PHARMACEUTICAL COMPOSITION CONTAINING PALBOCICLIB AND LETROZOLE

Abstract

A pharmaceutical composition containing palbociclib tosylate and letrozole, in which palbociclib tosylate and letrozole are in one dosage unit, and the particles of the active ingredient palbociclib tosylate and letrozole are not separated from each other, and the production of the pharmaceutical preparation, the granule containing palbociclib tosylate and letrozole, the use of the pharmaceutical preparation and special blister packaging that facilitates the use of a specific dosage regimen.

Claims

1-16. (canceled)

17. A method of treatment of cancer, or for the treatment of breast cancer, or for the treatment of cancer that is locally advanced or metastatic and the cancer cells have receptors of hormones on their surface and the cancer cells do not produce abnormally large amounts of A receptor called HER2 comprising administering to a subject in need thereof a pharmaceutical composition comprising the 4-toluenesulfonic acid salt of palbociclib and letrozole, and optionally, periodically administering alternately with letrozole; optionally wherein unit doses containing palbociclib 4-tosylate and letrozole are administered during the treatment for 21 days, and then letrozole mono composition is administered for 22-28 days, and then optionally, this 28-day treatment cycle is repeated; optionally wherein the amount of palbociclib tosylate in the unit doses containing palbociclib 4-tosylate and letrozole corresponds to 75 mg, 100 mg or 125 mg palbociclib base and letrozole content is 2.5 mg, and in mono unit doses containing letrozole, the amount of letrozole is 2.5 mg.

18. A method of treatment of HR-positive, HER-negative breast cancer, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising the 4-toluenesulfonic acid salt of palbociclib and letrozole, optionally wherein the administration of the composition is periodically replaced/supplemented with a mono composition containing letrozole alone, in which unit doses containing palbociclib 4-tosylate and letrozole are administered for 21 days, and then a mono composition containing letrozole is administered for 7 days, and then, optionally, this dosage regimen is repeated.

19. The method of claim 17, which is for the treatment of breast cancer.

20. The method of claim 17, which is for the treatment of cancer that is locally advanced or metastatic and the cancer cells have receptors of hormones on their surface and the cancer cells do not produce abnormally large amounts of A receptor called HER2.

21. The method of claim 20, wherein the cancer cells are HR-positive.

22. The method of claim 17, comprising administering to a subject in need thereof a pharmaceutical composition comprising the 4-toluenesulfonic acid salt of palbociclib and letrozole, and periodically administering alternately with letrozole.

23. The method of claim 17, wherein unit doses containing palbociclib 4-tosylate and letrozole are administered during the treatment for 21 days, and then letrozole mono composition is administered for 22-28 days, and then optionally, this 28-day treatment cycle is repeated.

24. The method of claim 17, wherein the amount of palbociclib tosylate in the unit doses containing palbociclib 4-tosylate and letrozole corresponds to 75 mg, 100 mg or 125 mg palbociclib base and letrozole content is 2.5 mg, and in mono unit doses containing letrozole, the amount of letrozole is 2.5 mg.

25. The method of claim 17, wherein in the pharmaceutical composition the 4-toluenesulfonic acid salt of Palbociclib and letrozole are not isolated from each other, and/or the 4-toluenesulfonic acid salt of Palbociclib and letrozole are homogenized in the composition.

26. The method of claim 17, wherein in the pharmaceutical composition the the palbociclib tosylate (1:1) is a salt form, and wherein the characteristic X-ray powder diffraction peaks of the 4-toluenesulfonic acid (1:1) salt of palbociclib are as follows: Cu Kα (1.1541874 Å) (±0.2° 2θ): 5.18; 10.25; 13.45; 16.08; 21.56.

27. The method of claim 17, wherein the pharmaceutical composition is in the form of granules comprising the 4-toluenesulfonic acid salt of palbociclib and letrozole.

28. The method of claim 18, wherein the administration of the composition is periodically replaced/supplemented with a mono composition containing letrozole alone, in which unit doses containing palbociclib 4-tosylate and letrozole are administered for 21 days, and then a mono composition containing letrozole is administered for 7 days, and then, optionally, this dosage regimen is repeated.

29. The method of claim 18, wherein in the pharmaceutical composition the 4-toluenesulfonic acid salt of Palbociclib and letrozole are not isolated from each other, and/or the 4-toluenesulfonic acid salt of Palbociclib and letrozole are homogenized in the composition.

30. The method of claim 18, wherein in the pharmaceutical composition the the palbociclib tosylate (1:1) is a salt form, and wherein the characteristic X-ray powder diffraction peaks of the 4-toluenesulfonic acid (1:1) salt of palbociclib are as follows: Cu Kα (1.1541874 Å) (±0.2° 2θ): 5.18; 10.25; 13.45; 16.08; 21.56.

