DESC:Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
The term " Eltrombopag" 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 "particle size" refers to the cumulative volume size distribution tested by any conventionally recognized method, such as a laser diffraction method. The term D90 or d (0.9) means the size at which 90% by volume of the particles are finer.

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 "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 Eltrombopag 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 Eltrombopag 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 Eltrombopag 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 Eltrombopag or pharmaceutically acceptable salt thereof, and one or more pharmaceutical acceptable excipients; wherein the particle size D90 or d (0.9) of the Eltrombopag Olamine is greater than 95 microns and the disintegrant in an amount of 1 - 20% by weight based on total weight of the composition.

In one embodiment, the present invention relates to the oral stable dosage composition comprising Eltrombopag or its pharmaceutical salt thereof, one or more Diluents, Binder, Disintegrant, Lubricant and one or more pharmaceutical acceptable excipients or combinations thereof; wherein the particle size D90 or d (0.9) of the Eltrombopag Olamine is greater than 95 microns and the disintegrant in an amount of 1 - 20% by weight based on total weight of the composition.

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 compound (Eltrombopag) 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 another embodiment, the solid oral pharmaceutical composition is in the form of tablet comprising Eltrombopag or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients; wherein the particle size D90 or d (0.9) of the Eltrombopag Olamine is greater than 95 microns and the disintegrant in an amount of 1 - 20% by weight based on total weight of the composition.

In another embodiment, the solid oral pharmaceutical composition is in the form of capsule comprising Eltrombopag or pharmaceutically acceptable salts or derivatives thereof, and one or more pharmaceutically acceptable excipients; wherein the particle size D90 or d (0.9) of the Eltrombopag Olamine is greater than 95 microns and the disintegrant in an amount of 1 - 20% by weight based on total weight of the composition.

In another embodiment, the present invention relates to solid oral pharmaceutical composition comprising Eltrombopag or its pharmaceutical salt thereof, one or more diluents, lubricant, disintegrants, binders and one or more pharmaceutically acceptable excipients;
wherein the particle size d (0.9) of the Eltrombopag Olamine is greater than 95 microns and the disintegrant in an amount of 1 - 20% by weight based on total weight of the composition.

In 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 oral stable tablet dosage form composition comprising 5mg to 200mg of Eltrombopag 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 Eltrombopag, 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 Eltrombopag.

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 Eltrombopag 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.

In another embodiment, the present invention relates to the oral stable composition comprising Eltrombopag 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 idiopathic thrombocytopenic purpura (ITP), aplastic anemia and thrombocytopenia in patients with chronic hepatitis C and interferon therapy.

In another embodiment, the present invention relates to oral stable pharmaceutical composition comprising
(a) intragranular portion consisting of Eltrombopag or its pharmaceutically acceptable salt thereof, Diluents, Binder and one or more pharmaceutical acceptable excipients;
(b) Extra granular portion consisting of Diluents, Disintegrant, Lubricant and one or more pharmaceutical acceptable excipients or combinations thereof.

wherein the particle size D90 or d (0.9) of the Eltrombopag Olamine is greater than 95 microns and the disintegrant in an amount of 1 - 20% by weight based on total weight of the composition.

In another embodiment, the present invention relates to oral stable pharmaceutical composition comprising
(a) intragranular portion consisting of Eltrombopag or its pharmaceutically acceptable salt thereof, Mannitol, Microcrystalline cellulose, Povidone and optionally one or more pharmaceutical acceptable excipients;
(b) Extra granular portion consisting of Microcrystalline cellulose, Sodium starch glycolate, Magnesium stearate and optionally one or more pharmaceutical acceptable excipients or combinations thereof.

wherein the particle size D90 or d (0.9) of the Eltrombopag Olamine is greater than 95 microns and the disintegrant in an amount of 1 - 20% by weight based on total weight of the composition.

In another embodiment, the present invention relates to oral stable composition of Eltrombopag, wherein said composition comprises on a total of 100 % by weight:
(a) from about 15 % to about 35 % of Eltrombopag or its pharmaceutical salt thereof,
(b) from about 25 % to about 65 % of one or more diluents;
(c) from 1 % to about 20 % of disintegrant;
(d) from about 1 % to about 10 % binder;
(e) from about 0.5 % to about 4 % lubricant; and
(f) optionally one or more pharmaceutical acceptable excipients.
wherein the particle size D90 or d (0.9) of the Eltrombopag Olamine is greater than 95 microns.

In another embodiment, the present invention relates to oral stable composition of Eltrombopag, wherein said composition comprises on a total of 100 % by weight:
(a) from about 15 % to about 35 % of Eltrombopag or its pharmaceutical salt thereof,
(b) from about 5 % to about 20 % of Mannitol;
(c) from about 10 % to about 35 % of Microcrystalline cellulose;
(c) from 1 % to about 20 % of Sodium starch glycolate;
(d) from about 1 % to about 10 % Povidone;
(e) from about 0.5 % to about 4 % Magnesium stearate; and
(f) optionally one or more pharmaceutical acceptable excipients.
wherein the particle size D90 or d (0.9) of the Eltrombopag Olamine is greater than 95 microns.

