DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents [Amendment] Rules, 2006

COMPLETE SPECIFICATION
(See Section 10 and rule 13)
TITLE OF THE INVENTION
STABLE PHARMACEUTICAL COMPOSITION OF RELUGOLIX
APPLICANT:
(a) Name : ALKEM LABORATORIES LIMITED
(b) Nationality : India
(c) Address : ALKEM HOUSE, S.B. MARG, LOWER
PAREL, MUMBAI – 400013, MAHARASHTRA, INDIA
PREAMBLE TO THE DESCRIPTION
COMPLETE
The following specification particularly describes the invention and the manner in which is to be performed.

FIELD OF THE INVENTION
The present invention relates to a stable pharmaceutical composition comprising relugolix or a pharmaceutically acceptable salt thereof; wherein the composition is devoid of sugar alcohols. The present invention, more particularly, relates to a stable tablet formulation comprising relugolix or a pharmaceutically acceptable salt thereof, methods of preparation thereof, and their use in medical therapy.

BACKGROUND OF THE INVENTION
Relugolix is the first oral gonadotrophin-releasing hormone (GnRH) receptor antagonist. Relugolix leads to rapid inhibition of testicular production of testosterone and its rapid recovery upon discontinuation. Based on the phase III HERO trial results, relugolix received Food and Drug Administration approval for adult patients with advanced prostate cancer (PCa). In the HERO trial, relugolix was associated with a superior cardiovascular safety profile compared to GnRH agonists. These attributes make relugolix a promising therapy for patients with pre-existing cardiovascular comorbidities, those pursuing intermittent androgen deprivation therapy, and those who desire rapid testosterone recovery during ‘off-treatment’ periods. In the HERO trial, very few patients received concomitant enzalutamide (n = 17, 2.7%) or docetaxel (n < 10, 1.3%). Safety of relugolix has not been established in combination with many androgen-receptor-axis targeted therapies (e.g. abiraterone, apalutamide), cabazitaxel, or lutetium Lu 177 vipivotide tetraxetan, which precludes its use in combination with these agents. In addition, being an oral drug, relugolix may also be associated with challenges of affordability, adherence, and compliance in this predominantly elderly population. Sahu et al, Expert Review of Anticancer Therapy Volume 22, 2022 - Issue 9.
Relugolix is the first (and currently only) orally-administered GnRH receptor antagonist approved for the treatment of prostate cancer - similar therapies such as degarelix require subcutaneous administration - and therefore provides a less burdensome therapeutic option for patients who might otherwise require clinic visits for administration by healthcare professionals. In addition to its relative ease-of-use, relugolix was shown to be superior in the depression of testosterone levels when compared to leuprolide, another androgen deprivation therapy used in the treatment of prostate cancer. In May 2021, the FDA approved the combination product made up of relugolix, estradiol, and norethindrone under the market name MYFEMBREE for the first once-daily treatment for the management of heavy menstrual bleeding associated with uterine fibroids in premenopausal women.
Relugolix is a nonpeptide small molecule, GnRH receptor antagonist. The chemical name for relugolix (TAK-385) is N-(4-{1[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4tetrahydrothieno [2,3-d] pyrimidin-6-yl}phenyl)-N’-methoxyurea.

