Dosage forms of elacridar

Abstract

This invention relates to a solid oral pharmaceutical dosage form comprising palbociclib and succinic acid as active pharmaceutical ingredients, wherein succinic acid has a concentration higher than 0.015 mg / mL. 2 / g of surface area.

Description

[0001] manual Technical Background

[0003] This invention relates to a solid oral pharmaceutical dosage form comprising 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (hereinafter referred to as palbociclib) and succinic acid. Background of the Invention

[0005] Palbociclib is a potent and selective inhibitor of CDK4 and CDK6, and has the following chemical structure:

[0006] .

[0007] Palbociclib is described in WHO Drug Information, Vol. 27, No. 2, page 172 (2013). Palbociclib and its pharmaceutically acceptable salts are disclosed, for example, in International Publication WO 2003 / 062236.

[0008] Palbociclib is approved in the European Union for use in women who have received prior endocrine therapy in combination with an aromatase inhibitor or with fulvestrant for the treatment of hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative locally advanced or metastatic breast cancer. In premenopausal or perimenopausal women, endocrine therapy should be combined with a luteinizing hormone-releasing hormone (LHRH) agonist.

[0009] Palbociclib is marketed by Pfizer under the brand name IBRANCE® and is available in oral immediate-release capsule and immediate-release tablet forms, both of which contain palbociclib in the free base form.

[0010] Palbociclib is a bibasic compound with two basic groups, exhibiting a pKa of approximately 7.3 (piperazine secondary nitrogen) and 4.1 (pyridine nitrogen). The solubility of the free palbociclib base is pH-dependent. Palbociclib is water-soluble at low pH levels (2.1–4.5), but its solubility decreases sharply above pH 4.5. Palbociclib exhibits poor water solubility (9 mg / mL) at pH 7.9. Concomitant administration of substances that increase gastric pH can alter the solubility and absorption of the free palbociclib base formulation.

[0011] When administered orally, the absorption and bioavailability of therapeutic agents can be affected by a variety of factors, including whether the subject is eating or fasting, the use of certain drugs such as proton pump inhibitors (PPIs) or H2 receptor antagonists, and certain medical conditions. Compounds with pH-dependent solubility, especially basic compounds, can exhibit undesirable pharmacokinetic properties, such as poor absorption and / or reduced bioavailability, which can lead to significant inter- and intra-patient variability.

[0012] EP 3 302 565 B1 discloses oral tablets of a mixture of palbociclib and succinic acid, which should have the desired pharmacokinetic properties and should exhibit sufficient storage stability and dissolution properties. This document teaches the influence and importance of the particle size distribution of succinic acid on the formation of the succinyl adduct of palbociclib.

[0013] However, there is still a need to develop palbociclib formulations with favorable dissolution properties and storage stability.

[0014] Purpose of the invention

[0015] The object of this invention is to provide a palbociclib formulation with favorable dissolution properties and storage stability.

[0016] Solutions to technical problems

[0017] The objective has been achieved by a dosage form comprising palbociclib free base and succinic acid as active pharmaceutical ingredients, wherein the succinic acid has a concentration greater than 0.015 mg / L. 2 / g of surface area.

[0018] Surprisingly, the dosage forms of the present invention have been found to exhibit advantageous and stable dissolution properties as well as good storage stability. In particular, the dosage forms of the present invention are characterized by particularly low levels of palbociclib-succinyl adduct, which is considered an impurity. Moreover, it has been found that even when the dosage forms of the present invention contain relatively low levels of succinic acid, they still exhibit advantageous dissolution properties.

[0019] According to the present invention, the surface area (also with respect to the second internal phase of the particles as described below) is the specific surface area, which must be determined by the following official provision: European Pharmacopoeia (German edition), 11th edition, pp. 534-537, Chapter 2.9.26 "Best immunization of spezifischen Oberfläche durch Gasadsorption", wherein the following conditions are preferably used:

[0020] Device Manufacturer: Jingwei Gaobo Science & Technology Co., Ltd.

