FIELD OF THE INVENTION

The present invention relates to stable pharmaceutical compositions comprising an ADP-receptor antagonist as an active agent, process of preparation thereof and method of using the same. Particularly the present invention relates to pharmaceutical compositions comprising ticagrelor, process of preparation and method of using the same.

BACKGROUND OF THE INVENTION

The main role of blood platelets is to ensure primary haemostasis, which means the maintenance of blood vessel integrity and the rapid cessation of bleeding in the event of loss of vascular integrity. They are also responsible for the formation of pathogenic thrombi at sites of rupture or erosion of an atherosclerotic plaque, promoting atherothrombotic diseases including acute coronary syndromes, ischaemic stroke and peripheral artery disease. Platelets also play an important role in inflammation and can influence the phenotype of other blood and vascular cells, thereby contributing to many other non-haemostatic disorders, from cystic fibrosis and arthritis to diabetes, atherosclerosis and cancer. Adenosine 5'-disphosphate (ADP) plays crucial roles in the physiological process of haemostasis and in the development and extension of arterial thrombosis. ADP is stored in dense bodies inside blood platelets and is released upon platelet activation. Adenine nucleotides act on platelets through three distinct P2 receptors: two are G protein-coupled ADP receptors, namely the P2Y1 and P2Y12 receptor subtypes, while the P2X1 receptor ligand-gated cation channel is activated by ATP.

The P2Y1 receptor is absolutely required for ADP-induced platelet aggregation. Its pharmacological inhibition or genetic deficiency results in complete absence of platelet aggregation and shape change in response to ADP. Its tissue distribution is very limited, although not entirely restricted to platelets as it is also present in brain, glial cells and possibly in vascular smooth muscle cells, where it could contribute to vessel contraction. This receptor is defective in patients with selective defects in platelet activation by ADP. It is the molecular target of the antiplatelet drugs clopidogrel and prasugrel, two thienopyridine compounds that covalently bind to the receptor, and of ticagrelor, cangrelor (AR-C69931MX) and elinogrel (PRT060128), which are competitive antagonists of the receptor. The P2Y12 receptor is responsible for completion of the platelet aggregation response to ADP initiated by P2Y1 {Beatrice et al, "P2 receptors and platelet function", Purinergic Signal. 2011 September; 7(3): 293-303.}. Ticagrelor (also referred to as AZD6140) and a cyclopentyltriazolopyrimidine is the first reversibly binding oral P2Y12 receptor antagonist that blocks ADP-induced platelet aggregation. UnJike thienopyridines, which irreversibly bind to the P2Y12 receptor for the lifetime of the platelet, ticagrelor binds reversibly to the receptor and exhibits rapid onset and offset of effect, which closely follow drug exposure levels.

Ticagrelor is chemically known as (IS,2S,3R)5S)-3-[7-{[(IR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[l,213]-tria2olo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol. The empirical formula of ticagrelor is C23H28F2N6O4S and its molecular weight is 522.57. Ticagrelor is a crystalline powder with an aqueous solubility approximately 10 ug/mL at room temperature. The chemical structure of ticagrelor is: Ticagrelor is currently marketed as Brilinta® tablets indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) (unstable angina, non-ST elevation myocardial infarction, or ST elevation myocardial infarction). The tablet formulation contains contain 90 mg of ticagrelor and the following ingredients: mannitol, dibasic calcium phosphate, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, talc, polyethylene glycol 400, and ferric oxide yellow. Ticagrelor is disclosed as an ADP-receptor antagonist in PCT Patent Application number PCT/SE99/02256 (publication number WO2000/34283) and International Patent Application number PCT/SEO1 /01239 (publication number WO2001/92262). US 7,265,124 patent discloses various polymorphs of ticagrelor characterized by an X-ray powder diffraction pattern containing specific peaks of high intensity.

