DESC:
F O R M 2

THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
(See section 10; rule 13)

“PHARMACEUTICAL COMPOSITION OF DAROLUTAMIDE”

ALEMBIC PHARMACEUTICALS LIMITED
An Indian Company
Alembic Campus, Alembic Road, Vadodara-390 003, Gujarat, India

The following specification particularly describes the invention and the manner in which it is to be performed:

TECHNICAL FIELD:

The present subject matter relates to a solid oral pharmaceutical composition comprising Darolutamide or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. The process to prepare such a pharmaceutical composition is also disclosed. The pharmaceutical composition of the present subject matter can be used as a medicament, for example for the treatment of prostate cancer.

BACKGROUND:

Darolutamide (ODM-201) is an androgen receptor inhibitor indicated for the treatment of patients with non-metastatic castration resistant prostate cancer (nmCRPC) and for the treatment of adult patients with metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel. It is developed jointly by Bayer and Orion Corporation for prostate cancer. Darolutamide is also known by the chemical name: N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1­yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide and is reported to have the following chemical structure:

Darolutamide in the form of 300 mg film coated tablet is approved in US under the brand name Nubeqa®. Nubeqa® is administered as 600 mg (two 300 mg film-coated tablets) orally, twice daily, which is equivalent to a total daily dose of 1200 mg, swallowed whole with food.

Darolutamide exhibits poor aqueous solubility. It’s solubility in aqueous buffer solutions at physiological pH range (pH 1-6.8) is in the range of 14-23 µg/mL.

United States Patent No. 8,975,254 (US’254 patent) discloses Darolutamide, its synthetic process and its pharmaceutical compositions. US’254 patent further disclose method for the treatment of androgen receptor dependent conditions such as prostate cancer, by administering Darolutamide or a pharmaceutically acceptable salt thereof.

United States Patent No. 10,010,530 discloses solid state form such as crystalline form I, form I' and form I? of Darolutamide with their X-ray powder diffraction pattern and method for preparation thereof.

United States Patent No. 11,168,058 discloses crystalline particles of Darolutamide having specific surface area (SSA) in the range of 8 - 16 m2/g. It also discloses crystalline particles of Darolutamide having rounded particle shape and a volume median diameter (Dv50) ranging from between 100 - 1000 µm.

United States Patent Application Publication US20220362216 (US’216 publication) discloses a pharmaceutical composition of Darolutamide comprising, Darolutamide or a pharmaceutically acceptable salt thereof in the concentration of 40 – 85 %, filler in the concentration of 5 – 60 %, disintegrant in the concentration of 0.5 – 10 %, binder in the concentration of 0.5 – 10 % and lubricant in the concentration of 0.2 – 5 % per weight of the composition.

The US’216 publication also discloses that pharmaceutical composition of Darolutamide, comprising, Darolutamide or a pharmaceutically acceptable salt thereof in the concentration of 40 – 85 %, calcium hydrogen phosphate as filler in the concentration of 5 – 20 %, lactose as filler in the concentration of 10 – 40 %, croscarmellose sodium as disintegrant in the concentration of 0.5 – 10 %, polyvinylpyrrolidone as binder in the concentration of 0.5 – 10 % and magnesium stearate as lubricant in the concentration of 0.2 – 5 % per weight of the composition.

There is a need in the art for alternative solid oral pharmaceutical composition of Darolutamide.

In an embodiment, the present subject matter relates to a solid oral pharmaceutical composition comprising Darolutamide or a pharmaceutically acceptable salt thereof and atleast one pharmaceutically acceptable excipient.

In an embodiment, the present subject matter relates to a solid oral pharmaceutical composition comprising Darolutamide or a pharmaceutically acceptable salt thereof and atleast one pharmaceutically acceptable excipient, wherein the atleast one pharmaceutically acceptable excipient is selected from a filler, a disintegrant, a binder, a lubricant or a glidant or combinations thereof.

In another embodiment, the present subject matter relates to a solid oral pharmaceutical composition comprising Darolutamide or a pharmaceutically acceptable salt thereof, filler, optionally disintegrant, optionally binder, lubricant and glidant. Furthermore, it also relates to methods for manufacturing such compositions and their use.

