-calorie meal (approximately 400-500 calories with 120, 250, and 28-35 calories from protein, carbohydrate, and fat, respectively); or between meals (1 hour / 2 hours before) a medium-fat and medium-calorie meal (approximately 500-700 calories consisting of 15% protein, 50% carbohydrate, and 35% fat).

[0054] A high-fat and high-calorie meal can be used as the test meal under fed conditions. An example of a high-fat test meal would be 2 eggs fried in butter, 2 slices of bacon, 2 slices of buttered toast, 4 ounces of hash brown potatoes, and 8 ounces of whole milk.

[0055] Calculation of the average area under the plasma concentration versus time curve (AUC) is a procedure well known in the pharmaceutical arts and is described, for example, in Welling, "Pharmacokinetics Processes and Mathematics," ACS Monograph 185 (1986). As used herein, AUC includes the area under the concentration-time curve extrapolated from time zero to infinity after a single dose or the area under the concentration-time curve from time zero to the end of the dosing interval at steady state / after multiple doses.

[0056] Furthermore, C max , C min,ss , T max Calculation of the elimination half-life (t1 / 2) is also known to those of skill in the art and is described, for example, in Shargel, Wu-Pong, and Yu, Applied Biopharmaceutics and Pharmacokinetics (2005).

[0057] To determine the mean fed / fasted ratio, the mean area under the plasma concentration versus time curve of palbociclib in the fed state (e.g., AUC 0~inf) vs. the mean area under the plasma concentration versus time curve (e.g., AUC 0~inf ) are first calculated and then the corresponding individual ratios are averaged together. In this way, it is the average value of each corresponding individual ratio that is determined.

[0058] Proton pump inhibitors (PPIs) are a well-known class of drugs that reduce the production of gastric acid, thereby altering gastric pH. Representative PPIs include, for example, rabeprazole, omeprazole (S- and B-forms, including Na and Mg salts), lansoprazole, pantoprazole, esomeprazole, and the like.

[0059] As used herein, the term "controlled immediate release (IR) oral capsule" refers to the commercial IR capsule formulation of palbociclib described in Example 11. This formulation, along with an isethionate salt formulation (ISE) and a free base tablet dosage form that lacks the water soluble acid but is otherwise substantially the same as the formulation of Example 1, may be referenced herein as a control.

[0060] "Dissolution Test 1" refers to the following test of a palbociclib dosage form: Dissolution testing is performed in a standard USP2 rotating paddle apparatus as described in United States Pharmacopeia (USP) Dissolution Testing Chapter 711, Apparatus 2. The paddles rotate at 50 rpm and the dosage form is added to 500 mL of 10 mM pH 5.5 acetate buffer at 37°C. At the appropriate time after initiation of the test (e.g., insertion of the dosage form into the apparatus), a filtered aliquot (usually 1.5 mL) from the test medium is analyzed for palbociclib by high performance liquid chromatography (HPLC). Dissolution results are reported as percent of the total dose of palbociclib tested dissolved versus time.

[0061] "Dissolution Study 2" refers to the following study of a palbociclib dosage form: Dissolution testing is performed in a standard USP2 rotating paddle apparatus as described in United States Pharmacopeia (USP) Dissolution Testing Chapter 711, Apparatus 2. The paddles rotate at 50 rpm and the dosage form is added to 500 mL of 50 mM pH 6.5 phosphate buffer and 0.1 M NaCl at 37°C. At the appropriate time after initiation of the study (e.g., insertion of the dosage form into the apparatus), a filtered aliquot (usually 1.5 mL) from the test medium is analyzed for palbociclib by high performance liquid chromatography (HPLC). Dissolution results are reported as percent of the total dose of palbociclib tested dissolved versus time.

[0062] The term "dry granulation" refers to the process of blending a bulk active product with at least one excipient. The blend is then compressed or compacted to form a compacted material or "compact". This material can be broken apart to form granules by crushing, grinding or cutting into dry granulated particles. Optionally, the particles can be further processed. Crushing, grinding or cutting processes include operations that reduce the size of the compacted material, such as accomplished by milling or other operations known to those skilled in the art.

[0063] The term "water-soluble" as used herein, with respect to the acid present in the composition, means an acid having 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 is preferably an organic acid having at least one pKa value that is at least one (preferably at least two) pK units lower than the highest pKa of the basic group present in the drug. In the case of palbociclib, which has a pKa value of about 4.1 and 7.3, the acid preferably has a pKa of less than 6.3, and more preferably has 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, preferably C4-C6 aliphatic mono- or poly-carboxylic acids. Particularly preferred are C4-C6 dicarboxylic acids, which may be saturated or unsaturated.

[0064] The solid dosage form of the present invention may contain a single water-soluble acid or may contain a combination of two or more such acids. In selected embodiments of the present invention, the water-soluble acid is selected from the group consisting of succinic acid, malic acid and tartaric acid. In certain preferred embodiments of the present invention, the water-soluble acid is succinic acid.

[0065] The water-soluble acid may be combined with the drug prior to granulation or may be incorporated into the dosage form along with extragranular excipients. In bilayer tablets, the water-soluble acid may be incorporated into a separate acid layer and present in the active layer containing palbociclib, or the water-soluble acid (which may be the same or different) may be incorporated into both the active layer and the acid layer.

[0066] Without wishing to be bound by any particular theory, it is believed that the presence of an acid in the solid dosage form in intimate contact with the drug increases solubilization due to an interaction between palbociclib and the acid. The solid dosage forms of the present invention thus provide an increased local concentration of drug in solution following oral administration to a subject, as compared to administration of a palbociclib formulation lacking a water-soluble acid.

[0067] In some embodiments, the solid dosage form of any of the embodiments described herein dissolves under the conditions of Dissolution Test 1 (pH 5.5 acetate buffer, 37° C.): (a) greater than or equal to 35% of palbociclib in 15 minutes; (b) greater than or equal to 45% of palbociclib in 30 minutes; (c) greater than or equal to 55% in 60 minutes; or (d) two or more of (a), (b), and (c).

[0068] In a further embodiment, in a solid dosage form of the invention under conditions of Dissolution Test 1: (a) greater than or equal to 25%, 30%, 35%, 40%, 45%, or 50% of palbociclib is dissolved in 15 minutes; (b) greater than or equal to 35%, 40%, 45%, 50%, 55%, or 60% of palbociclib is dissolved in 30 minutes; and / or (c) greater than or equal to 45%, 50%, 55%, 60%, 65%, or 70% of palbociclib is dissolved in 60 minutes.

[0069] In some embodiments, the solid dosage form of any of the embodiments described herein, under non-sinking conditions of Dissolution Test 2 (pH 6.5 phosphate buffer and 0.1 M NaCl, 37° C.): (a) greater than or equal to 40% of palbociclib in 15 minutes; (b) greater than or equal to 35% of palbociclib in 30 minutes; (c) greater than or equal to 25% of palbociclib in 60 minutes; or (d) two or more of (a), (b), and (c) dissolve.

[0070] In other embodiments, the solid dosage form of any of the embodiments described herein dissolves under non-sinking conditions of Dissolution Test 2 (pH 6.5 phosphate buffer and 0.1 M NaCl, 37° C.): (a) greater than or equal to 15% of palbociclib in 15 minutes; (b) greater than or equal to 20% of palbociclib in 30 minutes; (c) greater than or equal to 25% of palbociclib in 60 minutes; or (d) two or more of (a), (b), and (c).