[0021] Model: JW-BK200A

[0022] Instrument parameters:

[0023] Adsorbent: N2

[0024] Q value: Automated rapid testing

[0025] P0: Automation

[0026] Vacuum pumping rate: standard

[0027] End of experiment: Lowering the cup and backfilling

[0028] Backfill type: He

[0029] Cut-off control: Point inflation (P / Past<1)

[0030] Pressure setting: Relative pressure

[0031] Pressure deviation: Relative pressure: 5%; Absolute pressure: 0.6666 kPa

[0032] Absorption section:

[0033]

[0034] According to a preferred embodiment of the dosage form of the present invention, succinic acid has a concentration higher than 0.025 m. 2 The surface area per g is preferably greater than 0.03 m². 2 The surface area per g is preferably greater than 0.035 m². 2 The surface area per g is more preferably higher than 0.038 m². 2 / g of surface area.

[0035] In other preferred embodiments of the dosage form according to the invention, succinic acid has a concentration of less than 0.13 m. 2 The surface area per g is preferably less than 0.09 m². 2 The surface area per g is more preferably less than 0.045 m². 2 / g of surface area.

[0036] In other preferred embodiments of the dosage form according to the invention, succinic acid has a concentration of 0.026 m... 2 / g to 0.09 m 2 The surface area in the range of / g is preferably 0.03 m². 2 / g to 0.05 m 2 Surface area in the range of / g, more preferably 0.035 m 2 / g to 0.045 m 2 Surface area in the range of / g.

[0037] According to other preferred embodiments of the dosage form of the present invention, the dosage form is a capsule or a tablet, preferably a tablet, more preferably a film-coated tablet.

[0038] According to another preferred embodiment of the dosage form of the invention, the dosage form is a tablet, wherein:

[0039] a) The tablet comprises an internal particle phase and a continuous external particle phase, wherein palbociclib is contained in the internal particle phase and succinic acid is contained in the continuous external particle phase; or

[0040] (b) The tablet comprises a first internal phase, a second internal phase, and optionally a first continuous external phase, wherein palbociclib is contained in the first internal phase and succinic acid is contained in the second internal phase.

[0041] According to other preferred embodiments of the dosage form of the invention, the dosage form contains 10% to 35% by weight of palbociclib, preferably 10% to 20% by weight, based on the total weight of the dosage form.

[0042] According to other preferred embodiments of the dosage form of the invention, the dosage form contains 25 mg, 75 mg, 100 mg or 125 mg of palbociclib.

[0043] According to other preferred embodiments of the dosage form of the invention, the dosage form contains 5% to 1% by weight of succinic acid, preferably less than 5% to 1% by weight, more preferably 4.5% to 3% by weight, based on the total weight of the dosage form.

[0044] In other preferred embodiments of the dosage form according to the invention, the weight ratio of palbociclib to succinic acid is selected from the range of 1:0.1 to 1:0.5, preferably from 1:0.2 to 1:0.4, and more preferably from 1:0.2 to 1:0.3.

[0045] According to other preferred embodiments of the dosage form of the invention, the dosage form further comprises at least one diluent in an amount of 50% to 80% by weight, preferably 60% to 80% by weight, based on the total weight of the dosage form.

[0046] In other preferred embodiments of the dosage form according to the present invention, the diluent is selected from microcrystalline cellulose, lactose monohydrate, mannitol, sorbitol, xylitol, magnesium carbonate, dicalcium phosphate, and calcium phosphate.

[0047] According to other preferred embodiments of the dosage form of the present invention, the diluent is contained in a) the inner phase of the particles and the continuous outer phase of the particles, and b) the first inner phase of the particles and the second inner phase of the particles.

[0048] According to another preferred embodiment of the dosage form of the invention, the dosage form further comprises at least one lubricant in an amount of 0.5% to 5% by weight, preferably 1% to 2% by weight, based on the total weight of the dosage form.

[0049] In other preferred embodiments of the formulation according to the invention, the lubricant is selected from magnesium stearate, calcium stearate, zinc stearate and sodium stearoyl fumarate.

[0050] According to other preferred embodiments of the formulation of the present invention, the lubricant is respectively contained in a) an internal particle phase and a continuous external particle phase and b) a first internal particle phase and a first continuous external particle phase.

[0051] In other preferred embodiments of the dosage form according to the invention, the dosage form further comprises at least one disintegrant in an amount of 1% to 10% by weight, preferably 2% to 5% by weight, based on the total weight of the dosage form.

