DESC:TITLE OF THE INVENTION:
“STABLE PHARMACEUTICAL COMPOSITION OF ELAGOLIX”
FIELD OF THE INVENTION:
The present invention relates to stable pharmaceutical composition comprising Elagolix or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient. The present invention further relates to methods of preparing and administering such pharmaceutical compositions.

BACKGROUND OF THE INVENTION:
Elagolix is chemically known as 4-({(1R)-2-[5-(2-fluoro-3methoxyphenyl)-3-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-4-methyl-2,6-dioxo-3,6dihydropyrimidin-1(2H)-yl]-1-phenylethyl}amino)butanoate, represented by the chemical structure:

Elagolix is a gonadotropin-releasing hormone (GnRH) receptor antagonist approved by USFDA as ORILISSA Tablets for the treatment of moderate to severe pain associated with endometriosis.

Inactive ingredients in the ORILISSA Tablets consist of mannitol, sodium carbonate monohydrate, Pregelatinized starch, povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and carmine high tint.

US Patent Publication No. 20190054088, disclose pharmaceutical compositions comprising Elagolix sodium and an anti-gelling agent / stabilizer; wherein anti-gelling agent / stabilizer is alkali metal salt or a basic salt;

PCT Patent Publication No. WO2019036713 assigned to AbbVie Inc discloses solid dispersion composition comprising Elagolix and meltable binder selected from poloxamer 188, a cellulose derivative, such as hydroxypropylcellulose, a polyethylene glycol (PEG), glycerol monosteatrate and stearic acid.

PCT Patent Publication No. WO2018189213 assigned to Sandoz AG, discloses amorphous solid dispersion of Elagolix sodium and a silicon based inorganic compound is a material having a BET specific surface area of at least 1 m2/g.

There are challenges to develop pharmaceutical compositions comprising Elagolix sodium. One of the challenge is that Elagolix sodium is highly hygroscopic and has a tendency to form a gel upon moisture contact, particularly when present at an amount greater than about 10% by weight when administered orally in a solid dosage form. Such gel formation limits the dissolution of API and, ultimately, can lead to highly variable inter- and intra-patient bioavailability. Another challenge is that Elagolix sodium can degrade to form a compound having a lactam impurity. Reducing conversion of the Elagolix into its lactam impurity degradation product is desirable, for example, to maintain safety and efficacy over the life of the product and bioavailability.

The above patent applications followed different approaches to reduce gelling of Elagolix sodium in dosage form. In the above mentioned patent applications, the inventor attempts to provided compositions of Elagolix, which had shown less bioavailability and dissolution. As Elagolix sodium has tendency to form gel, requires special precautionary measures such as a controlled conditions during storage of API and pharmaceutical processing, which renders manufacturing cumbersome and expensive.
Therefore, there exists need to prepare alternate compositions of Elagolix that shows improved stability, dissolution and bioavailability with simple, reproducible and cost effective manufacturing process for pharmaceutical composition of Elagolix sodium tablet, which also offers desired pharmaceutical technical attributes.

In order to solve the above problem, the present inventors have developed compositions, which provides Elagolix product having improved stability, dissolution and bioavailability. The present invention relates to stable pharmaceutical compositions having reduce gelling of the Elagolix sodium and/or reduce generation of the lactam impurity.

SUMMARY OF THE INVENTION:

The present invention relates to a stable pharmaceutical composition comprising Elagolix or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient. The present invention further provides process for preparation of Elagolix.

Accordingly, the preferred pharmaceutical composition of the present invention contains various quantities ranging from about 10 mg to about 800 mg of Elagolix or a pharmaceutically acceptable salt thereof. Thus, for example, the preferred formulation can contain about 50, 100, 200, 300, 400, 500, 600, 700 or 800 mg of Elagolix base.

OBJECTIVES OF INVENTION:

In one aspect, the stable pharmaceutical composition comprising Elagolix sodium, absorbent or solubilizing agent and one or more pharmaceutical acceptable excipients; wherein the composition is devoid of anti-gelling agent and meltable binders which is basic in nature.

