darolutamide pharmaceutical composition

Abstract

The present invention provides a pharmaceutical composition for oral administration, particularly in the form of tablets, comprising darolutamide, a potent androgen receptor (AR) modulator, or a pharmaceutically acceptable salt thereof. [Solution] A pharmaceutical composition is provided comprising (a) at least 35%, preferably at least 40%, of darolutamide or a pharmaceutically acceptable salt thereof, relative to the weight of the composition; (b) 5 to 60% of filler, relative to the weight of the composition; (c) 0.5 to 10% of disintegrant, relative to the weight of the composition; (d) 0.5 to 10% of binder, relative to the weight of the composition; and (e) 0.2 to 5% of lubricant, relative to the weight of the composition.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition for oral administration, particularly in the form of a tablet, comprising darolutamide or a pharmaceutically acceptable salt thereof as an active ingredient. [Background Art]

[0002] Darolutamide, N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) and its chemical synthesis are disclosed in Patent Document 1 and Patent Document 2. Darolutamide is a potent androgen receptor (AR) modulator useful in the treatment of cancer, particularly AR-dependent cancers such as prostate cancer, and other diseases where AR antagonism is desired. Darolutamide has the structure: [Chemical Formula] represented by.

[0003] Where a hydrogen atom on the pyrazole ring exists in tautomerism between the 1-position and the 3-position, as would be appreciated by those skilled in the art, as cited herein, the above structure and chemical name "N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I)" encompasses the tautomer of compound (I), namely N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide.

[0004] Patent Document 3 discloses polymorphic crystalline Form I of darolutamide. Patent Document 4 discloses 8 to 16 m 2 / g crystalline particles of darolutamide having a specific surface area (SSA) in the range of.

[0005] Darolutamide is poorly soluble in water. Oral administration of poorly soluble active ingredients is often problematic. Oral dosage forms, such as tablets, should provide substantially all release of the active ingredient and offer sufficient solubility. While providing adequate release and dissolution of the active ingredient, the formulation should also have properties that allow for the industrial-scale manufacture of its dosage form. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] International Publication No. 2011 / 051540 [Patent Document 2] International Publication No. 2016 / 162604 [Patent Document 3] International Publication No. 2016 / 120530 [Patent Document 4] International Publication No. 2018 / 162793 [Overview of the project]

[0007] The present invention provides a pharmaceutical composition for oral administration, particularly in the form of tablets, comprising darolutamide or a pharmaceutically acceptable salt thereof as an active ingredient. The composition provides effective release of darolutamide and consistent solubility that produces effective and reproducible in vivo plasma concentrations. At the same time, the composition provides excellent tableting ability, good crush resistance, and low brittleness of the tableting mass, enabling the manufacture of tablets on a large industrial scale. The composition is robust against variations in the manufacturing process during operations and technical transfers, so that the properties of the composition are not affected. Furthermore, the composition allows for a high drug load, which is desirable in terms of patient compliance. Therefore, the composition of the present invention is particularly suitable as a dosage form for the treatment of patients suffering from androgen receptor-dependent diseases such as prostate cancer.

[0008] Accordingly, according to one embodiment, the present invention provides a pharmaceutical composition comprising (a) at least 35%, preferably at least 40%, of darolutamide or a pharmaceutically acceptable salt thereof, relative to the weight of the composition; (b) 5 to 60% of a filler, relative to the weight of the composition; (c) 0.5 to 10% of a disintegrant, relative to the weight of the composition; (d) 0.5 to 10% of a binder, relative to the weight of the composition; and (e) 0.2 to 5% of a lubricant, relative to the weight of the composition. [Brief explanation of the drawing]

[0009] [Figure 1] This graph compares the average tablet pressure-to-tensile strength curve of the "A-darolutamide" composition with the curve of the "paracetamol" composition, using either low-speed or high-speed compression. [Figure 2] This graph compares the average tablet pressure-to-tensile strength curve of the "A-darolutamide" composition with that of the "B-darolutamide" composition, using either low-speed or high-speed compression. [Modes for carrying out the invention]