31. The method of claim 18, wherein the pharmaceutical composition is in the form of granules comprising the 4-toluenesulfonic acid salt of palbociclib and letrozole.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0081] FIG. 1: Palbociclib dissolution curves in pH 4.5 buffer: PLE0400621 (Example R-2), AN0890721 (WE-1/C) and IBRANCE tablets

[0082] FIG. 2: Dissolution curves of letrozole in pH 4.5 buffer: Dissolution of PLE0400621 (Example R-2) and AN0890721 (Example WE-1/C) and IBRANCE tablets and Femara tablets in a container.

[0083] FIG. 3: XRD pattern of the 4-toluenesulfonic acid (1:1) salt of Palbociclib.

[0084] FIG. 4: Flow chart for preparing the granules described in the examples.

[0085] FIG. 5: Flow chart of tablet preparation described in the examples.

[0086] FIG. 6A: Blister pack form in which A is the location of the fixed dose combination formulation containing palbocilib tosylate and letrozole and B is the location of the letrozole mono formulation.

[0087] FIG. 6B: Blister pack form in which A is the location of the fixed dose combination formulation containing palbocilib tosylate and letrozole and B is the location of the letrozole mono formulation and the serial number below the tablets is the day of the cycle.

[0088] FIG. 6C: A blister combination consisting of a blister containing 21 combination preparations and a blister containing 7 letrozole monopreparations.

[0089] FIG. 7: Wallet (calendar) packaging plan

[0090] Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The preceding preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

[0091] In the foregoing and in the examples, all temperatures are set forth uncorrected in degrees Celsius and, all parts and percentages are by weight, unless otherwise indicated.

[0092] The entire disclosures of all applications, patents and publications, cited herein and of corresponding Hungarian application No. P2200147, filed May 10, 2022, are incorporated by reference herein.

[0093] The invention is illustrated in detail by the following examples, without limiting the scope of the invention to the following examples:

[0094] Active pharmaceutical ingredient:

REFERENCE EXAMPLES

Example R-1: Preparation of Palbociclib 4-Toluenesulfonate Salt (1:1)

[0095] Palbocycl base (1.0 g, 2.23 mmol), acetone (20 mL) and water (4 mL) were added to an vessel having intensive stirrer, and 4-toluenesulfonic acid monohydrate (424.2 mg, 2.23 mmol) was added at reflux temperature. The solution was cooled to room temperature, stirred for 48 hours, then the crystalline product was filtered, washed with a little cold acetone-water and air dried.

[0096] The resulting mixture was stirred in a mixture of ethanol (20 ml) and water (0.2 ml) at room temperature for 48 hours, then the crystalline product was filtered off, washed with a little cold acetone and air-dried.

[0097] Yield: 0.85 g (62.9%)

[0098] Mp.: no characteristic value, thermal decomposition occurs above 250° C.

[0099] Analysis calculated for C31H39N7O5S (621.76):

TABLE-US-00001 Calculated C: 59.89% H: 6.32% N: 15.77% S: 5.16% Measured C: 59.69% H: 6.08% N: 15.46% S: 5.69%

[0100] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz): 10.26 (bs, 1H), 8.97 (s, 1H), 8.71 (b, 2H), 8.12 (d, J=2.8 Hz, 1H), 7.91 (d, J=9.1 Hz, 1H), 7.57 (dd, J1=2.9 Hz, J2=9.1 Hz, 1H), 7.48 (˜d, J=8.0 Hz, 2H), 7.12 (˜d, J=8.4 Hz, 2H), 5.83 (m, 1H), 3.37 (m, 4H), 3.29 (m, 4H), 2.43 (s, 3H), 2.32 (s, 3H), 2.29 (s, 3H), 2.25 (m, 2H), 1.89 (m, 2H), 1.78 (m, 2H), 1.59 (m, 2H).