In another aspect, the present invention relates to the oral stable dosage composition comprising Elagolix or its pharmaceutical salt thereof, Polysorbate 80 and Magnesium aluminum silicate (Sepitrap 80), Talc, Mannitol, Pregelatinized starch, Povidone, Magnesium stearate and one or more pharmaceutical acceptable excipients or combinations thereof.

In another aspect, the present invention relates to oral stable pharmaceutical composition comprising Elagolix or its pharmaceutically acceptable salt thereof, absorbent / solubilizing agents and one or more pharmaceutical acceptable excipients, wherein the composition is substantially devoid of anti-gelling agents which are basic in nature and meltable binders.

In another aspect, the present invention relates to oral stable composition of Elagolix, wherein said composition comprises on a total of 100 % by weight:
(a) from about 25 % to about 45 % of Elagolix or its pharmaceutical salt thereof,
(b) from 10 % to about 30 % of adsorbent / solubilizing agent.
(c) from about 15 % to about 35 % of one or more diluents;
(d) from 5 % to about 15 % of disintegrant;
(e) from about 1 % to about 10 % binder;
(f) from about 0.5 % to about 2 % lubricant; and
(g) optionally one or more pharmaceutical acceptable excipients.

In another aspect, the present invention relates to the oral stable pharmaceutical composition as defined above for the treatment of moderate to severe pain associated with endometriosis.

In another aspect, the present invention relates to oral stable pharmaceutical composition as defined above having dissolution more than 90% within 45 minutes.

DETAILED DESCRIPTION OF THE INVENTION:
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
The term "Elagolix" as used herein includes the base, pharmaceutically acceptable salts, polymorphs, stereoisomers and mixtures thereof, the term "pharmaceutically acceptable salt" means a salt which is acceptable for administration to a patient, such as a mammal (e.g., salts having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.

The term, "pharmaceutically acceptable excipients" as used herein refers to diluents, disintegrants, binders, lubricants, glidants, polymers, coating agents, solvents, co-solvents, preservatives, wetting agents, thickening agents, antifoaming agents, sweetening agents, flavouring agents, antioxidants, colorants, solubulizers, plasticizer or dispersing agents and the like. The pharmaceutical compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable excipients.

The term "diluent" employed in a composition of the present invention is capable for providing bulkiness to obtain a desired pharmaceutical composition. The diluents of instant invention includes, but are not limited to inorganic phosphates such as dibasic calcium phosphate, calcium sulphate or dicalcium phosphate dihydrate; sugars such as lactose, lactose hydrate, lactose monohydrate, lactose anhydrate, sucrose, dextrose, erythritol, lactilol, xylitol, sorbitol, mannitol or malitol; cellulose or cellulose derivatives such as microcrystalline cellulose; Avicel, Avicel PH 101, Avicel PH 102 or Avicel PH 103, maize starch, Starcap-1500, Starlac and galenIQ-721.

The term "disintegrant" employed in a composition of the present invention is capable of facilitating the breakup of a pharmaceutical composition prepared from the composition when placed in contact with an aqueous medium. The disintegrants of instant invention includes, but are not limited to alginic acid or sodium alginate; cellulose or cellulose derivatives such as carboxymethylcellulose sodium, microcrystalline cellulose, croscarmellose sodium, powdered cellulose or croscarmellose; iron exchange resin such as amberlite, gums such as agar, locust bean, karaya, pectin and tragacanth, crospovidone (cross-linked homopolymer of N-vinyl-2-pyrrolidinone, i.e., cross-linked l-ethenyl-2-pyrrolidinone); Pregelatinized starch, sodium starch glycolate or starch.

The term "binder" employed in a composition of the present invention is capable for holding the ingredients together and forming the granules with required mechanical strength. The binders of instant invention include, but are not limited to, but are not limited to, polyvinylpyrrolidone (povidone), polyethlylene glycol (PEG), saccharides, gelatins, pregelatinized starches, microcrystalline cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose (HPMC) and cellulose ethers.

