DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

PHARMACEUTICAL COMPOSITIONS OF ELAGOLIX OR ACCEPTABLE SALTS THEREOF

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
GALAXY, FLOORS: 22-24,
PLOT No.1, SURVEY No.83/1,
HYDERABAD KNOWLEDGE CITY,
RAIDURG PANMAKTHA,
RANGA REDDY DISTRICT,
HYDERABAD – 500 032,
TELANGANA, INDIA

The following specification describes the nature of this invention and the manner in which it is to be performed.

FIELD OF THE INVENTION

This present invention relates to pharmaceutical composition comprising elagolix or its pharmaceutically acceptable salts, esters, solvates, derivatives, amides, polymorphs, enantiomers, prodrugs, analogues, active metabolites or mixtures thereof as an active agent and suitable pharmaceutical excipients. The invention also relates to the methods of preparation of the composition having improved dissolution profile and stability.

BACKGROUND OF THE INVENTION

Elagolix sodium is a gonadotropin-releasing hormone (GnRH) receptor antagonist. Commonly prescribed for the management of moderate to severe pain associated with endometriosis.

Elagolix sodium is a nonpeptide small molecule and chemically known as sodium 4-({(1R)-2-[5-(2-fluoro-3¬methoxyphenyl)-3-{[2-fluoro-6-(trifluoromethyl)phenyl] methyl}-4-methyl-2,6-dioxo-3,6¬dihydropyrimidin-1(2H)-yl]-1-phenyl ethyl} amino)butanoate and is represented by the following formula:

Elagolix sodium is a white to off white to light yellow powder and is freely soluble in water.

Elagolix sodium is commercially available under the brand name ORILISSA® in 150mg and 200mg film coated tablets and marketed by Abbvie Inc. Inactive ingredients of ORILISSA® tablets for 150mg are mannitol, sodium carbonate monohydrate, pregelatinized starch, povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and carmine high tint and for 200mg are mannitol, sodium carbonate monohydrate, pregelatinized starch, povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide red.

U.S. Publication No. 20190054088 discloses Elagolix sodium, a water soluble filler and an anti-gelling agent.

U.S. Patent No. 6,872,728 and 7,179,815 discloses compound elagolix or a pharmaceutically acceptable salt thereof and method for treating endometriosis using Elagolix sodium.

US Patent No. 7,419,983 discloses pharmaceutical composition comprising elagolix and a pharmaceutically acceptable carrier or diluent.

US Patent No. 9,949,973 discloses acoustically mixing elagolix sodium and a pharmaceutically acceptable excipient.

International patent publication No. 2020/020999 discloses process for preparing rapidly dissolving tablets, wherein the tablet comprises a granulate and a tablet base.

Literature suggests that formulating elagolix sodium into suitable solid oral dosage forms like tablets is challenging from the formulation development perspective because elagolix has a tendency to form gel when present in amount greater than 10% by weight in absence of appropriate anti-gelling agent when administered orally in solid dosage form and such gel formation limits dissolution of API and ultimately leads to intra and inter patient variability, compressibility issues, manufacturing process selection, control of process and degradation of product.

Hence, there is an unmet need in the art to develop composition of elagolix sodium tablets having an improved dissolution profile and stability.

The inventors of this invention have developed solid pharmaceutical composition of elagolix sodium and unexpectedly found that said composition have improved dissolution profile and stability coupled with simple manufacturing process at industrial scale and it is bioequivalent to commercially available ORILISSA® tablets.

SUMMARY OF THE INVENTION

In one aspect, the invention relates to a solid pharmaceutical composition comprising elagolix sodium with one or more pharmaceutically acceptable excipients.

In another aspect an invention provides a solid oral pharmaceutical composition comprising:
a) 30-37% of elagolix or pharmaceutically acceptable salts;
b) 40-55% of filler comprising mannitol and Pharmaburst®;
c) 3-15% of alkalizer selected from magnesium oxide or sodium caprylate; wherein the particle size distribution of elagolix sodium is such that 90% of the elagolix sodium particles are between 15-30µm.

In another aspect an invention provides a solid oral pharmaceutical composition comprising:
a) 30-37% of elagolix sodium;
b) 18-25% of first filler comprising mannitol;
c) 20-32% of second filler comprising Pharmaburst®;
d) 3-13% of alkalizer comprising magnesium oxide or sodium caprylate; wherein the particle size distribution of elagolix sodium is such that 90% of the particles are between 15-30µm.

In another aspect an invention provides a solid oral pharmaceutical composition comprising:
a) 30-37% of elagolix sodium;
b) 18-25% of first filler comprising mannitol;
c) 20-32% of second filler comprising Pharmaburst®;
d) 3-13% of alkalizer comprising magnesium oxide or sodium caprylate; wherein the w/w ratio of elagolix sodium to Pharmaburst® is 1:0.50 to1:1.

In another aspect an invention provides a solid oral pharmaceutical composition comprising:
a) 30-37% of elagolix sodium;
b) 18-25% of first filler comprising mannitol;
c) 20-32% of second filler comprising Pharmaburst®;
d) 3-13% of alkalizer comprising magnesium oxide or sodium caprylate;
e) 3-6% of disintegrant comprising croscarmellose sodium;
f) 1-5% of glidant comprising colloidal silicon dioxide;
g) 1-5% of lubricant comprising magnesium stearate; wherein the w/w ratio of elagolix sodium to Pharmaburst® is 1:0.50 to1:1.