[0010] The present invention relates to a pharmaceutical composition for oral administration, particularly in the form of a tablet, comprising darolutamide or a pharmaceutically acceptable salt thereof as an active ingredient. The term "darolutamide or a pharmaceutically acceptable salt thereof" includes solvates, tautomers, or crystalline forms of darolutamide or a pharmaceutically acceptable salt thereof. Darolutamide or a pharmaceutically acceptable salt thereof may be crystalline, including amorphous or microcrystalline states. A preferred form is crystalline form I of darolutamide, as described in Patent Document 3. It can be characterized by an X-ray powder diffraction pattern (Cu-filled X-ray tube, room temperature) containing characteristic peaks at approximately 8.5, 10.4, 16.6, 16.9, and 24.3°²θ. Preferably, the above crystal form I can also be characterized by an X-ray powder diffraction pattern (Cu-filled X-ray tube, room temperature) that includes characteristic peaks at approximately 6.4, 8.5, 9.6, 9.7, 10.4, 12.8, 13.6, 14.9, 15.9, 16.6, 16.9, 18.7, 19.2, 21.8, 24.3, and 25.5°2θ.

[0011] According to one embodiment of the present invention, a pharmaceutical composition is provided comprising (a) at least 35%, preferably at least 40%, of darolutamide or a pharmaceutically acceptable salt thereof, relative to the weight of the composition; (b) 5 to 60% of a filler, relative to the weight of the composition; (c) 0.5 to 10% of a disintegrant, relative to the weight of the composition; (d) 0.5 to 10% of a binder, relative to the weight of the composition; and (e) 0.2 to 5% of a lubricant, relative to the weight of the composition.

[0012] In the subclasses of the above embodiments, the composition comprises 40-85%, preferably 45-80%, of darolutamide or a pharmaceutically acceptable salt thereof, based on the weight of the composition, for example, 45-75%, 45-70%, 45-65%, 45-60%, or 45-55%.

[0013] In any subclass of the above embodiments, the composition comprises 5 to 55%, preferably 5 to 50%, for example, 5 to 45% or 25 to 50%, of the weight of the composition.

[0014] As used herein, “filler” means one or more pharmaceutically acceptable excipients that impart bulk to a pharmaceutical composition. Examples of fillers include lactose, calcium hydrogen phosphate, microcrystalline cellulose, sorbitol, starch, sugars (e.g., mannitol or sucrose) or any combination thereof. According to one preferred embodiment, the filler comprises calcium hydrogen phosphate. As used herein, the term “calcium hydrogen phosphate” also includes anhydrous calcium hydrogen phosphate and hydrates such as calcium hydrogen phosphate dihydrate. Anhydrous calcium hydrogen phosphate is preferred.

[0015] According to another preferred embodiment, the filler comprises calcium hydrogen phosphate in combination with lactose and / or microcrystalline cellulose. According to one particularly preferred embodiment, the filler comprises a combination of calcium hydrogen phosphate and lactose. According to one embodiment, the filler consists of a combination of calcium hydrogen phosphate and lactose. As used herein, the term "lactose" includes lactose monohydrate and anhydrous lactose. Lactose monohydrate is preferred.

[0016] In a subclass of any of the above embodiments, the composition comprises 5 to 20%, for example 7 to 15%, by weight of the composition of calcium hydrogen phosphate. In another subclass of any of the above embodiments, the composition comprises 5 to 20%, for example 7 to 15%, by weight of the composition of calcium hydrogen phosphate, and 10 to 40%, for example 15 to 40%, 20 to 40%, or 25 to 35% by weight of the composition of lactose.

[0017] In a subclass of any of the above embodiments, the composition comprises 0.5 to 8%, preferably 3 to 7% by weight of the composition of a disintegrant.

[0018] As used herein, "disintegrant" means one or more pharmaceutically acceptable excipients added to a pharmaceutical composition to cause disintegration of the pharmaceutical composition to support release of the active ingredient from the pharmaceutical composition. Examples of disintegrants include croscarmellose sodium, cross-linked polyvinylpyrrolidone, sodium starch glycolate, or any combination thereof.

[0019] According to one preferred embodiment, the disintegrant comprises croscarmellose sodium.