SUMMARY OF THESUBJECT MATTER:

The present subject matter relates to a solid oral pharmaceutical composition comprising Darolutamide or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. Processes to prepare such a pharmaceutical composition are also disclosed. The pharmaceutical composition of the present subject matter can be used as a medicament, for example for the treatment of prostate cancer.

Another aspect of the present subject matter provides a solid oral pharmaceutical composition comprising
(a) Darolutamide or a pharmaceutically acceptable salt thereof,
(b) at least one pharmaceutically acceptable filler,
(c) at least one pharmaceutically acceptable disintegrant,
(d) optionally pharmaceutically acceptable binder,
(e) at least one pharmaceutically acceptable lubricant, and
(f) at least one pharmaceutically acceptable glidant.

Another aspect of the present subject matter provides a solid oral pharmaceutical composition comprising
(a) Darolutamide or a pharmaceutically acceptable salt thereof,
(b) at least one pharmaceutically acceptable filler,
(c) optionally pharmaceutically acceptable disintegrant,
(d) at least one pharmaceutically acceptable binder,
(e) at least one pharmaceutically acceptable lubricant, and
(f) at least one pharmaceutically acceptable glidant.

Another aspect of the present subject matter provides a solid oral pharmaceutical composition comprising
(a) Darolutamide or a pharmaceutically acceptable salt thereof,
(b) at least one pharmaceutically acceptable filler,
(c) optionally pharmaceutically acceptable disintegrant,
(d) optionally pharmaceutically acceptable binder,
(e) at least one pharmaceutically acceptable lubricant, and
(f) at least one pharmaceutically acceptable glidant.

Another aspect of the present subject matter provides a solid oral pharmaceutical composition comprising
(a) Darolutamide or a pharmaceutically acceptable salt thereof,
(b) not more than one pharmaceutically acceptable filler,
(c) at least one pharmaceutically acceptable disintegrant,
(d) at least one pharmaceutically acceptable lubricant, and
(e) at least one pharmaceutically acceptable glidant,
wherein the composition is free of a binder.

Another aspect of the present subject matter provides a solid oral pharmaceutical composition comprising
(a) Darolutamide or a pharmaceutically acceptable salt thereof,
(b) not more than one pharmaceutically acceptable filler,
(c) at least one pharmaceutically acceptable disintegrant,
(d) optionally pharmaceutically acceptable binder,
(d) at least one pharmaceutically acceptable lubricant, and
(e) at least one pharmaceutically acceptable glidant.

Another aspect of the present subject matter provides a solid oral pharmaceutical composition comprising
(a) Darolutamide or a pharmaceutically acceptable salt thereof,
(b) not more than one pharmaceutically acceptable filler,
(c) optionally pharmaceutically acceptable disintegrant,
(d) at least one pharmaceutically acceptable binder,
(d) at least one pharmaceutically acceptable lubricant, and
(e) at least one pharmaceutically acceptable glidant.

Another aspect of the present subject matter provides a solid oral pharmaceutical composition comprising
(a) Darolutamide or a pharmaceutically acceptable salt thereof,
(b) not more than one pharmaceutically acceptable filler,
(c) at least one pharmaceutically acceptable disintegrant,
(d) at least one pharmaceutically acceptable binder, and
(d) at least one pharmaceutically acceptable lubricant,
wherein the composition is free of a glidant.

DETAILED DESCRIPTION OF THE INVENTION:

Accordingly, the present subject matter relates to a solid oral pharmaceutical composition comprising Darolutamide as an active ingredient and at least one pharmaceutically acceptable excipient.

In one embodiment, present subject matter relates to a solid oral pharmaceutical composition comprising Darolutamide as an active ingredient and at least one pharmaceutically acceptable excipient selected from, but not limited to, filler, disintegrant, binder, lubricant or glidant or combinations thereof.

In another embodiment, the present subject matter relates to a solid oral pharmaceutical composition comprising Darolutamide or a pharmaceutically acceptable salt thereof, filler, optionally disintegrant, optionally binder, lubricant and glidant. Furthermore, it also relates to methods for manufacturing such compositions and their use.