[0101] .sup.13C-NMR (DMSO-d.sub.6, 125 MHz): 202.62, 160.390, 158.62, 158.40, 154.94, 145.86, 145.45, 142.47, 142.21, 137.82, 135.98, 129.64, 128.25, 126.06, 125.67, 115.26, 106.98, 53.11, 45.87, 42.87, 31.49, 27.75, 25.32, 20.96, 13.84. [0102] X-ray powder diffraction peaks are as follows: Cu Kα (1.1541874 Å) (±0.2° 2θ): 5.18; 10.25; 13.45; 16.08; 21.56. In particular, it can be characterized by the following X-ray powder diffraction peaks: 2θ (±0.2° 2θ): 5.18; 9.49; 10.25; 10.76; 13.45; 16.08; 17.97; 19.39; 21.56; 22.33. More specifically, it can be characterized by the following X-ray powder diffraction peaks: 2θ (±0.2° 2θ): 5.18; 8.40; 9.49; 10.25; 10.76; 12.48; 12.80; 13.45; 13.92; 14.37; 14.56; 16.08; 16.86; 17.27; 17.97; 18.39; 19.07; 19.39; 20.59; 21.25; 21.56; 22.03; 22.33; 23.21; 23.57; 24.37; 24.99; 25.55; 25.82; 26.72; 27.10; 28.05; 28.99; 29.35; 29.78; 30.21; 30.71; 31.26; 33.43. Its typical X-ray powder diffractogram is shown in FIG. 3, and signals with an intensity greater than 1% are summarized in the table below:

TABLE-US-00002 X-ray powder diffraction data of palbociclib 4-toluenesulfonic acid (1:1) salt modification (relative intensities > 1%) (relative intensities > 1%) Peak 2θ (°) d (Å) (%) 1 5.18 17.06 10 2 8.40 10.52 2 3 9.49 9.31 36 4 10.25 8.62 55 5 10.76 8.22 25 6 12.48 7.09 9 7 12.80 6.91 17 8 13.45 6.58 23 9 13.92 6.36 14 10 14.37 6.16 14 11 14.56 6.08 4 12 16.08 5.51 65 13 16.86 5.25 10 14 17.27 5.13 11 15 17.97 4.93 42 16 18.39 4.82 4 17 19.07 4.65 25 18 19.39 4.57 30 19 20.59 4.31 22 20 21.25 4.18 18 21 21.56 4.12 100 22 22.03 4.03 29 23 22.33 3.98 57 24 23.21 3.83 19 25 23.57 3.77 9 26 24.37 3.65 31 27 24.99 3.56 6 28 25.55 3.48 16 29 25.82 3.45 31 30 26.72 3.33 11 31 27.10 3.29 3 32 28.05 3.18 9 33 28.99 3.08 7 34 29.35 3.04 13 35 29.78 3.00 5 36 30.21 2.96 3 37 30.71 2.91 3 38 31.26 2.86 11 39 31.53 2.84 5 40 33.43 2.68 6

[0103] General Procedure for the Preparation of Tablets According to R-2, Working Example 1 and Working Example 2:

[0104] Briefly, the inner phase is prepared and granulated, the resulting granulate is mixed with the materials of the outer phase and tableted.

[0105] In detail:

[0106] A) Production of Inner Phase:

[0107] A1. Preparation of Homogenate I:

[0108] Poliplasdone XL-10 GAF, Aerosil 200, and one-third of the amount of microcrystalline cellulose (PH 101 FMC) used in the formulation were weighed into a homogenizer and homogenized.

[0109] The resulting homogenate is sieved through an oscillating regranulation with a 0.8 mm screen.

[0110] A2. Preparation of a Premix Containing Letrozole:

[0111] Letrozole sand the second third of the microcrystalline cellulose (PH 101 FMC) used in the formulation was homogenized in a polyethylene bag. The premix thus obtained is sieved through an acid-proof hand sieve with a sieve spacing of 0.5 mm.

[0112] A3. Preparation of Homogenate II:

[0113] The homogenate I prepared in step A1 and the letrozole-containing premix prepared in the second step are weighed into a barrel homogenizer, and the resulting mixture is homogenized.

[0114] A4. Preparation of Homogenate III:

[0115] The active ingredient palbociclib * and one third of the amount of microcrystalline cellulose (PH 101 FMC) used in the formulation are homogenized in a homogenizer. The homogenate thus obtained is sieved on an oscillating regranulator using a sieve spacing of 0.8 mm.

[0116] (*For R-2, Balbociclib base is used, for Working examples 1 and 2, palbociclib tosylate is used)

[0117] A5. Preparation of Homogenate IV:

[0118] The A3. Homogenate II prepared in accordance with point A4. and the homogenate III was charged to a barrel homogenizer and the resulting mixture was homogenized. The resulting homogenate was sieved on an oscillating regranulator using a sieve spacing of 0.8 mm.

[0119] A6. Preparation of Homogenate V:

[0120] The A5. The Homogenate of Point IV is Rehomogenized in a Barrel Homogenizer

[0121] A7. Preparation of Homogenate VI:

[0122] The A6. The homogenate V and the homogenate V, previously sieved through an acid-resistant hand sieve with a yarn spacing of 0.5 mm, are charged to a homogenizer carrying half the amount of magnesium stearate used in the composition, and the resulting mixture is homogenized.