[0020] In a subclass of any of the above embodiments, the composition comprises 0.5 to 8%, preferably 3 to 7% of a binder.

[0021] As used herein, the term "binder" refers to one or more pharmaceutically acceptable excipients that impart enhanced cohesiveness by binding and consolidating the active ingredient and excipients into a mixture. Examples of binders include polyvinylpyrrolidone (PVP), polyvinyl acetate, polyvinyl alcohol, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), and combinations thereof.

[0022] According to one preferred embodiment, the binder comprises polyvinylpyrrolidone (PVP).

[0023] In any subclass of the above embodiments, the composition comprises 0.2 to 3%, preferably 0.3 to 2%, for example 0.5 to 2% of a lubricant, by weight of the composition.

[0024] As used herein, the term "lubricant" refers to one or more pharmaceutically acceptable excipients that are added to a pharmaceutical composition to reduce friction, heat and wear when introduced between solid surfaces. Examples of lubricants include magnesium stearate, stearic acid, talc, silica, calcium stearate, carnauba wax, sodium stearyl fumarate, and combinations thereof.

[0025] According to one preferred embodiment, the lubricant comprises magnesium stearate.

[0026] According to another embodiment, the composition comprises: (a) at least 35%, preferably at least 40%, for example 45% to 80% of darolutamide or a pharmaceutically acceptable salt thereof, by weight of the composition; (b) 5 to 20% of calcium hydrogen phosphate, by weight of the composition; (c) 0.5 to 10% of a disintegrant, by weight of the composition; (d) 0.5 to 10% of a binder, by weight of the composition; and (e) 0.2 to 5% of a lubricant, by weight of the composition.

[0027] In another embodiment, the composition comprises (a) at least 35%, preferably at least 40%, for example 45% to 80%, of darolutamide or a pharmaceutically acceptable salt thereof, relative to the weight of the composition; (b) 5 to 20% of calcium hydrogen phosphate, relative to the weight of the composition; (c) 10 to 40% of lactose, relative to the weight of the composition; (d) 0.5 to 10% of a disintegrant, relative to the weight of the composition; (e) 0.5 to 10% of a binder, relative to the weight of the composition; and (f) 0.2 to 5% of a lubricant, relative to the weight of the composition.

[0028] In another embodiment, the composition comprises (a) 45-80% darolutamide or a pharmaceutically acceptable salt thereof based on the weight of the composition; (b) 5-20% calcium hydrogen phosphate based on the weight of the composition; (c) 10-40% lactose based on the weight of the composition; (d) 0.5-10% croscarmellose sodium based on the weight of the composition; (e) 0.5-10% polyvinylpyrrolidone based on the weight of the composition; and (f) 0.2-5% magnesium stearate based on the weight of the composition.

[0029] In the subclasses of the above embodiments, the composition comprises 45-75%, 45-70%, 45-65%, 45-60%, or 45-55% of darolutamide or a pharmaceutically acceptable salt thereof, based on the weight of the composition.

[0030] The pharmaceutical composition of the present invention may be in the form of, for example, granules, pellets, capsules, or tablets. Such compositions may be manufactured, for example, by wet granulation, dry granulation, or dry compression. In a preferred embodiment, the pharmaceutical composition of the present invention may be in the form of coated tablets or uncoated tablets. According to one preferred embodiment, the tablets are manufactured by wet granulation.

[0031] According to one embodiment, the tablet comprises an internal granule and an external granule. According to another embodiment, the internal granule comprises a portion of darolutamide or a pharmaceutically acceptable salt thereof, a filler, a binder, and a disintegrant, while the external granule comprises a lubricant and the remainder of the disintegrant.

[0032] According to one embodiment of the present invention, the process for producing the pharmaceutical composition of the present invention is characterized by (a) mixing a first portion of darolutamide or a pharmaceutically acceptable salt thereof, fillers, binders and disintegrants; (b) granulating the mixture using water as a granulating liquid; (c) drying the wet granules; (d) mixing the remainder of the lubricant and disintegrant with the granules; (e) compressing the resulting mass into tablets; and optionally, coating the tablets with one or more pharmaceutically acceptable film coatings.