[0071] In other embodiments under Dissolution Test 2: (a) greater than or equal to 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% of palbociclib is dissolved in 15 minutes; (b) greater than or equal to 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% of palbociclib is dissolved in 30 minutes; and / or (c) greater than or equal to 15%, 20%, 25%, 30%, 35%, or 40% of palbociclib is dissolved in 60 minutes.

[0072] In further embodiments under Dissolution Test 2: (a) greater than or equal to 30%, 35%, 40%, 45%, or 50% of palbociclib is dissolved in 15 minutes; (b) greater than or equal to 25%, 30%, 35%, 40%, 45%, or 50% of palbociclib is dissolved in 30 minutes; and / or (c) greater than or equal to 15%, 20%, 25%, 30%, 35%, or 40% of palbociclib is dissolved in 60 minutes.

[0073] In some embodiments, the invention provides a solid dosage form comprising palbociclib, a water soluble acid, and a pharma- ceutically acceptable carrier, wherein the dosage form has: (a) a mean fed / fasted ratio of the area under the plasma concentration versus time curve (AUC) following administration of a single oral dose to a subject that is about 0.8 to about 1.25; (b) a mean fed / fasted ratio of the area under the plasma concentration versus time curve (AUC) following administration of a single oral dose to a subject that is about 0.8 to about 1.25; max ) the average fed / fasted ratio; or (c) resulting in both (a) and (b).

[0074] In some embodiments, the invention provides a solid dosage form comprising palbociclib, a water soluble acid, and a pharma- ceutically acceptable carrier, wherein the dosage form has: (a) a mean fasting AUC ranging from 80% to 125% of the mean fasting AUC for a controlled immediate release (IR) oral capsule containing an equivalent amount of palbociclib after administration of a single oral dose to a subject; (b) a mean fasting C for a controlled immediate release (IR) oral capsule containing an equivalent amount of palbociclib after administration of a single oral dose to a subject. max Average fasting C in the range of 80%~125% max or (c) resulting in both (a) and (b).

[0075] In a further embodiment, the invention provides a solid dosage form comprising palbociclib, a water soluble acid, and a pharma- ceutically acceptable carrier, wherein the dosage form has: (a) a mean AUC in the presence of a proton pump inhibitor (PPI), preferably rabeprazole, in the range of 80% to 125% of the mean AUC in the absence of a PPI after administration of a single oral dose to a subject; (b) a mean C in the absence of a proton pump inhibitor (PPI) after administration of a single oral dose to a subject. max Mean C in the presence of a PPI, preferably rabeprazole, in the range of 80% to 125% of max or (c) resulting in both (a) and (b).

[0076] In other embodiments, the invention provides a solid dosage form comprising palbociclib, a water soluble acid, and a pharma- ceutically acceptable carrier, wherein the dosage form exhibits less than 0.4%, 0.35%, 0.3%, 0.25%, 0.2%, 0.15%, or 0.1% by weight of acid adduct after storage for 96 days at 30° C. and 75% relative humidity (RH).

[0077] In yet other embodiments, the invention provides a solid dosage form comprising palbociclib, a water soluble acid, and a pharma- ceutically acceptable carrier, wherein the dosage form exhibits less than: 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4% or 0.3% acid adduct by weight after 2 years of storage at 30° C. and 75% RH.

[0078] In some embodiments of each of the aspects and embodiments of the present invention, the water-soluble acid is selected from the group consisting of succinic acid, malic acid, and tartaric acid. In certain embodiments of each of the aspects and embodiments herein, the water-soluble acid is succinic acid. In other embodiments, the water-soluble acid is malic acid. In further embodiments, the water-soluble acid is tartaric acid.

[0079] In some embodiments of each aspect of the invention, the water-soluble acid comprises about 5% to about 40% by weight of the dosage form. In certain embodiments, the water-soluble acid comprises about 5% to about 25% by weight of the dosage form. In some embodiments, the water-soluble acid comprises about 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% by weight of the dosage form.

[0080] In some embodiments of each aspect of the invention, palbociclib comprises about 10% to about 35% by weight of the dosage form. In certain embodiments, palbociclib comprises about 20% by weight of the dosage form. In some embodiments, palbociclib comprises about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% by weight of the dosage form.

[0081] In frequent embodiments of each aspect and embodiment herein, the solid dosage form is a tablet, preferably a tablet formed by dry granulation. In some such embodiments, the tablet is a bilayer tablet. In certain embodiments, the bilayer tablet comprises: (a) an active layer comprising palbociclib and a pharma- ceutically acceptable carrier; and (b) an acid layer comprising a water-soluble acid and a pharma- ceutically acceptable carrier. In some embodiments, the bilayer tablet comprises: (a) an active layer comprising palbociclib, a water-soluble acid, and a pharma- ceutically acceptable carrier; and (b) an acid layer comprising a water-soluble acid and a pharma- ceutically acceptable carrier, where the water-soluble acid in the active layer may be the same or different from the water-soluble acid in the acid layer. In certain embodiments, the water-soluble acid in the active layer is succinic acid, and the water-soluble acid in the acid layer is tartaric acid.

[0082] In another aspect, the present invention provides a method of treating cancer, comprising administering a therapeutically effective amount of a solid dosage form of any of the aspects and embodiments described herein to a subject in need thereof. In certain embodiments, the cancer is breast cancer. In some such embodiments, the breast cancer is hormone-receptor positive (HR+) breast cancer. In some such embodiments, the breast cancer is estrogen-receptor positive (ER+) breast cancer. In some such embodiments, the breast cancer is human epidermal growth factor receptor 2 negative (HER-) breast cancer. In other such embodiments, the breast cancer is human epidermal growth factor receptor 2 positive (HER+) breast cancer. In further embodiments, the breast cancer is advanced or metastatic breast cancer, and can be characterized as HR+, HER2- or ER+, HER2-.

[0083] Palbociclib can be administered alone or in combination with other drugs, particularly aromatase inhibitors such as letrozole, fulvestrant or exemestane, and will be administered in a formulation associated with one or more pharma- ceutically acceptable excipients. The term "excipient" describes any ingredient other than palbociclib or its salt.

[0084] Palbociclib can be administered orally, which may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be utilized by which the compound enters the bloodstream directly from the mouth.

[0085] The therapeutically effective amount of the dosage form of the present invention can be administered to a subject who needs such treatment.The term "therapeutically effective amount" as used herein means the amount of compound administered that relieves to some extent one or more symptoms of the disorder being treated.In the context of treating cancer, therapeutically effective amount means the amount that has the effect of (1) reducing tumor size, (2) inhibiting (i.e., slowing to some extent, preferably preventing) tumor metastasis, (3) inhibiting (i.e., slowing to some extent, preferably preventing) tumor growth or tumor invasiveness, and / or (4) relieving to some extent (or preferably eliminating) one or more signs or symptoms associated with cancer.

[0086] As used herein, "subject" means a human or animal subject. In certain preferred embodiments, the subject is a human. In some embodiments, the subject is a patient suffering from a pathological condition. In other embodiments, the subject may be a healthy volunteer.