Compound A: Relugolix
Myovant Sciences Gmbh / Takeda, the original developer, is marketing a tablet form (ORGOVYX – strength 120 MG) containing relugolix as an active ingredient. ORGOVYX® is indicated for the treatment of adult patients with advanced prostate cancer. RELUMINA® tablet (strength 40MG) is indicated for the treatment of uterine fibroids and their associated symptoms (excessive menstruation, lower abdominal pain, back pain, and anemia), and improvement of pain associated with endometriosis.
IN235678 discloses relugolix as the derivative of thienopyrimidine compound and their use in antagonism to gonadotropin-releasing hormone.
IN201737032982 discloses the pharmaceutical composition of relugolix or salt thereof. Further specifically discloses the tablet composition comprising not less than 25 mass % relugolix or a salt thereof and the method of stabilization and method of solid preparation of relugolix tablet. More specifically discloses varying the D-mannitol particle size while also increasing the mass% of relugolix or a salt thereof impacted formulation stability as stability demonstrates a clear nexus between relugolix mass %, D-mannitol particle size, and reduced relugolix degradation.
US10786501 discloses the relugolix use for the method of treatment of prostate cancer.
US10464945 discloses the crystalline form of a tetrahydrofuran solvate of relugolix with XRD values.
US 10350170 discloses composition of relugolix with D-mannitol and other excipients in the form of tablet.
According to Biopharmaceutics Classification System (BCS), relugolix is classified as a BCS Class 4 compound (low solubility, low permeability). Limited drug absorption due to poor solubility of BCS Class 4 drug results in poor bioavailability, ultimately hampering its therapeutic effectiveness.
A common challenge in developing pharmaceutical formulations is identifying the combinations of excipients and manufacturing processes which result in a pharmaceutical formulation having good compatibility. At the same time, excipients and active pharmaceutical ingredients (API) should be physically and chemically stable. Further, the combination of excipients and API in the pharmaceutical formulation should achieve the desired release characteristics.
Despite the above-mentioned prior art disclosing pharmaceutical compositions of relugolix or a pharmaceutically acceptable salt thereof comprising sugar alcohol preferably mannitol with a wet granulation process, there still exists a need for a stable oral pharmaceutical composition of relugolix or a pharmaceutically acceptable salt thereof which ensures the desired therapeutic effect, when correctly administered, without using any sugar alcohol and wet granulation process.
Hence, there is an unmet need in the art to develop a simple, direct compression process without using any sugar alcohol in the pharmaceutical composition of relugolix or a pharmaceutically acceptable salt thereof, which also offers desired pharmaceutical technical attributes such as dissolution, stability, bioequivalence, and manufactured by simple direct compression process at industrial scale.
Within the scope of the present invention, it has now surprisingly been found that a stable pharmaceutical composition of relugolix or a pharmaceutically acceptable salt thereof can be made without using any sugar alcohol and not using a wet granulation process disclosed in prior art.

OBJECT OF THE INVENTION
It is an object of the present invention to provide a stable pharmaceutical composition comprising relugolix or a pharmaceutically acceptable salt thereof; wherein the pharmaceutical composition is devoid of sugar alcohol.

It is another object of the invention is to provide a simple direct compression process for the preparation of the stable pharmaceutical composition of relugolix or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is devoid of sugar alcohol.

It is another object of the invention to provide a stable pharmaceutical composition of relugolix or a pharmaceutically acceptable salt thereof, wherein the total impurity in the said pharmaceutical composition is not more than 2% w/w after subjecting the pharmaceutical composition to a storage condition of 30 ± 2°C / 75 ± 5 % RH for a period of at least 24 hour.

It is another object of the present invention to provide a stable pharmaceutical composition, for oral administration comprising:
a) relugolix or a pharmaceutically acceptable salt thereof;
b) one or more solubility enhancers;
c) one or more pharmaceutically acceptable excipients; and
wherein the said pharmaceutical composition is devoid of sugar alcohol.

It is another object of the present invention to provide a stable pharmaceutical composition, for oral administration comprising:
a) relugolix or a pharmaceutically acceptable salt thereof;
b) one or more solubility enhancers selected from the group comprising 2-hydroxy propyl betacyclodextrin and polysorbate 80;
c) one or more pharmaceutically acceptable excipients; and
wherein the said pharmaceutical composition is devoid of sugar alcohol.

It is also another object of the present invention to provide a process for preparing stable pharmaceutical composition using a direct compression process comprising-
a) relugolix or a pharmaceutically acceptable salt thereof;
b) one or more solubility enhancers;
c) one or more pharmaceutically acceptable excipients; and
wherein the said pharmaceutical composition is devoid of sugar alcohol.

SUMMARY OF THE INVENTION
The present invention provides the following aspects, subject-matters and preferred embodiments, which respectively taken alone or in combination, further contribute to solving the object of the present invention.

The present invention provides a stable pharmaceutical composition comprising relugolix or a pharmaceutically acceptable salt thereof and a process for preparing thereof.