Further, the said patent also discloses anhydrous and amorphous forms of ticagrelor. US 8,425,934 patent discloses pharmaceutical compositions comprising ticagrelor, a filler consisting essentially of a mixture of mannitol and dibasic calcium phosphate dihydrate; a binder consisting essentially of hydroxypropyl cellulose; a disintegrant consisting essentially of sodium starch glycolate; and one or more lubricants. The major objective of the said patent was to enhance the bioavailability of the active agent. It is stated in the prosecution of the said patent that while developing the compositions, the manufacturing process resulted in disappointing yield, variable granule size distribution, poor tablet compression properties, poor stability of the formulated product and low bioavailability. The US 2008/0045548 Al patent publication discloses pharmaceutical compositions comprising ticagrelor, one or more fillers selected from mannitol, sorbitol, maltodextrin, maltose, dextrin, dibasic calcium phosphate dihydrate, dibasic calcium phosphate anhydrate, partially pre-gelled starch, and tribasic calcium phosphate, or any mixture thereof; one or more binders selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, alginic acid, carboxymethylcellulose sodium, copovidone, and methylcellulose, or any mixture thereof, optionally one or more disintegrants selected from sodium starch glycollate, croscarmellose sodium, and crospovidone, or any mixture thereof, and optionally one or more lubricants.

US patent publication US 2013/0028938 Al discloses a solid pharmaceutical dosage form comprising ticagrelor or a pharmaceutical^ acceptable salt or ester thereof, characterized in that at least 90 % by volume of the ticagrelor particles have a particle size in the range of 1 [im to 150 |im. PCT WO2012/164286 publication discloses co-crystal of ticagrelor with acetyl salicylic acid wherein the term co-crystal (or cocrystal) refers to a multicomponent system in which there exists a host API (active pharmaceutical ingredient) molecule or molecules and a guest (or co-former) molecule or molecules. PCT WO2013/079589 discloses crystalline form of ticagrelor characterized by an X-ray powder diffraction pattern. PCT WO2014/059955 discloses solid oral pharmaceutical formulation containing ticagrelor comprising at least one non-hygroscopic filler and/or at least one non- hygroscopic binder. The disclosure made in the prior art result in compositions with disappointing yield, variable granule size distribution, poor tablet compression properties, poor stability of the formulated product and low bioavailability. Inventors of the instant invention with considerable expense of intellectual effort and careful experimentation have developed compositions comprising ticagrelor which are simple and economical, and resolve the problems of the prior art stated above.

SUMMARY OF THE INVENTION

An aspect of the present invention provides stable pharmaceutical compositions comprising an ADP-receptor antagonist as an active agent(s), atleast one excipient(s) which is not a sugar alcohol, optionally with one or more other pharmaceutically acceptable excipient(s). An aspect of the present invention provides stable pharmaceutical compositions comprising an ticagrelor as an active agent(s), atleast one excipient(s) which is not a sugar alcohol, optionally with one or more other pharmaceutically acceptable excipient(s). Another aspect of the present invention provides stable pharmaceutical compositions comprising ticagrelor as an active agent(s), wherein atleast one excipient(s) which is not a sugar alcohol is a saccharide, optionally with one or more pharmaceutically acceptable excipient(s). Another, aspect of the present invention provides stable pharmaceutical compositions comprising ticagrelor as an active agent(s), atleast one saccharide(s) selected from group comprising monosaccharides, disaccharides, oligosaccharides and polysaccharides, optionally with one or more pharmaceutically acceptable excipients. An aspect of the present invention provides stable pharmaceutical compositions comprising ticagrelor as an active agent(s), acetyl salicylic acid as another active agent(s), atleast one saccharide(s) selected from group comprising monosaccharides, disaccharides, oligosaccharides and polysaccharides, optionally with one or more pharmaceutically acceptable excipients.

In an aspect, the present invention provides process for the preparation of stable oral pharmaceutical compositions, wherein the process comprises of the following steps:

(i) treating ticagrelor with atleast one excipient other than sugar alcohol,

(ii) optionally adding one or more other pharmaceutically acceptable excipients, and

(iii) formulating the material of step (i) and (ii) into a suitable dosage form.

In an aspect, the present invention provides process for the preparation of stable oral pharmaceutical compositions, wherein the process comprises of the following steps:

(i) treating ticagrelor with one or more saccharide(s),

(ii) treating acetyl salicylic acid with pharmaceutically acceptable excipients,

(iii) optionally adding one or more pharmaceutically acceptable excipients, and

(iv) formulating the material of step (i), (ii) and (iii) into a suitable dosage form.