For the purpose of the present subject matter, pharmaceutical composition may comprise Darolutamide in the ‘free base form’ or as a pharmaceutically acceptable salt, or as any mixture thereof.

In one embodiment, Darolutamide is in the amorphous form or in the crystalline form.

In another embodiment, the present subject matter, provides a pharmaceutical composition, wherein the active ingredient Darolutamide having specific surface area (SSA) in the range from about 2 to about 50 m2/g, preferably from about 8 to about 35 m2/g, more preferably from 20 to 35 m2/g. The surface area of the Darolutamide can be measured by techniques known in the art such as such as BET-nitrogen adsorption analysis method or by following the method given in WO2018162793 or its equivalent method.

In another embodiment, the present subject matter, provides a pharmaceutical composition, wherein the active ingredient Darolutamide having particle shape like sphere, needle, cube, plate, pollen, needle, prismatic, bladelike or irregular shape, preferably having irregular shape.

In another embodiment, the present subject matter, provides a pharmaceutical composition, wherein the active ingredient Darolutamide having a volume median diameter (Dv50) between 1-1000 µm, preferably between 10-100 µm, more preferably between 50-80 µm. The particle size of Darolutamide can be measured by techniques known in the art such as Laser light scattering (e.g. Malvern Light Scattering). Coulter counter, microscopy and the like or by following the method given in WO2018162793 or its equivalent method.

In another embodiment, pharmaceutical composition of Darolutamide according to the invention is prepared using crystalline Darolutamide having SSA from 20 to 35 m2/g, having volume median diameter (Dv50) from 50-80 µm and having irregular particle shape.

In another embodiment, the particles of Darolutamide of present subject matter may have particle size distribution, wherein D10 is less than 20 µm, less than 15 µm, less than 10 µm or less than 5 µm; wherein D50 is less than 100 µm, less than 90 µm, less than 80 µm, less than 70 µm, less than 60 µm, less than 50 µm, less than 40 µm, less than 30 µm, less than 20 µm or less than 10 µm; wherein D90 is less than 350 µm, less than 300 µm, less than 250 µm, less than 200 µm, less than 185 µm, less than 160 µm, less than 140 µm, less than 100 µm, less than 80 µm, less than 60 µm, less than 50 µm, less than 40 µm, less than 20 µm or less than 10 µm.

Particle size distributions of Darolutamide particles may be measured using any techniques known in the art. For example, particle size distributions of Darolutamide particles may be measured using microscopy or light scattering equipment, such as, for example, a Malvern Master Size 2000 from Malvern Instruments Limited, Malvern, Worcestershire, United Kingdom. The term “D10” as used herein means that 10% of the particles (based on volume) are smaller than or equal to the indicated size. The term “D50” as used herein means that 50% of the particles (based on volume) are smaller than or equal to the indicated size. The term “D90” as used herein means that 90% of the particles (based on volume) are smaller than or equal to the indicated size.

In an embodiment, Darolutamide of present subject matter can be micronized or milled by using conventional techniques to get the desired particle size to achieve desired solubility profile to suit to pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to jet milling, hammer milling, roller milling and ball milling. The starting material Darolutamide may be obtained according to any method known in the art.

An aspect of the present subject matter provides a solid oral pharmaceutical composition comprising,
(a) Darolutamide or a pharmaceutically acceptable salt thereof,
(b) at least one pharmaceutically acceptable filler,
(c) at least one pharmaceutically acceptable disintegrant,
(d) optionally pharmaceutically acceptable binder,
(e) at least one pharmaceutically acceptable lubricant, and
(f) at least one pharmaceutically acceptable glidant.
In further embodiments of the present subject matter the solid oral pharmaceutical composition as defined herein may have 30 – 60 % w/w of (a) Darolutamide or a pharmaceutically acceptable salt thereof.

