Claims:Claims:-

1. A pharmaceutical composition comprising unit hard gelatin capsule dosage composition comprising Enzalutamide, polyoxyethylene-polyoxypropylene block copolymers, butylated hydroxy anisole, butylated hydroxy toluene, mannitol, lactose monohydrate, croscarmellose sodium and magnesium stearate.

2. A Pharmaceutical composition according to claim 1, wherein the crystalline Enzalutamide is solubilized in an organic solvent with a specific combination of polyoxyethylene-polyoxypropylene block copolymers, butylated hydroxy anisole and butylated hydroxy toluene.

3. The pharmaceutical composition according to claim 2, wherein the organic solvent is selected from acetone or alcohol (C1-C3) or a mixture thereof.

4. The pharmaceutical composition according to claim 2, wherein the crystalline Enzalutamide in solubilized form exists as drug dispersed in a specific combination of polyoxyethylene-polyoxypropylene block copolymers, butylated hydroxy anisole and butylated hydroxy toluene.

5. Another aspect of the invention relates to the unit hard gelatin capsule dosage composition comprising Enzalutamide, polyvinyl pyyrolidone, butylated hydroxy toluene, butylated hydroxy anisole, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium and magnesium stearate.

6. A Pharmaceutical composition according to claim 6, wherein the crystalline Enzalutamide is solubilized in an organic solvent with a specific combination of polyoxyethylene-polyoxypropylene block copolymers, butylated hydroxy anisole and butylated hydroxy toluene.

7. The pharmaceutical composition according to claim 7, wherein the crystalline Enzalutamide in solubilized form exists as drug dispersed in a specific combination of polyvinyl pyyrolidone, butylated hydroxy toluene and butylated hydroxy anisole.

8. A process for preparing a unit hard gelatin capsule comprising Enzalutamide prepared by a process comprising the steps of
a) providing drug solution by dissolving Enzalutamide, polyoxyethylene-polyoxypropylene block copolymers, butylated hydroxy toluene and butylated hydroxy anisole in the organic solvent consisting of acetone and ethanol
b) spraying the drug solution of step a) on the dry mixture consisting of mannitol, lactose monohydrate and croscarmellose sodium to form the spray granulate
c) drying the granulate of step b)
d) milling the spray granulate of step c) to form the milled granules
e) compacting the milled granules of step d)
f) lubricating the above milled granules with atleast one lubricant to form the lubricated blend and
g) filling the above lubricated blend into the capsules.

9. A process for preparing unit hard gelatin capsule comprising Enzalutamide prepared by a process comprising the steps of
a) providing drug solution by dissolving Enzalutamide, polyvinyl pyrrolidone, butylated hydroxy toluene and butylated hydroxy anisole in the organic solvent consisting of acetone and ethanol
b) spraying the drug solution of step a) on the dry mixture consisting of microcrystalline cellulose, lactose monohydrate and croscarmellose sodium to form the spray granulate
c) drying the spray granulate of step b)
d) milling the spray granulate of step c) to form the milled granules
e) compacting the milled granules of step d)
f) lubricating the above milled granules with atleast one lubricant to form the lubricated blend and
g) filling the above lubricated blend into the capsules.

Dated this 10th Day of Sep 2015.

Dr.Akshay Kant Chaturvedi
Head-Corporate IPM & Legal Affairs
Shilpa Medicare Ltd.
, Description:The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION

The present invention relates to the pharmaceutical compositions comprising Enzalutamide and the process for the preparation thereof.

BACKGROUND OF THE INVENTION

Antiandrogens are often used to treat dreadful prostate cancer as remedy of choice. They alter the androgen pathway by blocking the appropriate receptors or affecting androgen production. Various known non-steroidal Antiandrogens include Flutamide, Nilutamide, Bicalutamide, and Enzalutamide.

Enzalutamide is a diarylhydantoin androgen receptor, which appears to be derived as combination molecule of Nilutamide and Bicalutamide. Enzalutamide is indicated for the treatment of castration resistant prostate cancer (CRPC). The chemical name of Enzalutamide is 4-{3-[4-cyano-3­(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide.

Sawyers, etal in US Patent 7,709,517 disclosed the structure of Enzalutamide and its use for the treatment of castration resistant prostate cancer. Enzalutamide is available commercially as a soft gelatin capsule (brand name "XTANDI®") filled with a liquid comprising 40 mg of Enzalutamide per one capsule and inactive ingredients. The inactive ingredients are caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, and black iron oxide. The recommended daily dosage is about 160 mg, and a patient therefore is required to take four capsules daily.