[0033] For the manufacture of pharmaceutical compositions, darolutamide is preferably in its unsalted form and crystalline form I, and is generally attracted to particle sizes having a volume median diameter (Dv50) of 200 μm or less, preferably 150 μm or less, more preferably 100 μm or less, for example between 10 and 100 μm, more typically between 15 and 95 μm, for example between 20 and 90 μm. The particle size distribution can be analyzed by laser diffraction, for example, using a Beckman Coulter LS13320 laser diffraction particle size analyzer equipped with a Tornado Dry Powder System using air as the dispersion medium, with a measurement pressure of 24”H2O±2”H2O, a sample volume of 10 ml, a system-controlled label obscuration of 5%, and the Fraunhofer optical model.

[0034] The active ingredients can be ground using appropriate feeders and grinding equipment, such as single or twin-screw / auger feeders, hammer mills, pin mills, jet mills, or sieve mills, with an appropriate rotor rotation speed, such as 3,000 to 10,000 rpm. Grinding can be carried out at an appropriate temperature, such as below room temperature.

[0035] The compositions of the present invention can be appropriately prepared, for example, by first mixing darolutamide or a pharmaceutically acceptable salt thereof, a filler, a binder, and a disintegrant of the first part (e.g., 20-80% by weight of the total) in a suitable granulation vessel, such as a wet high-shear granulator. The mixture is then appropriately granulated in the granulator using purified water as the granulation liquid. The wet granules are then screened, for example, using a screening mill unit (rotating impeller), and then dried, for example, in a fluidized bed dryer.

[0036] Next, the dried granules may be screened using a screening device, such as a screening mill. Then, the remaining disintegrant can be added to the granules and the mixture can be blended, for example, in a diffusion mixer. After that, a lubricant is added to the mass from the previous step and blended. Then, the tablet mass is compressed into tablet nuclei, for example, in an electric rotary tablet press.

[0037] The tablet nucleus may, if desired, be coated with a water-soluble film to facilitate swallowing, protect from direct contact with the drug, and improve aesthetics. Suitable film coating agents may be selected from the group consisting of plasticizers, film-forming agents, and colorants. Optionally, anti-tack agents or opaque agents may be used. Plasticizers such as polyethylene glycol (PEG), film-forming agents such as hydroxypropyl methylcellulose (HPMC), and pigments such as iron oxide and titanium dioxide are combined with a film coating solution, preferably water, to produce a homogeneous coating suspension that is brought up, preferably sprayed, onto the tablet using a suitable coating device, such as a perforated drum coater.

[0038] According to one embodiment of the present invention, the pharmaceutical composition of the present invention is in an immediate-release dosage form, preferably a tablet. The composition preferably provides dissolution of at least 80% of darolutamide or a pharmaceutically acceptable salt thereof after 60 minutes in 0.01 M hydrochloric acid containing 1.0% sodium lauryl sulfate using a paddle device (USP device 2) at a paddle speed of 75 rpm and 37 ± 0.5°C.

[0039] Darolutamide or a pharmaceutically acceptable salt thereof is suitably administered to a patient, for example, for the treatment of prostate cancer, in amounts ranging from about 100 mg to about 3000 mg per day, preferably about 300 mg to about 2500 mg, more preferably about 500 mg to about 2000 mg, for example, in amounts ranging from about 800 mg to about 1500 mg, or about 1200 mg. The patient is, for example, a mammal, particularly a human, in need of treatment for prostate cancer. The dose can be administered once a day or in several divided doses per day, for example, in two divided doses per day. The composition of the present invention, such as a tablet, may contain darolutamide or a pharmaceutically acceptable salt thereof in amounts ranging from about 50 mg to about 1000 mg, preferably about 100 mg to about 800 mg, more preferably about 150 mg to about 600 mg, for example, in amounts ranging from about 200 mg to about 400 mg, or 300 mg. Such compositions can be administered once a day or several times a day, for example, once a day, twice a day, or several times a day, in the form of one or several tablets, or two 300 mg tablets twice a day.

[0040] The present invention will be further explained by the following examples.