In another aspect an invention provides a solid oral pharmaceutical composition comprising:
a) 30-37% of elagolix sodium;
b) 18-25% of first filler comprising mannitol;
c) 20-32% of second filler comprising Pharmaburst®;
d) 3-13% of alkalizer comprising magnesium oxide or sodium caprylate; wherein the w/w ratio of elagolix sodium to magnesium oxide is 1:0.10 to 1:0.20 and w/w ratio of elagolix sodium to sodium caprylate is 1:0.30 to1:0.50.

In another aspect an invention provides a solid oral pharmaceutical composition comprising:
a) 30-37% of elagolix sodium;
b) 18-25% of first filler comprising mannitol;
c) 20-32% of second filler comprising Pharmaburst®;
d) 3-13% of alkalizer comprising magnesium oxide or sodium caprylate; wherein the bulk density of lubricated blend is from about 0.46 g/ml to about 0.6 g/ml and tapped density of lubricated blend is ranging from about 0.6 g/ml to about 0.8 g/ml.

In another aspect an invention provides a solid oral pharmaceutical composition comprising:
a) 30-37% of elagolix sodium;
b) 18-25% of first filler comprising mannitol;
c) 20-32% of second filler comprising Pharmaburst®;
d) 3-13% of alkalizer comprising magnesium oxide or sodium caprylate; wherein at least 90% of elagolix sodium dissolves within 45 minutes in 900ml phosphate buffer of pH 6.8 at 50 rpm with paddle or within 60 minutes in 900ml 0.1 N HCl at 50 rpm with paddle.

In another aspect an invention provides a solid oral pharmaceutical composition comprising:
a) 150-210mg of elagolix or pharmaceutically acceptable salts;
b) 170-340mg of filler comprising mannitol and Pharmaburst®;
c) 20-85mg of alkalizer selected from magnesium oxide or sodium caprylate; wherein the particle size distribution of elagolix sodium is such that 90% of the elagolix sodium particles are between 15-30 µm.

In another aspect an invention provides a solid oral pharmaceutical composition comprising:
a) 150-210mg of elagolix or pharmaceutically acceptable salts;
b) 170-340mg of filler comprising mannitol and Pharmaburst®;
c) 20-85mg of alkalizer comprising magnesium oxide or sodium caprylate;
d) 20-35mg of disintegrant comprising croscarmellose sodium;
e) 8-15mg of glidant comprising colloidal silicon dioxide;
f) 8-15mg of lubricant comprising magnesium stearate; wherein the particle size distribution of elagolix sodium is such that 90% of the elagolix sodium particles are between 15-30 µm.

In another aspect an invention provides a solid oral pharmaceutical composition comprising:
a) 150-210mg of elagolix or pharmaceutically acceptable salts;
b) 170-340mg of filler comprising mannitol and Pharmaburst®;
c) 20-85mg of alkalizer comprising magnesium oxide or sodium caprylate or magnesium citrate or sodium citrate;
d) 1-4mg of solubilizer comprising poloxamer or sodium lauryl sulphate or polysorbate 80;
e) 20-35mg of disintegrant comprising croscarmellose sodium;
f) 8-15mg of glidant comprising colloidal silicon dioxide;
g) 8-15mg of lubricant comprising magnesium stearate;

In another aspect an invention provides a solid oral pharmaceutical composition comprising:
a) 150-210mg of elagolix sodium;
b) 85-145mg of first filler comprising mannitol;
c) 90-200mg of second filler comprising Pharmaburst®;
d) 20-85mg of alkalizer comprising magnesium oxide or sodium caprylate;
a) wherein the particle size distribution of elagolix sodium is such that 90% of the elagolix sodium particles are between 15-30µm.

In another aspect an invention provides a solid oral pharmaceutical composition comprising:
a) 150-210mg of elagolix sodium;
b) 85-145mg of first filler comprising mannitol;
c) 90-200mg of second filler comprising Pharmaburst®;
d) 20-85mg of alkalizer comprising magnesium oxide or sodium caprylate;
wherein the w/w ratio of elagolix sodium to Pharmaburst® is 1:0.50 to 1:1.

In another aspect an invention provides a solid oral pharmaceutical composition comprising:
a) 150-210mg of elagolix sodium;
b) 85-145mg of first filler comprising mannitol;
c) 90-200mg of second filler comprising Pharmaburst®;
d) 20-85mg of alkalizer comprising magnesium oxide or sodium caprylate;
wherein the w/w ratio of elagolix sodium to magnesium oxide is 1:0.10 to 1:0.20 and w/w ratio of elagolix sodium to sodium caprylate is 1:0.30 to 1:0.50.

In another aspect an invention provides a solid oral pharmaceutical composition comprising:
a) 150-210mg of elagolix sodium;
b) 85-145mg of first filler comprising mannitol;
c) 90-200mg of second filler comprising Pharmaburst®;
d) 20-85mg of alkalizer comprising magnesium oxide or sodium caprylate;
wherein the bulk density of lubricated blend is from about 0.46 g/ml to about 0.6 g/ml and tapped density of lubricated blend is ranging from about 0.6 g/ml to about 0.8 g/ml.

In another aspect an invention provides a solid oral pharmaceutical composition comprising:
a) 150-210mg of elagolix sodium;
b) 85-145mg of first filler comprising mannitol;
c) 90-200mg of second filler comprising Pharmaburst®;
d) 20-85mg of alkalizer comprising magnesium oxide or sodium caprylate;
wherein at least 90% of elagolix sodium dissolves within 45 minutes in a 900 ml phosphate buffer of pH 6.8 at 50 rpm with paddle or within 60 minutes in 900ml 0.1 N HCl at 50 rpm with paddle.