[0052] In other preferred embodiments of the dosage form according to the present invention, the disintegrant is selected from crospovidone, croscarmellose sodium, and starch glycolate sodium.

[0053] According to other preferred embodiments of the dosage form of the present invention, the disintegrant is contained in a) the internal phase of the particles and b) the first internal phase of the particles, the second internal phase of the particles, and the first continuous external phase of the particles.

[0054] According to other preferred embodiments of the dosage form of the present invention, a) the intraparticle phase is prepared by dry granulation, and b) respectively, the first intraparticle phase is prepared by dry granulation and the second intraparticle phase is prepared by wet granulation.

[0055] In other preferred embodiments of the dosage form according to the invention, palbociclib exists in crystalline form.

[0056] In another preferred embodiment of the dosage form according to the invention, the dosage form is an immediate-release dosage form.

[0057] According to other preferred embodiments of the dosage form of the invention, when added to a test medium containing 900 mL of 10 mM pH 5.5 acetate buffer at 37°C in a standard USP 2 rotary paddle apparatus in which the paddle rotates at 75 rpm, the dosage form dissolves as follows: (a) 50% to 90% of palbociclib dissolves within 15 minutes; (b) 60% to 95% of palbociclib dissolves within 30 minutes; and (c) 75% to 100% of palbociclib dissolves within 60 minutes.

[0058] According to other preferred embodiments of the dosage form of the invention, when added to a test medium containing 900 mL of 10 mM pH 6.8 phosphate buffer at 37°C in a standard USP 2 rotary paddle apparatus in which the paddle rotates at 75 rpm, the dosage form dissolves as follows: (a) 10% to 35% of palbociclib dissolves within 15 minutes; (b) 15% to 40% of palbociclib dissolves within 30 minutes; and (c) 15% to 50% of palbociclib dissolves within 60 minutes.

[0059] According to other preferred embodiments of the dosage form of the present invention, succinic acid has the following particle size distribution: D90 value in the range of 100 µm to 1000 µm, D50 value in the range of 50 µm to 700 µm, and D10 value in the range of 20 µm to 500 µm.

[0060] According to other preferred embodiments of the dosage form of the present invention, succinic acid has the following particle size distribution: D90 value in the range of 500 µm to 700 µm, D50 value in the range of 300 µm to 450 µm, and D10 value in the range of 150 µm to 260 µm.

[0061] According to other preferred embodiments of the dosage form of the present invention, palbociclib has a particle size distribution in the range of 60-120 mesh to 40-100 mesh, or has a particle size distribution with a D90 value in the range of 350 µm to 650 µm, a D50 value in the range of 150 µm to 400 µm, and a D10 value in the range of 40 µm to 250 µm.

[0062] According to other preferred embodiments of the dosage form, the second intraparticle phase has the following particle size distribution: D90 value in the range of 350 µm to 700 µm, D50 value in the range of 200 µm to 400 µm, and D10 value in the range of 100 µm to 200 µm.

[0063] According to other preferred embodiments of the dosage form, the second particle internal phase has a density higher than 10 μm. 2 Surface area per g, preferably greater than 12 m² 2 / g surface area, more preferably 15 m 2 / g to 30 m 2 / g of surface area.

[0064] The particle size distribution of succinic acid, palbociclib, and the second internal phase should be determined in accordance with Chapter 2.9.31 "Determination of particle size by laser diffraction" of the European Pharmacopoeia (Ph. Eur.) 10.0, pages 373-377, preferably by a Malvern Mastersizer 3000 HYDRO MV having the parameters described in Example 1 below.

[0065] In other preferred embodiments of the dosage form according to the invention, succinic acid is needle-shaped succinic acid.

[0066] The present invention also relates to a first method for preparing the dosage form of the present invention, wherein the dosage form is a tablet, the tablet comprising palbociclib and succinic acid as active pharmaceutical ingredients, wherein the tablet comprises an internal phase and a continuous external phase, and wherein palbociclib is contained in the internal phase and succinic acid is contained in the continuous external phase, wherein the method comprises the following steps:

[0067] a) Dry granulation of palbociclib and optionally one or more pharmaceutically acceptable excipients to obtain dry granules forming an internal phase of the granules;

[0068] b) The dry granules are mixed with succinic acid and optionally with one or more pharmaceutically acceptable excipients to obtain a mixture;

[0069] c) Compress the mixture to obtain tablets;

[0070] d) Optionally, the tablets are film-coated to obtain film-coated tablets.

