Pharmaceutical composition of darolutamide

Abstract

To provide a pharmaceutical composition in the form of a tablet comprising darolutamide or a pharmaceutically acceptable salt thereof with improved releasability.SOLUTION: A tablet composition comprises at least 40%, per weight of the composition, of darolutamide or a pharmaceutically acceptable salt thereof. The composition has a dissolution of at least 80% of darolutamide or a pharmaceutically acceptable salt thereof after 60 minutes in 0.01 M hydrochloric acid with 1.0% of sodium lauryl sulfate using a paddle apparatus (USP apparatus 2) with a paddle speed of 75 rpm at room temperature.SELECTED DRAWING: None

Description

[Technical field]

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

[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 U.S. Pat. No. 5,399,433 and U.S. Pat. No. 5,499,446. 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 in which AR antagonism is desired. Darolutamide has the structure: [ka] It is expressed by:

[0003] When the hydrogen atom of the pyrazole ring is present in tautomeric parallel between the 1-position and the 2-position, it is understood by those skilled in the art that 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)" as referred to herein includes the tautomeric form of compound (I), i.e., 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 crystal form I of darolutamide. Patent Document 4 discloses polymorphic crystal form I of darolutamide having a molecular weight of 8 to 16 m. 2 Crystalline particles of darolutamide having a specific surface area (SSA) in the range of 1 / g are disclosed.

[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 full release of the active ingredient and provide sufficient dissolution characteristics. While providing adequate release and dissolution of the active ingredient, the formulation should also have properties that allow the preparation of the dosage form on an industrial scale. [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 Summary of the Invention

[0007] The present invention provides a pharmaceutical composition, particularly in the form of a tablet, for oral administration, comprising darolutamide or a pharma- ceutically acceptable salt thereof as an active ingredient. The composition provides an effective release of darolutamide, and a constant solubility that produces effective and reproducible in vivo plasma concentrations. At the same time, the composition provides excellent tabletability, good resistance to crushing and low friability of the tableting mass, allowing the production of tablets on a large industrial scale. The composition is robust against variations in the manufacturing process during operations and technological transfers, so that the properties of the composition are not affected. Furthermore, the composition allows for a high drug loading, which is desirable in terms of patient compliance. The composition of the present invention is therefore particularly suitable as a dosage form for the treatment of patients suffering from androgen receptor-dependent diseases, such as prostate cancer.

[0008] Thus, according to one embodiment, the present invention provides a pharmaceutical composition comprising: (a) at least 35%, preferably at least 40%, by weight of the composition of darolutamide or a pharma- ceutically acceptable salt thereof; (b) 5-60% by weight of the composition of a filler; (c) 0.5-10% by weight of the composition of a disintegrant; (d) 0.5-10% by weight of the composition of a binder; and (e) 0.2-5% by weight of the composition of a lubricant. [Brief description of the drawings]

[0009] [Figure 1] 1 is a graph comparing the average compression pressure versus tensile strength curves of the "A-Darolutamide" composition with that of the "Paracetamol" composition using low speed compression or high speed compression. [Diagram 2] 1 is a graph comparing the average compression pressure vs. tensile strength curve of the "A-darolutamide" composition with that of "B-darolutamide" using low speed compression or high speed compression. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] The present invention relates to a pharmaceutical composition, particularly in the form of a tablet, for oral administration, comprising darolutamide or a pharma- ceutically acceptable salt thereof as an active ingredient. The term "darolutamide or a pharma- ceutically acceptable salt thereof" includes solvates, tautomers or crystalline forms of darolutamide or a pharma- ceutically acceptable salt thereof. Darolutamide or a pharma- ceutically acceptable salt thereof may be crystalline, including amorphous or microcrystalline. A preferred form is crystalline form I of darolutamide, described in US Pat. No. 5,399,613. It can be characterized by an X-ray powder diffraction pattern (Cu-filled X-ray tube, room temperature) that includes characteristic peaks at about 8.5, 10.4, 16.6, 16.9, and 24.3° 2θ. Preferably, said crystalline form I may also be characterized by an X-ray powder diffraction pattern (Cu filled X-ray tube, room temperature) comprising characteristic peaks at about 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 degrees 2θ.

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

[0012] In a subclass of the above embodiment, the composition comprises 40 to 85%, preferably 45 to 80%, for example 45 to 75%, 45 to 70%, 45 to 65%, 45 to 60% or 45 to 55% of darolutamide or a pharma- ceutically acceptable salt thereof by weight of the composition.