[0087] The term "treating" as used herein, unless otherwise indicated, refers to reversing, alleviating, inhibiting, or preventing the progression of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment" as used herein, unless otherwise indicated, refers to the act of treating as defined immediately above. The term "treating" also includes adjuvant and neoadjuvant treatment of a subject. Palbociclib can be administered alone or in combination with an aromatase inhibitor, such as letrozole, fulvestrant, or exemestane.

[0088] As used herein, "cancer" refers to any malignant and / or invasive growth or tumor resulting from abnormal cell proliferation. As used herein, "cancer" refers to solid tumors named after the type of cells that form them (e.g., breast cancer), and cancers of the blood, bone marrow, or lymphatic system. Examples of solid tumors include, but are not limited to, sarcomas and carcinomas. Examples of blood cancers include, but are not limited to, leukemia, lymphoma, and myeloma. The term "cancer" includes, but is not limited to, primary cancers that arise at a particular site in the body, metastatic cancers that have spread from where it began to other parts of the body, recurrences from the original primary cancer after remission, and second primary cancers, which are new primary cancers in people with a history of a previous cancer of a different type than the latter.

[0089] More specifically, examples of cancers related to the present invention include breast cancer, among others, and are preferably combined with aromatase inhibitors.For example, the cancer may be hormone receptor positive (HR+) breast cancer, particularly estrogen receptor positive (ER+) breast cancer.In some embodiments, the ER+ breast cancer is human epidermal growth factor 2 (HER2)-negative.In further embodiments, the cancer is ER+, HER2- advanced metastatic breast cancer, where the drug is administered in combination with aromatase inhibitors to treat metastatic disease.

[0090] Formulations suitable for oral administration include solid formulations such as tablets, capsules, powders, lozenges (including liquid-filled), sachets, etc. In a preferred aspect of the present invention, the solid dosage form provided herein is a tablet. In some such embodiments, the tablet is film-coated. In other such embodiments, the tablet is a bilayer tablet.

[0091] For tablet dosage forms, depending on the dose, palbociclib can comprise 1 wt% to 80 wt% of the dosage form, typically 5 wt% to 60 wt% of the dosage form, more typically about 10 wt% to about 35 wt%, or even more typically about 15 wt% to about 25 wt%. In certain embodiments, palbociclib comprises about 20 wt% of the dosage form by weight.

[0092] In the solid dosage forms of the present invention, the carriers can include various pharma- ceutically acceptable excipients, including, for example, diluents, disintegrants, binders, glidants, lubricants, and surfactants. The formulations can also include excipients such as preservatives, antioxidants, flavorings, and coloring agents, as well as other excipients known in the art.

[0093] Solid dosage forms such as tablets typically contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, compressed sugar, microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, dextrates, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamer, polyethylene oxide, hydroxypropylmethylcellulose and mixtures thereof. Different types of microcrystalline cellulose may be suitable for use in the formulations described herein. Examples of microcrystalline cellulose include Avicel® types: PH101, PH102, PH103, PH105, PH112, PH113, PH200, PH301, and other types of microcrystalline cellulose such as silicified microcrystalline cellulose (SMCC). In some embodiments, the diluent is selected from the group consisting of microcrystalline cellulose, lactose monohydrate, mannitol, sorbitol, xylitol, magnesium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, or mixtures thereof. In some embodiments, the diluent comprises microcrystalline cellulose. In certain embodiments, the diluent comprises one or more types of microcrystalline cellulose, such as Avicel® PH 105, Avicel® PH 200, or mixtures thereof. In some such embodiments, the diluent excludes lactose monohydrate. In other such embodiments, the diluent comprises microcrystalline cellulose and further comprises lactose monohydrate. The diluent often comprises about 25% to about 75% by weight of the solid dosage form, preferably about 50% to about 75% by weight of the dosage form.

[0094] Solid dosage forms often contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. In some embodiments, the disintegrant is crospovidone. Any grade of crospovidone can be used; for example, CL, CL-SF, and XL grades of crospovidone are suitable for use in the formulations described herein. Specific examples include Kollidon, Kollidon CL®, Kollidon CL-M®, Polyplasdone XL®, Polyplasdone XL-10®, and Polyplasdone INF-10®. In some embodiments, the carrier comprises at least one disintegrant selected from the group consisting of crospovidone, croscarmellose sodium, and sodium starch glycolate. In certain embodiments, the disintegrant is crospovidone. Disintegrants often comprise from about 1 wt% to about 25 wt%, preferably from about 5 wt% to about 20 wt%, and more preferably from about 5 wt% to about 10 wt% of the dosage form.

[0095] Binders can be used to impart cohesiveness to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. In some embodiments, the binder is selected from the group consisting of microcrystalline cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. In certain embodiments, the binder is microcrystalline cellulose, such as Avicel® PH105. When present, the binder may comprise from about 0 wt% to about 15 wt%, or from about 0.2 wt% to about 10 wt% of the dosage form. In some embodiments, the binder comprises from about 5 wt% to about 10 wt% of the dosage form. In certain embodiments, the binder comprises about 10 wt% of the dosage form.

[0096] Solid dosage forms often contain one or more lubricants. Examples of lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, a mixture of magnesium stearate and sodium lauryl sulfate, or a mixture of two or more thereof. In some embodiments, the lubricant is magnesium stearate and / or sodium stearyl fumarate. In some embodiments, the lubricant is magnesium stearate. In some such embodiments, the solid dosage form is a tablet comprising intragranular and extragranular magnesium stearate. In other embodiments, the solid dosage form is a tablet comprising intragranular magnesium stearate and extragranular sodium stearyl fumarate. When present, lubricants often comprise from about 0.25 wt% to about 10 wt%, preferably from about 0.5 wt% to about 6 wt%, of the dosage form.

[0097] The tablet may also contain a lubricant, such as silicon dioxide, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc, and other forms of silicon dioxide, such as aggregated silicates and hydrated silica. In some embodiments, the lubricant is silicon dioxide. When present, the lubricant may comprise about 0 wt% to about 10 wt%, preferably about 0.2 wt% to about 5 wt%, or about 0.5 wt% to about 2 wt% of the tablet.

[0098] The tablet may also contain surfactants such as sodium lauryl sulfate and polysorbate 80. When present, the surfactants may comprise from 0 wt% to 10 wt%, or preferably from 0.2 wt% to 5 wt% of the tablet.

[0099] In general, the solid dosage forms of the present invention are prepared according to conventional methods in pharmaceutical chemistry. Selected excipients can be incorporated along with the API in either the extragranular or intragranular compartments or both.

[0100] An exemplary tablet formulation contains about 10 wt% to about 35 wt% palbociclib, typically about 15 wt% to about 25 wt% palbociclib; about 5 wt% to about 15 wt% water soluble acid; about 25 wt% to about 75 wt% diluent; about 5 wt% to about 10 wt% disintegrant; about 0.5 wt% to about 6 wt% lubricant; optionally about 0 wt% to about 5 wt% lubricant, and about 0 wt% to about 15 wt% binder.