In another embodiment, the weight ratio of Eltrombopag Olamine to the disintegrant 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: The Eltrombopag tablet composition of Example 1 are prepared by wet granulation.
S.No. Ingredients Functional Category Eltrombopag olamine Tablets
12.5 % w/w 25 % w/w 50 % w/w 75 % w/w
1 Eltrombopag olamine (D 90- more than 95 µm) Active 15.95 17.87 31.90 17.87 63.80 17.87 95.70 17.87
2 Mannitol Diluents 7.45 8.35 14.90 8.35 29.80 8.35 44.70 8.35
3 Microcrystalline cellulose 101 Diluents 14.85 16.64 29.70 16.64 59.40 16.64 89.10 16.64
4 Povidone K12 Binder 5.50 6.16 11.00 6.16 22.00 6.16 33.00 6.16
Binder Solution
3 Povidone K12 Binder 4.50 5.04 9.00 5.04 18.00 5.04 27.00 5.04
4 Purified Water Solvent q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
Extra granular
5 Microcrystalline cellulose 102 Diluents 25.25 28.29 50.50 28.29 101.00 28.29 151.50 28.29
9 Sodium starch glycolate type A Disintegrant 14.00 15.69 28.00 15.69 56.00 15.69 84.00 15.69
10 Magnesium stearate Lubricant 1.75 1.96 3.50 1.96 7.00 1.96 10.50 1.96
Total weight(mg) 89.25 100.00 178.50 100.00 357.00 100.00 535.50 100.00
Film Coating (4% w/w)
11 Opadry II White Coating agent 3.57 4%w/w build up 4%w/w build up 4%w/w build up -- 4%w/w build up
12 Opadry II Orange Coating agent -- 7.14
13 Opadry II Blue Coating agent -- -- 14.28
14 Opadry II pink Coating agent 21.42
15 Purified water Solvent Q.s Q.s Q.s Q.s
Coated Tablet Weight (mg) 92.82 185.64 371.28 556.92

BRIEF MANUFACTURING PROCESS OF EXAMPLE 1:
1. Brief Manufacturing Procedure:
Sifting:
I. Co-sift Eltrombopag Olamine drug substance, Mannitol, Povidone K12 and Microcrystalline cellulose 101 through 30 # mesh.
Wet Granulation:
II. Dissolve Povidone K12 in purified water and wet granulate the blend of step I in RMG
Drying and milling:
III. Dry the blend in FBD till to get LOD -1.2.5%w/w and mill through suitable quadro co mill for desired granules.
Prelubrication:
IV. Sodium starch glycolate type A and Microcrystalline cellulose 101 pass through #40 then blend with the materials of step III through suitable blender and mix for 15 mins.
Lubrication:
V. Magnesium stearate pass through #40 then blend with the materials of step IV through suitable blender and mix for 5 mins.
Compression:
VI. Compress the above lubricated blend by using suitable punches.
Film Coating:
Prepare the coating dispersion by dispersing Opadry II w.r t strength wise in purified water under stirring and coat the compressed tablets of step-VI with the coating dispersion.
,CLAIMS:1) A stable pharmaceutical composition comprising Eltrombopag or pharmaceutically acceptable salt contain particle size D90 of the Eltrombopag is greater than 95 microns and one or more pharmaceutically acceptable excipient contain disintegrant in an amount of 1- 20% by weight based on total weight of the composition.

2) The stable pharmaceutical composition as claimed in claim 1, where in the composition comprising of;
(a) 15-35% of Eltrombopag or its pharmaceutical salt;
(b) 25 % to 65 % of diluents;
(b) 1 % to 20 % of disintegrant;
(c) 1 % to 15 % of binder;
(d) 0.5 % to 8 % of lubricant; and
(e) optionally one or more pharmaceutical acceptable excipients.

3) The stable pharmaceutical composition as claimed in claim 1, where in the composition comprising Eltrombopag or a pharmaceutically acceptable salt ranging from about 5 mg to about 200 mg and one or more pharmaceutically acceptable excipients.

4) The stable pharmaceutical composition as claimed in claim 1, pharmaceutical composition having dissolution more than 90% within 45 minutes.

5) The stable pharmaceutical composition as claimed in claim 1, where composition is prepared by granulation method preferably wet granulation method.

6) The stable pharmaceutical composition as claimed in claim 1, where composition is a solid oral dosage form contain tablet or capsule.

7) The process for the preparation of pharmaceutical composition as claimed in claim 1, co-sift Eltrombopag olamine, mannitol, povidone and microcrystalline cellulose, prepare the binder solution with Povidone, perform the FBD, pre-lubrication with Sodium starch glycolate and Microcrystalline cellulose, lubrication with Magnesium stearate, Compress the lubricated blend by using suitable punches.

8) A stable pharmaceutical composition as claimed in claim 1, where in the composition is used for the treatment of idiopathic thrombocytopenic purpura (ITP), aplastic anemia and thrombocytopenia in patients with chronic hepatitis C and interferon therapy.