[0071] The present invention also relates to a second method for preparing the dosage form of the present invention, wherein the dosage form is a tablet, the tablet comprising a first internal phase, a second internal phase, and optionally a first continuous external phase, wherein palbociclib is contained in the first internal phase, and succinic acid is contained in the second internal phase, wherein the method comprises the following steps:

[0072] a) Dry granulation of palbociclib and optionally one or more pharmaceutically acceptable excipients to obtain dry granules forming a first internal phase of the granules;

[0073] b) Succinic acid and optionally one or more pharmaceutically acceptable excipients are wet-granulated to obtain wet-granules that form a second internal phase of the particles;

[0074] c) The dry granules and the wet granules are optionally mixed with one or more pharmaceutically acceptable excipients to obtain a mixture;

[0075] d) Compress the resulting mixture into tablets;

[0076] e) Optionally, the tablets are film-coated to obtain film-coated tablets.

[0077] A typical dosage form provided by this invention is a tablet, preferably a film-coated tablet, which contains palbociclib free base and succinic acid as active pharmaceutical ingredients, wherein the succinic acid has a concentration of 0.026 mg / mL. 2 / g to 0.09 m 2 The surface area in the range of / g is preferably 0.03 m². 2 / g to 0.05 m 2 Surface area in the range of / g, more preferably 0.035 m 2 / g to 0.045 m 2 The dosage form contains a surface area in the range of / g, wherein the dosage form contains 25 mg, 75 mg, 100 mg or 125 mg of palbociclib free base, and wherein the dosage form contains 5% to 1% by weight of succinic acid, preferably less than 5% to 1% by weight, more preferably 4.5% to 3% by weight, based on the total weight of the tablet core (excluding the weight of the tablet coating).

[0078] Example 1

[0079] A film-coated palbociclib tablet having the following composition was prepared as the dosage form of the present invention.

[0080]

[0081] The tablets were prepared according to the method of the present invention as follows.

[0082] method

[0083] (Papoxetine granules)

[0084] Step 1: Dry mix the excipients (palbociclib, MCC, crospovidone, colloidal SiO2, magnesium stearate).

[0085] Step 2: Rolling

[0086] Step 3: Grinding

[0087] (Succinic acid granules)

[0088] Step 4: Dry mix the excipients (MCC, crospovidone, succinic acid).

[0089] Step 5: Preparation of coating solution (HPMC, pure water)

[0090] Step 6: Fluidized bed coating

[0091] (Final Mix)

[0092] Step 7: Mix (palbociclib particles and succinic acid particles, colloidal SiO2, crospovidone and magnesium stearate)

[0093] Step 8: Tableting

[0094] Step 9: Coating

[0095] Step 10: Packaging in Al / Al blister packs

[0096] Two tablet formulations were prepared using the composition and methods described above (Examples 1.1 and 1.2). Succinic acid was obtained from two suppliers and sieved using #60-120 to ensure the use of the same particle size distribution (PSD). The PSD was determined by routine PSD laser diffraction testing, and the obtained D10, D50, and D90 values ​​confirmed that the succinic acid obtained from the two suppliers had similar ranges. Surprisingly, very different dissolution properties were obtained, as shown in the table below.

[0097]

[0098] Under the same particle size distribution, tablets containing succinic acid from one supplier have significantly different dissolution rates compared to tablets containing succinic acid from another supplier. Therefore, particle size distribution is not a suitable characteristic for obtaining stable dissolution profiles.

[0099] The surface area of ​​the succinic acid used in Examples 1.1 and 1.2 was measured as described below, and the results are shown in the table below.

[0100]

[0101] Surprisingly, the surface areas of the succinic acid particles were found to be significantly different, even though the selected succinic acid grade and particle size distribution were the same.

[0102] Example 2

[0103] A film-coated palbociclib tablet having the following composition was prepared as the dosage form of the present invention.

[0104]

[0105] The tablets were prepared according to the method of the present invention as follows.