An aspect of the present subject matter provides a solid oral pharmaceutical composition comprising,
(a) Darolutamide or a pharmaceutically acceptable salt thereof,
(b) at least one pharmaceutically acceptable filler,
(c) optionally pharmaceutically acceptable disintegrant,
(d) at least one pharmaceutically acceptable binder,
(e) at least one pharmaceutically acceptable lubricant, and
(f) at least one pharmaceutically acceptable glidant.
In further embodiments of the present subject matter the solid oral pharmaceutical composition as defined herein may have 30 – 60 % w/w of (a) Darolutamide or a pharmaceutically acceptable salt thereof.

Another aspect of the present subject matter provides a solid oral pharmaceutical composition comprising
(a) Darolutamide or a pharmaceutically acceptable salt thereof,
(b) at least one pharmaceutically acceptable filler,
(c) optionally pharmaceutically acceptable disintegrant,
(d) optionally pharmaceutically acceptable binder,
(d) at least one pharmaceutically acceptable lubricant, and
(e) at least one pharmaceutically acceptable glidant.
In further embodiments of the present subject matter the solid oral pharmaceutical composition as defined herein may have 30 – 60 % w/w of (a) Darolutamide or a pharmaceutically acceptable salt thereof.

Another aspect of the present subject matter provides a solid oral pharmaceutical composition comprising
(a) 30 – 60 % w/w Darolutamide or a pharmaceutically acceptable salt thereof,
(b) not more than one pharmaceutically acceptable filler,
(c) at least one pharmaceutically acceptable disintegrant,
(d) at least one pharmaceutically acceptable lubricant,
(e) at least one pharmaceutically acceptable glidant, and
wherein the composition is free of a binder.

Another aspect of the present subject matter provides a solid oral pharmaceutical composition comprising
(a) 30 – 60 % w/w Darolutamide or a pharmaceutically acceptable salt thereof,
(b) not more than one pharmaceutically acceptable filler,
(c) at least one pharmaceutically acceptable disintegrant,
(d) at least one pharmaceutically acceptable binder,
(e) at least one pharmaceutically acceptable lubricant, and
wherein the composition is free of a glidant.

In one embodiment the present subject matter relates to a solid oral pharmaceutical composition comprising Darolutamide or a pharmaceutically acceptable salt thereof and at least one of the following excipients:
(a) 30 – 60 % w/w Darolutamide or a pharmaceutically acceptable salt thereof,
(b) 20 – 65 % w/w Filler(s),
(c) 0 – 30 % w/w Disintegrant(s),
(d) 0.5 – 10 % w/w Binder(s),
(e) 0.5 – 4 % w/w Lubricant(s),
(f) 0 – 3 % w/w Glidant(s).

In one embodiment the present subject matter relates to a solid oral pharmaceutical composition comprising Darolutamide or a pharmaceutically acceptable salt thereof and at least one of the following excipients:
(a) 30 – 60 % w/w Darolutamide or a pharmaceutically acceptable salt thereof,
(b) 20 – 65 % w/w Filler(s),
(c) 15 – 30 % w/w Disintegrant(s),
(d) 0 – 10 % w/w Binder(s),
(e) 0.5 – 4 % w/w Lubricant(s),
(f) 0.2 – 3 % w/w Glidant(s).

In one embodiment the present subject matter relates to a solid oral pharmaceutical composition comprising Darolutamide or a pharmaceutically acceptable salt thereof and at least one of the following excipients:
(a) 30 – 60 % w/w Darolutamide or a pharmaceutically acceptable salt thereof,
(b) 20 – 65 % w/w Filler(s),
(c) 15 – 30 % w/w Disintegrant(s),
(d) 0.5 – 4 % w/w Lubricant(s),
(e) 0 – 3 % w/w Glidant(s).

In this specification the terms “filler” and “fillers” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable filler according to the present subject matter can be selected from the group of, but not limited to mannitol, lactose, fructose, isomalt, lactitol, maltitol, erythritol, erythritol, maltose, polydextrose, sucrose, trehalose, xylitol, calcium carbonate, dicalcium phosphate, tricalcium phosphate, pregelatinized starch, calcium sulfate, cellulose acetate, ethylcellulose, inulin, magnesium carbonate, magnesium oxide, maltodextrin, sodium bicarbonate, sodium carbonate, sodium chloride, microcrystalline cellulose and combinations thereof. In some embodiments, the filler comprises Mannitol, pregelatinized starch and/or microcrystalline cellulose.