[0101] Further exemplary tablet formulations contain about 20 wt% palbociclib; about 10 wt% water-soluble acid, preferably succinic acid; about 50 wt% to about 75 wt% diluent, preferably microcrystalline cellulose; about 5 wt% to about 10 wt% disintegrant, preferably crospovidone; about 0.5 wt% to about 6 wt% lubricant, preferably magnesium stearate or sodium stearyl fumarate, or both; optionally about 0 wt% to about 5 wt% lubricant; and optionally about 0 wt% to about 15 wt% binder. If present, the lubricant is preferably silicon dioxide, and the binder is preferably microcrystalline cellulose of a type suitable as a dry binder (e.g., Avicel® PH105).

[0102] The solid formulation for oral administration can be formulated to be immediate release and / or modified release.Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release.For a summary of modified release formulations, see US Patent No. 6,106,864.

[0103] Pharmaceuticals in the form of solid tablets are usually manufactured by compressing the materials that make up the final product into the desired tablet form. Such materials may include active pharmaceutical ingredients as well as pharma- ceutical inactive excipients that impart necessary or useful properties to the product during and after the manufacturing process. Tablet hardness, or tensile strength, can be used as a measure of the cohesiveness of the tablet's ingredients. If the tablet does not have sufficient cohesive properties, it may break apart when handled. The final formulation may include one or more layers and may be coated or uncoated.

[0104] As known in the art, granulation is a process used to improve the handling and manufacturing properties of a formulation, for example by increasing particle size to improve flowability. Granulation does not substantially change the physical form of the drug, such as its crystalline or amorphous characteristics. Various processes are used by those skilled in the art to prepare tablet dosage forms. Examples of such processes include dry granulation, wet granulation, fluidized bed granulation, and direct compression. The type of method used may depend on factors such as the physical characteristics of the active pharmaceutical ingredient in the formulation, the type of excipients used, and the desired physical characteristics of the final product. All of these processes include a step that involves mixing the ingredients of the dosage form. In certain embodiments of the present invention, dry granulation is preferred.

[0105] Some mixing of the components of a dosage form is usually necessary to obtain a uniform and consistent final product. However, in the preparation of pharmaceutical tablets by wet and dry granulation, it has been found that the degree and intensity of mixing of the components prior to compression is associated with loss of compressibility and cohesiveness of the formulation, resulting in reduced tablet hardness.

[0106] For example, similar results can be observed when roller compaction is used in dry granulation. Roller compaction can be used as a method to form granules that are then compressed into tablets. Roller compaction can reduce the compressibility and cohesiveness of the subsequent dosage form.

[0107] Dry granulation is a process of forming granules by a compaction step followed by size grading of the compacts into easily processable particles. It is often used to improve flow properties and / or densify the formulation, which can facilitate further manufacturing processes such as tableting, encapsulation and powder filling. Compacts are usually made directly from a powder blend containing the active ingredient and other excipients, including lubricants.

[0108] The use of dry granulation techniques can be preferred to wet granulation methods due to shorter processing times and cost advantages. However, dry granulation is generally limited to situations where the drug or active ingredient has suitable physical characteristics for forming pharma- ceutically acceptable dosage forms such as granules and tablets.

[0109] The addition of at least one excipient to a formulation is generally required and contributes to the increase in tablet size of the final product. Since the tablet size must be within certain parameters to function as a suitable dosage form, it is not practical to increase the tablet size beyond the limit to accommodate increased amounts of excipients to enhance compactability. As a result, manufacturers are often limited to using dry granulation for formulations that contain low doses of active ingredient per compressed tablet, so that the formulation can accommodate sufficient levels of excipients to make dry granulation practical.

[0110] In developing a pharmaceutical dosage form, it is important to balance several different objectives: It is important to prepare the pharmaceutical dosage form as economically as possible. It would be desirable to have a simple method of production involving few processing steps. The dosage form should also allow optimal patient availability of the active compound contained therein. In addition, the dosage form should be easy to swallow. Smaller dosage forms are better accepted by patients, improving patient compliance.

[0111] The final pharmaceutical composition is processed into a unit dosage form (e.g., tablet or capsule) and then packaged for distribution. The processing steps will vary depending on the particular unit dosage form. For example, tablets are generally compressed under pressure into the desired shape, while capsules use a simple filling operation. Those skilled in the art are familiar with the procedures used to manufacture the various unit dosage forms.

[0112] Tablets are usually formed by applying pressure to the material to be compressed on a tablet press. The formulation must have good flow properties for accurate volumetric delivery of the material to the die cavity, as well as suitable compressibility, moldability, and ejection properties to form tablets.

[0113] There are several tablet presses, each with different productivity, but similar basic functions and operation. All compress the tablet formulation in a die cavity by pressure applied between two steel punches, a lower punch and an upper punch. Tablet presses are usually designed with a hopper to hold and feed the formulation, a feeding mechanism to feed the formulation to the die cavity, provisions for positioning the punches and dies, and a cam track to guide the movement of the punches in a rotary tablet press. Two types of tablet presses are single station or single punch presses and multi-station rotary presses. Some tablet presses offer longer dwell times than others, resulting in increased binding. Other presses can offer precompression.

[0114] Wet granulation can also be used to prepare granules of pharmaceutical compositions. Wet granulation is described in Remington: The Science and Practice of Pharmacy, Mack Publishing Company, Easton, Pa., 19th Edition 1995. These and other methods are generally known to those skilled in the art. When wet granulation is used, volatilizable agents can be incorporated into the mixture before, during or after the ingredients are mixed, but prior to the formation of granules. For example, solid volatilizable agents can be blended with the powder of the mixture before, during or after adding the binder solution. Other solid dosage forms can be prepared using techniques including rotary bed granulation or spray drying dispersion (SDD).

[0115] The invention is illustrated in the following non-limiting examples. EXAMPLES

[0116] Example 1 Free Base + Succinic Acid Tablets containing the free base form of API (palbociclib) dry granulated with succinic acid were prepared using the following procedure. The tablets had the composition in Table 1.

[0117] [Table 1]

[0118] Microcrystalline cellulose (Avicel PH105) was added to a blender (bin blender or equivalent) and mixed at low speed for approximately 25 revolutions (2 minutes at 12 rpm). The API was added to the blender and a portion of the lactose monohydrate was used to rinse the API container and mixed in. The batch amounts of succinic acid, lactose monohydrate, crospovidone, and colloidal silicon dioxide were added to the blender and mixed at low speed for approximately 180 revolutions (15 minutes at 12 rpm).

[0119] The mill and bag were pre-coated with 50% of the batch amount of microcrystalline cellulose (Avicel PH102). The blend was passed through the mill from above. The mill was flushed with the remaining portion of the microcrystalline cellulose (Avicel PH102) and the milled material was transferred from the bag to a blender (bin blender or equivalent) and mixed at low speed for approximately 180 revolutions (15 minutes at 12 rpm). The intragranular magnesium stearate was sieved through an appropriate size screen and added to the blender from the previous step. The mixture was mixed at low speed for approximately 60 revolutions (5 minutes at 12 rpm). The blend was roller compacted (Gerteis Minipactor or equivalent) without separating or recycling the fines. If in-line milling was not utilized, the roller compacted blend was passed through a Comil U5 or U10 equipped with a 1601 impeller, with a screen size of 050G and a speed of 1000 or 700 rpm, respectively.