[0123] A8. Granulation:

[0124] The A7. The homogenate VI is filled into the feed hopper of the compactor and compacted.

[0125] B) Tablet Production:

[0126] B1. Preparation of Final Homogenate:

[0127] The excipients used in the composition are added to the granules prepared in A8. step in accordance with the table below in a barrel homogenizer and the thus given mixture is homogenized before adding the next excipient.

[0128] B2. Tableting:

[0129] A B1. The final homogenate prepared according to the above is added to the funnel of a tableting machine and tableted.

[0130] C. Coating:

[0131] The tablets of B2. are poured into the coating pan and the temperature of the outlet air is heated to 39-45° C. while the vessel is rotated intermittently, and the coating suspension is sprayed onto the tablets.

[0132] Preparation of Coating Suspension:

[0133] Purified water is measured in a beaker and stirred at such a rate that a liquid funnel is formed without air bubbles. The coating material (Vivacoat PA-3P-468) should be sprayed into the liquid funnel. After adding the entire amount of material, the stirring speed should be reduced until the liquid funnel disappears. The resulting dispersion is filtered through a 0.4 mm acid-proof sieve. The thus obtained coating suspension is stirred until and during the use.

[0134] The following experiments were performed with using Vivacoat PA-3P-468, a commercially available coating material having the following composition:

TABLE-US-00003 quality composition Hypromellose (HPMC) 6 Ph. Eur./USP/E464 39.00% Titanium dioxide Ph. Eur./USP/E171 23.00% Talc Ph. Eur./NF/E553b 16.36% Polydextrose E1200 15.00% Polyethylene glycol (PEG) 3350 Ph. Eur./USP 6.00% Ferrosoferric oxide black NF/E172 0.22% Indigotine LK E132 0.18% Carmine DYE E120 0.14% Ferric oxide red NF/E172 0.10%

[0135] The tools used in the examples are:

[0136] Homogenization: barrel homogenizer, QUICKBIN 22 homogenizer, using 5 or 10 1 barrels at 17 rpm for 3-5 minutes.

[0137] Sieving: If a non-acid-resistant hand sieve is used, a Frewitt MF LAB oscillating regranulator with a 0.8 mm sieve insert at 110-140 rpm was used.

[0138] Granulation: Fitzpatrik CCS-220 dry granulator isolator is used to control the particle size with the following settings: [0139] Regranulation sieve (perforated plate) 1.0 mm perforation

TABLE-US-00004 Dry granulator data Roller set knurled Regranulation unit cutler Operational parameters Operation Prescribed parameter to set Horizontal feed screw 12-16 rpm (recommended: 14 rpm) speed (HFS) Vertical feed screw 90-110 rpm (recommended: 100 rpm) speed (VFS) Distance of rollers 1.00-1.50 mm (recommended: 1.25 mm) Roller force 9.5-10.5 kN/cm (recommended: 10 kN/cm) Roller speed 2.5-3.5 rpm (recommended: 3 rpm) Regranulator speed 1000-1200 rpm (recommended: 1100 rpm) Duration of the approx. 30 minutes operation

[0140] Tableting:

TABLE-US-00005 Device type: Dott Bonapace tableting isolator Press tool data: Mold shape: oblong, concave Length: ~16.0 mm Width:  ~8.5 mm Number of press tools: 8 Table speed: Maximum allowed: 12/minutes Recommended: 10 minutes Forced feed speed: Recommended:  8/minutes

Example R-2

[0141] Comparative formulation containing 125 mg of Palbociclib base, 2.5 mg of letrozole and succinic acid

TABLE-US-00006 Batch No.: PLE 040 0620 Palbociclib/Letrozol filmtablet 125/2.5 mg 125/2.5 mg mg/ftbl Inner phase (kompaktum) Palbociclib base 125.00 Letrozole 2.50 Cellulose, Microcrystalline 364.50 Crospovidone 18.00 Silica, Colloidal Anhydrous 3.00 Magnesium Stearate 3.00 Outer phase Succinic acid 60.00 Crospovidone 18.00 Magnesium Stearate 6.00 Tablet core 600.00 Film coating 18.00 Filmtablet 618.00

[0142] Brief Process for Preparation of Tablets:

[0143] Tablets were prepared according to the general procedure above, except that the final homogenate was prepared as follows:

[0144] The granules and the succinic acid used in the external phase are weighed and homogenized in a barrel homogenizer. To the homogenate thus obtained was added the Poliplasdone XL-10 GAF used in the outer phase and the resulting mixture was homogenized, and then charged to a homogenizer carrying half the amount of magnesium stearate used in the composition, previously sieved through an acid-resistant hand sieve with a span of 0.5 mm. The resulting mixture is homogenized.