Lorenz; Douglas Alan; etal in US Publication No. 20140100256A1 disclose the tablet formulations comprising a solid dispersion of Enzalutamide and at least one polymer, selected from the group consisting of hydroxypropyl methyl cellulose, HPMCAS (Hypromellose acetate succinate) and polyvinylpyrrolidone/vinyl acetate.

Peddy; Vishweshwar; etal in US Publication No. 2015239848A1 discloses the amorphous solid dispersion comprising Enzalutamide and one or more pharmaceutically acceptable carriers.

Grahek, Rok; etal in PCT Publication No. 2015118015A1 discloses a solid pharmaceutical composition comprising Enzalutamide, a carrier and a surfactant, wherein Enzalutamide is amorphous.

It is often observed that combining drugs with solubilizing polymers may not always improve bioavailability for a poorly soluble drug. To achieve solubilization of a poorly soluble drug may apparently depend on its chemical structure and physico-chemical properties. Hence, it is not firmly predicted by any means, as to how solubilize a poorly soluble drug. Plethora of literature still in the want of adequate literature mentions that drug-polymer interaction is poorly understood.

Hence there exists a need to develop, a pharmaceutical compositions of molecules like Enzalutamide in a single hard gelatin capsule possessing advantageous solubility, dissolution stability and absorption.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1:- is an exemplification of Powder X-Ray diffraction pattern of crystalline SEZ Enzalutamide used in the pharmaceutical compositions according to the present invention.

Figure 2:- is an exemplification of results of dissolution rate for Enzalutamide capsules of present invention compared with XTANDI (Enzalutamide) soft gelatin capsules. (According to Example-1).

Figure 3:- is an exemplification of results of dissolution rate for Enzalutamide capsules of present invention compared with XTANDI soft gelatin capsules (Enzalutamide) soft gelatin capsules (According to Example-2).

SUMMARY OF THE INVENTION

The present invention discloses the pharmaceutical compositions, including unit dosage forms specifically hard gelatin capsules, comprising Enzalutamide as well as process for producing such compositions.

In one aspect according to present invention, it provides the unit hard gelatin capsule dosage composition comprising Enzalutamide, atleast one polymer and pharmaceutically acceptable carrier thereof.

In another aspect according to present invention, it relates to pharmaceutical composition comprising unit hard gelatin capsule dosage composition comprising Enzalutamide, polyoxyethylene-polyoxypropylene block copolymers, butylated hydroxy anisole, butylated hydroxy toluene, mannitol, lactose monohydrate, croscarmellose sodium and magnesium stearate.

The crystalline Enzalutamide used in the pharmaceutical composition according to present invention is having powder XRPD according to figure-1.

The crystalline Enzalutamide is solubilized and exists as drug dispersed in a specific combination of polyoxyethylene-polyoxypropylene block copolymers, butylated hydroxy anisole and butylated hydroxy toluene.

The solubilization of crystalline Enzalutamide comprising dissolving in an organic solvent with a specific combination of polyoxyethylene-polyoxypropylene block copolymers, butylated hydroxy anisole and butylated hydroxy toluene.

In another aspect of present invention, it relates to a process for preparing a unit hard gelatin capsule comprising Enzalutamide prepared by a process comprising the steps of
a) providing drug solution by dissolving Enzalutamide, polyoxyethylene-polyoxypropylene block copolymers, butylated hydroxy toluene and butylated hydroxy anisole in the organic solvent consisting of acetone and ethanol
b) spraying the drug solution of step a) on the dry mixture consisting of mannitol, lactose monohydrate and croscarmellose sodium to form the spray granulate
c) drying the granulate of step b)
d) milling the spray granulate of step c) to form the milled granules
e) compacting the milled granules of step d)
f) lubricating the above milled granules with atleast one lubricant to form the lubricated blend and
g) filling the above lubricated blend into the capsules.

Yet another aspect according to the present invention, it relates to the unit hard gelatin capsule dosage composition comprising Enzalutamide, polyvinyl pyyrolidone, butylated hydroxy toluene, butylated hydroxy anisole, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium and magnesium stearate.

The pharmaceutical composition comprising crystalline Enzalutamide remains in solubilized form and exists as drug dispersed in a specific combination of polyvinyl pyrrolidone, butylated hydroxy anisole and butylated hydroxy toluene.

In a further another aspect of the present invention, it relates to a process for preparing unit hard gelatin capsule comprising Enzalutamide prepared by a process comprising the steps of
a) providing drug solution by dissolving Enzalutamide, polyvinyl pyrrolidone, butylated hydroxy toluene and butylated hydroxy anisole in the organic solvent consisting of acetone and ethanol
b) spraying the drug solution of step a) on the dry mixture consisting of microcrystalline cellulose, lactose monohydrate and croscarmellose sodium to form the spray granulate
c) drying the spray granulate of step b)
d) milling the spray granulate of step c) to form the milled granules
e) compacting the milled granules of step d)
f) lubricating the above milled granules with atleast one lubricant to form the lubricated blend and
g) filling the above lubricated blend into the capsules.