In another aspect, an invention provides the process for producing a pharmaceutical solid dosage form which comprises steps of:
a) mix elagolix sodium, mannitol, magnesium oxide or sodium caprylate or magnesium citrate or sodium citrate or poloxamer or sodium lauryl sulphate or polysorbate 80 and colloidal silicon dioxide;
b) load ingredients of step (a) in double cone blender and blended for 15 minutes;
c) add magnesium stearate into above ingredients and blend for 15 minutes;
d) load material of step (c) in roller compactor for roller compaction and perform sizing;
e) sift Pharmaburst®, croscarmellose sodium, colloidal silicon dioxide through 20# and add into step-d material and blend it for 10 minutes;
f) add magnesium stearate into above ingredients and blend for 5 minutes;
g) compress the lubricated blend obtained in step (f) on compression machine into tablet and the tablet is further film coated.

Another aspect of an invention provides pharmaceutical composition of the present invention in the manufacture of a medicament for the management of moderate to severe pain associated with endometriosis.

DETAILED DESCRIPTION OF THE INVENTION

The term “composition”, as in solid pharmaceutical composition, is intended to encompass a drug product comprising elagolix or its pharmaceutically acceptable salts thereof, and other inert ingredient(s). Pharmaceutical composition of the invention include, but is not limited to, granules, tablets, immediate release tablets, caplets, capsules and the like. Preferably, the pharmaceutical composition refers to tablets and capsules. More preferably, the pharmaceutical composition refers to immediate release oral tablets, which may be uncoated or film coated.

The term “excipient”, means a pharmacologically inactive component such as a filler, alkalizer or anti-gelling agent, glidant, lubricant, binder, disintegrant and coloring agent or the like.

The term “Elagolix” is used in broad sense to include not only " Elagolix" per se but also its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, derivatives, isomers, polymorphs, prodrugs thereof, and also its various crystalline and amorphous forms. According to the present invention elagolix sodium is present in an amount from 25 to 45% by weight based on total weight of the composition, preferably, 25% to 40% w/w, more preferably 30% to 40%, most preferably 30% to 37% w/w.

The term "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counter ions including sodium, mesylate, fumarate, maleate, phosphate, L-tartrate, citrate, acetate, oxalate, and sulfate.

The term “bulk density” as used herein according to the present invention is bulk density of a powder or granules and is the ratio of the mass of an untapped powder or granules sample and its volume including the contribution of the interparticulate void volume. The bulk density of lubricated blend according to the present invention is from 0.2 g/ml to 1 g/ml, preferably from 0.3 g/ml to 1 g/ml more preferably from 0.3 g/ml to 0.8 g/ml and most preferably the bulk density of lubricated blend is 0.4 g/ml to 0.7 g/ml, 0.46 g/ml to about 0.6 g/ml and more specifically 0.54 g/ml.

The term “tapped density” as used herein according to the present invention is an increased bulk density attained after mechanically tapping a container containing the powder sample. The tapped density of lubricated blend according to the present invention is from 0.5 g/ml to 1 g/ml, preferably from 0.5 g/ml to 0.9 g/ml, more preferably 0.6 g/ml to 0.9 g/ml and most preferably the tapped density of lubricated blend is 0.6 g/ml to 0.87g/ml, 0.6 g/ml to 0.8g/ml and more specifically 0.69 g/ml.

The term “degradation product” are unwanted chemicals that can develop during the manufacturing, transportation, and storage of drug products and can affect the efficacy of pharmaceutical products.

The dissolution is performed as per conditions mentioned or provided in office of generic drugs dissolution database and as determined by the USP. The dissolution profile of tablets dosage form was measured in 900 ml phosphate buffer of pH 6.8 at 50 rpm, Paddle and in 900 ml 0.1 N HCl at 50 rpm, paddle for 200mg strength of elagolix.

The term “about” is used herein to mean approximately, roughly, around, or in the regions of. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 10 percent.

The term “loss on drying” is a widely used test method to determine the water content of a sample, although occasionally it may refer to the loss of any volatile matter from the sample. The step of drying is obtained by heating the granules to a temperature above room temperature and maintaining the elevated temperature, until the LOD of the granules reaches a desired value.

The term "particle(s)" as used herein refers to individual particles of elagolix sodium or pharmaceutically acceptable salt thereof, whether the particles exist singly or are agglomerated. The term “particle size” of elagolix sodium having a particle size distribution such that more than 90% of the particles are between 10µm-40µm and most preferably 10µm–35µm, 15µm-35µm, 15µm-30µm. The particle size of elagolix sodium was measured using a Malvern light scattering technique.

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 the acceptable limit.

The term "diluent" or "filler" as used herein is defined as an inert agent designed to increase the weight and/or the size of the pharmaceutical composition and to improve dissolution, fillers according to present invention contains first filler and second filler, examples of fillers include but not limited to microcrystalline cellulose, silicified MCC, microfine cellulose, anhydrous lactose, lactose monohydrate, mannitol, Pharmaburst and mixtures thereof. First filler is present in an amount from 15-30% and preferably from 18-25%, second filler is present in an amount from 15-35% and preferably from 20-32%. Preferred fillers according to the present invention are Pharmaburst and mannitol.