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

[0014] As used herein, "filler" refers to one or more pharma- ceutically acceptable excipients that provide bulk to a pharmaceutical composition. Examples of fillers include lactose, calcium dihydrogen phosphate, microcrystalline cellulose, sorbitol, starch, sugar (e.g., mannitol or sucrose), or any combination thereof. According to one preferred embodiment, the filler comprises calcium dihydrogen phosphate. As used herein, the term "calcium dihydrogen phosphate" also includes anhydrous calcium dihydrogen phosphate and hydrates such as calcium dihydrogen phosphate dihydrate. Anhydrous calcium dihydrogen 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 5-20%, e.g., 7-15%, calcium hydrogen phosphate by weight of the composition. In another subclass of any of the above embodiments, the composition comprises 5-20%, e.g., 7-15%, calcium hydrogen phosphate by weight of the composition and 10-40%, e.g., 15-40%, 20-40%, or 25-35% lactose by weight of the composition.

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

[0018] As used herein, "disintegrant" refers to one or more pharma- ceutically acceptable excipients added to a pharmaceutical composition that cause its disintegration to support the 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, "binder" refers to one or more pharma- ceutically acceptable excipients that bind and solidify the mixture of active ingredient and excipients, thereby providing enhanced cohesion. Examples of binders include polyvinylpyrrolidone (PVP), polyvinyl acetate, polyvinyl alcohol, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and combinations thereof.

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

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

[0024] As used herein, "lubricant" refers to one or more pharma- ceutically acceptable excipients 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 yet another embodiment, the composition comprises: (a) at least 35%, preferably at least 40%, for example 45% to 80%, of darolutamide or a pharma- ceutically 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] According to yet another embodiment, the composition comprises: (a) at least 35%, preferably at least 40%, for example 45% to 80%, of darolutamide or a pharma- ceutically acceptable salt thereof by weight of the composition; (b) 5 to 20% of calcium hydrogen phosphate by weight of the composition; (c) 10 to 40% of lactose by weight of the composition; (d) 0.5 to 10% of a disintegrant by weight of the composition; (e) 0.5 to 10% of a binder by weight of the composition; and (f) 0.2 to 5% of a lubricant by weight of the composition.

[0028] According to yet another embodiment, the composition comprises: (a) 45-80% darolutamide or a pharma- ceutically acceptable salt thereof by weight of the composition; (b) 5-20% dibasic calcium phosphate by weight of the composition; (c) 10-40% lactose by weight of the composition; (d) 0.5-10% croscarmellose sodium by weight of the composition; (e) 0.5-10% polyvinylpyrrolidone by weight of the composition; and (f) 0.2-5% magnesium stearate by weight of the composition.

[0029] In a subclass of the above embodiment, the compositions comprise 45-75%, 45-70%, 45-65%, 45-60%, or 45-55% darolutamide or a pharma- ceutically acceptable salt thereof by weight of the composition.

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

[0031] According to one embodiment, the tablet comprises an intragranular portion and an extragranular portion, according to another embodiment, the intragranular portion comprises the darolutamide or a pharma- ceutically acceptable salt thereof, the filler, the binder, and a portion of the disintegrant, and the extragranular portion comprises the 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 the steps of: (a) mixing darolutamide or a pharma- ceutically acceptable salt thereof, a filler, a binder and a first portion of a disintegrant; (b) granulating the mixture using water as the granulation fluid; (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 pharma- ceutically acceptable film coating agents.

[0033] For the preparation of the pharmaceutical composition, darolutamide, preferably in its non-salt form and in crystalline form I, is ground to a particle size having a median diameter by volume (Dv50) generally below 200 μm, preferably below 150 μm, more preferably below 100 μm, 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 light 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, applying a measuring 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 milling of the active ingredient can be carried out using suitable feeder and milling equipment, such as single or twin screw / auger feeders, hammer mills, pin mills, jet mills, or sieve mills, with suitable rotor rotation speeds, such as, for example, 3000-10000 rpm. The milling can be carried out at a suitable temperature, such as room temperature or below.

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

[0036] The dried granules may then be screened in a screening device, e.g., a screening mill. The remainder of the disintegrant can then be added to the granules and the mixture blended, e.g., in a diffusion mixer. The lubricant is then added to the previous mass and blended. The tablet mass is then compressed into tablet cores, e.g., in an electric rotary tablet press.

[0037] The tablet core may be coated with a water-soluble film coating, if desired, to facilitate tablet swallowing, to protect against direct contact with the drug, and to improve aesthetics. Suitable film coating agents may be selected from the group consisting of plasticizers, film formers, and colorants. Optionally, anti-tack or opacifiers may be used. Plasticizers such as polyethylene glycol (PEG), film formers such as hydroxypropylmethylcellulose (HPMC), and pigments such as iron oxide and titanium dioxide are combined with a film coating liquid, preferably water, to produce a homogeneous coating suspension that is brought up, preferably sprayed, onto the tablet in 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 an immediate release dosage form, preferably a tablet. The composition preferably provides at least 80% dissolution of darolutamide or a pharma- ceutical acceptable salt thereof after 60 minutes in 0.01M hydrochloric acid containing 1.0% sodium lauryl sulfate using a paddle apparatus (USP Apparatus 2) at room temperature with a paddle speed of 75 rpm.