More particularly, the present invention relates to
A) A stable pharmaceutical composition comprising:
a) Relugolix or a pharmaceutically acceptable salt thereof;
b) one or more solubility enhancers;
c) one or more pharmaceutically acceptable excipients; and
Wherein the pharmaceutical composition is devoid of sugar alcohol.

B) The stable pharmaceutical composition according to A), wherein one or more solubility enhancer is selected from the group comprising 2-hydroxy propyl betacyclodextrin and polysorbate 80.

C) The stable pharmaceutical composition according to A), wherein the composition is in the tablet dosage form.

D) The stable pharmaceutical composition according to A), wherein one or more pharmaceutically acceptable excipient(s) is selected from diluent, binder, disintegrant, glidant, lubricant, and the like.

E) The stable pharmaceutical composition according to A), wherein the diluent is selected from the group consisting of lactose monohydrate, microcrystalline cellulose and combinations thereof.

F) The stable pharmaceutical composition according to A), wherein the binder is selected from the group consisting of pregelatinized starch, hydroxypropyl methyl cellulose and combinations thereof.

G) The stable pharmaceutical composition according to A), wherein the disintegrant is selected from the group consisting if pregelatinized starch, croscarmellose sodium and combinations thereof.

H) The stable pharmaceutical composition according to A), wherein the glidant is selected from the group consisting of colloidal silicon dioxide, talc, Silica and Magnesium stearate and combinations thereof.

I) The stable pharmaceutical composition according to A), wherein the lubricant is selected from the group consisting of calcium stearate, magnesium stearate, sodium stearyl fumarate, stearic acid and combinations thereof .

J) The stable pharmaceutical composition according to A), wherein the composition is suitable for use in the treatment of adult patients with advanced prostate cancer and/or treatment of uterine fibroids and its associated symptoms (excessive menstruation, lower abdominal pain, back pain, and anemia), and improvement of pain associated with endometriosis.

K) A process to prepare a stable pharmaceutical composition comprising:
a) Relugolix or a pharmaceutically acceptable salt thereof;
b) one or more solubility enhancers;
one or more pharmaceutically acceptable excipients;
Wherein the process comprises a direct compression process comprising: (a) mixing relugolix with a diluent, disintegrant, binder, solubility enhancer, glidant and lubricant; (b) compressing the composition obtained in (a) to form the compressed relugolix tablet in the unit dosage form.

DESCRIPTION OF THE INVENTION
Before the present process and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas, or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is to describe particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds, and reference to "the step" includes reference to one or more steps and equivalents thereof known to those skilled in the art, and so forth.

The publications discussed herein are provided solely for their availability to the applicant before the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by the prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

According to one embodiment, the present invention provides a stable pharmaceutical composition for oral administration comprising:
a) relugolix or a pharmaceutically acceptable salt thereof;
b) one or more solubility enhancer;
c) one or more pharmaceutically acceptable excipients; and
wherein the pharmaceutical composition is devoid of sugar alcohol.

In an embodiment, the present invention provides a stable pharmaceutical composition in a tablet dosage form.

In an embodiment, the present invention provides a stable pharmaceutical composition in a tablet dosage form comprising 30 mg to 130 mg of relugolix or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a stable pharmaceutical composition in a tablet dosage form comprising 40 mg to 120 mg of relugolix or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a stable pharmaceutical composition in a tablet dosage form comprising 02 % to 90 % of relugolix or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a stable pharmaceutical composition in a tablet dosage form comprising 02 % to 24 % of relugolix or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention relates to a stable solid pharmaceutical composition for oral administration comprising:
(i) relugolix or a pharmaceutically acceptable salts thereof,
(ii) diluent,
(iii) disintegrant,
(iv) binder,
(v) solubility enhancer,
(vi) glidant, and
(vii) lubricant.

In another embodiment, the present invention provides a stable pharmaceutical composition in a tablet dosage form wherein the tablet comprises:
a) about 2-90% relugolix or a pharmaceutically acceptable salts thereof,
b) about 5-15% lactose monohydrate,
c) about 30-45% microcrystalline cellulose,
d) about 5-15% pregelatinized starch,
e) about 5-15% 2-hydroxy propyl betacyclodextrin,
f) about 1-8% hydroxypropyl methyl cellulose,
g) about 1-5% polysorbate 80 powder,
h) about 1-7% croscarmellose sodium,
i) about 0.5-5% colloidal silicon dioxide, and
j) about 0.5-5% calcium stearate.
k) The optional film coating can be instacoat aqua II A02D00476Pink (mixture of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide and red iron oxide.