The unit hard gel capsule dosage form of Enzalutamide according to the present invention, wherein a 40mg or 80 mg or 160 mg dose of unit hard gel capsule dosage form may be bioequivalent to the equivalent unit dose in desired multiple of XTANDI®, which is available in the form of soft gel capsule dosage form.

The unit hard gel capsule dosage composition according to present invention possesses properties such as improvement in solubility and absorption of Enzalutamide. These unit hard gel capsule dosage compositions provide usually improved enhancements in aqueous concentration in an environment of use. These compositions also provide the opportunity to dose the entire therapeutic dose of Enzalutamide in four or two or in single hard gel capsule dosage unit by improving the oral bioavailability of the drug.

In a further aspect according to the present invention, it also relates to pharmaceutical compositions, wherein preceding unit hard gel capsule dosage composition comprising Enzalutamide additionally one solubility enhancing agent or combinations thereof.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment according to present invention, it provides the unit hard gelatin capsule dosage composition comprising Enzalutamide, atleast one polymer and pharmaceutically acceptable carrier thereof.

The crystalline Enzalutamide used in the pharmaceutical composition was having powder XRPD according to figure-1, which was characterized by XRPD diffraction angle peaks comprising at least 7 characteristic peaks possessing peaks selected from 6.5, 9.8, 13.1, 15.8, 16.0, 16.7, 18.9, 19.5, 19.7, 21.2, 22.6, 25.5 ± 0.2°2?. Crystalline Enzalutamide is solubilized in organic solvent and existing as the Enzalutamide dispersed with the pharmaceutically acceptable polymer. In some of the embodiments, Enzalutamide is amorphous, Amorphous Enzalutamide dissolves more quickly and to a greater extent than crystalline Enzalutamide in an aqueous use environment, such as an aqueous dissolution medium of an in vitro dissolution test (e.g., phosphate buffered saline or model fasted duodenal fluid or simulated gastric fluid) or the in vivo environment of the stomach or small intestine. This enhanced dissolution results in higher Enzalutamide oral bioavailability, compared to crystalline drug.

In one embodiment the composition according to the present invention contain from about 1 to about 80 wt% enzalutamide, depending on the dose of the drug and the effectiveness of the concentration-enhancing polymer. In some embodiments the compositions comprise enzalutamide from about 5 wt% to about 75 wt%.

The pharmaceutically acceptable polymers that are used in above embodiment of the present invention are cellulosic or non-cellulosic polymers. The cellulosic polymers are selected from the group consisting of hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethyl cellulose. The non-cellulosic polymers are selected from the group consisting of polyvinyl pyrrolidone, polyvinyl alcohol polyvinyl acetate copolymers, and polyoxyethylene-polyoxypropylene block copolymers (poloxamer). Specifically the pharmaceutically acceptable polymers used in the present invention are non-cellulosic polymers, preferably polyvinyl pyrrolidone or polyoxyethylene-polyoxypropylene block copolymers (poloxamer) or combinations thereof. In some embodiments the composition according to the present invention preferably contains enzalutamide and pharmaceutically acceptable polymer in the ratio from about 1: 25 to about 25:1, more preferably in the ratio of about 1:10 to about 10:1 and more preferably in the ratio of about 1:4 to about 4:1.

In one embodiment according to the present invention, it provides unit hard gelatin capsule dosage composition comprising Enzalutamide, atleast one pharmaceutically acceptable polymer or combinations thereof and atleast one antioxidant or combinations thereof.

In embodiments of the invention antioxidants are selected from the group consisting of butylated hydroxy anisole (BHA) or butylated hydroxy toluene (BHT) or combination thereof.

In one embodiment the pharmaceutical composition according to present invention comprises the crystalline Enzalutamide in solubilized in an organic solvent with atleast one pharmaceutically acceptable polymer or combinations thereof and atleast one antioxidants or combinations thereof. In the preferred embodiments the specific combination of atleast one pharmaceutically acceptable polymer and atleast one antioxidant or combinations thereof comprises pharmaceutically acceptable polymer selected from polyoxyethylene-polyoxypropylene block copolymers or polyvinyl pyyrolidone and antioxidant selected from butylated hydroxy anisole and butylated hydroxy toluene.