In this specification the terms “disintegrant” and “disintegrants” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable disintegrants according to the present subject matter can be selected from but not limited to croscarmellose sodium, alginic acid, sodium alginate, carboxymethylcellulose calcium, chitosan, crospovidone, glycine, pregelatinized starch, guar gum, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, sodium alginate, sodium carboxymethylcellulose, sodium starch glycolate, starch and combinations thereof. In some embodiments, the disintegrant comprises croscarmellose sodium.

In this specification the terms “binder” and “binders” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable pharmaceutical binder according to the present subject matter can be selected from but not limited to povidone, hypromellose, sodium carboxy methyl cellulose, polyvinyl acetate, polyvinyl alcohol, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, starches and combinations thereof. In some embodiments, the binder comprises povidone.

In this specification the terms “lubricant” and “lubricants” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable pharmaceutical lubricant according to the present subject matter can be selected from but not limited to magnesium, aluminium, zinc or calcium stearate, glyceryl behenate, glyceryl dibehenate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium stearyl fumarate, myristic acid, palmitic acid, stearic acid, talc, tribehenin and combinations thereof. In some embodiments, the lubricant comprises sodium stearyl fumarate, magnesium stearate or talc.

Glidants are frequently used in tablet formulations to improve flow. In this specification the terms “glidant” and “glidants” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable glidants according to the present subject matter can be selected from but not limited to magnesium oxide, silicon dioxide, pyrogenic silica, hydrated sodium silioaluminate magnesium stearate, stearic acid, calcium phosphate, magnesium carbonate, starch, corn starch, talc and combinations thereof. In some embodiments, the glidant comprises silicon dioxide.

In this specification, the word “comprise” or “comprising” describes components that must be present, but leaves open the possibility that other unspecified components may also be present within the scope of the relevant term.

In one embodiment the solid oral pharmaceutical composition of the present subject matter can be, for example, in the form of tablets, pellets, capsules or granules. Such compositions can be prepared, for example, by wet granulation, dry granulation or direct compression. In a preferred embodiment, the pharmaceutical composition of the present subject matter is in the form of a coated or uncoated tablet. According to one preferred embodiment, the tablet is prepared by dry granulation.

In one aspect there is provided a pharmaceutical tablet comprising the pharmaceutical composition as defined herein.

In one embodiment there is provided a pharmaceutical tablet comprising a tablet core wherein the tablet core comprises the pharmaceutical composition as defined herein and wherein the tablet core has a coating. In one embodiment the coating is a film coating.

When the tablet has a film coating, the film coating may be applied using conventional methods. A coating can be used to provide protection against, for example, moisture ingress or degradation by light, to colour the formulation, or to modify or to control the release of the Darolutamide from the formulation.

In one embodiment the pharmaceutical composition is a pharmaceutical tablet composition (for oral administration).

In one embodiment the pharmaceutical composition of the present subject matter is a pharmaceutical tablet composition suitable for oral administration to a human.

In one embodiment the pharmaceutical composition of the present subject matter is a pharmaceutical tablet composition suitable for oral administration to a human who has cancer, particularly prostate cancer, for example nmCRPC, mHSPC.

In one embodiment the pharmaceutical tablet comprising 100 mg - 600 mg Darolutamide.

In one embodiment the pharmaceutical tablet comprising 300 mg Darolutamide.

In a further aspect of the present subject matter, there is provided the use of a pharmaceutical composition, as defined herein, for the manufacture of a medicament.

In one embodiment there is provided the use of a pharmaceutical composition, as defined herein, for the manufacture of a medicament for the treatment of cancer.

In one aspect of the present subject matter, there is provided a pharmaceutical composition, as defined herein, for use as a medicament.

In one embodiment there is provided a pharmaceutical tablet, as defined herein, for use as a medicament.

In one embodiment there is provided a pharmaceutical composition, as defined herein, for use in the treatment of cancer.

In one embodiment there is provided a pharmaceutical tablet, as defined herein, for use in the treatment of prostate cancer.