The term "Adsorbent / solubilizing agent" employed in a composition of the present invention is capable of increasing solubility of poorly soluble drugs and preventing gel formation of Elagolix. Example of Adsorbent / solubilizing agent of instant invention includes, but are not limited to polyethylene glycols, Tween 80 (polysorbate 80), Tween 20 (polysorbate 20), talc, Sepitrap (Polysorbate 80 (45-65%) and Magnesium Aluminometasilicate (35-55%)), Dibasic Calcium Phosphate (DCP; Fujicalin), sodium taurocholate (NaTC), Labrasol, polyethylene glycol 400 (PEG 400), Aerosil 200, Amorphous micronized silica (Sylysia 350), diethylene glycol monoethyl ether (Transcutol P), propylene glycol, tocopherols (tocopheryl polyethylene glycol 1000 succinate), propylene glycol, monocaprylate, caprylocaproyl macrogol-8 glycerides, glycerylcaprylate, poloxamers, PEG-40 hydrogenated castor oil, lecithin, propylene glycol stearates, and polyethylene glycol glycerides, sodium lauryl sulfate, anionic emulsifying wax, glycerol, nonionic emulsifying wax, glyceryl monooleate, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyoxylglycerides, sorbitan esters, triethyl citrate, vitamin E polyethylene glycol succinate, microcrystalline cellulose, carboxymethylcellulose sodium, diethanolamine, ethylene glycol palmitostearate, glycerin monostearate, hypromellose, hypromellose acetate succinate, lecithin, polyethylene alkyl ethers, aluminum oxide, poly(methylvinyl ether/maleic anhydride), calcium carbonate, cyclodextrins, fructose, hydroxpropyl betadex, oleyl alcohol, povidone, benzalkonium chloride, benzethonium chloride, benzyl alcohol, benzyl benzoate, cetylpyridinium chloride, meglumine, poloxamer, pyrrolidone, sodium bicarbonate, stearic acid, sulfobutylether b-cyclodextrin, tricaprylin, triolein, docusate sodium, glycine, self-emulsifying glyceryl monooleate, cationic benzethonium chloride, cetrimide, xanthan gum, lauric acid, myristyl alcohol, butylparaben, ethylparaben, methylparaben, propylparaben, sorbic acid or the like.

The term "lubricant" employed in a composition of the present invention is capable of preventing the ingredients from clumping together and from sticking to the apparatus on which it is formed, for example, preventing adherence to the face of the upper punch (picking) or lower punch (sticking) of a compression machine. Preferred lubricants of instant invention includes, but are not limited to fatty acids or fatty acid derivatives such as calcium stearate, glyceryl monostearate, glyceryl palmitostearate, talc, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid or hydrogenated vegetable oil; polyalkylene glycols such as polyethylene glycol (PEG) or sodium benzoate and the like.

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

The term "excipient" means a pharmacologically inactive component such as diluent, disintegrant, carrier, filler, lubricant, binder, and solvent, coating agent or the like. These are generally safe, nontoxic. Reference to an excipient includes both one and more than one such excipient.

The term "stable" as used herein refers to formulations that substantially retain the label amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug-related impurity contents in the formulations remain within acceptable limits.

The term "about" as used herein refers to a defined range of the value by + 10 %. For example, about 2 % means 1.8 % to 2.2 %, about 5 % means 4.5 % to 5.5 %, about 10 % means 9 % to 11 % and about 40 % means 36 % to 44 %.

The term "oral dosage forms" includes all conventional oral solid dosage forms like a Tablet, capsule, Syrups, Suspension, granules, a pill, a tablet, a caplet, pellets, a powder or a sachet, or any other orally ingestible dosage form comprising Elagolix and its salts as an active ingredient mixed with other pharmaceutically acceptable excipients.

The terms “prevent” and “preventing” as used herein refers the prevention of the recurrence, spread or onset. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced.

The terms “treat” and “treating” as used herein refers are not limited to the case where the subject (e.g., patient) is cured and the disease is eradicated. Rather, embodiments, of the present disclosure also contemplate treatment that merely reduces symptoms, and/or delays disease progression.

The term "oral dosage forms" includes all conventional oral solid dosage forms like a Tablet, capsule, Syrups, Suspension, granules, a pill, a tablet, a caplet, pellets, a powder or a sachet, or any other orally ingestible dosage form comprising Elagolix or its salts as an active ingredient mixed with other pharmaceutically acceptable excipients.