An aspect of the present invention relates to method of using such compositions indicated to treat diseases caused by thrombus or embolus, for example, diseases induced by platelet aggregation, including stable or unstable angina; cardiovascular or cerebrovascular associated disorders.

DETAILED DESCRIPTION OF THE INVENTION

The term 'stable' 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. Further, the term 'stable' also optionally refers to formulations that contain polymorphically stable active ingredient. The phrase "substantially pure polymorphic form of ticagrelor", unless otherwise specified is to be understood as a substance free of other polymorphic and/or pseudopolymorphic forms at amounts detectable with typical analytical methods such as X-ray powder diffraction and/or solid state infrared absorption, i.e. containing less than 10% of other polymorphic and/or pseudopolymorphic forms. The term 'pharmaceutical^ acceptable' as used herein, refers to materials that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, in keeping with a reasonable benefit-risk ratio, and effective for their intended use. The term "particle size" unless indicated otherwise in the specification relates to particles of ticagrelor free base as well as pharmaceutically acceptable salt, amorphous or crystalline, anhydrous, esters, or isomer or derivative, hydrate, prodrug or solvates thereof.

Ticagrelor with specific "particle size" and distribution, or surface area would provide a fast dissolution of the active ingredient, would be easy to prepare and stable while maintaining the beneficial .properties with respect to fast solubility and bioavailability. Particularly, according to the present invention, ticagrelor having an average particle size less than 200 microns, and/or surface area less that 5 m2/gm are useful. Particularly according to the present invention, 90% of particles with particle size less than about 50 jam and/or surface area less that about 5 m2/gm are useful. Unless indicated otherwise, the term "acetyl salicyclic acid" and "aspirin" can be used interchangeably in the entire specification. According to the present invention, the use in combination of ticagrelor or a pharmaceutically acceptable salt thereof, and acetyl salicylic acid, results in more potent effectiveness than the use of each component alone. Furthermore, plasma levels of these agents do not have to be maintained at a certain level and higher during the same period, in order to produce their effects. Unless indicated otherwise when the other component of the pharmaceutical composition is administered later, the therapeutic effect of the compound administered later is expected to add to the therapeutic effects of the previously administered component. However, it is convenient clinically that both components are administered at the same time. Thus ticagrelor or a pharmaceutically acceptable salt thereof and acetyl salicylic acid are simultaneously administered as a combination drug. In the case that both agents cannot be mixed technically, each component can be administered separately. Moreover, since each component produces significant effects as a single form, each component can be sequentially administered at appropriate intervals. The maximum intervals between administration of each of the two components that can be accepted to elicit significant effects could be confirmed by clinical trials or animal studies!

The term "composition" or "pharmaceutical composition" or "dosage form" as used herein synonymously include soJid dosage forms such as granules, multiunit particulate systems (MUPS), pellets, spheres, tablets, capsules, mini-tablets, layered 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 a diluent, disintegrant, carrier, or the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient. The term "ticagrelor" unless indicated otherwise in the entire specification, refers to ticagrelor in its free base form, or as a pharmaceutical I y acceptable salt, amorphous or crystalline, anhydrous, esters, or isomer or derivative, hydrate, prodrug or solvates thereof. Preferably ticagrelor is in the form of free base. As used in this specification, the singular forms, "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus for example, a reference to "a process" includes one or more process, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth. The present invention provides stable pharmaceutical compositions comprising an ADP-receptor antagonist as an active agent(s), atleast one excipient(s) which is not a sugar alcohol, optionally with one or more other pharmaceutically acceptable excipient(s).