The organic solvents used in this invention as per the above embodiment are selected from the group of acetone or (C1-C3) alcohols such as methanol, ethanol (dehydrated alcohol) and isopropyl alcohol, dimethyl acetamide, tertiary butyl alcohol or combinations thereof, preferably the solvents are selected the combination of ethanol and acetone.

In one embodiment the pharmaceutical composition according to present invention comprises the crystalline Enzalutamide in solubilized from exists as drug dispersed in specific combination of atleast one pharmaceutically acceptable polymer or combinations thereof and atleast one antioxidants or combinations thereof. In the preferred embodiments the specific combination of atleast one pharmaceutically acceptable polymer and atleast one antioxidant or combinations thereof comprises pharmaceutically acceptable polymer selected from polyoxyethylene-polyoxypropylene block copolymers or polyvinyl pyyrolidone and antioxidant selected from butylated hydroxy anisole and butylated hydroxy toluene.

In the embodiments of the present invention the unit hard gelatin capsule dosage composition comprises the pharmaceutically acceptable carriers that includes filler, a binder, an effervescent agent, an artificial sweetener, a disintegrant a flavor, a lubricant, a coloring agent, and a glidant.

The filler may be selected from, for example, mannitol, lactose, starch, corn starch, dicalcium phosphate, magnesium carbonate, calcium carbonate, purified sucrose and glucose. In the preferred embodiment the fillers are preferably microcrystalline cellulose, mannitol and lactose monohydrate.

The disintegrant may be selected from, for example, corn starch, starches, crystalline cellulose, carmellose calcium, carmellose sodium, croscarmellose sodium, light anhydrous silicic acid, calcium silicate, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, sodium carboxymethyl starch, agar powder, crospovidone, synthetic aluminum silicate, sucrose fatty acid esters. The preferred disintegrant as per this invention is croscarmellose sodium.

The lubricant may be selected from, for example, magnesium stearate, calcium stearate, sucrose fatty acid esters, sodium stearyl fumarate, polyethylene glycol, talc, and stearic acid. The preferred lubricant as per this invention is magnesium stearate.

The binder may be selected from, for example, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, methyl cellulose and gum arabic.

The effervescent agent may be selected from, for example sodium bicarbonate.

The artificial sweetener may be selected from, for example, saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and thaumatin.

The flavor may be selected from, for example, lemon, lemon-lime, orange and menthol.

The coloring agent may be selected from, for example, yellow ferric oxide, red ferric oxide, food yellow No. 4, food yellow No. 5, food red No. 3, food red No. 102 and food blue No. 3.

The glidant may be selected from, for example, light anhydrous silicic acid, titanium oxide, stearic acid, colloidal silica, colloidal 20 silicon dioxide, fumed silica, CAB-O-SIL®M-5P, AEROSIL®, talc, starch, and magnesium aluminum silicates.

In one embodiment according to present invention, it provides the unit hard gelatin capsule dosage form composition comprising Enzalutamide, atleast one pharmaceutically acceptable polymer or combinations thereof, atleast one antioxidant or combinations thereof, atleast one filler or combinations thereof, atleast one disintegrant or combinations thereof and atleast one lubricant.

In a particular embodiment the present invention provides unit hard gelatin capsule dosage composition comprising Enzalutamide, atleast one pharmaceutically acceptable polymer selected from the group consisting of polyvinyl pyyrolidone or polyoxyethylene-polyoxypropylene block copolymers, atleast one antioxidant selected from the group consisting of butylated hydroxy anisole, or butylated hydroxy toluene or combinations thereof, at least one filler selected from the group consisting of microcrystalline cellulose, lactose monohydrate, disintegrant selected from croscarmellose sodium and atleast one lubricant selected from group consisting of magnesium stearate or sodium stearyl fumarate.

In one embodiment the present invention provides the unit hard gelatin capsule dosage composition comprising Enzalutamide, polyvinyl pyyrolidone, butylated hydroxy toluene, butylated hydroxy anisole, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium and magnesium stearate.

In another embodiment the present invention provides the unit hard gelatin capsule dosage composition comprising Enzalutamide, polyoxyethylene-polyoxypropylene block copolymers, butylated hydroxy anisole, butylated hydroxy toluene, mannitol, lactose monohydrate, croscarmellose sodium and magnesium stearate.

In a particular embodiment, the present invention provides the hard gelatin capsule dosage composition comprising Enzalutamide, atleast one pharmaceutically acceptable polymer or combinations thereof and atleast one solubility enhancing agent or combinations thereof.