[0120] The extragranular crospovidone was added to the blender from the previous step. The mixture was blended at low speed for approximately 180 revolutions (15 minutes at 12 rpm). The extragranular magnesium stearate was sieved through an appropriate size screen. It was added to the blender from the previous step and blended for approximately 60 revolutions (5 minutes at 12 rpm).

[0121] A single station press (Korsch XP 1 or equivalent) or a rotary press was used to form the tablets.

[0122] Example 2 Bilayer tablet formulation A bilayer tablet was prepared containing an active layer and an acid layer. The active layer consisted of the granule blend from Example 1.

[0123] The active and acid layers had the compositions in Table 2.

[0124] [Table 2]

[0125] An acid layer blend was formed by combining microcrystalline cellulose, tartaric acid and crospovidone in an appropriately sized container. The combination was blended for approximately 120 revolutions and then passed through a Comil U5 or U10 equipped with a 1601 impeller, screen size 018R and speeds of 1000 rpm or 700 rpm, respectively.

[0126] The milled material was transferred to a blender and the ingredients were then blended for approximately 120 revolutions. The magnesium stearate was sieved through an appropriate size screen (1 mm screen, US Sieve #20) and then added to the blender and blended for approximately 50 revolutions.

[0127] Bilayer tablets were formed using the following procedure using a suitable rotary bilayer tablet press, such as a Korsch XP1: The active layer granulation (formed according to the procedure outlined in Example 1) was compressed to a target active layer weight of 625 mg and recommended active layer thickness of 6.66 mm. The acid layer blend was added and the acid layer and active layer were compressed to the desired fill weight of 985 mg.

[0128] Example 3 Fluid Bed Granulation The fluid bed coater (Niro MP-2 fluid bed coater with MP-1 bowl, top spray granulation set up) was preheated using the following conditions until the inlet dew point (12° C.) and product bowl temperature stabilized to the target (above 45° C.): The spray nozzle was a Schlick 970 with a 0.8 mm fluid tip, and the distance from the nozzle to the bottom of the bowl was 33 cm.

[0129] To form the fluid bed granulation, succinic acid was first hand milled using a mortar and pestle. Periodically, the milled powder was placed on a #60 mesh screen and shaken by hand to allow material to pass through into a collection vessel. Material retained on the screen was returned to the mortar and more material not subjected to milling was added. Milling was continued until the required amount passed through the screen.

[0130] In addition to succinic acid, the required amounts of the following dry bed components were each individually screened through a #30 mesh into individual collection vessels.

[0131] [Table 3]

[0132] A binder suspension was formed by adding water to an appropriately sized container. The mannitol and hydroxypropyl cellulose were then added to the container. The solution was mixed for a minimum of 2 hours and was visually free of clumps.

[0133] The API was then slowly added to the solution to form a binder suspension. The binder suspension was stirred during processing until it was used. The binder suspension contained the following ingredients in Table 4:

[0134] [Table 4]

[0135] After the product bowl temperature of the fluid bed had stabilized, the dry bed materials were then charged to the fluid bed in the following order: mannitol, microcrystalline cellulose, succinic acid, and crospovidone.

[0136] Fluid bed granulation was then carried out at a bed temperature of 29-31°C, a spray rate of 12-30 g / min, and a pressure of 70-115 CMH(m 3 Fluid bed granulation was carried out starting with an air flow of 1.5 g / h and an atomization pressure of 1.1 bar.

[0137] Example 4 Fluid Bed Granulation Tablets Tablets were formed from the fluid bed granulation (FBG) of Example 3 using the following procedure. First, the granulation was dry-sized by passing the granulation through a Comil U5 equipped with a 1601 impeller, with a screen size of 018R and a speed of 1500 rpm. The granulation was fed into the Comil as uniformly as possible by visual assessment (20-25 minutes for a 2 kg granulation). The milled granulation was passed through a #60 mesh screen and the material passing through the screen was collected in a bag and set aside. The material retained on the #60 mesh screen was milled a second time in the Comil. The milled granulation was passed through a #60 mesh screen and the material was collected in a bag. The material retained on the #60 mesh screen after the second pass was gently pushed through the screen using a spatula / scraper until all had passed. The material was added to the bag.

[0138] The final tablet blend for the FBG tablets is shown in Table 5:

[0139] [Table 5]

[0140] The adjusted weight of the extragranular components was calculated relative to the total weight of the milled granules from the previous step, if necessary.

[0141] The succinic acid was ground by hand (using a mortar and pestle) into small aliquots. A sufficient amount was used to ensure that the amount of ground material was sufficient. The ground material was passed through a #60 mesh screen and collected in a new bag. Any material retained on the screen was returned to the mortar with the next aliquot. The required amount of ground succinic acid was subdivided.

[0142] Next, the microcrystalline cellulose and crospovidone were passed through a #30 mesh screen and added to the blender. The milled succinic acid and dry sized fluid bed granules were added to an appropriate size blender. The bulk density was 0.39 g / cc. The mixture was blended for 11.25 minutes (180 revolutions) at 16 rpm.

[0143] Next, magnesium stearate was combined with 3-10 times (by volume, visual estimate) the blend from the previous step in an appropriate sized bottle. The mixture was mixed by gentle shaking by hand for approximately 30 seconds and then passed through a 30-mesh screen. The contents were added to a blender and blended for 3.75 minutes (60 revolutions) at 16 rpm.

[0144] Batches were compressed to target specifications using a suitable tablet press, such as a Korsch XM12.

[0145] Example 5 spray dried dispersion A solution of hypromellose (HPMC E3 Prem) was prepared by dissolving 3.25 wt% HPMC E3 in a solvent blend of 90 / 10 methanol / water (w / w) to form a 3.25 wt% HPMC solution. A sufficient amount of palbociclib (API) was added to this solution to form a spray suspension with the following composition: 1.75 wt% API, 3.25 wt% hypromellose, 85.5 wt% methanol, and 9.5 wt% water. The suspension was then continuously stirred to prevent the API from settling in the suspension tank.

[0146] The spray dryer was preheated using heated drying gas (nitrogen) at a flow rate of 1850 g / min and an inlet drying gas temperature of 130°C. After preheating, a 90 / 10 (w / w) methanol / water blend was sprayed until steady-state thermodynamic conditions were achieved. After the spray dryer reached steady state, the spray suspension was then introduced into the spray dryer via flash atomization at a feed rate of 130 g / min, a solution temperature of 130°C, and a pressure of 250 psi. A secondary nitrogen gas flow was used around the nozzle at a pressure of 60 psi to prevent nozzle fouling. Particles were collected at the outlet of the spray dryer at a temperature of 45°C.

[0147] After recovery, the particles were placed in a convection tray dryer operated at 40° C. / 15% relative humidity for a minimum of 6 hours, which reduced the residual solvent in the particles to 0.3 wt % or less (residual methanol).

[0148] The particle size of the secondary dried particles was measured by a Malvern particle size analyzer available from Malvern Instruments Ltd., Framingham, Massachusetts, using a low dispersion pressure of 0.5 to 1.0 bar, where D(4,3) is the volume mean diameter; DV 10 is the diameter that constitutes 10% of the total volume containing the particle; DV 50 is the diameter that constitutes 50% of the total volume containing the particle; and DV 90 is the diameter that constitutes 90% of the total volume containing the particles. The particle sizes are shown in Table 6:

[0149] [Table 6]

[0150] Particle Span (DV 90 -DV 10 ) / DV 50 The bulk specific volume of the particles was 5.6 cc / g, while the tapped specific volume was 3.0 cc / g.