In an embodiment, the present invention provides stable pharmaceutical compositions comprising an ticagrelor as an active agent(s), atleast one excipient(s) which is not a sugar alcohol, optionally with one or more other pharmaceutically acceptable excipient(s). In an embodiment, the atleast one excipient(s) which is not a sugar alcohol, may be selected from but not limited to a group comprising saccharides, celluloses, cellulose derivatives, , dicalcium phosphate, tribasic calcium phosphate, dihydrogen sodium phosphate, carbonates or bicarbonates or oxides or hydroxides of metals such as alkali or alkaline earth metals, alginates, carboxyalkyl celluloses, gums, amido group containing polymers, amino group containing polymers, sugars, hydrophobic compounds such as waxes, and the like and mixtures thereof. In another embodiment, the present invention provides stable pharmaceutical compositions comprising ticagrelor as an active agent(s), wherein atleast one excipient(s) which is not a sugar alcohol is a saccharide, optionally with one or more pharmaceutically acceptable excipient(s). In an embodiment, the present invention provides stable oral pharmaceutical compositions comprising ticagrelor as an active agent(s), atleast one saccharide(s) selected from group comprising monosaccharide(s), disaccharide(s), oligosaccharide(s) and polysaccharide(s), optionally with one or more pharmaceutically acceptable excipients. In an embodiment, the present invention provides ticagrelor as an active agent(s) or acetyl salicylic acid as another active agent(s), atleast one saccharide(s) selected from group comprising monosaccharides, disaccharides, oligosaccharides and polysaccharides, optionally with one or more pharmaceutically acceptable excipients.

In an embodiment, the monosaccharide(s) useful in the present invention are selected from but not limited to group comprising xylose, glucose, dextrose, fructose, mannose and maltose; disaccharide(s) selected from but not limited to group comprising glucose, maltose, lactose, cellobiose, trehalose, and galactose; oligosaccharide(s) selected from but not limited to group comprising raffinose, dextrates, cyclodextrins and maltodextrins (e.g.Glucidex®); polysaccharide(s) selected from but not limited to group comprising xanthan gum, guar gum, gum arabic, carrageenan gum, karaya gum, locust bean gum, acacia gum, tragacanth gum, agar, pectin, furcellaran, zein, casein, starches selected from but not limited to group comprising corn, waxy com, high amylose com, potato, tapioca, rice, sago, wheat or waxy sorghum starch and the like thereof used either alone or in combination thereof. In one of the embodiments, the present invention provides stable oral pharmaceutical compositions comprising ticagrelor as an active agent(s) or pharmaceutically acceptable salts, esters, hydrates and solvates thereof from about 0.1% w/w to about 99% w/w of the composition, saccharide(s) from about 0.1% to about 99% w/w of the composition, optionally with one or more pharmaceutical ly acceptable excipients, from about 0.9% to about 97% w/w of the composition. In an embodiment the present invention provides stable oral pharmaceutical compositions, wherein the ratio of active agent(s) to saccharide(s) is from about 0.1:100 to about 100:0.1. Preferably the ratio of active agent(s) to saccharide(s) is from about 0.1:90 to about 90:0.1.

In an embodiment, acetyl salicylic acid may be administered with ticagrelor at an initial loading dose of 325 mg followed by daily maintenance dose of 75-100 mg. In an embodiment, the present invention provides process for the preparation of stable oral pharmaceutical compositions, wherein the process comprises of the following steps:

(i) treating ticagrelor with atleast one excipient other than sugar alcohol,

(ii) optionally adding one or more other pharmaceutically acceptable excipients, and

(iii) formulating the material of step (i) and (ii) into a suitable dosage form

In another embodiment is provided process for the preparation of stable oral pharmaceutical compositions, wherein the process comprises of the following steps:

(i) treating ticagrelor with one or more saccharide(s),

(ii) treating acetyl salicylic acid with pharmaceutically acceptable excipients,

(iii) optionally adding one or more pharmaceutically acceptable excipients, and

(iv) formulating the material of step (i), (ii) and (iii) into a suitable dosage form

As used herein, unless indicated otherwise, references to total weight of the pharmaceutical composition refers to the total weight of the active agent(s) and pharmaceutically acceptable excipient(s). "Pharmaceutically acceptable excipient(s)" are components added to active agent pharmaceutical formulation other than the active ingredient ticagrelor. Excipients may be added to facilitate manufacture, enhance stability, enhance product characteristics, enhance bioavailability, enhance patient acceptability, etc. Pharmaceutically acceptable excipient(s) includes, but not limited to, one or more of diluents/fillers, binders, disintegrants, lubricants, glidants, compression aids, colors, sweeteners, preservatives, surfactants, suspending agents, dispersing agents, film formers, flavors, printing inks, etc. It will be appreciated by the person skilled in the art that a particular excipient may act as both a binder and filler, or as a binder, filler and a disintegrant.