In another embodiment, the present invention provides a stable pharmaceutical composition in a tablet dosage form wherein the tablet comprises:
a) about 2-24% relugolix or a pharmaceutically acceptable salts thereof,
b) about 5-15% lactose monohydrate,
c) about 30-45% microcrystalline cellulose,
d) about 5-15% pregelatinized starch,
e) about 5-15% 2-hydroxy propyl betacyclodextrin,
f) about 1-8% hydroxypropyl methyl cellulose,
g) about 1-5% polysorbate 80 powder,
h) about 1-7% croscarmellose sodium,
i) about 0.5-5% colloidal silicon dioxide, and
j) about 0.5-5% calcium stearate.
k) The optional film coating can be instacoat aqua II A02D00476Pink (mixture of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide and red iron oxide.

In another embodiment, the present invention provides a stable pharmaceutical composition in a tablet dosage form wherein the tablet comprises:
a) about 24 % w/w of relugolix or a pharmaceutically acceptable salts thereof,
b) about 8.4 % w/w of lactose monohydrate,
c) about 36.2 % w/w of microcrystalline cellulose,
d) about 9.2% w/w of pregelatinized starch,
e) about 8 % w/w of 2-hydroxy propyl betacyclodextrin,
f) about 3 % w/w of hydroxypropyl methyl cellulose,
g) about 2 % w/w of polysorbate 80 powder,
h) about 3 % w/w of croscarmellose sodium,
i) about 1.2 % w/w of colloidal silicon dioxide, and
j) about 1 % w/w of calcium stearate
k) The optional film coating can be instacoat aqua II A02D00476Pink (mixture of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide and red iron oxide.

In another embodiment, the present invention provides a stable pharmaceutical composition in a tablet dosage form wherein the tablet consists of:
a) about 40 mg to about 120 mg relugolix,
b) about 48 mg lactose monohydrate,
c) about 175 mg microcrystalline cellulose,
d) about 40 mg pregelatinized starch,
e) about 46 mg 2-hydroxy propyl betacyclodextrin,
f) about 10 mg hydroxypropyl methyl cellulose,
g) about 15 mg polysorbate 80 powder,
h) about 10 mg croscarmellose sodium,
i) about 11 mg colloidal silicon dioxide, and
j) about 5 mg calcium stearate.
k) The optional film coating can be instacoat aqua II A02D00476Pink (mixture of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide and red iron oxide.

In another embodiment, the present invention provides a stable pharmaceutical composition in a tablet dosage form wherein the tablet consists of:
a) about 120 mg relugolix,
b) about 42 mg lactose monohydrate,
c) about 181 mg microcrystalline cellulose,
d) about 42 mg pregelatinized starch,
e) about 40 mg 2-hydroxy propyl betacyclodextrin,
f) about 15 mg hydroxypropyl methyl cellulose,
g) about 10 mg polysorbate 80 powder,
h) about 15 mg croscarmellose sodium,
i) about 6 mg colloidal silicon dioxide, and
j) about 5 mg calcium stearate.
k) The optional film coating can be instacoat aqua II A02D00476Pink (mixture of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide and red iron oxide.

In yet another embodiment, the stable pharmaceutical composition is optionally coated with about 1-7 % w/w of Instacoat aqua based on the total weight of the composition.

In yet another embodiment, the stable pharmaceutical composition is optionally coated with about 4 % w/w of Instacoat aqua based on the total weight of the composition.

The term "sugar alcohol" as used hereinafter in the present invention relates to the hydrogenated form of carbohydrate, whose carbonyl group has been reduced to a primary or secondary hydroxyl group. Examples of sugar alcohols include inositol, erythritol, xylitol, mannitol, sorbitol, dulcitol, iditol, isomalt, maltitol, lactitol, ribitol, arabitol and the like thereof.