The term “Pharmaburst” as used herein is used as filler which contains mannitol, sorbitol, maltitol, crospovidone, silica, copovidone.

The term "binder" as used herein is defined as an agent able to bind particles which cannot be bound only by a compression force. Examples of binders include, but are not limited to acacia, dextrin, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose sodium, povidone and/ or mixtures thereof.

The term "alkalizer" or “anti-gelling agent” as used herein is defined as a compound used to improve solubility or dissolution of the product. The pharmaceutical composition of present invention may further comprise an ‘anti-gelling agent’. Examples of anti-gelling agent include, but are not limited to calcium carbonate, disodium hydrogen phosphate, trisodium orthophosphate, sodium hydroxide, sodium carbonate, potassium hydroxide, sodium bicarbonate, dipotasium carbonate, tromethamine, aluminum trihydroxide, magnesium dihydroxide, aluminium oxide, magnesium oxide, sodium caprylate or mixture thereof. Preferably, the anti-gelling agent is magnesium oxide or sodium caprylate. Anti-gelling agent is present in an amount from 2 to 20%, preferably, the amount of anti-gelling agent is from 2-15% w/w, and more preferably anti-gelling agent is from 3 to 15%, preferred anti-gelling agent according to the present invention is magnesium oxide or sodium caprylate.

Preferred alkalizers according to the present invention is magnesium oxide or sodium caprylate or Magnesium citrate or Sodium citrate or like thereof.

The term "solubilizer” as used herein is used to improve solubility or dissolution of the product. The pharmaceutical composition of present invention may further comprise a “solubilizer”. Examples of “solubilizer” include, but not limited to sodium lauryl sulfate, poloxamer, polysorbate and docusate sodium.

The term "disintegrant" as used herein is defined as an accelerating agent of the disintegration of the tablet and the dispersion of the active ingredient in water or gastrointestinal fluids. Examples of disintegrants according to present invention include, but not limited to croscarmellose sodium, carboxymethyl cellulose calcium, crospovidone, polacrilin potassium, sodium starch glycolate and/or combinations thereof. Disintegrant is present in an amount from 2 to 8% w/w, preferably, the amount of disintegrant is from 2% to 7% w/w, more preferably, the amount of disintegrant is from 3% to 6% w/w, preferred disintegrant according to the present invention is croscarmellose sodium.

The term “glidant” as used herein is defined as an agent improving the fluidity of the powder and thus the filling of the compression chamber of the tablet press. Examples of glidant include, but are not limited to calcium silicate, magnesium silicate, magnesium trisilicate, talc and colloidal silicon dioxide or mixtures thereof. Glidant is present in an amount from 1 to 5%, preferred glidant according to the present invention is colloidal silicon dioxide.

The term "lubricant" as used herein is defined as an agent able to decrease adhesion of a powder to punches and friction between particles. Examples of lubricants according to present invention include, but are not limited to stearic acid, zinc stearate, sodium stearyl fumarate, magnesium stearate. Lubricant is present in an amount from 0.5 to 6%, preferably, the amount of lubricant is from 1-5% w/w, preferred lubricant according to the present invention is magnesium stearate.

The term "coated tablet" as used herein is defined as a tablet provided with a coating layer is preferable to achieve long-term storage stability and prevent degradation due to light and the like. The coating layer comprise pharmaceutical additives, such as a coating agent, plasticizer, dispersant, defoaming agent, and the like, usually used for coating (for providing a coat to) orally administrable pharmaceutical preparations. Colorants are added to the coating agent for coating the tablet. Examples of film coating material includes opadry, one-step film coating system which combines polymer, plasticizer, opacifier and pigment, as required, in a dry concentrate. Examples of opadry coating material according to present invention include, but not limited to opadry pink, opadry orange, opadry white.

Composition of opadry orange to light orange contains polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide red, opadry pink to light pink contains polyvinyl alcohol, polyethylene glycol, talc, titanium oxide and carmine.

In one embodiment, the invention relates to a solid pharmaceutical composition comprising elagolix sodium with one or more pharmaceutically acceptable excipients.

In another embodiment there is provided a solid pharmaceutical composition comprising:
a) 30-37% of elagolix or pharmaceutically acceptable salts;
b) 40-55% of filler comprising mannitol and Pharmaburst®;
c) 3-15% of alkalizer selected from magnesium oxide or sodium caprylate; wherein the particle size distribution of elagolix sodium is such that 90% of the elagolix sodium particles are between 15-30µm.

In one embodiment there is provided a solid pharmaceutical composition comprising:
a) 30-37% of elagolix sodium;
b) 18-25% of first filler comprising mannitol;
c) 20-32% of second filler comprising Pharmaburst®;
d) 3-13% of alkalizer comprising magnesium oxide or sodium caprylate; wherein the particle size distribution of elagolix sodium is such that 90% of the particles are between 15-30µm.

In another embodiment there is provided a solid pharmaceutical composition comprising:
a) 30-37% of elagolix sodium;
b) 18-25% of first filler comprising mannitol;
c) 20-32% of second filler comprising Pharmaburst®;
d) 3-13% of alkalizer comprising magnesium oxide or sodium caprylate; wherein the w/w ratio of elagolix sodium to Pharmaburst® is 1:0.50 to1:1.