In one embodiment the solubility enhancing agents used in the present invention are surfactants. The surfactants are selected from the group consisting of sodium lauryl sulfate, polyethylene glycol 4000, Tween 20 or Tween 80 and most preferably the surfactant is sodium lauryl sulfate. The surfactant is present in the range of about 1% w/w to about 10%w/w of the total composition filled into capsule.

In another embodiment the present invention provides the unit hard gelatin capsule dosage composition comprising Enzalutamide, atleast one pharmaceutically acceptable polymer or combinations thereof, atleast one solubility enhancing agent or combinations thereof, and atleast one antioxidant or combinations thereof.

In a further embodiment the present invention provides the unit hard gelatin capsule dosage composition comprising granules consisting of atleast one pharmaceutically acceptable polymer or combinations thereof, atleast one antioxidant or combination thereof, atleast one solubility enhancing agent or combinations thereof, atleast one filler or combinations thereof, atleast one disintegrant or combinations thereof and atleast one lubricant or combinations thereof, wherein the whole amount of solubility enhancing agent is intragranular and wherein the lubricant is extra granular.

In another embodiment the present invention provides the unit hard gelatin capsule dosage composition comprising granular composition consisting of atleast one pharmaceutically acceptable polymer or combinations thereof, atleast one antioxidant or combination thereof, atleast one solubility enhancing agent or combinations thereof, atleast one filler or combinations thereof, atleast one disintegrant or combinations thereof and atleast one lubricant or combinations thereof, wherein half the amount of solubility enhancing agent is intragranular and half the amount of solubility enhancing agent together with the whole the amount of lubricant are extra granular.

In another embodiment the present invention provides the process for the preparation of unit hard gel capsule dosage forms of Enzalutamide.

In a particular embodiment the present invention provides a process for preparing unit hard gelatin capsule comprising Enzalutamide prepared by a process comprising the steps of
a) providing drug solution by dissolving Enzalutamide, atleast one pharmaceutically acceptable polymer or combinations thereof, atleast one antioxidant or combinations thereof in organic solvent
b) spraying the drug solution of step a) on the dry mixture consisting of atleast one filler or combinations thereof and atleast one disintegrant to form the spray granulate
c) drying the spray granulate of step b)
d) milling the spray granulate of step c) to form milled granules
e) compacting the milled granules of step d)
f) lubricating the above milled granules with atleast one lubricant to form the lubricated blend and
g) filling of the above lubricated blend into the capsules.

In the embodiments of the present invention the preferred method for producing the spray granulate of Enzalutamide involves spraying of granulating liquid or solution onto dry mixture consisting of atleast one filler or combinations thereof and atleast one disintegrant. The spraying process preferably uses Fluidized bed technology equipment i.e Fluid Bed Processor (FBP) where the particles are suspended in a vertical column with a rising air stream. While the particles are fluidized, the granulating solution is sprayed into the column. This spraying can be carried out by any one of three methods; top spray, bottom spray and a “tangential” or powder spray. Preferably the spraying is carried out by a top spray method.

In another embodiment the present invention provides a process for preparing unit hard gelatin capsule comprising Enzalutamide prepared by a process comprising the steps of
a) providing drug solution by dissolving Enzalutamide, polyvinyl pyrrolidone, butylated hydroxy toluene and butylated hydroxy anisole in the organic solvent consisting of acetone and ethanol
b) spraying the drug solution of step a) on the dry mixture consisting of microcrystalline cellulose, lactose monohydrate and croscarmellose sodium to form the spray granulate
c) drying the spray granulate of step b)
d) milling the spray granulate of step c) to form the milled granules
e) compacting the milled granules of step d)
f) lubricating the above milled granules with atleast one lubricant to form the lubricated blend and
g) filling the above lubricated blend into the capsules.

In a further embodiment the present invention provides a process for preparing a unit hard gelatin capsule comprising Enzalutamide prepared by a process comprising the steps of
a) providing drug solution by dissolving Enzalutamide, polyoxyethylene-polyoxypropylene block copolymers, butylated hydroxy toluene and butylated hydroxy anisole in the organic solvent consisting of acetone and ethanol
b) spraying the drug solution of step a) on the dry mixture consisting of mannitol, lactose monohydrate and croscarmellose sodium to form the spray granulate
c) drying the granulate of step b)
d) milling the spray granulate of step c) to form the milled granules
e) compacting the milled granules of step d)
f) lubricating the above milled granules with atleast one lubricant to form the lubricated blend and
g) filling the above lubricated blend into the capsules.