[0041] Example 1. Immediate-release tablets of darolutamide TIFF2026143567000002.tif107147

[0042] Example 2. Immediate-release tablets of darolutamide TIFF2026143567000003.tif100147

[0043] Example 3. Immediate-release tablets of darolutamide TIFF2026143567000004.tif103147

[0044] Example 4. Immediate-release tablets of darolutamide TIFF2026143567000005.tif103147

[0045] Example 5. Immediate-release tablets of darolutamide TIFF2026143567000006.tif104147

[0046] The tablet compositions of Examples 1-5 are prepared by mixing the drug, lactose monohydrate, polyvinylpyrrolidone, anhydrous calcium hydrogen phosphate, and a portion of croscarmellose sodium in a high-shear granulator. The mixture is granulated by spraying water into the mixture. The granules are dried in a fluidized bed dryer. The remaining croscarmellose sodium is mixed with the granules. Then, magnesium stearate is added and mixed. The resulting mixture is compressed into tablets using a tablet press. Water is combined with a mixture of coating excipients to prepare a coating suspension. Finally, the tablets are coated by spraying the coating suspension onto the tablet nucleus in a heated pan coater until the theoretical weight increase of the tablet is reached.

[0047] Example 6. Comparative test of tablet formation ability A first mass for tableting was prepared according to Example 1 ("A-Dalorutamide" composition). The same procedure was repeated except that paracetamol was used as a model drug instead of darolutamide ("Paracetamol" composition). A third mass was prepared according to Example 1 except that lactose monohydrate was replaced with microcrystalline cellulose ("B-Dalorutamide" composition). The actual compositions produced are shown in Table 1 below.

[0048] [Table 1]

[0049] The tablets were compressed to approximately 300 mg unit weight and at least seven different compression heights using a single-stroke hydraulic tablet press with a 10 mm elliptical tooling. A single-ended sinusoidal profile was used for high-speed compression with a target dwell time of 10 ms and for low-speed compression with a target dwell time of 100 ms. The diameter, height, and fracture resistance of the tablets were measured using a caliper and hardness tester, respectively.

[0050] The average compressive strength was measured as the average of the upper punch peak strength and the lower punch peak strength, and converted to pressure by dividing by the punch tip area. Tensile strength was given by the following equation: Tensile strength=2P / (π·D·t) (In the formula, P = Destruction Resistance π=mathematical constant pi D = Tablet diameter (t = tablet thickness) It was determined using [this method].

[0051] Figure 1 shows the average tablet pressure versus tensile strength curves for the "A-darolutamide" and "paracetamol" compositions under low-speed or high-speed compression.

[0052] The tableting profile shown in Figure 1 clearly demonstrates that the tablet mass of Example 1 ("A-darolutamide") is particularly well-suited to the tableting process of darolutamide under both low-speed and high-speed compression. Comparison with similar compositions, except for the model drug (paracetamol) as the active ingredient, shows that the same composition using other drugs failed to produce tablets with acceptable tensile strength within the range of compressive forces suitable for tablet production.

[0053] Figure 2 compares the average tableting pressure versus tensile strength curve of the "A-darolutamide" composition with the curve of "B-darolutamide," in which lactose is replaced with microcrystalline cellulose. Surprisingly, the composition containing microcrystalline cellulose did not show improved tableting ability. Instead, this composition poses a risk to tablet production due to insufficient tensile strength, especially under high-speed compression.

Claims

1. (a) at least 35%, preferably at least 40%, of darolutamide or a pharmaceutically acceptable salt thereof, relative to the weight of the composition; (b) Filler in an amount of 5-60% relative to the weight of the composition; (c) 0.5 to 10% of the composition by weight of a disintegrant; (d) a binder in an amount of 0.5 to 10% relative to the weight of the composition; and (e) 0.2 to 5% lubricant relative to the weight of the composition A pharmaceutical composition containing the following:

2. The pharmaceutical composition according to claim 1, comprising 40 to 85%, preferably 45 to 80%, of darolutamide or a pharmaceutically acceptable salt thereof, based on the weight of the composition.