WORKING EXAMPLES ACCORDING TO THE INVENTION

Working Example 1: Preparation of Film-Coated Tablets Containing Palbociclib Tosylate and Letrozole with Different Drug Ratios

[0145]

TABLE-US-00007 Palbociclib/Letrozol filmtablet WE-1/C WE-1/A WE-1/B AN0890721 75/2.5 mg 100/2.5 mg 125/2.5 mg mg/ftbl Inner phase (kompaktum) Palbociclib tozilát 103.875 138.50 173.125 Letrozole 2.50 2.50 2.50 Cellulose. Microcrystalline 219.425 293.40 367.375 Crospovidone 18.00 24.00 30.00 Silica. Colloidal Anhydrous 1.80 2.40 3.00 Magnesium Stearate 3.60 4.80 6.00 Outer phase Crospovidone 7.20 9.60 12.00 Magnesium Stearate 3.60 4.80 6.00 Tablet core 360.00 480.00 600.00 Filmcoating 14.40 19.20 24.00 Filmtablet 374.40 499.20 624.00

[0146] Brief Process for Preparation of Tablets:

[0147] Tablets were prepared according to the general procedure above, except that the final homogenate was prepared as follows:

[0148] The granules and the Poliplasdone XL-10 GAF used in the external phase are weighed and the resulting mixture is homogenized in a barrel homogenizer, then the resulting mixture is charged to a homogenizer carrying half the amount of magnesium stearate used in the composition, which was previously sieved through an acid-resistant hand sieve with a sieve spacing of 0.5 mm, and the resulting mixture is homogenized.

Working Example 2: Preparation of Film-Coated Tablets Containing Palbociclib Tosylate and Letrozole with Different Drug Ratios

[0149]

TABLE-US-00008 Palbociclib/Letrozol filmtablet WE-2/A WE-2/B WE-2/C 75/2.5 mg 100/2.5 mg 125/2.5 mg mg/ftbl Inner phase (kompaktum) Palbociclib tozilát 103.875 138.50 173.125 Letrozole 2.50 2.50 2.50 Cellulose. Microcrystalline 237.425 317.40 397.375 Crospovidone 7.20 9.60 12.00 Silica. Colloidal Anhydrous 1.80 2.40 3.00 Magnesium Stearate 3.60 4.80 6.00 Outer phase fazis Magnesium Stearate 3.60 4.80 6.00 Tablet core 360.00 480.00 600.00 Film coating 14.40 19.20 24.00 Filmtablet 374.40 499.20 624.00

[0150] Brief Process for Preparation of Tablets:

[0151] Tablets were prepared according to the general procedure above, except that the final homogenate was prepared by loading the granulate and a homogenizer carrying half the amount of magnesium stearate used in the composition, previously sieved through an acid-resistant hand sieve with a sieve spacing of 0.5 mm, and the resulting mixture is homogenized.

Example 3 Dissolution Tests

[0152] The studies were conducted by the Guidance for Industry; 10740430 FNL08/09/2018 Dissolution testing and acceptance criteria for high solubility pharmaceutical preparations in immediate release solid oral dosage form; DHHS, FDA, CDER; 2018. The dissolution test was performed on a USP 2 device, and the concentration of the dissolved drug was measured by UHPLC on the following equipment:

[0153] Equipment: Waters H-Class UPLC:

[0154] Column: Waters Acquity BEH C18, 2.1×50 mm, 1.7 μm

[0155] Solvent (Diluent): 0.2% perchloric acid solution/Acetonitrile=50/50 (V/V %)

[0156] Eluent: A: 0.1% perchloric acid solution

[0157] B: Acetonitrile

[0158] Gradient profile:

TABLE-US-00009 Time [min] Eluent A [%] Eluent B [%] kezdeti 80 20 1.7 65 35 2.0 10 90 3.1 10 90 3.2 80 20 4.5 80 20

[0159] Flow rate: 0.6 mL/min

[0160] Column temperature: 38° C.

[0161] Column pressure: ˜620 bar

[0162] Sample temperature: 20° C.

[0163] Injected sample: 3.0 μL

[0164] Detection: UV, 300 nm Palbociclib; 240 nm Letrozole

[0165] Evaluation: External standard calibration method based on peak areas

[0166] K-1: Investigation of Palbociclib Dissolution

[0167] The reference formulation of Example R-2, a formulation containing palbociclib tosylate and letrozole prepared by the E-1/C method, and an IIBRANCE tablet containing palbociclib base and succinic acid were compared.

[0168] The results are shown in FIG. 1.