In one embodiment there is provided a solid pharmaceutical composition comprising:
a) 30-37% of elagolix sodium;
b) 18-25% of first filler comprising mannitol;
c) 20-32% of second filler comprising Pharmaburst®;
d) 3-13% of alkalizer comprising magnesium oxide or sodium caprylate;
e) 3-6% of disintegrant comprising croscarmellose sodium;
f) 1-5% of glidant comprising colloidal silicon dioxide;
g) 1-5% of lubricant comprising magnesium stearate; wherein the w/w ratio of elagolix sodium to Pharmaburst® is 1:0.50 to1:1.

In another embodiment there is provided a solid pharmaceutical composition comprising:
a) 30-37% of elagolix sodium;
b) 18-25% of first filler comprising mannitol;
c) 20-32% of second filler comprising Pharmaburst®;
d) 3-13% of alkalizer comprising magnesium oxide or sodium caprylate; wherein the w/w ratio of elagolix sodium to magnesium oxide is 1:0.10 to 1:0.20 and w/w ratio of elagolix sodium to sodium caprylate is 1:0.30 to1:0.50.

In one embodiment there is provided a solid pharmaceutical composition comprising:
a) 30-37% of elagolix sodium;
b) 18-25% of first filler comprising mannitol;
c) 20-32% of second filler comprising Pharmaburst®;
d) 3-13% of alkalizer comprising magnesium oxide or sodium caprylate; wherein the bulk density of lubricated blend is from about 0.46 g/ml to about 0.6 g/ml and tapped density of lubricated blend is ranging from about 0.6 g/ml to about 0.8 g/ml.

In another embodiment there is provided a solid pharmaceutical composition comprising:
a) 30-37% of elagolix sodium;
b) 18-25% of first filler comprising mannitol;
c) 20-32% of second filler comprising Pharmaburst®;
d) 3-13% of alkalizer comprising magnesium oxide or sodium caprylate; wherein at least 90% of elagolix sodium dissolves within 45 minutes in 900ml phosphate buffer of pH 6.8 at 50 rpm with paddle or within 60 minutes in 900ml 0.1 N HCl at 50 rpm with paddle.

In one embodiment there is provided a solid pharmaceutical composition comprising:
a) 150-210mg of elagolix or pharmaceutically acceptable salts;
b) 170-340mg of filler comprising mannitol and Pharmaburst®;
c) 20-85mg of alkalizer selected from magnesium oxide or sodium caprylate; wherein the particle size distribution of elagolix sodium is such that 90% of the elagolix sodium particles are between 15-30 µm.

In another embodiment an invention provides a solid oral pharmaceutical composition comprising:
a) 150-210mg of elagolix or pharmaceutically acceptable salts;
b) 170-340mg of filler comprising mannitol and Pharmaburst®;
c) 20-85mg of alkalizer comprising magnesium oxide or sodium caprylate or magnesium citrate or sodium citrate;
d) 1-4mg of solubilizer comprising poloxamer or sodium lauryl sulphate or polysorbate 80
e) 20-35mg of disintegrant comprising croscarmellose sodium;
f) 8-15mg of glidant comprising colloidal silicon dioxide;
g) 8-15mg of lubricant comprising magnesium stearate;

In another embodiment there is provided a solid pharmaceutical composition comprising:
a) 150-210mg of elagolix or pharmaceutically acceptable salts;
b) 170-340mg of filler comprising mannitol and Pharmaburst®;
c) 20-85mg of alkalizer comprising magnesium oxide or sodium caprylate;
d) 20-35mg of disintegrant comprising croscarmellose sodium;
e) 8-15mg of glidant comprising colloidal silicon dioxide;
f) 8-15mg of lubricant comprising magnesium stearate; wherein the particle size distribution of elagolix sodium is such that 90% of the elagolix sodium particles are between 15-30 µm.

In one embodiment there is provided a solid pharmaceutical composition comprising:
a) 150-210mg of elagolix sodium;
b) 85-145mg of first filler comprising mannitol;
c) 90-200mg of second filler comprising Pharmaburst®;
d) 20-85mg of alkalizer comprising magnesium oxide or sodium caprylate;
wherein the particle size distribution of elagolix sodium is such that 90% of the elagolix sodium particles are between 15-30µm.

In another embodiment there is provided a solid pharmaceutical composition comprising:
a) 150-210mg of elagolix sodium;
b) 85-145mg of first filler comprising mannitol;
c) 90-200mg of second filler comprising Pharmaburst®;
d) 20-85mg of alkalizer comprising magnesium oxide or sodium caprylate; wherein the w/w ratio of elagolix sodium to Pharmaburst® is 1:0.50 to 1:1.

In one embodiment there is provided a solid pharmaceutical composition comprising:
a) 150-210mg of elagolix sodium;
b) 85-145mg of first filler comprising mannitol;
c) 90-200mg of second filler comprising Pharmaburst®;
d) 20-85mg of alkalizer comprising magnesium oxide or sodium caprylate; wherein the w/w ratio of elagolix sodium to magnesium oxide is 1:0.10 to 1:0.20 and w/w ratio of elagolix sodium to sodium caprylate is 1:0.30 to 1:0.50.

In another embodiment there is provided a solid pharmaceutical composition comprising:
a) 150-210mg of elagolix sodium;
b) 85-145mg of first filler comprising mannitol;
c) 90-200mg of second filler comprising Pharmaburst®;
d) 20-85mg of alkalizer comprising magnesium oxide or sodium caprylate;
wherein the bulk density of lubricated blend is from about 0.46 g/ml to about 0.6 g/ml and tapped density of lubricated blend is ranging from about 0.6 g/ml to about 0.8 g/ml.