[0151] The glass transition temperature (Tg) of the particles, as measured by differential scanning calorimetry (DSC), was 117.5°C, measured at less than 5% relative humidity. Powder X-ray diffraction (PXRD) showed that there was no detectable crystallinity and the API was amorphous. Particle morphology, as measured by scanning electron microscopy (SEM), showed that the particles had perfect and collapsed spheres.

[0152] Example 6 Comparative spray dried dispersion tablets Tablets lacking water-soluble acid were formed from the spray dried dispersion (SDD) of Example 5 using the following procedure: Half the microcrystalline cellulose was added to a blender (bin blender or equivalent) and mixed at low speed for approximately 25 revolutions (2 minutes at 12 rpm). The SDD was added to the blender. The blender was rinsed with a portion of the sodium chloride and mixed.

[0153] The batch amounts of sodium chloride, croscarmellose sodium, and colloidal silicon dioxide were added and mixed at low speed for approximately 180 revolutions (15 minutes at 12 rpm). The final blend is shown in Table 7.

[0154] [Table 7]

[0155] The mill and bag were pre-coated with 25 wt% of the amount of microcrystalline cellulose. The blend was passed through the mill from the above step using a Comil U5 equipped with a 1601 impeller, screen size 032R, speed 1000 rpm. The mill was flushed with the remaining batch portion of microcrystalline cellulose and the ground material was transferred from the bag to a blender (bin blender or equivalent) and mixed at low speed for approximately 180 revolutions (15 minutes at 12 rpm).

[0156] The intragranular magnesium stearate was sieved through an appropriate size screen and added to the blender from the previous step, then mixed at low speed for approximately 60 revolutions (5 minutes at 12 rpm).

[0157] The blends were compressed using a Korsch XP 1 or equivalent.

[0158] The compacted blend was passed through a mill using a Comil U5 equipped with a 1601 impeller, with a screen size of 050G and a speed of 1000 rpm.

[0159] The granulation was transferred from the bag to a blender (bin blender or equivalent). The amount of extragranular colloidal silicon dioxide was calculated and added to the blender from the previous step, then mixed for approximately 180 revolutions (15 minutes at 12 rpm). The amount of extragranular magnesium stearate required was calculated, sieved through an appropriately sized screen, added to the blender from the previous step, then mixed for approximately 60 revolutions (5 minutes at 12 rpm).

[0160] Tablets were compressed using a single station press (Korsch XP 1 or equivalent).

[0161] Example 7 Spray dried dispersion tablets Tablets were formed from the SDD of Example 5 using the following procedure: Half the microcrystalline cellulose was added to a blender (bin blender or equivalent) and mixed at low speed for approximately 25 revolutions (2 minutes at 12 rpm). The SDD was added to the blender, the blender was rinsed with a portion of the sodium chloride and mixed. The batch amounts of succinic acid, sodium chloride, croscarmellose sodium, and colloidal silicon dioxide were added and mixed at low speed for approximately 180 revolutions (15 minutes at 12 rpm). The final composition of the blend is shown in Table 8.

[0162] [Table 8]

[0163] The mill and bag were pre-coated with 25 wt% of the amount of microcrystalline cellulose. The blend was passed through the mill from the above step using a Comil U5 equipped with a 1601 impeller, screen size 018R, speed 1000 rpm. The mill was flushed with the remaining batch portion of microcrystalline cellulose and the ground material was transferred from the bag to a blender (bin blender or equivalent) and mixed at low speed for approximately 180 revolutions (15 minutes at 12 rpm).

[0164] The intragranular magnesium stearate was sieved through an appropriate size screen and added to the blender from the previous step, then mixed at low speed for approximately 60 revolutions (5 minutes at 12 rpm).

[0165] The blends were compressed using a Korsch XP 1 or equivalent.

[0166] The compacted blend was passed through a mill using a Comil U5 equipped with a 1601 impeller, screen size 050G and speed 1000 rpm. The amount of extragranular magnesium stearate required was calculated, sieved through the appropriate size screen and added to the blender from the previous step. The mixture was mixed for approximately 60 revolutions (5 minutes at 12 rpm).

[0167] Tablets were compressed using a single station press (Korsch XP 1 or equivalent).

[0168] Example 8 Dissolution test 1 at pH 5.5 Test tablet formulations containing palbociclib free base form (API), water soluble acid, microcrystalline cellulose (Avicel PH102), lactose monohydrate (Fast Flo 316), crospovidone (Kollidon CL), and magnesium stearate were prepared for dissolution testing. Test tablets of the following acids: malic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, tosylic acid, benzoic acid, and benzenesulfonic acid were prepared using the dry granulation (DG) method described in Example 1. Test tablets of malic acid and citric acid were prepared by direct compression (DC) (without dry granulation).

[0169] Tablets were dissolution tested in 500 mL of 10 mM sodium acetate buffer at pH 5.5 and temperature of 37° C. with paddles rotating at 50 rpm in a USP2 apparatus. At each withdrawal point, 6 mL of sample was collected and passed through a 10 μm full-flow filter. Analysis was performed offline at a UV wavelength of 367 nm.

[0170] A blend lacking water soluble acid was used to generate comparative dissolution data for palbociclib isethionate (ISE) capsules and free base API tablets prepared using the dry granulation method of Example 1. The results of dissolution testing of tablets containing succinic acid, maleic acid, malic acid, fumaric acid, and tartaric acid are shown in Figure 1. Tablets containing succinic acid, malic acid, and tartaric acid demonstrated superior dissolution performance, with more than 50% of the drug dissolved in 30 minutes as shown in Figure 2.

[0171] Example 9 Chemical stability of the formulation The test tablets prepared in Example 8 were stored at 70° C. / 75% RH for 8 days. The tablets were crushed and analyzed for impurities using a high performance liquid chromatography (HLPC) method as follows: Waters CSH C18, 2.1×100 mm, 1.7 μm column; mobile phase (gradient elution) A: 0.03% trifluoroacetic acid, and B: 0.03% trifluoroacetic acid in acetonitrile; column temperature 45° C.; flow rate 0.5 mL / min; UV detection at 234 nm; injection volume 2 μL; and run time 10.72 min. The results are summarized in Table 9.

[0172] [Table 9]

[0173] Tablets containing malic, succinic, benzoic, tosylic, tartaric and benzenesulfonic acids had acceptable total impurities after 8 days of storage at 70°C / 75% RH. Based on excellent dissolution and stability studies, the formulations containing succinic, malic and tartaric acids were selected for further development.