[0106] Step 1: Dry mix the excipients (palbociclib, MCC, crospovidone, colloidal SiO2, magnesium stearate)

[0107] Step 2: Rolling

[0108] Step 3: Grinding

[0109] Step 4: Mixing (milled particles, MCC, colloidal SiO2, succinic acid, and magnesium stearate)

[0110] Step 5: Tableting

[0111] Step 6: Coating

[0112] Step 7: Packaging in Al / Al blister packs

[0113] Different succinic acid varieties, as shown in the table below, were used for tablet preparation according to the methods and compositions given herein.

[0114]

[0115] Particle size distribution and surface area determination:

[0116] Before determining the D90-, D50-, D10-, and D4.3 values ​​and surface area of ​​different succinic acid varieties, the probes were pretreated by storing 5g of the probes of the succinic acid varieties at 90°C for 4 hours.

[0117] According to Chapter 2.9.31 of the European Pharmacopoeia (Ph. Eur.) 10.0, "Determination of particle size by laser diffraction," the D90, D50, D10, and D4.3 values ​​of different succinic acid varieties were determined using a Malvern Mastersizer 3000 HYDRO MV with the following parameters:

[0118] Instrument: Malvern Mastersizer 3000

[0119] Sample dispersion unit: HYDRO MV

[0120] Particle type: Non-spherical

[0121] Sample refractive index: 1.48

[0122] Sample absorbance: 0.01

[0123] Dispersant: Isopar G

[0124] Refractive index of dispersant: 1.42

[0125] Background time: 12 seconds

[0126] Measurement time: 20 s

[0127] Test frequency: The average of three tests is taken.

[0128] Light blocking range: 10%-20%

[0129] Mixer speed: 1700 rpm

[0130] Analysis Model: General

[0131] Advanced Options: Sensitivity: Normal

[0132] Particle size range: 0.005-5000 µm

[0133] Sample suspension: Weigh approximately 700 mg of sample into a 50 mL beaker, add 10 mL of Isopar G and 1 drop of Span80, stir for 1 minute, and use a disposable dropper to quickly aspirate and blow the sample into the syringe until the observation range reaches 10%-20%. After observation and stabilization, perform three measurements on the sample.

[0134] Sample injector cleaning: Clean the middle of the test with isopropanol at least 3 times, and then clean with Isopar G at least 3 times.

[0135] The surface area, i.e., specific surface area, of different succinic acid varieties was determined according to Chapter 2.9.26, “Bestimmung derspezifischen Oberfläche durch Gasadsorption”, pages 534-537, 11th edition of the European Pharmacopoeia (German version), under the following conditions:

[0136] Equipment Manufacturer: Jingwei Gaobo Science & Technology Co., Ltd.

[0137] Model: JW-BK200A

[0138] Instrument parameters:

[0139] Adsorbate: N2

[0140] Q value: Automated rapid testing

[0141] P0: Automation

[0142] Vacuuming speed: standard

[0143] End of experiment: Lowering the cup and backfilling

[0144] Backfill type: He

[0145] Cut-off control: Point inflation (P / Past<1)

[0146] Pressure setting: Relative pressure

[0147] Pressure deviation: Relative pressure: 5%; Absolute pressure: 0.6666 kPa

[0148] Absorption section:

[0149]

[0150] Dissolution test – Example 2:

[0151] Dissolution tests have been performed on the tablets using five different succinic acid surface areas. Each formulation has been prepared as described above (Example 2). The dissolution test refers to the dissolution of palbociclib. The dissolution test was performed using the standard USP 2 rotary paddle apparatus disclosed in Chapter 711, Apparatus 2, United States Pharmacopeia (USP) Dissolution Tests. The paddle was rotated at 75 rpm, adding the dosage form to 900 mL of 10 mM pH 5.5 acetate buffer at 37°C. At an appropriate time after the start of the test (e.g., after adding the dosage form to the apparatus), an aliquot (typically 1.5 mL) was taken from the test medium and filtered, and palbociclib was analyzed by high-performance liquid chromatography (HPLC). The dissolution results are reported as the percentage of palbociclib dissolved from the total dose over time (in minutes).

[0152] The results of the dissolution test are shown in the table below:

[0153]

[0154] Dissolution data at pH 5.5 showed that the surface area of ​​succinic acid affected dissolution. Specifically, the data indicated that the larger the surface area of ​​the succinic acid variety, the higher the dissolution rate of palbociclib.