The term "composition" or "formulation" or "dosage form" as used herein synonymously include solid dosage forms such as granules, multiunit particulate systems (MUPS), pellets, spheres, tablets, capsules, mini-tablets, layered tablets (e.g. bilayer or trilayer), beads, particles, granules and the like; and liquid dosage forms such as solutions, suspensions, emulsions, colloids and the like, meant for oral administration.

The compositions in accordance with the present invention are prepared by direct compression or dry granulation process.

As term “active ingredient” as used herein means an ingredient or compound having an intended biological effect. “Active ingredient” may be broadly construed to include an active compound and vice versa. Such active ingredients or active compounds are thus considered to be “biologically active”.

The term "pharmaceutically acceptable salt" is suitable for use in contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., within the scope of a reasonable medical evaluation, and has a reasonable benefit. As salt of relugolix, a physiologically acceptable acid addition salt is preferable. As such salt, salt with inorganic acid (e.g., hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid), salt with organic acid (e.g., formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid) and the like are used.

The term "excipient" as used herein means a pharmacologically inactive component such as, but not limited to, a diluent or filler, binder, disintegrant, lubricant, glidant, surfactant, colorant, or the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic, and acceptable for human use.

The term "stable", as used herein, refers to chemical stability, in which not more than the limits of ICH standard for the total related substances is formed during storage under accelerated conditions of stability at 40 ºC ± 2ºC / 75% ± 5% relative humidity and at 30 ± 2°C / 75 ± 5 % relative humidity for the period necessary for using the composition.

The terms “solubility enhancer” or “solubilizing agent” are used interchangeably to refer to any chemical and/or biological agent which is able to improve the solubility of an active ingredient in a solvent. Exemplary solubility enhancers include propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol- 15-hydroxystearate, phospholipids, lecithin, purified and/or enriched lecithin, phosphatidylcholine fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives thereof, SAE-CD derivatives, SBE-of-CD, SBE-0-CD, SBEl -#-CD, SBE4-/3-CD, SBE7-/3-CD (Captisol®), SBE-?-CD, dimethyl /3-CD, hydroxypropyl-/3-cyclodextrin, 2-HP-/3-CD, hydroxyethyl-ø-cyclodextrin, hydroxyprspyl-?-cyclodexftin, hydroxyethyl-?-cyclodextrin, 2-hydroxy propyl betacyclodextrin, dihydroxypropyl-/3-cyclodextrin, glucosyl-a-cyclodextrin, glucosyl-/3- cyclodextrin, diglucosyl-jS-cyclodextrin, maltosyl-ot-cyclodextrin, maltosyl-/3-cycIodextrin, maltosyl-7- cyclodextrin, maltotriosyl-jS-cyclodextrin, maltotriosyl-?-cyclodextrin, dima1tosyl-/3-cyclodextrin, methyl-ß- cyclodextrin, carboxyalkyl thioether derivatives, ORG 26054, ORG 25969, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, copolymers of vinyl acetate, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof. In a further embodiment, the solubility enhancer used in the composition of the present invention is preferably selected from one or a combination of 2-hydroxy propyl betacyclodextrin and polysorbate 80. The solubility enhancers may be used in the range of 0.5 - 25 % w/w of the total weight of the stable oral pharmaceutical composition.
The term “impurity” refers to undesired contents present or produced in a pharmaceutical composition.
The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.
The term “wet granulation” as used herein, refers to the formation of granules using a granulation liquid (water, organic solvent, or a solution).
The term “direct compression” as used herein, refers to a method and can be defined as basically mixing and processing of formulation ingredients and then compressing them into tablets without using any granulation fluid. The tablets are obtained directly from the powder API and other excipients.
In a further embodiment, the fillers or diluents used in the composition of the present invention are selected from sugars such as lactose, dextrose, glucose, sucrose, cellulose, starches, carbohydrate derivatives, polysaccharides (including dextrose and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, calcium carbonates, magnesium carbonates, microcrystalline cellulose, combinations thereof, and the like. In certain preferred embodiments, the filler or diluent is lactose, microcrystalline cellulose, or a combination thereof. Several types of microcrystalline cellulose are suitable for use in the formulations described herein, for example, microcrystalline cellulose selected from the group consisting of Avicel® types: PH101, PH102, PH103, PH105, PH112, PH113, PH200, PH301, and other types of microcrystalline cellulose, such as silicified microcrystalline cellulose. Several types of lactose are suitable for use in the formulations described herein, for example, lactose is selected from the group consisting of anhydrous lactose, lactose monohydrate, lactose fast flow, directly compressible anhydrous lactose, and modified lactose monohydrate. Preferably, the filler or diluent, if present, is a one or combination of microcrystalline cellulose and lactose monohydrate. The fillers or diluents may be used in the range of 5 - 50 % w/w of the total weight of the stable oral pharmaceutical composition.
In a further embodiment, the binders used in the composition of the present invention are selected from cellulose derivatives (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, ethyl cellulose, and sodium carboxymethyl cellulose), sugar (including sucrose, glucose, dextrose, molasses, lactose, dextrin, xylitol, sorbitol), glycol, corn syrup, polysaccharides (including acacia, tragacanth, guar, alginates, and starch), corn starch, pregelatinized starch, modified corn starch, gelatin, polyvinylpyrrolidone, polyethylene, polyethylene glycol, combinations thereof and the like. Preferably, the binding agent, if present, is hydroxypropyl methyl cellulose. The binder may be used in the range of 1 - 8 % w/w of the total weight of the stable oral pharmaceutical composition.
In a further embodiment, the disintegrants used in the composition of the present invention are selected from starches, clays, celluloses, alginates, and gums, and crosslinked starches, celluloses, and polymers, combinations thereof, and the like. Representative disintegrants include microcrystalline cellulose, croscarmellose sodium, alginic acid, sodium alginate, crospovidone, cellulose, agar, and related gums, sodium starch glycolate, corn starch, potato starch, pregelatinized starch, sodium starch glycolate, Veegum HV, methylcellulose, agar, bentonite, carboxymethylcellulose, alginic acid, guar gum combinations thereof, and the like. Preferably, the disintegrant, if present, is a one or combination of croscarmellose sodium and pregelatinized starch. The disintegrants may be used in the range of 1 - 15 % w/w of the total weight of the stable oral pharmaceutical composition,