Binders hold the ingredients in the composition together. Exemplary binders are selected from, but not limited to, cellulose and its derivatives including, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose and hydroxyethyl cellulose, carboxymethyl cellulose; gelatin, liquid glucose; starch and its derivatives (e.g. corn starch); hydrocolloids; sugars; polyvinyl pyrrolidone, sodium alginate, acacia, alginic acid, tragacanth, used either alone or combinations comprising one or more of the foregoing binders. The binder may be used in the range of 1-10% by weight of the composition. Diluents increase the bulk of the composition. Diluents according to the present invention are selected from, but not limited to, sugars such as lactose, sucrose, dextrose; sugar alcohols such as sorbitol, xylitol, lactitol; starlac, starch, modified starches, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, calcium sulfate, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, magnesium carbonate, magnesium oxide, magnesium alumino metasilicate and the like used either alone or in combinations thereof. The diluent may be used in the range of 20-98% by weight of the composition.

Disintegrants according to the present invention are selected from, but not limited to, cellulose and its derivatives including low-substituted hydroxypropyl cellulose; cross-linked polyvinylpyrrolidone; cross-linked sodium carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose; sodium starch glycolate; ion-exchange resins; starch and modified starches including pregelatinized starch; formalin-casein; used either alone or in combinations comprising one or more of the foregoing water swellable substances. The disintegrant may be used in the range of 4-20% by weight of the composition. Lubricants and glidants aids in the processing of powder materials. Exemplary lubricants are selected from, but not limited to, calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, vegetable oil, and zinc stearate, used either alone or in combinations comprising one or more of the foregoing lubricants. Exemplary glidants include, but not limited to, talc, silicon dioxide; cornstarch and the like used either alone or in combination thereof. Surfactants are compounds which are capable of improving the wetting of the drug and/or enhancing the dissolution. The surfactants can be selected from hydrophilic surfactants or lipophilic surfactants or mixtures thereof. The surfactants can be anionic, nonionic, cationic, and zwitterionic surfactants.

Surfactants according to the present invention are selected from, but not limited to, polyoxyethylene alkylaryl ethers such as polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether; polyethylene glycol (PEG) fatty acid esters such as PEG monolaurate, PEG dilaurate, PEG distearate, PEG dioleate; polyoxyethylene sorbitan fatty acid ester such as polysorbate 40, polysorbate 60, polysorbate 80; sorbitan fatty acid mono esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, polyoxyethylene castor oil derivates such as polyoxyl castor oil, polyoxyl hydrogenated castor oil, sodium lauryl sulphate and the like used either alone or in combination thereof. "Suitable solvent" according to the present invention can be any solvent in which the binder is soluble or dispersible and is selected from isopropyl alcohol, ethanol, water, acetone, methylene chloride and the like or mixtures thereof. It must be appreciated that the pharmaceutical compositions of the present invention can include all the dosage forms known to a person skilled in art, viz. formulations such as single unit dosage forms in the form of tablets, bilayer tablets, inlaid tablets, tablet in tablet, multilayered tablets, minitablets filled in capsules and the like; beads, pellets presented in a sachet, capsule or tablet capsules such as soft and hard gelatin; lozenges or sachets; granulates, microparticles, multiparticulates, powder and the like. The tablets in accordance with the present invention can be prepared by either direct compression, dry compression (slugging), or by wet granulation.

In an embodiment, the compositions of the present invention may additionally comprise of a colorant in order to produce a desirable color. Colors known to be 'FD&C certified may be used to provide coloring to the product and are within the purview of the present invention. Suitable colorants include natural colorants i.e., pigments and dyes obtained from mineral, plant, and animal sources. Examples of natural colorants include red ferric oxide, yellow ferric oxide, annattenes, alizarin, indigo, rutin, quercetin, and the like. Synthetic colorants may also be used, which is typically an FD&C or D&C dye, e.g., an approved dye selected from the so-called 'coal-tar' dyes, such as a nitroso dye, a nitro dye, an azo dye, an oxazine, a thiazine, a pyrazolone, a xanthene, an indigoid, an anthraquinone, an acridine, a rosaniline, a phthalein, a quinoline, or a 'lake' thereof, i.e. an aluminum or calcium salt thereof. Particularly preferred colorants are food colorants in the 'GRAS' (Generally Regarded as Safe) category. In an embodiment, the tablet compositions of the present invention may be film coated. A film forming agent may provide smooth film-forming coating suspensions and enhance the rheological mechanical strength properties of film coating gel matrices. Film forming agents include, for example, polyvinylpyrrolidone, natural gums, starches, and cellulosic polymers.