3. The pharmaceutical composition according to claim 1 or 2, comprising 5 to 55%, preferably 5 to 50%, of the weight of the composition as a filler.

4. A pharmaceutical composition according to any one of claims 1 to 3, wherein the filler comprises calcium hydrogen phosphate.

5. The pharmaceutical composition according to claim 4, wherein the composition comprises 5 to 20% calcium hydrogen phosphate relative to the weight of the composition.

6. The pharmaceutical composition according to claim 4 or 5, wherein the filler comprises calcium hydrogen phosphate in combination with lactose and / or microcrystalline cellulose.

7. The pharmaceutical composition according to claim 4 or 5, wherein the filler comprises a combination of calcium hydrogen phosphate and lactose.

8. The pharmaceutical composition according to claim 7, wherein the composition comprises 5 to 20% calcium hydrogen phosphate and 10 to 40% lactose by weight of the composition.

9. A pharmaceutical composition according to any one of claims 1 to 8, comprising 0.5 to 8%, preferably 3 to 7%, of a disintegrant based on the weight of the composition.

10. The pharmaceutical composition according to claim 9, wherein the disintegrant is croscarmellose sodium.

11. A pharmaceutical composition according to any one of claims 1 to 10, comprising 0.5 to 8%, preferably 3 to 7%, of a binder based on the weight of the composition.

12. The pharmaceutical composition according to claim 11, wherein the binder is polyvinylpyrrolidone.

13. A pharmaceutical composition according to any one of claims 1 to 12, comprising 0.2 to 3%, preferably 0.3 to 2%, of a lubricant based on the weight of the composition.

14. The pharmaceutical composition according to claim 13, wherein the lubricant is magnesium stearate.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the composition is in the form of a tablet.

16. The pharmaceutical composition according to claim 15, wherein the tablets are wet-granulated.

17. The pharmaceutical composition according to claim 16, wherein the tablet comprises an internal part and an external part.

18. The pharmaceutical composition according to claim 17, wherein the inside of the granules comprises a portion of darolutamide or a pharmaceutically acceptable salt thereof, a filler, a binder, and a disintegrant, and the outside of the granules comprises a lubricant and the remainder of the disintegrant.

19. (a) at least 35%, preferably at least 40%, of darolutamide or a pharmaceutically acceptable salt thereof, relative to the weight of the composition; (b) 5-20% calcium hydrogen phosphate by weight of the composition; (c) 0.5 to 10% of the composition by weight of a disintegrant; (d) a binder in an amount of 0.5 to 10% relative to the weight of the composition; and (e) 0.2 to 5% lubricant relative to the weight of the composition A pharmaceutical composition according to any one of claims 1 to 18, comprising:

20. (a) at least 35%, preferably at least 40%, of darolutamide or a pharmaceutically acceptable salt thereof, relative to the weight of the composition; (b) 5 to 20% calcium hydrogen phosphate by weight of the composition; (c) 10 to 40% lactose relative to the weight of the composition; (d) 0.5 to 10% of the composition by weight of a disintegrant; (e) a binder in an amount of 0.5 to 10% relative to the weight of the composition; and (f) 0.2 to 5% lubricant relative to the weight of the composition A pharmaceutical composition according to any one of claims 1 to 19, comprising:

21. (a) 45-80% by weight of darolutamide or a pharmaceutically acceptable salt thereof; (b) 5-20% calcium hydrogen phosphate by weight of the composition; (c) 10 to 40% lactose relative to the weight of the composition; (d) 0.5 to 10% croscarmellose sodium relative to the weight of the composition; (e) 0.5 to 10% polyvinylpyrrolidone relative to the weight of the composition; and (f) 0.2 to 5% magnesium stearate relative to the weight of the composition A pharmaceutical composition according to any one of claims 1 to 20, comprising:

22. The pharmaceutical composition according to any one of claims 1 to 21, wherein the composition provides the dissolution of at least 80% of darolutamide or a pharmaceutically acceptable salt thereof after 60 minutes in 0.01 M hydrochloric acid containing 1.0% sodium lauryl sulfate using a paddle device (USP device 2) at a paddle speed of 75 rpm and 37 ± 0.5°C.

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