In one aspect of the present subject matter, there is provided a method of treating cancer in a patient in need thereof, which method comprises the oral administration of an effective amount of the pharmaceutical composition, as defined herein, to the patient.

In one embodiment there is provided a method of treating cancer in a patient in need thereof, which method comprises the oral administration of an effective number of the pharmaceutical tablet(s), as defined herein, to the patient.

In any aspect, embodiment or claim where “cancer” is mentioned in this specification, the cancer may be further defined according to the embodiments listed below, unless such a definition would be inappropriate in a particular context.

In one embodiment the cancer is prostate cancer.

In one embodiment the cancer is non-metastatic castration resistant prostate cancer.

In one embodiment the cancer is metastatic hormone-sensitive prostate cancer.

Embodiments provided herein may be more fully understood by reference to the following examples. These examples are meant to be illustrative of pharmaceutical compositions and dosage forms provided herein, but are not in any way limiting.

Example 1
Table 1 - Pharmaceutical composition of Darolutamide
Sr. No. Ingredients % of ingredient by weight of core tablet

1 Darolutamide 30 – 60 %
2 Filler(s) (e.g. Microcrystalline cellulose, Mannitol, pregelatinized starch, etc.) 20 – 65 %
3 Optionally Disintegrant(s) (e.g. croscarmellose sodium, etc.) 0 – 30 %
4 Optionally Binder(s) (e.g. povidone, etc.) 0 – 10 %
5 Lubricant(s) (e.g. Magnesium stearate, talc, etc.) 0.5 – 4 %
6 Glidant(s) (e.g. colloidal silicon dioxide, etc.) 0 – 3 %
7 Optionally Film Coating q.s

Example 2
Table 2 - Pharmaceutical composition of Darolutamide
Sr. Ingredient Prototype I
Intragranular:
1 Darolutamide 47.67 %
2 Pregelatinized starch 21.88 %
3 Povidone 3.81 %
4 Silicon dioxide 0.49 %
5 Magnesium stearate 0.24 %
Extragranular:
6 Pregelatinized starch 22.25 %
7 Silicon dioxide 0.97 %
8 Magnesium stearate 0.73 %
Core tablet weight 98.04 %
9 Opadry Coating 1.96 %
Coated tablet weight 100.00 %

Example 3
Table 3 - Pharmaceutical composition of Darolutamide
Sr. Ingredient Prototype I Prototype II Prototype III
Intragranular:
1 Darolutamide 47.67 % 47.67 % 47.67 %
2 Mannitol 21.88 % 26.97 % 24.43 %
3 Croscarmellose sodium 11.60 % 6.51 % 9.06 %
4 Silicon dioxide 0.49 % 0.49 % 0.49 %
5 Magnesium stearate 0.24 % 0.24 % 0.24 %
Extragranular:
6 Mannitol 7.94 % 7.94 % 7.94 %
7 Croscarmellose sodium 6.51 % 6.51 % 6.51 %
8 Silicon dioxide 0.97 % 0.97 % 0.97 %
9 Magnesium stearate 0.73 % 0.73 % 0.73 %
Core tablet weight 98.03 % 98.03 % 98.04 %
10 Opadry Coating 1.96 % 1.96 % 1.96 %
Coated tablet weight 100.00 % 100.00 % 100.00 %

Example 4
Table 4 - Pharmaceutical composition of Darolutamide
Sr. Ingredient Prototype I
Intragranular:
1 Darolutamide 47.67 %
2 Mannitol 20.22 %
3 Microcrystalline cellulose 5.88 %
4 Dicalcium Phosphate Anhydrous 8.82 %
5 Low-substituted Hydroxy propyl cellulose 4.13 %
6 Magnesium stearate 0.73 %
Extragranular:
7 Low-substituted Hydroxy propyl cellulose 7.94 %
8 Silicon dioxide 0.97 %
9 Magnesium stearate 0.73 %
Core tablet weight 97.09 %
10 Opadry Coating 2.91 %
Coated tablet weight 100.00 %