In another embodiment the present invention provides a process for preparing unit hard gelatin capsule comprising Enzalutamide prepared by a process comprising the steps of
a) providing drug solution by dissolving Enzalutamide, atleast one pharmaceutically acceptable polymer or combinations thereof, atleast one antioxidant or combinations thereof and atleast one solubility enhancing agent or combination thereof in organic solvent
b) spraying the drug solution of step a) on the dry mixture consisting of atleast one filler or combinations thereof and atleast one disintegrant to form the spray granulate
c) drying the spray granulate of step b)
d) milling the spray granulate of step c) to form the milled granules
e) compacting the milled granules of step d)
f) lubricating the above milled granules with atleast one lubricant to form the lubricated blend and
g) filling of the above lubricated blend into the capsules.

In another embodiment the present invention provides the process for preparing unit hard gelatin capsule comprising Enzalutamide prepared by a process comprising the steps of
a) providing drug solution by dissolving Enzalutamide, atleast one pharmaceutically acceptable polymer or combinations thereof, atleast one antioxidant or combinations thereof and atleast one solubility enhancing agent or combination thereof in the half amount of the total amount of the fill weight of the capsule in organic solvent.
b) spraying the drug solution of step a) on the dry mixture consisting of atleast one filler or combinations thereof and atleast one disintegrant to form the spray granulate
c) drying the granules of step b)
d) milling the granules of step c) to form the milled granules
e) compacting the milled granules of step d).
f) lubricating the above milled granules with the other half amount of atleast one solubility enhancing agent or combination thereof and atleast one lubricant to from the final blend
g) filling of the above final blend into the capsules.

In one embodiment according to present invention, it provides the unit hard gelatin capsule dosage form of Enzalutamide, wherein a 40mg dose of unit hard gelatin capsule dosage form is bioequivalent to a 40mg dose of XTANDI® that is in the form of soft gelatin capsule dosage form.

In another embodiment according to present invention, it provides the unit hard gelatin capsule dosage form of Enzalutamide, wherein an 80mg dose of unit hard gelatin capsule dosage form is bioequivalent to 2x40mg dose of XTANDI® that is in the form of soft gelatin capsule dosage form.

In another embodiment according to present invention, it provides the unit hard gelatin capsule dosage form of Enzalutamide, wherein a 160mg dose of unit hard gelatin capsule dosage form is bioequivalent to 4x40mg dose of XTANDI® that is in the form of soft gelatin capsule dosage form.

In another embodiment, the present invention provides the method for treating castration resistant prostate cancer comprising administering to a patient in need thereof a therapeutically effective dose of 160mg of Enzalutamide/day. The therapeutically effective dose is administered as unit hard gelatin capsules of the present invention containing 40mg (4 capsules daily once), 80mg (2 capsule daily once) and 160mg (one capsule daily once).

EXAMPLES

The following examples are provided to illustrate the present invention. It should be understood, however, that the invention is not limited to the specific conditions or details described in the examples below.

Example-1:- Hard gelatin Capsule Composition comprising 40mg of Enzalutamide.

S.No Contents mg/cap
Dry mix
1 Mannitol 179.81
2 Lactose monohydrate 40
3 Croscarmellose sodium 36
Drug solution
4 Crystalline Enzalutamide 40
5 Polyoxyethylene-polyoxypropylene block copolymers 80
6 Butylated hydroxyanisole 0.095
7 Butylated hydroxytoluene 0.095
8 Acetone* (ml) 0.2
9 Dehydrated alcohol* (ml) 0.3
Extra granulation
10 Magnesium stearate 4
Capsule filling
11 capsule
Size ‘00’ -
Total fill weight 380 mg
*removed during the process
Process for preparation:-
1) Dissolve crystalline Enzalutamide, polyoxyethylene-polyoxypropylene block copolymers, butylated hydroxy anisole and butylated hydroxy toluene in Acetone and Ethanol mixture (40:60).
2) Sift lactose monohydrate; Mannitol and Croscarmellose sodium through mesh # 30 and load in Fluid bed processor.
3) Granulate the above material by spraying the drug solution of step 1 (Top spray granulation).
4) Dry the granules at inlet temperature of 45°C in Fluid bed processor (FBP) and mill the dried granules using 1 mm screen in co-mil.
5) Compact the above milled granules using roller compactor and mill the compacts using 1 mm screen in co-mil to make dense granules.
6) Add 60# mesh sifted magnesium stearate to above material and blend for 5 minutes in bin blender.
7) Fill the lubricated blend in ‘size ‘00’ hard gelatin capsules.