[0169] The measurement method: The dissolution rate was determined in each case in 500 ml of 10 mM sodium acetate buffer at pH 5.5 in a USP 2 with a rotating paddle at 50 rpm.

[0170] The reference product is Ibrance 125 mg film-coated tablets containing Palbociclib base and succinic acid; serial number: EX 4261. The test products are Palbociclib-Letrozole 125 mg/2.5 mg film-coated tablets containing Palbociclib base and succinic acid; Serial No. PLE0400620 and Palbociclib-Letrozole 125 mg/2.5 mg film-coated tablets containing Palbociclib tosylate; batch number: AN0890721

[0171] The results are summarized in the table below:

TABLE-US-00010 TABLE 1 Dissolution data of Palbociclib - Ibrance EX4261 Batch No: EX4261 Dissolved [%] - Palbociclib Time (min) Units (n) 5 10 15 20 30 45 60 1 6.04 22.66 47.67 63.98 71.74 76.91 79.84 2 6.09 32.15 62.41 68.47 73.75 78.04 80.34 3 5.51 33.47 60.46 67.56 72.86 77.03 79.88 4 4.59 26.00 59.09 64.01 70.96 75.79 78.45 5 5.29 26.99 46.65 57.80 64.07 68.67 71.39 6 3.16 28.19 62.80 68.94 74.34 77.86 80.58 Mean [%] 5.1 28.2 56.5 65.1 71.3 75.7 78.4 SD 1.10 4.01 7.38 4.19 3.75 3.54 3.52 RSD [%] 21.6 14.2 13.1 6.4 5.3 4.7 4.5 Min. [%] 3.2 22.7 46.7 57.8 64.1 68.7 71.4 Max. [%] 6.1 33.5 62.8 68.9 74.3 78.0 80.6 Conf. Lim (p = 0.95) 1.2 4.2 7.7 4.4 3.9 3.7 3.7

TABLE-US-00011 TABLE 2 Dissolution data of Palbociclib - PLE 040 0620 Batch No: PLE 040 0620 Dissolved [%] - Palbociclib Time (min) Units (n) 5 10 15 20 30 45 60 1 8.05 49.34 65.15 69.95 74.68 78.16 80.18 2 7.78 31.81 56.88 64.12 70.58 74.96 77.66 3 5.74 34.10 61.50 68.77 74.92 79.35 82.18 4 6.06 53.05 67.81 73.13 78.48 82.11 84.17 5 5.57 57.60 66.54 70.73 74.73 77.96 79.94 6 2.92 18.42 56.66 68.74 77.81 83.37 86.04 Mean [%] 6.0 40.7 62.4 69.2 75.2 79.3 81.7 SD 1.85 15.05 4.86 2.98 2.81 3.05 3.06 RSD [%] 30.8 37.0 7.8 4.3 3.7 3.8 3.7 Min. [%] 2.9 18.4 56.7 64.1 70.6 75.0 77.7 Max. [%] 8.1 57.6 67.8 73.1 78.5 83.4 86.0 Conf. Lim (p = 0.95) 1.9 15.8 5.1 3.1 2.9 3.2 3.2

TABLE-US-00012 TABLE 3 Dissolution data of Palbociclib - AN 089 0721 Batch No: AN 089 0721 Dissolved [%] - Palbociclib Time (min) Units (n) 5 10 15 20 30 45 60 1 34.17 50.95 59.71 65.61 71.77 76.56 78.96 2 33.00 49.13 60.01 66.44 73.21 78.36 80.37 3 34.36 51.90 61.26 66.70 72.68 76.76 79.54 4 33.59 51.99 61.98 68.24 75.19 79.13 81.77 5 33.63 52.78 61.36 67.21 74.95 78.82 81.29 6 29.65 48.75 58.02 65.82 73.67 78.05 80.14 Mean [%] 33.1 50.9 60.4 66.7 73.6 77.9 80.3 SD 1.74 1.64 1.45 0.97 1.32 1.07 1.05 RSD [%] 5.3 3.2 2.4 1.5 1.8 1.4 1.3 Min. [%] 29.7 48.8 58.0 65.6 71.8 76.6 79.0 Max. [%] 34.4 52.8 62.0 68.2 75.2 79.1 81.8 Conf. Lim (p = 0.95) 1.8 1.7 1.5 1.0 1.4 1.1 1.1

[0172] It is clear from the results that palbociclib is similarly dissolved from all three formulations.