The term "Parenteral dosage forms” includes all conventional oral solid dosage forms like a
Intramuscular injection, Intravenous injection, subcutaneous injection any other Parenteral dosage forms comprising Elagolix or its salts as an active ingredient mixed with other pharmaceutically acceptable excipients.

The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "a diluent" means one diluent or more than one diluent.

Throughout this specification and the appended claims, it is to be understood that the words "comprise", “have”, “contain” and "include" and variations such a "comprises", "comprising", "having", "containing" "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.

The present invention relates to a stable pharmaceutical compositions comprising Elagolix or pharmaceutically acceptable salt thereof, and one or more pharmaceutical acceptable excipients.

In one embodiment, the present invention relates to solid oral pharmaceutical composition comprising Elagolix or its pharmaceutical salt thereof, absorbent / solubilizing agents and one or more pharmaceutical acceptable excipients, wherein the composition is substantially devoid of anti-gelling agents which are basic in nature and meltable binders.

In certain exemplary embodiments, the pharmaceutical composition comprises, or is in the form of a pharmaceutically acceptable salt, as generally described below. Some preferred, but non-limiting examples of suitable pharmaceutically acceptable organic and/or inorganic acids are hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid and citric acid, as well as other pharmaceutically acceptable acids known per se (for which reference is made to the references referred to below).

In certain exemplary embodiments, the exemplary compound (elagolix) contain an acidic group as well as a basic group, the compound can form internal salts, which can also be used in the compositions and methods described herein. When an exemplary compound contains a hydrogen-donating heteroatom (e.g., NH), salts are contemplated to cover isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule. Pharmaceutically acceptable salts of the exemplary compounds include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases can also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth, incorporated herein by reference. Physiologically acceptable salts of the exemplary compounds are those that are formed internally in a subject administered compound for the treatment or prevention of disease. Suitable salts include those of lithium, sodium, potassium, magnesium, calcium, manganese, bile salts.

In certain embodiments, the present invention relates to a pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a compound disclosed herein, pharmaceutical composition is in the form of solid dosage form, semi-solid dosage form, liquid dosage form, gaseous dosage form, oral dosage forms, topical dosage forms and parenteral dosage forms.

In certain embodiments compounds described herein can be formulated in a variety of ways. Formulations containing one or more compounds can be prepared in various pharmaceutical forms, such as granules, tablets, capsules, suppositories, powders, controlled release formulations, suspensions, emulsions, creams, gels, ointments, salves, or lotions and the like. In certain embodiments, the formulations are employed in solid dosage forms suitable for simple, and preferably oral, administration of precise dosages. Solid dosage forms for oral administration include, but are not limited to, tablets, soft or hard gelatin or non-gelatin capsules, and caplets. However, liquid dosage forms, such as solutions, syrups, suspension etc. can also be utilized. In another embodiment, the formulation is administered topically. Suitable topical formulations include, but are not limited to lotions, ointments, creams, and gels. In a preferred embodiment, the topical formulation is a gel.

In another embodiment, the solid oral pharmaceutical composition is in the form of tablet comprising Elagolix or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients.

In another embodiment, the solid oral pharmaceutical composition is in the form of capsule comprising Elagolix or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients.

In another embodiment, the solid oral pharmaceutical composition is in the form of Syrups comprising Elagolix or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients.

In another embodiment, the solid oral pharmaceutical composition is in the form of Suspension comprising Elagolix or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients.

In another embodiment, the parenteral pharmaceutical composition is in the form of Intramuscular injection comprising Elagolix or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients.

In another embodiment, the parenteral pharmaceutical composition is in the form of Intravenous injection comprising Elagolix or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients.

In another embodiment, the parenteral pharmaceutical composition is in the form of subcutaneous injection comprising Elagolix or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention relates to solid oral pharmaceutical composition comprising Elagolix or its pharmaceutical salt thereof, diluent, adsorbent / solubulizers, lubricant, disintegrants, binders and one or more pharmaceutically acceptable excipients.