Example 5
Table 5 - Pharmaceutical composition of Darolutamide
Sr. Ingredient Prototype I Prototype II Prototype III
Intragranular:
1 Darolutamide 47.67 % 47.67 % 47.67 %
2 Mannitol 30.47 % 24.11 % 27.92 %
3 Pregelatinized starch 1.59 % 1.59 % 4.13 %
4 Povidone 3.81 % 3.81 % 3.81 %
5 Magnesium stearate 0.73 % 0.73 % 0.73 %
Extragranular:
6 Pregelatinized starch 11.12 % 11.12 % 11.12 %
7 Mannitol - 6.36 % -
8 Silicon dioxide 0.97 % 0.97 % 0.97 %
9 Magnesium stearate 0.73 % 0.73 % 0.73 %
Core tablet weight 97.09 % 97.09 % 97.08 %
10 Opadry Coating 2.91 % 2.91 % 2.91 %
Coated tablet weight 100.00 % 100.00 % 100.00 %

Example 6
Table 6 - Pharmaceutical composition of Darolutamide
Sr. Ingredient Prototype I
Intragranular:
1 Darolutamide 49.37 %
2 Mannitol 13.16 %
3 Tricalcium phosphate, anhydrous granular 6.58 %
4 Hypromellose 3.95 %
5 Sodium starch glycolate 1.65 %
6 Silicon dioxide 0.49 %
7 Talc 0.82 %
8 Sodium stearyl fumarate 0.82 %
Extragranular:
9 Mannitol 11.52 %
10 Tricalcium phosphate, anhydrous granular 6.58 %
11 Silicon dioxide 0.49 %
12 Talc 0.82 %
13 Sodium stearyl fumarate 0.82 %
Core tablet weight 97.07 %
10 Opadry Coating 2.91 %
Coated tablet weight 100.00 %

Example 7
Table 7 - Pharmaceutical composition of Darolutamide
Sr. Ingredient Prototype I
Intragranular:
1 Darolutamide 49.37 %
2 Lactose monohydrate 13.16 %
3 Tricalcium phosphate, anhydrous granular 6.58 %
4 Hypromellose 3.95 %
5 Sodium starch glycolate 1.65 %
6 Silicon dioxide 0.49 %
7 Talc 0.82 %
8 Sodium stearyl fumarate 0.82 %
Extragranular:
9 Lactose monohydrate 11.52 %
10 Tricalcium phosphate, anhydrous granular 6.58 %
11 Silicon dioxide 0.49 %
12 Talc 0.82 %
13 Sodium stearyl fumarate 0.82 %
Core tablet weight 97.07 %
10 Opadry Coating 2.91 %
Coated tablet weight 100.00 %

Example 8
Manufacturing process:
Examples 2 - 7 can be prepared using wet granulation process, dry granulation process or direct compression process. Preferably compositions can be prepared using dry granulation process.
Dry granulation process for compositions disclosed herein may typically involve:
• Sifting Darolutamide and intragranular material through mesh using vibro sifter,
• Mixing above obtained material in blender,
• Lubricating above blend with lubricant sifted through mesh and mixing in blender using suitable parameters,
• Loading the above blended material into roller compactor and compacting the material with suitable parameters,
• Sifting extragranular material through mesh using vibro sifter,
• Sifting lubricant through mesh using vibro sifter,
• Mixing the above materials together in blender using suitable parameters,
• Lubricating the above blend with lubricant sifted through mesh and mixing in a blender,
• Compressing the above blend with appropriate tooling,
• Coating the above compressed tablet using suitable coating material.

Example 9
Dissolution study:
The dissolution study was conducted for the Darolutamide compositions of the present invention in comparison with the Nubeqa® (Darolutamide) 300 mg tablets (Marketed by Bayer healthcare pharmaceuticals inc) in 0.01N HCl+1% SLS media at 75 rpm using USP type II apparatus. The samples were analyzed using HPLC technique.