[0174] Example 10 Non-sinking dissolution test 2 A non-sinking in vitro dissolution method was developed to screen the formulations. In this method, tablets were placed in a USP2 (paddle) apparatus containing 500 mL of 50 mM phosphate buffer + 0.1 M NaCl (pH 6.5) at a temperature of 37° C., rotating at 50 rpm. Samples were periodically collected and filtered through a 10 μm filter. The concentration of API was measured offline at UV at 367 nm. Dissolution data was generated for tablets prepared in Example 1 (FB + succinic acid, tablet), Example 2 (FB + succinic acid, bilayer tablet), Example 4 (FB + succinic acid, FBG tablet), Example 6 (SDD, tablet) and Example 7 (SDD + succinic acid, tablet). The dissolution profile is shown in Figure 3. Also shown is the dissolution data for the commercial palbociclib free base capsule (free base capsule) with the formulation in Table 10:

[0175] [Table 10]

[0176] As shown in FIG. 3, when the dosage forms of Examples 1, 2, and 4 are subjected to non-sinking dissolution conditions, (a) greater than or equal to 40% of palbociclib in 15 minutes; (b) greater than or equal to 35% of palbociclib in 30 minutes; (c) greater than or equal to 25% of palbociclib in 60 minutes; or (d) two or more of (a), (b), and (c) dissolve.

[0177] Example 11 Drug exposure levels from commercial free base capsules. A randomized, single-dose, open-label, four-series, four-period crossover study was conducted in healthy volunteers. Twenty-eight (28) subjects received a single dose of palbociclib 125 mg each under four different conditions or treatments (overnight fasting [A], high-fat meal before dosing [B], low-fat meal before dosing [C], and moderate-fat meal 1 hour before dosing and 2 hours after dosing [D]).

[0178] The treatment sequences used in Periods 1 through 4 are shown in Table 11. There was a washout period of at least 10 days between study periods. After treatment administration, subjects underwent 144-hour PK sampling. Pharmacokinetic parameter values ​​are shown in Table 12.

[0179] [Table 11]

[0180] [Table 12]

[0181] The 125 mg commercial capsule formulation of palbociclib demonstrated lower AUC and Cmax when administered under fasted conditions compared to the exposure levels under the three fed conditions; therefore, it is recommended that the commercial capsule be administered with food.

[0182] Example 12 Effect of antacids on the bioavailability of palbociclib The objective of this study was to investigate the potential effect of increased gastric pH achieved by treatment with multiple doses of proton pump inhibitors (PPIs, specifically rabeprazole) on the pharmacokinetics (PK) of a single oral 125 mg commercial capsule of palbociclib given under fasting conditions.

[0183] The results are summarized below in Table 13. The commercial capsule formulation of palbociclib 125 mg demonstrated significantly lower AUC and Cmax when administered in the presence of rabeprazole compared to administration of palbociclib alone.

[0184] [Table 13]

[0185] (Example 13) Effect of antacids on the bioavailability of the test formulation A crossover, open-label, non-randomized, pharmacokinetic study in healthy volunteers was conducted to estimate the effect of antacid treatment on the bioavailability of 125 mg tablets (single dose) of six experimental formulations of palbociclib in the presence of rabeprazole compared to administration of palbociclib alone under fasting conditions. Tables 14(A)-(F) show the results for Cohorts 1-6, Example 1; Example 6; Example 7; Example 2; Example 4; and 125 mg palbociclib oral solution, respectively.

[0186] [Table 14-1]

[0187] [Table 14-2]

[0188] Example 14 Accelerated Stability Testing Tablets of Example 1 (dry granulation + succinic acid) were placed on accelerated stability using the following conditions: Tablets were placed in a beaker at the conditions listed below. Humidity control was achieved by either oven control or a saturated salt solution. Samples were removed from the conditions periodically as shown in Table 15 below. Samples (including the unexposed control) were stored in a refrigerator until analysis.

[0189] The following saturated salt solutions maintained the specified relative humidity: potassium acetate controlled at 22% RH; sodium bromide controlled at 50% RH at 30° and 40° C.; and a humidity controlled oven controlled at 75% RH.

[0190] [Table 15]

[0191] The breakdown products are:

[0192] [ka] It is a succinyl adduct of an API having the structure:

[0193] Samples were prepared by adding each tablet to a 100 mL volumetric flask and adding a stir bar and approximately 100 mL of dissolution solvent (1440 mL water: 400 mL acetonitrile: 160 mL 1N HCl; 80:20 0.1N HCl: acetonitrile). The flask was placed on a stir plate and the sample was stirred for 1 hour at the highest stirring speed suitable for use. An aliquot was then removed and centrifuged in a polypropylene tube at 3000 rpm for 5 minutes. The supernatant was diluted 1:5 with dissolution solvent and sampled in an HPLC vial for analysis. Each tablet contains 125 mg of API for a final solution concentration of 0.25 mg / mL. The samples were analyzed using the following HPLC method. The results are presented in Table 15 above and show excellent long-term stability.

[0194] Dissolving solvent (diluent): 1440mL water: 400mL acetonitrile: 160mL 1N HCl / / / (0.1N HCl: acetonitrile 80:20) Mobile phase: Mobile phase A: 0.03% trifluoroacetic acid (0.6 mL trifluoroacetic acid in 2000 mL water) Mobile phase B: 0.03% trifluoroacetic acid in acetonitrile (0.6 mL trifluoroacetic acid in 2000 mL acetonitrile) 0.5mL / min gradient Initial 88%A 12%B 0.22 minutes 88%A 12%B 8.72 minutes 15%A 85%B 8.82 minutes 88%A 12%B 10.72 minutes total run time 234 nm, area % vs. palbociclib (major band) Sample injection was 2 μL (prepared as indicated below). The sample chamber was maintained at 5°C.

[0195] Sample preparation Samples were prepared by adding each tablet to a 100 mL volumetric flask and adding a stir bar and approximately 100 mL of dissolution solvent. The flask was placed on a stir plate and the sample was stirred for 1 hour at the highest stirring speed suitable for use. An aliquot was then removed and centrifuged in a polypropylene tube at 3000 rpm for 5 minutes. The supernatant was diluted 1:5 with dissolution solvent and sampled in an HPLC vial for analysis. Each tablet contains 125 mg of palbociclib, resulting in a final solution concentration of 0.25 mg / mL.

[0196] Additionally, tablets from Example 4 (fluid bed granulation + succinic acid) were analyzed in the same manner, and the results are presented in Table 16 below, showing that the degradant levels were inadequate for long term stability.

[0197] [Table 16]

[0198] Example 15 Long-term storage stability Tablets of Example 1 were packaged in a bottle with a desiccant canister using a heat induction seal. After one year of storage at 25°C / 60%RH, the succinyl adduct level of the tablets was less than 0.05%. Tablets of Example 4 were packaged in a HDPE bottle with a desiccant canister using a heat induction seal. After six months of storage at 25°C / 60%RH, the succinyl adduct level of the tablets was 0.23%.

[0199] Example 16 Film-coated tablet formulations Table 17 describes the optimized formulations A1, A2 and B, which showed acceptable manufacturing performance for commercialization of solid dosage forms. The following procedure was used to form tablets: Microcrystalline cellulose PH102, colloidal silicon dioxide, intragranular crospovidone CL and API were blended together and passed through Comil for homogenization. Intragranular magnesium stearate was blended. The mixture was dry granulated using roller compaction and granule milling.

[0200] Sieved succinic acid, microcrystalline cellulose PH-200, and extragranular crospovidone (CL or CL-SF grades) were blended into the granules. Extragranular magnesium stearate or sodium stearyl fumarate were incorporated into the final blend as tableting lubricants. Tablets were formed using a rotary tablet press with precompression. Formulation A2 used an external lubrication system (ELS) to apply a negligible amount of lubricant directly to the tip of the tablet punch.