[0155] Stress stability test – Example 2:

[0156] Strong stability tests have been conducted on the tablets using five different varieties of succinic acid.

[0157] In the robust stability test, Al / Al packaged tablets were placed in a constant temperature and humidity chamber adjusted to 60°C / 75% RH. After the time periods shown in the table below, the tablets were pulverized, and impurities were analyzed using the following high-performance liquid chromatography (HPLC): Column: Waters CSH C18, 2.1 x 100 mm, 1.7 mm column; Mobile phase (gradient elution): A: 0.03% trifluoroacetic acid aqueous solution, and B: 0.03% trifluoroacetic acid solution in acetonitrile; Column temperature: 45°C; Flow rate: 0.5 mL / min; UV detection: 234 nm; Injection volume: 2 mL; Run time: 10.72 min. The total amount of impurities was determined by summing the peak areas in the HPLC chromatogram. The peak area was calculated as a percentage of the total peak area in the HPLC chromatogram. The results are summarized in the table below.

[0158]

[0159]

[0160] The data specifically shows that the larger the surface area of ​​succinic acid varieties, the greater the impurity content, and the less stable palbociclib is in tablets.

[0161] Example 3

[0162] A film-coated palbociclib tablet having the following composition was prepared as the dosage form of the present invention.

[0163]

[0164] The tablets were prepared using different succinic acid varieties as described in the table below, which presents dissolution data.

[0165] Tablets with different percentages of succinic acid were prepared according to the method of the present invention as follows.

[0166] Step 1: Dry mix the excipients (API, MCC, crospovidone, colloidal SiO2, magnesium stearate)

[0167] Step 2: Rolling

[0168] Step 3: Grinding

[0169] Step 4: Mixing (milled particles and colloidal SiO2, succinic acid and magnesium stearate)

[0170] Step 5: Tableting

[0171] Step 6: Coating

[0172] Step 7: Packaging in Al / Al blister packs

[0173] Dissolution test - Example 3

[0174] Dissolution tests were conducted using the tablets according to Example 3 with different percentages and different succinic acid surface areas.

[0175] The results of the dissolution test are shown in the table below:

[0176]

[0177] The data clearly show that even by reducing the amount of succinic acid, sufficient dissolution can still be maintained by increasing the surface area of ​​succinic acid.

[0178] Dissolution test - Palbociclib PSD:

[0179] Three different tablets according to Example 1 were prepared, each using a 0.087 μm... 2 Succinic acid varieties with a surface area of ​​ / g and palbociclib varieties with D90 values ​​of 30µm, 14µm or 4µm.

[0180] The D90 values ​​of three different palbociclib and succinic acid varieties were determined as described above.

[0181] The table below shows the results of the dissolution test:

[0182]

[0183] Dissolution data showed that particle size distribution (PSD) had no effect on the dissolution rate, as the dissolution retention was similar when using three different palbociclib varieties with different D90 values ​​and the same succinic acid surface area. This indicates that succinic acid quality is a key factor affecting the dissolution rate of palbociclib.

[0184] Bioequivalence study – Example 1:

[0185] Using a 0.087 m 2 Bioequivalence studies were conducted on tablets of Example 1 with a succinic acid variety having a surface area of ​​ / g and a palbociclib variety having a D90 value of 4 µm.

[0186]

[0187] As is clear from the table above, the tablets have passed the bioequivalence study.

[0188] Example 4

[0189] The following tablets underwent strength stability tests:

[0190] - a) The tablet of Example 1, using a 0.087 m 2 Succinic acid varieties with a surface area of ​​ / g and palbociclib varieties with a D90 value of 4 µm;

[0191] - b) The tablet of Example 2, having a succinic acid content of 4% by weight and using a 0.075 m... 2 Succinic acid with a surface area of ​​ / g;

[0192] - c) The tablet of Example 3, having a succinic acid content of 4% by weight and using a 0.098 m 2 / g surface area of ​​succinic acid.

[0193] For the robust stability test, Al / Al packaged tablets were placed in a constant temperature and humidity chamber adjusted to 60°C / 75% RH. After the time periods shown in the table below, the tablets were pulverized, and impurities were analyzed using high-performance liquid chromatography (HPLC) as described above. The results are summarized in the table below.