[0173] K-2 Letrozole Dissolution Test:

[0174] The reference products are Ibrance 125 mg film-coated tablets containing Palbociclib base and succinic acid; Serial No. EX 4261 and Femara 2.5 mg film-coated tablets containing letrozole; dissolution of SNT20 was performed together in the same vessel. The test product was Palbociclib-Letrozole 125 mg/2.5 mg film-coated tablets containing Palbociclib base and succinic acid (PLE0400620) and Palbociclib-Letrozole 125 mg/2.5 mg film-coated tablets containing Palbociclib-tosylate and letrozole (AN0890721).

[0175] Dissolution results are shown in FIG. 2 and the data in the tables below

TABLE-US-00013 TABLE 4 Dissolution data of Letrozole - Femara SNT20 Batch No: SNT20 Dissolved [%] - Letrozole Time (min) Units (n) 5 10 15 20 30 45 60 1 52.97 75.45 83.39 86.03 88.19 90.12 90.57 2 48.43 70.62 79.23 83.66 86.79 88.59 89.35 3 60.41 78.35 84.06 86.90 89.19 91.10 92.27 4 49.53 73.43 81.66 85.10 88.10 90.16 91.26 5 60.33 78.05 83.33 85.80 88.36 89.51 90.98 6 64.31 80.02 85.92 88.43 91.24 93.16 94.33 Mean [%] 56.0 76.0 82.9 86.0 88.6 90.4 91.5 SD 6.57 3.51 2.28 1.61 1.49 1.57 1.70 RSD [%] 11.7 4.6 2.8 1.9 1.7 1.7 1.9 Min. [%] 48.4 70.6 79.2 83.7 86.8 88.6 89.4 Max. [%] 64.3 80.0 85.9 88.4 91.2 93.2 94.3 Conf. Lim (p = 0.95) 6.9 3.7 2.4 1.7 1.6 1.6 1.8

TABLE-US-00014 TABLE 5 Dissolution data of Letrozole - PLE 040 0620 Batch No: PLE 040 0620 Dissolved [%] - Letrozole Time (min) Units (n) 5 10 15 20 30 45 60 1 7.18 41.48 64.83 72.46 79.06 82.93 84.87 2 7.14 29.20 57.86 69.29 77.57 83.27 87.02 3 5.48 30.43 60.79 72.58 80.99 86.40 89.34 4 5.36 43.61 67.60 75.92 82.76 86.84 88.55 5 4.48 50.26 67.00 73.24 78.18 81.46 83.46 6 2.61 15.03 50.70 69.64 81.21 87.50 90.07 Mean [%] 5.4 35.0 61.5 72.2 80.0 84.7 87.2 SD 1.72 12.67 6.46 2.46 2.01 2.49 2.61 RSD [ %] 31.9 36.2 10.5 3.4 2.5 2.9 3.0 Min. [%] 2.6 15.0 50.7 69.3 77.6 81.5 83.5 Max. [%] 7.2 50.3 67.6 75.9 82.8 87.5 90.1 Conf. Lim (p = 0.95) 1.8 13.3 6.8 2.6 2.1 2.6 2.7

TABLE-US-00015 TABLE 6 Dissolution data of Letrozole - AN 089 0721 Batch No: AN 089 0721 Dissolved [%] - Letrozole Time (min) Units (n) 5 10 15 20 30 45 60 1 57.88 77.24 83.72 86.64 88.69 89.71 90.58 2 56.13 73.09 83.45 86.95 89.16 90.21 90.44 3 57.52 77.43 83.88 86.31 87.96 89.09 90.00 4 57.41 79.30 86.11 88.82 91.12 92.04 93.20 5 56.78 78.78 85.01 87.38 89.56 90.27 90.83 6 51.33 74.07 81.19 87.57 91.10 92.13 92.77 Mean [%] 56.2 76.7 83.9 87.3 89.6 90.6 91.3 SD 2.45 2.52 1.66 0.89 1.29 1.24 1.34 RSD [%] 4.4 3.3 2.0 1.0 1.4 1.4 1.5 Min. [%] 51.3 73.1 81.2 86.3 88.0 89.1 90.0 Max. [%] 57.9 79.3 86.1 88.8 91.1 92.1 93.2 Conf. Lim (p = 0.95) 2.6 2.6 1.7 0.9 1.4 1.3 1.4

[0176] Evaluation of K-1 and K-2 Dissolution Experiments:

[0177] For immediate-release solid oral formulations containing a high solubility drug, the dissolution criterion is Q=80% over 30 minutes according to the above-mentioned Guideline, where Q is the amount of drug dissolved as a percentage of the indicated content per dosage unit. The requirement of section 1 (n=6) is met if each unit is not less than Q+5% of the dissolution test.

[0178] Based on this, it can be concluded that the dissolution of palbociclib (K-1 experiment) is achieved for both combination products and IBRANCE using pH 5.5 buffer under standard conditions.