The parameters of the hard gelatin Capsule exemplified in this example are as follows:-

S.No. Parameters 40 mg
1 Description White opaque hard gelatin capsule
2 Average weight of fill content 380.0 ± 3%
(368.6 – 391.4)
3 Individual weight of fill content 380.0 ± 5%
(361.0 – 399.0)
3 Disintegration NMT 15 minute
4 Lock length 21.7 mm ± 0.3mm

The dissolution rates of the Hard Gelatin 40mg capsules of Enzalutamide prepared as described above were measured in USP II Apparatus (Paddle) with sinker, 50rpm in 900mL of 0.3% cetyl trimethyl ammonium bromide (CTAB) in 0.1 N HCl. Samples were analyzed by HPLC. Additionally for comparison purposes, XTANDI® tablets were tested with same dissolution conditions. The results of the analysis are shown in Table-1

Table-1
Formulation / Batch No. % Drug release (n=6)
5 min 10 min 15 min 20 min 30 min 45 min 60 min
XTANDI Enzalutamide Soft gelatin capsule 40 mg 1 86 94 91 91 91 91
Example- 1 formulation Enzalutamide Hard gelatin capsule 40 mg 35 65 86 93 95 97 95

Example-2:- Hard gelatin capsule Composition comprising 40mg of Enzalutamide.
S.No Contents mg/cap
Dry mix
1 Microcrystalline cellulose 159.81
2 Lactose monohydrate 100
3 Croscarmellose sodium 36
Drug solution
4 Crystalline Enzalutamide 40
5 Polyvinyl Pyrrolidone (Plasdone 29/32) 120
6 Butylated hydroxyanisole 0.095
7 Butylated hydroxytoluene 0.095
8 Acetone* (ml) 0.2
9 Dehydrated alcohol* (ml) 0.3
Extra granulation
10 Magnesium stearate 4.000
Capsule filling
11 capsule
Size ‘00’ -
Total fill weight 460 mg
*removed during the process
Process for preparation:-
1) Dissolve Crystalline Enzalutamide, Polyvinyl pyrrolidone, butylated hydroxy anisole and butylated hydroxy toluene in Acetone and Ethanol mixture (40:60)
2) Sift lactose monohydrate, microcrystalline cellulose and Croscarmellose sodium through mesh # 30 and load in Fluid bed processor.
3) Granulate the above material by spraying the drug solution of step 1 (Top spray granulation)
4) Dry the granules at inlet temperature of 45°C in FBP and mill the dried granules using 1 mm screen in co-mil
5) Compact the above milled granules using roller compactor and mill the compacts using 1 mm screen in co-mil to make dense granules
6) Add 60# mesh sifted magnesium stearate to above material and blend for 5 minutes in bin blender
7) Fill the lubricated blend in ‘size ‘00’ hard gelatin capsules.

The parameters of the hard gelatin Capsule exemplified in this example are as follows:-

S.No. Parameters 40 mg
1 Description White opaque hard gelatin capsule
2 Average weight of fill content 460.0 ± 3% (446.2 – 473.8)
3 Individual weight of fill content 460.0 ± 5% (437.0 – 483.0)
3 Disintegration NMT 15 minute
4 Lock length 21.7 mm ± 0.3mm

The dissolution rates of the Hard Gelatin 40mg capsules of Enzalutamide prepared as described above were measured in USP II Apparatus (Paddle) with sinker, 50rpm in 900mL of 0.3% cetyl trimethyl ammonium bromide (CTAB) in 0.1 N HCl. Samples were analyzed by HPLC. Additionally for comparison purposes, XTANDI® tablets were tested with same dissolution conditions. The results of the analysis are shown in Table-2.

Table-2
Formulation / Batch No. % Drug release (n=6)
5 min 10 min 15 min 20 min 30 min 45 min 60 min
XTANDI Enzalutamide Soft gelatin capsule 40 mg 1 86 94 91 91 91 91
Example-2 Enzalutamide Hard gelatin capsule 40 mg 48 83 88 91 95 95 94

Examples: - 3-7:- Hard gelatin Capsule Composition comprising 40mg of Enzalutamide.

S.No Contents Example Number mg/Cap
3 4 5 6 7
Dry Mix
1 Lactose monohydrate 30 50 - - -
2 Microcrystalline cellulose 24.5 - - 54.55 54.55
3 Mannitol - 44.5 30 - -
4 Dicalcium phosphate - - 24.55 - -
5 Croscarmellose sodium 9 9 9 9 9
Drug Solution
6 Crystalline Enzalutamide 40 40 40 40 40
7 Polyvinyl pyrrolidone (Plasdone 29/32) 120 - 120 - -
8 polyoxyethylene-polyoxypropylene block copolymers - 80 - - -
9 Hydroxy propyl cellulose - - - 120 -
10 Hypromellose 3cps - - - - 120
11 Butylated hydroxyanisole 0.225 0.225 0.225 0.225 0.225
12 Butylated hydroxytoluene 0.225 0.225 0.225 0.225 0.225
13 Acetone*(ml) 0.2 0.2 0.2 0.2 0.2
14 Dehydrated alcohol*(ml) 0.3 0.3 0.3 0.3 0.3
Extra granular
15 Magnesium stearate 1 1 1 1 1
Capsule filling
16 capsule
Size ‘1’ 1 No 1 No 1 No 1 No 1 No
Total fill Weight 225 mg 225 mg 225 mg 225 mg 225 mg
*removed during the process