[0194]

[0195]

[0196] Data shows that all impurities are within the limits specified in the ICH guidelines. Using the succinic acid surface area according to the present invention, different production methods can provide suitable tablets that meet the impurity requirements.

Claims

1. A solid oral dosage form comprising palbociclib and succinic acid as active pharmaceutical ingredients, wherein succinic acid has a concentration higher than 0.015 mg / mL. 2 / g of surface area.

2. The dosage form according to claim 1, characterized in that, Succinic acid has a concentration higher than 0.025 m. 2 The surface area per g is preferably greater than 0.03 m². 2 The surface area per g is more preferably higher than 0.035 m². 2 The surface area per g is preferably higher than 0.038 m². 2 / g of surface area.

3. The dosage form according to any one of the preceding claims, characterized in that, Succinic acid has a concentration of less than 0.13 m. 2 The surface area per g is preferably less than 0.09 m². 2 The surface area per g is more preferably less than 0.045 m². 2 / g of surface area.

4. The dosage form according to claim 1, characterized in that, Succinic acid has a concentration of 0.026 m. 2 / g to 0.09 m 2 The surface area in the range of / g is preferably 0.03 m². 2 / g to 0.05 m 2 Surface area in the range of / g, more preferably 0.035 m 2 / g to 0.045 m 2 Surface area in the range of / g.

5. The dosage form according to any one of the preceding claims, characterized in that, The dosage form is a tablet, preferably a film-coated tablet.

6. The dosage form according to claim 5, characterized in that, a) The tablet comprises an internal particle phase and a continuous external particle phase, wherein palbociclib is contained in the internal particle phase and succinic acid is contained in the continuous external particle phase; or (b) The tablet comprises a first internal phase, a second internal phase, and optionally a first continuous external phase, wherein palbociclib is contained in the first internal phase and succinic acid is contained in the second internal phase.

7. The dosage form according to any one of the preceding claims, characterized in that, The dosage form contains 10% to 35% by weight of palbociclib, preferably 10% to 20% by weight, based on the total weight of the dosage form.

8. The dosage form according to any one of the preceding claims, characterized in that, The dosage form contains palbociclib in amounts of 25 mg, 75 mg, 100 mg, or 125 mg.

9. The dosage form according to any one of the preceding claims, characterized in that, The dosage form contains 5% to 1% by weight of succinic acid, preferably less than 5% to 1% by weight, more preferably 4.5% to 3% by weight, based on the total weight of the dosage form.

10. The dosage form according to any one of the preceding claims, characterized in that, The weight ratio of palbociclib to succinic acid is selected from the range of 1:0.1 to 1:0.5, preferably from 1:0.2 to 1:0.4, and more preferably from 1:0.2 to 1:0.

3.

11. The dosage form according to any one of the preceding claims, characterized in that, The dosage form further comprises at least one diluent in an amount of 50% to 80% by weight, preferably 60% to 80% by weight, based on the total weight of the dosage form.

12. The dosage form according to claim 11, characterized in that, The diluent is selected from microcrystalline cellulose, lactose monohydrate, mannitol, sorbitol, xylitol, magnesium carbonate, dicalcium phosphate, and calcium phosphate.

13. The dosage form according to any one of the preceding claims, characterized in that, The formulation further comprises at least one lubricant in an amount of 0.5% to 5% by weight, preferably 1% to 2% by weight, based on the total weight of the formulation.

14. The dosage form according to claim 13, characterized in that, The lubricant is selected from magnesium stearate, calcium stearate, colloidal silica, talc, zinc stearate, and sodium stearoyl fumarate.

15. The dosage form according to any one of the preceding claims, characterized in that, The dosage form further comprises at least one disintegrant in an amount of 1% to 10% by weight, preferably 2% to 5% by weight, based on the total weight of the dosage form.

16. The dosage form according to claim 15, characterized in that, The disintegrant is selected from crosspovidone, croscarmellose sodium, and starch hydroxyacetic acid sodium.

17. The dosage form according to any one of the preceding claims, characterized in that, Palbociclib exists in crystalline form.

18. The dosage form according to any one of the preceding claims, characterized in that, The dosage form is an immediate-release dosage form.