In an yet another embodiment, the present invention relates to a pharmaceutical tablet dosage form composition comprising Elagolix or its pharmaceutical salt thereof, polysorbate 80 and Magnesium aluminum silicate (Sepitrap 80), Mannitol, Povidone, Pregelatinized starch, Magnesium stearate and one or more pharmaceutically acceptable excipients.

In an yet another embodiment, the pharmaceutical composition of the present invention can be formulated as dosage forms which include, but are not limited to, powders, granules, pills, tablets, coated tablets, capsules, pellets, patches, implants, films, liquids, semi-solids, gels, aerosols, emulsions, elixirs and the like.

In another embodiment, the pharmaceutical composition of the present invention can be formulated as oral dosage forms selected from powders, granules, tablets, and capsules, powders for reconstitution, granules for reconstitution.

In another embodiment, the present invention relates to the oral stable pharmaceutical composition comprising Elagolix or its pharmaceutical salt thereof, wherein the composition is in the form of tablet or capsule.

In another embodiment, the present invention relates to oral stable tablet dosage form composition comprising 100mg, 125 mg, 150mg, 175mg, 200mg of Elagolix base.

In another embodiment, the present invention composition relates to the oral stable pharmaceutical composition having excellent stability, good purity profile with improved dissolution profile and bioavailability.

In further embodiments of the present invention, the pharmaceutical compositions are prepared by known technological procedures, e.g. direct compression, dry granulation or wet aqueous granulation, using well known and readily available excipients. In the preparation of the compositions of Elagolix, the active ingredient will usually be mixed with an excipient or mixture of excipients, or diluted by an excipient or mixture of excipients, or enclosed within an excipient or mixture of excipients which may be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it may be a solid, semisolid or liquid material which acts as a vehicle or medium for the Elagolix.

The composition of the present invention can be produced by sizing and milling a mixture of the drug substance with excipients. For example, one method for the production includes mixing the Elagolix with the materials for the preparation by a suitable mixer, and lubrication the mixture to tablet or capsule.

The pharmaceutical compositions can be prepared by using any suitable method known in the art such as direct compression, dry or wet granulation (aqueous/non-aqueous or combination), extrusion spheronization, melt extrusion, melt granulation, coating over inert spheres, spray coating, spray drying and solvent evaporation.

The pharmaceutical composition is meant for once daily or twice daily administration.

In another embodiment, the present invention relates to the oral stable composition comprising Elagolix or its pharmaceutical salt thereof, having dissolution more than 90% within 45 minutes.

In another embodiment, the present invention relates to the pharmaceutical composition as defined above for the treatment of moderate to severe pain associated with endometriosis.

In another embodiment, the present invention relates to the oral stable dosage composition comprising Elagolix or its pharmaceutical salt thereof, Polysorbate 80 and Magnesium aluminum silicate (Sepitrap 80), Talc, Mannitol, Pregelatinized starch, Povidone, Magnesium stearate and one or more pharmaceutical acceptable excipients or combinations thereof.

In another embodiment, the present invention relates to the oral stable dosage composition comprising Elagolix sodium, Polysorbate 80 and Magnesium aluminum silicate (Sepitrap 80), Talc, Mannitol, Pregelatinized starch, Povidone, Magnesium stearate and one or more pharmaceutical acceptable excipients or combinations thereof.

In another embodiment, the present invention relates to oral stable dosage composition of Elagolix, wherein said composition comprises on a total of 100 % by weight:
(a) from about 25 % to about 45 % of Elagolix or its pharmaceutical salt thereof,
(b) from 10 % to about 30 % of adsorbent / solubilizing agent.
(c) from about 15 % to about 35 % of one or more diluents;
(d) from 5 % to about 15 % of disintegrant;
(e) from about 1 % to about 10 % binder;
(f) from about 0.5 % to about 2 % lubricant; and
(g) optionally one or more pharmaceutical acceptable excipients.

In another embodiment, the present invention relates to oral stable tablet of Elagolix, wherein said composition comprises on a total of 100 % by weight:
(a) from about 25 % to about 45 % of Elagolix or its pharmaceutical salt thereof,
(b) from 10 % to about 30 % of adsorbent / solubilizing agent.
(c) from about 15 % to about 35 % of one or more diluents;
(d) from 5 % to about 15 % of disintegrant;
(e) from about 1 % to about 10 % binder;
(f) from about 0.5 % to about 2 % lubricant;
(g) optionally one or more pharmaceutical acceptable excipients.