In a further embodiment, the glidants used in the composition of the present invention are selected from silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel, or mixtures thereof. Preferably, the glidant, if present, is a colloidal silicon dioxide. Glidant may be used in the range of 0.5 - 5 % w/w of the total weight of the stable oral pharmaceutical composition.

In a further embodiment, the lubricants used in the composition of the present invention are selected from metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, and the like and mixtures thereof. Preferably, the lubricant, if present, is a calcium stearate. Lubricant may be used in the range of 0.5 - 5 % w/w of the total weight of the stable oral pharmaceutical composition.

“Colorants” may be selected from, but are not limited to, iron oxide yellow, iron oxide red, titanium dioxide, or mixtures thereof. The colorants may be used in the range of 2 - 8 % w/w of the total weight of the stable oral pharmaceutical composition.

The stable pharmaceutical compositions of the present invention may be further coated with a functional or non-functional coating. The coating composition may be comprised of pharmaceutically acceptable excipients such as coating agents, binders, plasticizers, coloring agents, and opacifiers. The total weight gain after coating may be about 1% w/w to 10% w/w of the uncoated pharmaceutical composition.

“Coating agents” which are useful in the coating process, may be selected from, but not limited to, water-soluble polymers such as, but not limited to, polyvinylpyrrolidone or water-soluble cellulose such as, but not limited to, hydroxypropyl methylcellulose or hydroxypropyl cellulose. It may be selected from, but not limited to, soluble agents such as polysorbate 80, polysaccharides such as maltodextrin, acacia, com, sucrose, gelatin, shellac, cellulose acetate phthalate, lipids, synthetic resins, acrylic polymers, opadry, instacoat aqua, polyvinyl alcohol, copolymers of vinylpyrrolidone, vinyl acetate or combinations thereof. These may be applied from aqueous or non-aqueous systems or combinations of the aqueous and non-aqueous systems as appropriate.