[0179] However, we have shown that with the recommended standard dissolution test conditions to increase gastric pH (500 ml of 10 mM sodium acetate buffer at pH 5.5 in a USP 2, 50 rpm paddle), the dissolution requirement for letrozole is limited to Palbociclib tosylate in fixed-dose formulation with letrozole and the co-administered mono Palbociclib and mono Letrozole tablets. However, the dissolution criterion is not met for a fixed-dose combination of Letrozole and Palbociclib base if the formulation contains succinic acid which is used for improve the dissolution of palbociclib base.

Example 4: Testing the Moisture Content of a Preparation

[0180] The water content of the formulations was determined by a Karl-Fisher titration coulometric method connected to an oven. In the initial state, a water content of 3.0-3.5% was measured at room temperature. Stored in an HDPE container with silica gel.

Example 5: Stability Tests

[0181] Stability Testing of a Composition According to the Invention

[0182] The stability of the combination product containing palbociclib tosylate and letrozole stored in an HDPE container under silica gel at 40° C. under 75% RH was tested, and both results were stable for 6 months.

[0183] Stability—Palbociclib-Letrozole Film-Coated Tablets

TABLE-US-00016 Batch no. AN 089 0721 Strength/Pharmaceutical form 125 mg/2.5 mg filmtablet Active substance Palbociclib-tosilate/Letrozole Storage conditions 40° C./75% RH Start 1 hó 2 hó 3 hó 6 hó Water content 4.29% 2.57 2.59% 2.66 2.69 Palbociclib Active substance content 99.0 99.9 100.4 99.8 101.5 (UPLC) [%] contamination (UPLC) [%] Total known contaminants <RL <RL <RL <RL <RL Total unknown contaminants <RL <RL <RL <RL <RL [%] Total contaminants [%] <RL <RL <RL <RL <RL Letrozole Active substance content 97.1 96.8 97.9 97.1 97.4 (UPLC) [%] contamination (UPLC) [%] LET IMP A <RL <RL <RL <RL <RL LET IMP B <RL <RL <RL <RL <RL Total unknown contaminants 0.20 <RL <RL <RL <RL [%] Total contaminants [%] 0.20 <RL <RL <RL <RL [0184] RL: Reporting limit [0185] The active ingredient content was measured using the HPLC method: [0186] Equipment: Waters Acquity H-Class UPL-C system or equivalent [0187] Column: Waters XSelect HSS PFP, 3.0×100 mm, 2.5 μm [0188] Solvent (Diluent): 0.2% perchloric acid/Acetonitrile=50/50 (V/V %) [0189] Eluent: A: 20 mM Ammonium acetate+0.1% perchloric acid buffer solution (pH=2.9) [0190] B: Acetonitrile/Methanol=75/25 (V/V %) [0191] Gradient profile:

TABLE-US-00017 Time [min] Eluent A [%] Eluent B [%] starting 99.0 1.0 1.0 99.0 1.0 3.0 77.5 22.5 10.0 65.0 35.0 20.0 1.0 99.0 21.0 1.0 99.0 21.5 99.0 1.0 23.0 99.0 1.0 [0192] Flow rate: 0.7 mL/min [0193] Column temperature: 26° C. [0194] Column pressure: ˜500-600 bar [0195] Sample temperature: 20° C. [0196] Injected sample: 2.0 μL Palbociclib; 5.0 μL Letrozole [0197] Detection: UV, 254 nm Palbociclib; 240 nm Letrozole [0198] Evaluation: External standard calibration method based on peak areas [0199] Ignore limit: 0.05%

[0200] 5. Compatibility Tests:

[0201] The compatibility test was performed at room temperature (25° C.), 40° C. under 75% RH and 50° C., for 1 months with the various components tested in proportion to the intended composition.

[0202] 5.1. Compatibility of Letrozole-Palbociclib Tosylate Salt

[0203] No detectable decomposition products were found in the powder mixture at 25° C., 40° C. and 50° C. after one months.

[0204] 5.2. Letrozole—Para-Toluenesulphonic Acid Compatibility Test

[0205] PTSA caused 5% degradation of letrozole at 25° C., 12% at 40° C. and 15% at 50° C. after 1 months, which is definitely above the limit and is already significant at room temperature.

[0206] 5.3. Palbociclib Base—Para-Toluenesulphonic Acid Compatibility Test

[0207] PTSA at 25° C., 40° C. and 50° C. did not induce degradation at the palbociclib base even after one moths.

Example 6: Tablet Containing Letrozole

[0208] We proceed according to the general procedure using the WE-1 composition of embodiment 1, with the difference that palbociclib tosylate is omitted from the composition.

[0209] The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

[0210] From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.