Process for Preparation:-

1) Dissolve Crystalline Enzalutamide, butylated hydroxy anisole, butylated hydroxy toluene and Povidone or polyoxyethylene-polyoxypropylene block copolymers or hydroxypropyl cellulose or hydroxypropyl methyl cellulose in Acetone and Ethanol mixture (2:8).
2) Sift lactose monohydrate; microcrystalline cellulose and Croscarmellose sodium through mesh # 30 and load in Fluid bed processor.
3) Granulate the above material by spraying the drug solution of step 1 (Top spray granulation) solvent to get less than 3000 PPM of methanol.
4) Dry the granules at inlet temperature of 35°C in FBP and mill the dried granules using 1 mm screen in co-mil
5) Compact the above milled granules using roller compactor and mill the compacts using 1 mm screen in co-mil to make dense granules
6) Add 60# mesh sifted magnesium stearate to above material and blend for 5 minutes in bin blender
7) Fill the lubricated blend in size ‘1’ hard gelatin capsule (40 mg).

The parameters of the hard gelatin Capsule exemplified in this example are as follows:-

S.No. Parameters 40 mg
1 Description White opaque hard gelatin capsule
2 Average weight (mg) 225.0 ± 3% (218.25 – 231.75)
3 Disintegration NMT 15 minute
4 Lock length 19.4 mm ± 0.3mm

Examples: - 8-12:- Hard gelatin Capsule Composition comprising 80mg of Enzalutamide
S.No Contents Example Number mg/Cap
8 9 10 11 12
Dry Mix
1 Lactose monohydrate 60 100 - -
2 Microcrystalline cellulose 49 - - 109 109
3 Mannitol - 89 60 - -
4 Dicalcium phosphate - - 49 - -
5 Croscarmellose sodium 18 18 18 18 18
Drug Solution
6 Crystalline Enzalutamide 80 80 80 80 80
7 Povidone (Plasdone 29/32) 240 - 240 - -
8 polyoxyethylene-polyoxypropylene block copolymers - 160 - - -
9 Hydroxy propyl cellulose - - - 240 -
10 Hypromellose 3cps - - - - 240
11 Butylated hydroxyanisole 0.45 0.45 0.45 0.45 0.45
12 Butylated hydroxytoluene 0.45 0.45 0.45 0.45 0.45
13 Acetone*(ml) 0.4 0.4 0.4 0.4 0.4
14 Dehydrated alcohol*(ml) 0.6 0.6 0.6 0.6 0.6
Extra granular
15 Magnesium stearate 2 2 2 2 2.000
Capsule filling
16 capsule
Size ‘00’ 1 No’s 1 No’s 1 No’s 1 No’s 1 No’s
Total fill Weight 450mg 450 mg 450 mg 450 mg 450 mg
*removed during the process

Process for Preparation:-

1) Dissolve crystalline Enzalutamide, butylated hydroxy anisole, butylated hydroxy toluene and Povidone or polyoxyethylene-polyoxypropylene block copolymers or Hydroxypropyl cellulose or Hypromellose in Acetone and Ethanol mixture (2:8).
2) Sift lactose monohydrate; microcrystalline cellulose and Croscarmellose sodium through mesh # 30 and load in Fluid bed processor.
3) Granulate the above material by spraying the drug solution of step 1 (Top spray granulation) solvent to get less than 3000 PPM of methanol.
4) Dry the granules at inlet temperature of 35°C in FBP and mill the dried granules using 1 mm screen in co-mil.
5) Compact the above milled granules using roller compactor and mill the compacts using 1 mm screen in co-mil to make dense granules
6) Add 60# mesh sifted magnesium stearate to above material and blend for 5 minutes in bin blender
7) Fill the lubricated blend in size ‘00’ hard gelatin capsule (80 mg).

The parameters of the hard gelatin capsule exemplified in this example are as follows:-

S.No. Parameters 80 mg
1 Description Red opaque hard gelatin capsule
2 Average weight (mg) 450.0 ± 3% (436.5 – 463.5)
3 Disintegration NMT 15 minute
4 Lock length 23.3 mm ± 0.3mm