Examples of binders for coating include cellulose or cellulose derivatives such as, but not limited to, methylcellulose, hydroxypropylmethylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose sodium, and microcrystalline cellulose, alginic acid, sodium alginate and gelatin, polyvinyl pyrrolidone, crospovidone, starch, pregelatinized starch, or mixtures thereof. Examples of plasticizers for coating include, but are not limited to, propylene glycol, triethyl citrate, tributyl citrate, dibutyl sebacate, triacetin, polyethylene glycol, diethyl phthalate, acetylated monoglycerides, or mixtures thereof. Examples of opacifiers for coating include, but are not limited to, titanium dioxide, talc, calcium carbonate, behenic acid, cetyl alcohol, or mixtures thereof. Antitacking agents such as, but are not limited to, talc, stearic acid, magnesium stearate, colloidal silicon dioxide, or the like. Examples of coloring agents for coating include but are not limited to, FDA-approved colorants such as iron oxide, the lake of tartrazine, allura red, the lake of quinoline yellow, the lake of erythrosine, titanium dioxide, or mixtures thereof. Suitable solvents for the coating include but are not limited to, ethanol, methanol, isopropyl alcohol, methylene chloride, acetone, or mixtures thereof.

In further embodiments, the disclosed pharmaceutical compositions are prepared using “direct compression” which refers to the general process of directly compressing the ingredients in the pharmaceutical formulation (i.e., therapeutic agent and excipients) without changing the physical and chemical properties of the therapeutic agent. The therapeutic agent, along with pharmaceutically acceptable excipients, in the form of powders, are blended in a low-shear apparatus, for example, a twin-shell blender and the like. The blended composition is then filled into a die and directly compressed into a punch. A tablet press, for example, can accomplish this compression step. Useful excipients in a direct compression process include, but are not limited to fillers, binders, lubricants, and glidants.

Another aspect of the present invention provides a tablet formulation comprising relugolix or a pharmaceutically acceptable salt thereof, used for the treatment of adult patients with advanced prostate cancer, uterine fibroids and its associated symptoms (excessive menstruation, lower abdominal pain, back pain, and anemia), and improvement of pain associated with endometriosis.

In yet another aspect of the present invention is to provide a process of preparation of tablet formulation comprising relugolix or a pharmaceutically acceptable salt thereof.

A stability study carried out for the relugolix tablet provided a satisfactory data for all the physical and chemical parameters, wherein initial, 3 Month and 6 Month stability studies were performed at 30 ± 2°C / 75 ± 5 % RH and 40 ± 20C / 75 ± 5 % RH.

It should be appreciated that the invention can be embodied / aspects in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will convey the scope of the invention to those skilled in the art. Other features and embodiments of the invention will become apparent from the following examples, which are given for illustration of the invention rather than for limiting its intended scope.

The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto.

Examples
Example 1:
Sr. No. Ingredients mg/tablet
1A 1B
1 Relugolix 120 120
2 Lactose monohydrate 42 48
3 Microcrystalline cellulose 181 175
4 Pregelatinized starch 46 40
5 2-Hydroxy propyl betacyclodextrin 40 46
6 Hydroxypropyl methyl cellulose 15 10
8 Polysorbate 80 powder 10 15
9 Croscarmellose Sodium 15 10
10 Colloidal silicon dioxide 6 11
11 Calcium stearate 5 5
Coating
12 Instacoat aqua II A02D00476 (Pink) (Idealcure)# 20 20
13 Purified water q.s. q.s.
Total 500 500

Manufacturing Process:
1) Relugolix, Polysorbate 80, 2-Hydroxy propyl beta-cyclodextrin, and croscarmellose sodium were co-sifted through #40 S.S. Sieve and collected separately in double Polythene lined labelled container.
2) Lactose monohydrate, microcrystalline cellulose, pregelatinized starch, hydroxypropylmethylcellulose, and colloidal silicon dioxide were co-sifted through #30 S.S. Sieve and collected separately in double Polythene lined labelled container.
3) Above steps, 1 & 2, sifted material was added in blender at slow speed for 20 minutes. Calcium stearate was added to the blended material and lubricated at a slow speed for 5 minutes.
4) The lubricated blend was compressed and were coated with a suitable coating agent.