[0039] For example, for the treatment of prostate cancer, darolutamide or a pharma- ceutically acceptable salt thereof is suitably administered to a patient in an amount ranging from about 100 mg to about 3000 mg, preferably about 300 mg to about 2500 mg, more preferably about 500 mg to about 2000 mg, for example, about 800 mg to 1500 mg, about 1200 mg, etc. per day. 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 divided doses several times a day, for example, twice a day. The composition of the present invention, such as a tablet, may contain darolutamide or a pharma- ceutically acceptable salt thereof in an amount 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, about 200 mg to about 400 mg, 300 mg, etc. Such compositions may be administered once a day, or several times a day, for example, once daily, twice daily, or several times daily, as one or several tablets, such as two 300 mg tablets twice daily.

[0040] The present invention is further illustrated by the following examples.

[0041] Example 1. Darolutamide immediate release tablets TIFF2025013941000002.tif107147

[0042] Example 2. Darolutamide immediate release tablets TIFF2025013941000003.tif100147

[0043] Example 3. Darolutamide immediate release tablets TIFF2025013941000004.tif103147

[0044] Example 4. Darolutamide immediate release tablets TIFF2025013941000005.tif103147

[0045] Example 5. Darolutamide immediate release tablets TIFF2025013941000006.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 the croscarmellose sodium in a high shear granulator. The mixture is granulated by spraying water into the mixture. The granules are dried in a fluid bed dryer. The remaining croscarmellose sodium is mixed with the granules. Magnesium stearate is then added and mixed. The resulting mixture is compressed into tablets in a tablet press. Water is combined with the mixture of coating excipients to prepare a coating suspension. Finally, the tablets are coated by spraying the coating suspension onto the tablet cores in a heated pan coater until the theoretical tablet weight gain is reached.

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

[0048] [Table 1]

[0049] Tablets were compressed in a single punch hydraulic tablet press equipped with 10 mm oval tooling to an approximate unit weight of 300 mg and a minimum of seven different compressed heights. A single-end sinusoidal profile was used with a target 10 ms dwell time for high speed compression and a target 100 ms dwell time for low speed compression. Tablet diameter, height and fracture resistance were measured by calipers and hardness tester, respectively.

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

[0051] FIG. 1 shows the average compression pressure versus tensile strength curves for "A-darolutamide" and "Paracetamol" compositions at low and high speed compression.

[0052] The tabletability profile depicted in Figure 1 clearly demonstrates that the tableting mass of Example 1 ("A-Darolutamide") is exceptionally suitable for the tableting process of darolutamide at low and high compression speeds. Comparison with similar compositions but with a model drug (paracetamol) as the active ingredient shows that the same composition using the other drug failed to produce tablets with acceptable tensile strength within the range of compression forces suitable for tablet production.

[0053] Figure 2 compares the average compression pressure vs. tensile strength curves of the "A-darolutamide" composition with that of "B-darolutamide" in which lactose was 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 in the case of high speed compression.

Claims

1. (a) at least 35%, preferably at least 40%, by weight of the composition of darolutamide or a pharma- ceutically acceptable salt thereof; (b) 5 to 60% by weight of the composition of a filler; (c) 0.5 to 10% by weight of the composition of a disintegrant; (d) 0.5 to 10% by weight of the composition of a binder; and (e) 0.2 to 5% by weight of the composition of a lubricant 23. A pharmaceutical composition comprising:

2. 2. The pharmaceutical composition according to claim 1, comprising 40-85%, preferably 45-80%, of darolutamide or a pharma- ceutically acceptable salt thereof by weight of the composition.

3. 3. A pharmaceutical composition according to claim 1 or 2, which comprises 5 to 55%, preferably 5 to 50%, of a filler by weight of the composition.

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

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

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

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

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

10. 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 by weight of the composition.

12. 12. The pharmaceutical composition of 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 by weight of the composition.

14. 14. The pharmaceutical composition of 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. 16. The pharmaceutical composition of claim 15, wherein the tablet is wet granulated.

17. 17. The pharmaceutical composition of claim 16, wherein the tablet comprises an intragranular portion and an extragranular portion.

18. 18. The pharmaceutical composition of claim 17, wherein the intragranular portion contains darolutamide or a pharma- ceutically acceptable salt thereof, a filler, a binder, and a portion of the disintegrant, and the extragranular portion contains the lubricant, and the remainder of the disintegrant.

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

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

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

22. 22. The pharmaceutical composition of any one of claims 1 to 21, wherein the composition provides at least 80% dissolution of darolutamide or a pharma- ceutically acceptable salt thereof after 60 minutes in 0.01 M hydrochloric acid containing 1.0% sodium lauryl sulfate using a paddle apparatus (USP Apparatus 2) at a paddle speed of 75 rpm at room temperature.

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