19. The dosage form according to any one of the preceding claims, characterized in that, When added to a test medium containing 900 mL of 10 mM pH 5.5 acetate buffer at 37°C in a standard USP 2 rotary paddle apparatus in which the paddle rotates at 75 rpm, the dosage form dissolves as follows: (a) 50% to 90% of palbociclib dissolves within 15 minutes; (b) 60% to 95% of palbociclib dissolves within 30 minutes; and (c) 75% to 100% of palbociclib dissolves within 60 minutes.

20. The dosage form according to any one of the preceding claims, characterized in that, When added to a test medium containing 900 mL of 10 mM pH 6.8 phosphate buffer at 37°C in a standard USP 2 rotary propeller apparatus in which the propeller rotates at 75 rpm, the dosage form dissolves as follows: (a) 10% to 35% of palbociclib dissolves within 15 minutes; (b) 15% to 40% of palbociclib dissolves within 30 minutes; and (c) 15% to 50% of palbociclib dissolves within 60 minutes.

21. The dosage form according to any one of the preceding claims, characterized in that, Succinic acid has the following particle size distribution: D90 values ​​in the range of 100 µm to 1000 µm, D50 values ​​in the range of 50 µm to 700 µm, and D10 values ​​in the range of 20 µm to 500 µm.

22. The dosage form according to any one of the preceding claims, characterized in that, Succinic acid has the following particle size distribution: D90 values ​​in the range of 500 µm to 700 µm, D50 values ​​in the range of 300 µm to 450 µm, and D10 values ​​in the range of 150 µm to 260 µm.

23. The dosage form according to any one of the preceding claims, characterized in that, Succinic acid has the following particle size distribution: D90 values ​​in the range of 500 µm to 700 µm, D50 values ​​in the range of 300 µm to 450 µm, and D10 values ​​in the range of 150 µm to 260 µm.

24. The dosage form according to any one of the preceding claims, characterized in that, Palbociclib has the following particle size distribution: D90 values ​​in the range of 300 µm to 650 µm, D50 values ​​in the range of 150 µm to 400 µm, and D10 values ​​in the range of 40 µm to 250 µm.

25. The dosage form according to any one of claims 6-24, characterized in that, The second intraparticle phase has the following particle size distribution: D90 values ​​in the range of 350 µm to 700 µm, D50 values ​​in the range of 200 µm to 400 µm, and D10 values ​​in the range of 100 µm to 200 µm.

26. The dosage form according to any one of claims 6-25, characterized in that, The second particle internal phase has a density higher than 10m. 2 Surface area per g, preferably greater than 12 m² 2 / g surface area, more preferably 15 m 2 / g to 30 m 2 / g of surface area.

27. A method for preparing a dosage form according to any one of the preceding claims, wherein the dosage form is a tablet, the tablet comprising palbociclib and succinic acid as active pharmaceutical ingredients, wherein the tablet comprises an internal particle phase and a continuous external particle phase, and wherein palbociclib is contained in the internal particle phase and succinic acid is contained in the continuous external particle phase, wherein the method comprises the following steps: a) Dry granulation of palbociclib and optionally one or more pharmaceutically acceptable excipients to obtain dry granules forming an internal phase of the granules; b) The dry granules are mixed with succinic acid and optionally with one or more pharmaceutically acceptable excipients to obtain a mixture; c) Compress the mixture to obtain tablets; d) Optionally, the tablets are film-coated to obtain film-coated tablets.

28. A method for preparing a dosage form according to any one of the preceding claims, wherein the dosage form is a tablet, the tablet comprising a first internal particle phase, a second internal particle phase, and optionally a first continuous external particle phase, wherein palbociclib is contained in the first internal particle phase, and succinic acid is contained in the second internal particle phase, wherein the method comprises the following steps: a) Dry granulation of palbociclib and optionally one or more pharmaceutically acceptable excipients to obtain dry granules forming a first internal phase of the granules; b) Succinic acid and optionally one or more pharmaceutically acceptable excipients are wet-granulated to obtain wet-granules that form a second internal phase of the particles; c) The dry granules and the wet granules are optionally mixed with one or more pharmaceutically acceptable excipients to obtain a mixture; d) Compress the resulting mixture into tablets; e) Optionally, the tablets are film-coated to obtain film-coated tablets.

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