Example 2:
Sr. No. Ingredients % w/w
2A 2B
1 Relugolix 2-24 2-90
2 Lactose monohydrate 5-15 5-15
3 Microcrystalline cellulose 30-45 30-45
4 Pregelatinized starch 5-15 5-15
5 2-Hydroxy propyl betacyclodextrin 5-15 5-15
6 Hydroxypropyl methyl cellulose 1-8 1-8
8 Polysorbate 80 powder 1-5 1-5
9 Crosscarmellose sodium 1-7 1-7
10 Colloidal silicon dioxide 0.5-5 0.5-5
11 Calcium stearate 0.5-5 0.5-5
Coating
12 Instacoat aqua II A02D00476 (Pink) (Idealcure)# 2-8 2-8
13 Purified water q.s. q.s.

Manufacturing process as described in example 1.
Table 1 : Stability study of example 1 at 30 ± 2°C / 75 ± 5 % RH
S.No. TEST Initial 3M 6 M
1 Dissolution
Mean- 100
Min- 96
Max- 102 Mean- 97
Min- 94
Max- 98 Mean- 102
Min- 98
Max- 106
2 Assay - Relugolix 99.7 99.9 99.7
3 Related Substance (By HPLC, w/w) 0.190 0.204 0.192
0.527 0.544 0.628
4 Microbial Limit Test <10 cfu/g <10 cfu/g <10 cfu/g
<10 cfu/g <10 cfu/g <10 cfu/g
Absent/g Absent/g Absent/g

All the physical and chemical parameters including the impurity levels were found to be satisfactory. Stability data for initial, 3 Months and 6 Months at 30 ± 2°C / 75 ± 5 % RH were also found to be satisfactory and within acceptable limits.

Although the inventions herein have been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described.
All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.

,CLAIMS:We claim:
1. A stable pharmaceutical composition comprising: a) relugolix or a pharmaceutically acceptable salt thereof; b) one or more solubility enhancer; and c) pharmaceutically acceptable excipients.

2. The stable composition as claimed in claim 1, wherein the solubility enhancer is selected from the group consisting of 2-hydroxy propyl betacyclodextrin, polysorbate 80 or mixture thereof.

3. The stable composition as claimed in claim 1, wherein the composition is devoid of any sugar alcohol.

4. The stable composition as claimed in claim 1, wherein the composition is prepared using wet granulation, dry granulation or direct compression method.

5. A stable pharmaceutical composition comprising: a) about 24 % w/w of relugolix or a pharmaceutically acceptable salts thereof, b) about 8.4 % w/w of lactose monohydrate, c) about 36.2 % w/w of microcrystalline cellulose, d) about 9.2% w/w of pregelatinized starch, e) about 8 % w/w of 2-hydroxy propyl betacyclodextrin, f) about 3 % w/w of hydroxypropyl methyl cellulose, g) about 2 % w/w of polysorbate 80 powder, h) about 3 % w/w of croscarmellose sodium, i) about 1.2 % w/w of colloidal silicon dioxide, and j) about 1 % w/w of calcium stearate.

6. The stable composition as claimed in claim 5, wherein the composition is optionally coated with mixture of polyvinyl alcohol and polyethylene glycol.

7. The stable composition as claimed in claim 6, wherein the composition further comprises one of more excipients selected from the group consisting of talc, titanium dioxide and red iron oxide.

8. The stable composition as claimed in claim 6 or 7, wherein the composition contains coating agent in an amount of about 1-7 % w/w based on the total weight of the composition.

9. The stable composition as claimed in any of the preceding claims, wherein the composition is stable for at least 24 hours at 30 ± 2°C / 75 ± 5 % relative humidity.

10. A stable pharmaceutical composition comprising: a) about 120 mg relugolix, b) about 42 mg lactose monohydrate, c) about 181 mg microcrystalline cellulose d) about 42 mg pregelatinized starch, e) about 40 mg 2-hydroxy propyl betacyclodextrin, f) about 15 mg hydroxypropyl methyl cellulose, g) about 10 mg polysorbate 80 powder, h) about 15 mg croscarmellose sodium, i) about 6 mg colloidal silicon dioxide, j) about 5 mg calcium stearate.