In one embodiment there is provided a solid pharmaceutical composition comprising:
a) 150-210mg of elagolix sodium;
b) 85-145mg of first filler comprising mannitol;
c) 90-200mg of second filler comprising Pharmaburst®;
d) 20-85mg of alkalizer comprising magnesium oxide or sodium caprylate;
wherein at least 90% of elagolix sodium dissolves within 45 minutes in a 900 ml phosphate buffer of pH 6.8 at 50 rpm with paddle or within 60 minutes in 900ml 0.1 N HCl at 50 rpm with paddle.

In another embodiment, an invention provides the process for producing a pharmaceutical solid dosage form which comprises steps of:
a) mix elagolix sodium, mannitol, magnesium oxide or sodium caprylate or magnesium citrate or sodium citrate or poloxamer or sodium lauryl sulphate or polysorbate 80 and colloidal silicon dioxide;
b) blend ingredients of step (a) in double cone blender and blend for 15 minutes;
c) add magnesium stearate into above ingredients and blend for 15 minutes;
d) load material of step (c) in roller compactor and perform sizing;
e) sift Pharmaburst®, croscarmellose sodium, colloidal silicon dioxide through 20 mesh screen and add into step-d material and blend it for 10 minutes;
f) add magnesium stearate into above ingredients and blend for 5 minutes;
g) compress the lubricated blend obtained in step (f) on compression machine into tablet and the tablet is further film coated.

It has been found that the pharmaceutical composition of the present invention is having improved dissolution profile and stability coupled with simple manufacturing process at industrial scale and it is bioequivalent to commercially available ORILISSA® tablets.

The following examples serve to illustrate the embodiments of the present invention. However, they do not intend to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known in the industry.

Examples: The following examples further illustrate the invention and do not limit the scope of the invention.

Example 1: Elagolix sodium tablets composition given in Table 1:

Table – 1:
S. No Material name Function mg/tab
(for 200 mg) mg/tab
(for 150 mg) %w/w
1 Elagolix sodium Active moiety 207.00 155.20 33.17
2 Mannitol 200 SD Filler 117-143
87-107.31 20-21.48
3 Pharmaburst® Filler 161-196.90 120-147.68 27-29.58
4 Magnesium oxide Alkalizer 27-33 20-24.75 4-4.96
5 Croscarmellose Sodium Disintegrant 27-33 20-24.75 4-4.96
6 Colloidal silicon dioxide Glidant 10-13.20
8-9.90
1-1.98
7 Magnesium stearate Lubricant 10-13.20
8-9.90 1-1.98
Core tablet weight 560-639.3 420-479.48 96-97
Film coating 21-26.5 16-20 3-4
Weight of coated tablets 582-666 436-500 100

Manufacturing process:
a) Mix elagolix sodium, mannitol, magnesium oxide and colloidal silicon dioxide;
b) Blend ingredients of step (a) in double cone blender and blend for 15 minutes;
c) Add magnesium stearate into above ingredients and blend for 15 minutes;
d) Load material of step (c) in roller compactor and perform sizing;
e) Sift Pharmaburst®, croscarmellose sodium, colloidal silicon dioxide through 20 mesh screen and add into step-d material and blend it for 10 minutes;
f) Add magnesium stearate into above ingredients and blend for 5 minutes;
g) Compress the lubricated blend obtained in step (f) on compression machine into tablet and the tablet is further film coated.

Example 2: Elagolix sodium tablets composition given in Table 2:

Table 2:

S. No Material name Function mg/tab
(for 200 mg) mg/tab
(for 150 mg) %w/w
1 Elagolix sodium Active moiety 207.0 155.2 33.17
2 Mannitol 200 SD Filler 130.0 97.55 20.83
3 Pharmaburst® Filler 134 100.5 21.47
4 Sodium caprylate Alkalizer 75 56.25 12.01
5 Croscarmellose Sodium Disintegrant 30.0 22.50 4.80
6 Colloidal silicon dioxide Glidant 12 9.00 1.92
7 Magnesium stearate Lubricant 12 9.00 1.92
Core tablet weight 600 mg 450 96.16
Film coating 24 18 3.84
Weight of coated tablets 624.0 mg 468 100
Manufacturing process:
a) Mix elagolix sodium, mannitol, sodium caprylate and colloidal silicon dioxide;
b) Blend ingredients of step (a) in double cone blender and blend for 15 minutes;
c) Add magnesium stearate into above ingredients and blend for 15 minutes;
d) Load material of step (c) in roller compactor and perform sizing;
e) Sift Pharmaburst®, croscarmellose sodium, colloidal silicon dioxide through 20 mesh screen and add into step-d material and blend it for 10 minutes;
f) Add magnesium stearate into above ingredients and blend for 5 minutes;
g) Compress the lubricated blend obtained in step (f) on compression machine into tablet and the tablet is further film coated.