[0201] Tablets were film-coated with Opadry Pink (03K140024) and purified water at 12% w / w solids to a weight gain of 2-4%.

[0202] [Table 17]

[0203] (Example 17) Optimizing lubricant levels Formulations were prepared as described in Formulation A2 in Example 16 with different levels of intragranular and extragranular magnesium stearate lubricant as shown in Table 17. For each formulation, hardness (tablet breaking force, USP <1217> ), friability (USP <1216> 100 rpm), Extended Friability (USP <1216> Tablet sticking (at 375 revolutions) and punch sticking (Hutchins, MacDonald, Mullarney, Assessing Tablet-Sticking Propensity, Pharmaceutical Technology, Volume 36, Issue 1, 2012) were measured. Reduced sample sizes were used for the USP method.

[0204] Reducing both intragranular and extragranular lubricant levels significantly increased tablet hardness and reduced friability. Tablet sticking was more sensitive to extragranular lubricant levels than intragranular lubricant levels. Sticking was significantly reduced by increasing extragranular magnesium stearate levels. No difference was observed in knurled / smooth roller sticking at different intragranular magnesium stearate levels. As shown in Table 18, reducing the intragranular / extragranular lubricant ratio from 1 wt% / 0 wt% to 0.33 wt% / 0.5 wt% provided good tablet strength, reduced friability, and reduced sticking for tablets of Formulation A2. Lubricant levels of approximately 5 wt% sodium stearyl fumarate or 2 wt% fine grade stearate (CaSt 2249) reduced punch sticking and tablet defects.

[0205] [Table 18]

[0206] (Example 18) Optimizing tablet hardness and friability Formulations were prepared generally as described for Formulation A2 in Example 16, with varying orders of acid addition, lactose monohydrate addition, dry binder addition (Kollidon SF, Avicel PH105, Klucel EXF), and varying the intragranular to extragranular ratio of microcrystalline cellulose. Properties of these different formulations: Bulk density of the initial blend (USP <616> ), roller compaction ribbon tensile strength (Zinchuk AV, Mullarney MP, Hancock BC.Simulation of roller compaction using a laboratory scale compaction simulator.Int J Pharm. 2004 Jan 28;269(2):403~15.), punch sticking (Hutchins, MacDonald, Mullarney, Assessing Tablet-Sticking Propensity, Pharmaceutical Technology, Volume 36, Issue 1, 2012), tablet hardness (tablet breaking force, USP <1217> ), friability (USP <1216> 375 rpm), and disintegration time (USP <701> ) was measured. A reduced sample size was used for the USP method.

[0207] The lactose-free formulation showed higher tablet hardness and lower friability. Moreover, the addition of SF (extrafine) grade Kollidon helped to decrease the disintegration time while increasing the tablet hardness. The addition of extragranular acid was found to be favorable for obtaining shorter disintegration time.

[0208] Removal of lactose from the formulation resulted in tablets with reduced friability that maintained rapid disintegration. The inclusion of a dry binder did not provide any additional benefit in reducing friability, but did slightly reduce sticking. However, the inclusion of a binder may in some cases adversely affect disintegration / swelling.

[0209] [Table 19]

[0210] (Example 19) In vitro dissolution of formulations A1, A2 and B The in vitro dissolution of optimized formulations A1, A2 and B was determined using dissolution test 2 under non-sinking conditions (pH 6.5, 50 mM phosphate buffer, 0.1 M NaCl) as described in Example 10. The dissolution profiles of these formulations were compared to tablets prepared according to Examples 1-7. Tablets of Example 1 showed no drug-drug interactions with proton pump inhibitors in fasted human volunteers and were set at the lowest target dissolution profile. Comparative dissolution data are shown in Figure 4. Formulations A1, A2 and B were all superior to both the commercial free base capsules (prepared as described in Example 10) and the palbociclib isethionate (ISE) capsules used in early development with the formulations in Table 20. After 10 minutes, formulations A1, A2 and B were all superior to tablets of Examples 1-7 and therefore met the solid dosage form dissolution targets.

[0211] [Table 20]

[0212] (Example 20) Effect of particle size distribution of succinic acid The effect of particle size distribution of succinic acid on the rate of formation of succinyl adducts was evaluated for neat acid (broad particle size distribution up to 1 mm diameter) and three sieve cuts of the acid. Smaller acid particle size resulted in a greater rate of impurity formation because its larger specific surface area allows for more frequent contact of the acid with the free base API. Therefore, to improve chemical stability, an acid with a particle size greater than about 100 microns was preferred in the drug product formulation.

[0213] [Table 21]

[0214] Example 21 Physical stability analysis A quantitative Raman spectroscopy method was developed to determine the physical stability of the formulations. The Raman method used a Kaiser Optical Systems PhAT probe, and a quantitative model was constructed using a set of calibration standards prepared from the API, API succinate complex, and excipients. The relative stability of Formulations A1 and B was evaluated by determining the amount of API succinate complex in the formulation after storage of tablets at 30-50 °C up to 75% RH for up to one month.

[0215] Formulation B showed a lower conversion to the succinate complex compared to formulation A1. The amount of conversion increased over time and was enhanced by storage conditions at higher temperature and humidity.

[0216] The amount of API succinate complex formed under various temperature and humidity conditions for Formulations A1 and B as a function of time is shown in Table 22, where "LOD" means limit of detection and "LOQ" means limit of quantification.

[0217] [Table 22]

[0218] The physical stability of the prototype uncoated tablet formulation A1 under open conditions was evaluated. The tablets were exposed to high temperature and humidity. Raman spectroscopy was used to observe the conversion to succinate complex in the stressed samples.

[0219] The chemical purity of formulations A1 and B was compared after one month of storage at 40° C. / 75% RH. As shown in Table 23, formulation B showed a significantly lower degree of total impurity formation compared to formulation A1.

[0220] [Table 23]

[0221] Based on these data, it was determined that humidity (% RH) had a significant effect on the rate of API conversion from the free base to the succinate complex. Increasing temperature also affected the conversion to the complex, but to a lesser extent than humidity.

[0222] Tablets pre-equilibrated at 60% RH prior to foil packaging showed rapid succinate complex formation. Nine-week stability data indicated that control of water activity in the tablets is required to minimize palbociclib succinate complex formation in the drug product. Formulation B (containing extragranular sodium stearyl fumarate as a lubricant) showed lower succinate complex conversion compared to Formulation A1 (incorporating magnesium stearate as an extragranular lubricant) under conditions of high humidity (75% RH).

Claims

1. A tablet consisting essentially of an intragranular component consisting of 125.000 mg palbociclib, 244.812 mg microcrystalline cellulose, 6.250 mg colloidal silicon dioxide, 18.750 mg crospovidone, and 2.063 mg magnesium stearate, and an extragranular component consisting of 62.500 mg succinic acid (100-350 microns), 134.375 mg microcrystalline cellulose, 18.750 mg crospovidone, and 12.500 mg magnesium stearate (fine grade).

2. A tablet as described in claim 1, film-coated to a weight gain of 2 to 4%.

Images