In another embodiment, the present invention relates to oral stable tablet of Elagolix, wherein said composition comprises on a total of 100 % by weight:
(a) from about 25 % to about 45 % of Elagolix or its pharmaceutical salt thereof,
(b) from 10 % to about 30 % of Sepitrap.
(c) from about 15 % to about 35 % of Mannitol;
(d) from 5 % to about 15 % of Pregelantized starch;
(e) from about 1 % to about 10 % Povidone;
(f) from about 0.5 % to about 2 % Magnesium stearate;
(g) optionally one or more pharmaceutical acceptable excipients.

In another embodiment, the present invention relates to oral stable tablet of Elagolix, wherein said composition comprises on a total of 100 % by weight:
(a) from about 25 % to about 45 % of Elagolix sodium,
(b) from 10 % to about 30 % of Talc.
(c) from about 15 % to about 35 % of Mannitol;
(d) from 5 % to about 15 % of Pregelantized starch;
(e) from about 1 % to about 10 % Povidone;
(f) from about 0.5 % to about 2 % Magnesium stearate;
(g) optionally one or more pharmaceutical acceptable excipients.

In another embodiment, the weight ratio of Elagolix sodium to the adsorbent / solubilizing agent is from about 1:1 to about 10:1. The weight ratios may be selected in varying ranges, selected from a group consisting of 1:1, to 10:1. The preferred ratio for example may range from 1:1 to 2:1 or 1:1 to 4:1 or 1 :1 to 6:1.

In another embodiment, the present invention relates to a pharmaceutical stable dosage form composition comprising immediate release tablet.

The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Example-1
S. No. Ingredients Category Tablet strength % w/w
150 mg 200mg
Intra granular Part
1 Elagolix Sodium API 155.20 207.00 34.11
2 Mannitol (200 c) Diluent 100.77 134.40 22.15
3 Pregelatinized Starch (starch 1500 LM) Disintegrate 45.50 60.68 10.00
4 Povidone (PVP k30) Binder 22.75 30.34 5.00
5 Sepitrap™ 80 Absorbent / Solubilizing agent 81.90 109.24 18.00
6 Magnesium Stearate Lubricant 1.14 1.54 0.25
Extra granular Part
7 Pregelatinized Starch (starch 1500 LM) Diluent 45.50 60.68 10.00
8 Magnesium Stearate Lubricant 2.27 3.02 0.50
Core Tablets weight 455.03 606.88 100.00
Film coating:
9 Opadry II Pink Colouring agent 13.65 - 3.00
10 Opadry II Orange Colouring agent - 18.00 3.00
11 Purified water - QS QS --
Coated Tablets weights 468.68 624.88 -

Example – 2:
S. No. Ingredients Category Tablet strength % w/w
150 mg 200mg
Intra granular Part
1 Elagolix Sodium API 155.20 207.00 34.11
2 Mannitol (200 c) Diluent 100.77 134.40 22.15
3 Pregelatinized Starch (starch 1500 LM) Disintegrate 45.50 60.68 10.00
4 Povidone (PVP k30) Binder 22.75 30.34 5.00
5 Talc Diluent 81.90 109.24 18.00
6 Magnesium Stearate Lubricant 1.14 1.54 0.25
Extra granular Part
7 Pregelatinized Starch (starch 1500 LM) Diluent 45.50 60.68 10.00
8 Magnesium Stearate Lubricant 2.27 3.02 0.50
Core Tablets weight 455.03 606.88 100.00
Film coating:
9 Opadry II Pink Colouring agent 13.65 - 3.00
10 Opadry II Orange Colouring agent - 18.00 3.00
11 Purified water - QS QS --
Coated Tablets weights 468.68 624.88 -

The Elagolix tablet composition of examples 1 and 2 are prepared by direct compression or dry granulation.
BRIEF MANUFACTURING PROCESS OF EXAMPLE 1 AND 2:

1. Brief Manufacturing Procedure
Co-sift the Elagolix sodium, Mannitol, Pregelatinised starch and Crosspovidone through sieve # 30.
2. Then Sift Magnesium stearate through # 60 mesh.
3. Load the sifted materials of step-1 in Blender and mix for 20 minutes.
4. Add Magnesium stearate through # 60 mesh to the above step and mix for 5 minutes.
5. Perform Compaction, by using step 4 with suitable granulating parameters.
6. Mill compacted granules of step 5 through 2 mm screen. Granules were Seived throught # 20 mesh and mill retentions through 1.00 mm untill all the material passed through # 20 mesh.
7. Sift Mannitol, Cross povidone and Sepitrap 80 through sieve #40 ASTM
8. Sift Magnesium stearate through # 60 mesh.
9. Load step 6 and step 7 into blender and mixed for 10 minutes.
10. Add of Step 8 to step 9 and blended for 5 minutes.

Dissolution data:
Dissolution data in pH 6.8 Sodium Phosphate buffer, 900mL, 50 RPM, Paddle
Time points RLD Data Test Data Proposed limits
5 min 10.00 7.00 NMT 15 %
10 min 31.00 28.00 NMT 40 %
20 min 65.00 61.00 NMT 50 %
45 min 98.00 92.00 NLT 15 %
,CLAIMS:1. A solid oral pharmaceutical composition comprising:
(a) an intragranular portion comprising Elagolix or its pharmaceutical salt thereof, atleast one solubilizing agent and one or more pharmaceutical acceptable excipients or combinations thereof;
(b) an extragranular portion comprising atleast one diluent and lubricant; and one or more pharmaceutical acceptable excipients or combinations thereof.

2. A solid oral pharmaceutical composition as claimed in claim 1, the solubilizing agent is selected from the group of polysorbate 80, polysorbate 20, talc, Magnesium aluminum silicate, sodium taurocholate, Labrasol and combinations thereof.

3. A solid oral pharmaceutical composition as claimed in claim 1, the diluent is selected from the group of pregelatinized Starch, mannitol, dibasic calcium phosphate, dicalcium phosphate dihydrate, lactose monohydrate, lactose anhydrate, sucrose and combinations thereof.

4. A solid oral pharmaceutical composition as claimed in claim 1, the lubricant is selected from the group of calcium stearate, glyceryl monostearate, glyceryl palmitostearate, talc, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid and combinations thereof.

5. A oral stable dosage composition of Elagolix, wherein said composition comprises on a total of 100 % by weight:
(a) from about 25 % to about 45 % of Elagolix or its pharmaceutical salt thereof,
(b) from 10 % to about 30 % of one or more diluents adsorbent or solubilizing agent.
(c) from about 15 % to about 35 % of one or more diluents;
(d) from 5 % to about 15 % of disintegrant;
(e) from about 1 % to about 10 % binder;
(f) from about 0.5 % to about 2 % lubricant; and
(g) optionally one or more pharmaceutical acceptable excipients.

6. The oral stable dosage composition as claimed in claim 5, comprises on a total of 100 % by weight:
(a) from about 25 % to about 45 % of Elagolix or its pharmaceutical salt thereof,
(b) from 10 % to about 30 % of Sepitrap.
(c) from about 15 % to about 35 % of Mannitol;
(d) from 5 % to about 15 % of Pregelantized starch;
(e) from about 1 % to about 10 % Povidone;
(f) from about 0.5 % to about 2 % Magnesium stearate;

7. The oral stable dosage composition as claimed in claim 5, wherein said composition comprises on a total of 100 % by weight:
(a) from about 25 % to about 45 % of Elagolix sodium,
(b) from 10 % to about 30 % of Talc.
(c) from about 15 % to about 35 % of Mannitol;
(d) from 5 % to about 15 % of Pregelantized starch;
(e) from about 1 % to about 10 % Povidone;
(f) from about 0.5 % to about 2 % Magnesium stearate;
(g) optionally one or more pharmaceutical acceptable excipients.

8. A oral stable composition as claimed on claim 5 comprising Elagolix or its pharmaceutical salt thereof, having dissolution more than 90% within 45 minutes.

9. A oral stable composition as claimed on claim 5, for the treatment of moderate to severe pain associated with endometriosis.