Example 3: Elagolix sodium tablets composition given in Table 3:
Table 3:

S. No Material name Function mg/tab
(for 200 mg) mg/tab
(for 150 mg) %w/w
1 Elagolix sodium Active moiety 207.0 155.2 31.10
2 Mannitol 200 SD Filler 143 107.31 21.48
3 Pharmaburst® Filler 147.4 110.55 22.14
4 Sodium caprylate Alkalizer 82.5 61.87 12.39
5 Croscarmellose Sodium Disintegrant 33 24.75 4.96
6 Colloidal silicon dioxide Glidant 13.2 9.9 1.98
7 Magnesium stearate Lubricant 13.2 9.9 1.98
Core tablet weight 639.3 mg 479.48 96.03
Film coating 26.4 19.8 3.97
Weight of coated tablets 665.7 mg 499.28 100

Manufacturing process: Same as example 2

Example 4: Elagolix sodium tablets composition given in Table 4:
Table 4:

S. No Material name Function mg/tab
(for 200 mg) mg/tab
(for 150 mg) %w/w
1 Elagolix sodium Active moiety 207.0 155.2 35.55
2 Mannitol 200 SD Filler 117 87.80 20.09
3 Pharmaburst® Filler 120.6 90.45 20.71
4 Sodium caprylate Alkalizer 67.5 50.62 11.59
5 Croscarmellose Sodium Disintegrant 27 20.25 4.64
6 Colloidal silicon dioxide Glidant 10.8 8.1 1.85
7 Magnesium stearate Lubricant 10.8 8.1 1.85
Core tablet weight 560.7 mg 420.5 96.29
Film coating 21.6 16.2 3.71
Weight of coated tablets 582.3 mg 436.7 100

Manufacturing process: Same as example 2.
Example 5-6: Elagolix sodium tablets composition given in Table 5:
Table 5:
S. No Material name Function Example 5 in mg Example 6 in mg
150 200 150 200
1 Elagolix sodium Active 155.20 207 155.20 207
2 Mannitol 200 SD Filler 85-110 110-145 85-110 117-145
3 Pharmaburst® Filler 110-140 145-183 95-125 130-165
4 Magnesium oxide Alkalizer 15-30 25-35 - -
5 Magnesium citrate/ Sodium citrate Alkalizer - - 30-45 40-60
6 Poloxamer 407 / SLS/ Polysorbate 80 Solubilizer 1-3 2-4 - -
7 Croscarmellose Sodium Disintegrant 15-30 25-35 15-30 25-35
8 Colloidal silicon dioxide Glidant 7-12 8-16 7-12 8-16
9 Magnesium stearate Lubricant 15-22 18-28 15-22 18-28
Core tab weight (mg) 403.2-502.2 540-653 402.2-499 545-656
10 Film coating Coating 15-22 18-30 15-22 18-30
Film coated Tablet weight 418.2-524.2 558-683 417-521 563-649

Manufacturing process:
a) mix elagolix sodium, mannitol, magnesium oxide or magnesium citrate or sodium citrate or poloxamer or sodium lauryl sulphate or polysorbate 80 and colloidal silicon dioxide;
b) blend ingredients of step (a) in double cone blender and blend for 15 minutes;
c) add magnesium stearate into above ingredients and blend for 15 minutes;
d) load material of step (c) in roller compactor and perform sizing;
e) sift Pharmaburst®, croscarmellose sodium, colloidal silicon dioxide through 20 mesh screen and add into step-d material and blend it for 10 minutes;
f) add magnesium stearate into above ingredients and blend for 5 minutes;
g) compress the lubricated blend obtained in step (f) on compression machine into tablet and the tablet is further film coated.

Dissolution study: The dissolution profile of the tablets (200mg, 150mg) prepared using quantitative composition as mentioned in example 1-4 is shown in Table 5 and 6.

Table 5: Dissolution profile of commercially marketed elagolix sodium tablets (ORILISSA®) and Example 1, Example 2 for 200mg tablets

Table 5: 0.1 N HCl Paddle 50 rpm 900ml
Strength 200 mg
Product ORILISSA Example 1 Example 2
Time points (minutes) % Elagolix sodium released (±5%)
10 13 15 16
15 29 29 -
30 64 63 65
45 85 82 83
60 98 94 90

Table 6: 6.8 Buffer, Paddle 50rpm, 900ml: Dissolution profile of commercially marketed elagolix sodium tablets (ORILISSA®) and Example 1, Example 2 for 200mg tablets and example 1 for 150mg tablets.
Strength 200 mg 150 mg
Product ORILISSA Example 1 Example 2 ORILISSA Example 1
Time points (minutes) % Elagolix sodium released (±5%)
10 33 41 51 46 43
15 50 61 - 67 66
20 - - - 83 -
30 87 77 101 99 98
45 100 97 104 100 102
60 101 99 103 100 103

Stability studies:
Tablet dosage form prepared in Example 1 was subjected to Accelerated stability testing as per the ICH guidelines at temperature 40°±2°C and relative humidity of 75%±5% for 6 months and evaluated the data at 1.5 months, 3 months and 6 months. The tablet dosage form was placed in a high density polyethylene (HDPE) bottles exposed to above mentioned condition and then evaluated for Assay %, Water by KF, Related substances and Dissolution which is shown in Table 7:

Table 7: Results of Assay, Water by KF, Dissolution data and Related substances on stability samples for Example 1:

Elagolix sodium tablets 150 mg:
Initial 40°C/75%RH
1.5M 40°C/75%RH
3M 40°C/75%RH
6M
Assay (By HPLC)
% Labeled amount 101.2
101.0 100.1 100.5
Water content (%w/w) 3.11 3.99 4.21 4.31
Dissolution (By HPLC) : pH 6.8 phosphate buffer, 900ml, 100 rpm, Basket (#20 mesh)
Dissolution (45 minutes) 97% (94-100) 99%(96-102) 97%(96-97) 98% (96-100)
Related Substances (% w/w, By HPLC)
Impurity A
3-[(2R)-2-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl-1-{[2-fluoro-6-(trifluoromethyl) phenyl] methyl}-6-methylpyrimidine-2,4-(1H,3H)-dione. 0.031 0.054 0.077 0.086
Impurity D
5-(2-fluoro-3-methoxyphenyl)-1-{[2-fluoro-6-(trifluoromethyl)Phenyl]methyl}-6-methyl-3-[(2R)-2-(methylamino)-2-phenylethyl)pyrimidine-2,4(1H,3H)-dione Below limit of quantification Below limit of quantification Not detected Not detected
Impurity E (R)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methyl-3-(2-(2-oxopyrrolidin-1-yl)-2-phenylethyl)pyrimidine-2,4(1H,3H)-dione. Below limit of quantification 0.055 0.104 0.115
Any unspecified degradation product
Not detected Below limit of quantification 0.05 0.05
Total impurities 0.031 0.109 0.228 0.251

Elagolix sodium tablets 200 mg:
Initial 40°C/75%RH
1.5M 40°C/75%RH
3M 40°C/75%RH
6M
Assay (By HPLC)
% Labeled amount 101.8 100.2 99.3 100.6
Water content (%w/w) 3.08 3.98 4.15 4.22
Dissolution (By HPLC) : pH 6.8 phosphate buffer, 900ml, 100 rpm, Basket (#20 mesh)
Dissolution (45 minutes) 99% (96-101) 99% (99-100) 97% (96-98) 99% (98-101)
Related Substances (% w/w, By HPLC)
Impurity A
3-[(2R)-2-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl-1-{[2-fluoro-6-(trifluoromethyl) phenyl] methyl}-6-methylpyrimidine-2,4-(1H,3H)-dione. Below limit of quantification 0.050 0.077 0.079
Impurity D
5-(2-fluoro-3-methoxyphenyl)-1-{[2-fluoro-6-(trifluoromethyl)Phenyl]methyl}-6-methyl-3-[(2R)-2-(methylamino)-2-phenylethyl)pyrimidine-2,4(1H,3H)-dione Below limit of quantification Below limit of quantification Below limit of quantification Below limit of quantification
Impurity E (R)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methyl-3-(2-(2-oxopyrrolidin-1-yl)-2-phenylethyl)pyrimidine-2,4(1H,3H)-dione. Below limit of quantification 0.048 0.099 0.102
Any unspecified degradation product
Not detected Not detected Not detected Not detected
Total impurities Not detected 0.098 0.176 0.181

The present formulation clearly indicates excellent chemical stability upon storage at accelerated stability conditions at 40°±2°C and 75%±5% relative humidity for six months. ,CLAIMS:WE CLAIM:

1. A pharmaceutical composition comprising:
a) about 30-37% of elagolix or pharmaceutically acceptable salts;
b) about 40-55% of filler comprising mannitol and Pharmaburst®;
c) about 3-15% of alkalizer selected from magnesium oxide, sodium caprylate;
d) optionally said composition is film coated; wherein the particle size distribution of elagolix sodium is such that about 90% of the elagolix sodium particles are between 15-30µm.

2. A pharmaceutical composition according to claim 1, wherein the Pharmaburst® comprises mannitol, sorbitol, maltitol, crospovidone, silica and copovidone.

3. A pharmaceutical composition according to claim 1, wherein the composition is prepared by dry granulation technique.

4. A pharmaceutical composition according to claim 1, wherein particle size distribution of elagolix sodium is such that about 90% of the elagolix sodium particles are between 20-30µm and 20-25µm in size.

5. A pharmaceutical composition comprising:
a) 150-210mg of elagolix or pharmaceutically acceptable salts;
b) 170-340mg of filler comprising mannitol and Pharmaburst®;
c) 20-85mg of alkalizer selected from magnesium oxide, sodium caprylate, magnesium citrate and sodium citrate;
d) 1-4mg of solubilizer selected from poloxamer, sodium lauryl sulphate and polysorbate 80;
e) 20-35mg of disintegrant comprising croscarmellose sodium;
f) 8-15mg of glidant comprising colloidal silicon dioxide;
g) 8-15mg of lubricant comprising magnesium stearate;

6. A pharmaceutical composition comprising:
a) about 30-37% of elagolix sodium; b) about 18-25% of first filler comprising mannitol; c) about 20-32% of second filler comprising Pharmaburst®; d) about 3-13% of alkalizer selected from magnesium oxide and sodium caprylate.

7. A pharmaceutical composition comprising:
a) about 150-210mg of elagolix or pharmaceutically acceptable salts; b) about 170-340mg of filler comprising mannitol and Pharmaburst®; c) about 20-85mg of alkalizer selected from magnesium oxide and sodium caprylate; wherein the particle size distribution of elagolix sodium is such that about 90% of the elagolix sodium particles are between 15-30 µm.

8. A pharmaceutical composition according to claim 7, wherein the composition further comprising: a) about 20-35mg of disintegrant comprising croscarmellose sodium; b) about 8-15mg of glidant comprising colloidal silicon dioxide; c) about 8-15mg of lubricant comprising magnesium stearate.

9. A pharmaceutical composition comprising: a) about 150-210mg of elagolix sodium; b) about 85-145mg of first filler comprising mannitol; c) about 90-200mg of second filler comprising Pharmaburst®; d) about 20-85mg of alkalizer selected from magnesium oxide and sodium caprylate.

10. A pharmaceutical composition according to claim 9, wherein the w/w ratio of elagolix sodium to Pharmaburst is 1:0.50 to 1:1.