Table 8A - Comparative Dissolution profile of RLD and Darolutamide compositions of present invention
Time points
(min) Nubeqa® 300 mg tablet Example 2
(Prototype-I) Example 3
(Prototype-I) Example 3
(Prototype-II) Example 4
(Prototype-I)
% drug release
10 55 22 52 52 77
15 69 36 61 62 86
30 82 59 73 74 95
45 88 69 79 81 98
60 92 75 83 85 98
75 95 79 86 88 99
90 96 84 88 91 99
120 97 89 92 94 99

Table 8B - Comparative Dissolution profile of RLD and Darolutamide compositions of present invention
Time points
(min) Nubeqa®
300 mg tablet Example 5
(Prototype-I) Example 5
(Prototype-II) Example 6
(Prototype-I) Example 7
(Prototype-I)
% drug release
10 55 11 11 42 51
15 69 17 18 57 64
30 82 38 37 76 79
45 88 64 55 87 84
60 92 84 71 91 87
75 95 93 82 93 89
90 96 97 89 94 90
120 97 98 - 95 90

Results of dissolution study shows that Darolutamide compositions of the present invention showed no significant difference from the Nubeqa® (Darolutamide) 300 mg tablets (Marketed by Bayer healthcare pharmaceuticals inc). Dissolution studies were also conducted at predefined time intervals for on-stability samples of Darolutamide compositions of the present invention.

Example 10
Bioequivalence study:
An open label, balanced, randomized, single oral dose, crossover, oral bioequivalence study of Darolutamide Tablets 300 mg in comparison with Nubeqa® (Darolutamide) 300 mg tablets (Marketed by Bayer healthcare pharmaceuticals inc) was performed in healthy, adult, human subjects under fasting and fed conditions.
The outcome of the bioequivalence study for Darolutamide compositions of the present invention under fed and fasting state complies with pre-defined bioequivalence criteria for Cmax, AUC0-t and AUC0-8. ,CLAIMS:We claim:

1. A solid oral pharmaceutical composition comprising,
(a) Darolutamide or a pharmaceutically acceptable salt thereof,
(b) not more than one pharmaceutically acceptable filler,
(c) at least one pharmaceutically acceptable disintegrant,
(d) at least one pharmaceutically acceptable lubricant,
(e) at least one pharmaceutically acceptable glidant, and
wherein, the composition is free of a binder.

2. The solid oral pharmaceutical composition as claimed in claim 1, comprising 30 – 60 % w/w, preferably 35 – 55 % w/w of Darolutamide or a pharmaceutically acceptable salt thereof, based on the total weight of the composition.

3. The solid oral pharmaceutical composition as claimed in claim 1, comprising 20 – 65 % w/w, preferably 25 – 50 % w/w of not more than one pharmaceutically acceptable filler, based on the total weight of the composition.

4. The solid oral pharmaceutical composition as claimed in claim 3, wherein, the filler is selected from sucrose, mannitol, pregelatinized starch and microcrystalline cellulose.

5. The solid oral pharmaceutical composition as claimed in claim 1, comprising 15 – 30 % w/w of at least one pharmaceutically acceptable disintegrant, based on the total weight of the composition.

6. The solid oral pharmaceutical composition as claimed in claim 1, comprising 0 – 3 % w/w, preferably 0.2 – 2.5 % w/w of at least one pharmaceutically acceptable glidant, based on the total weight of the composition.

7. The solid oral pharmaceutical composition as claimed in claim 6, wherein the glidant is selected from talc, pyrogenic silica, corn starch, silicon dioxide, magnesium carbonate and/or combination thereof.

8. A solid oral pharmaceutical composition comprising,
(a) 30 – 60 % w/w Darolutamide or a pharmaceutically acceptable salt thereof,
(b) 20 – 65 % w/w filler,
(c) 15 – 30 % w/w disintegrant,
(d) 0 – 10 % w/w binder,
(e) 0.5 – 4 % w/w lubricant, and
(f) 0.2 – 3 % w/w glidant.

9. The solid oral pharmaceutical composition as claimed in claim 1 or 8, comprising using Darolutamide or a pharmaceutically acceptable salt thereof as active ingredient in the composition, with specific surface area (SSA) preferably in the range from about 8 to about 35 m2/g, more preferably in the range from about 20 to about 35 m2/g.

10. The solid oral pharmaceutical composition as claimed in claims 1 to 9, wherein the composition is a film coated tablet, for use as a medicament in the treatment of prostate cancer.