A cellulosic polymer may include a molecule comprising at least one cellulose polymer or derivative modified with small amounts of propylene glycol ether groups attached to the cellulose anhydroglucose chain affording binding properties that enhance the reinforcing film properties of film applications. Examples of cellulosic polymers include, but are not limited to, hydroxypropyl methyl cellulose ("HPMC"), carboxymethyl cellulose ("CMC") or salts thereof, hydroxypropyl cellulose ("HPC"), methylcellulose ("MC"), hydroxyethyl cellulose ("HEC"), and the like. In addition, cellulosic polymers may be characterized as ionic or non-ionic. Ionic cellulosic polymers include, for example, sodium CMC. Non-ionic cellulosic polymers include, for example, HPMC, HPC, HEC, and MC. Varieties of commercially available cellulosic polymers exist and may include, for example, Spectracel® HPMC compositions (available from Sensient Technologies). Further, other commercially available coating materials are available marketed under the brand name Opadry® for example Opadry II Gray which contains: lactose monohydrate NF, hypromellose type 2910 USP, titanium dioxide USP, triacetin USP, and iron oxide black JPE; Opadry II Pink which contains: hypromellose type 2910 USP, titanium dioxide USP, lactose monohydrate NF, polyethylene glycol 3350 NF, triacetin USP, and FD&C Red #40; Opadry II Blue which contains: hypromellose type 2910 USP, lactose monohydrate NF, FD&C Blue #1, polyethylene glycol 3350 NF, FD&C Blue #2, ■titanium dioxide USP, triacetin USP, and D&C Yellow #10; Opadry II Yellow which contains: hypromellose type 2910 USP, lactose monohydrate NF, titanium dioxide USP, iron oxide yellow NF, polyethylene glycol 3350 NF, and triacetin USP; Opadry II Purple which contains: hypromellose type 2910 USP, lactose monohydrate NF, titanium dioxide USP, D&C Red #27, polyethylene glycol 3350 NF, triacetin USP, and FD&CBlue#l and the like.

It is also desirable that the compositions are chemically stable as degradation by oxidation, hydrolysis, isomerisation, photolysis, polymerization, or any other method of degradation, either as a result of mixing with excipients or by any other method, could lead to a change in bioavailability and could also lead to toxicity. Chemical stability can be measured by a suitable, stability indicating chromatographic method for determining degradation products (see Auhon Me., Pharmaceutics—The Science of Dosage Form Design, 2.sup.nd Edition, 2002, Churchill Livingstone). In another embodiment, the present invention provides a method to treat diseases caused by thrombus or embolus, for example, diseases induced by platelet aggregation, including stable or unstable angina; cardiovascular or cerebrovascular associated disorders, using the compositions of the present invention. The compositions of the present invention can be packed into suitable containers such as bottles, blisters or pouch. Further, the packages may optionally contain a dessicant or an antioxidant or oxygen absorbant or combinations thereof. 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 to the industry.

Manufacturing process:

i) Ticagrelor, microcrystalline cellulose, fructose and crospovidone were sifted together,

ii) Binder solution was prepared by dissolving methyl cellulose in purified water,

iii) The blend of step (i) was granulated with binder solution of step (ii) and dried,

iv) The granules of step (iii) were lubricated with sodium stearyl fumarate.

v) The lubricated granules of step (iv) was filled into capsules. * Los! in processing Manufacturing process

(Example 2): i) Ticagrelor, calcium sulfate, sucrose and sodium starch glycollate were sifted together, ii) Binder solution was prepared by dissolving hydroxypropyl cellulose in purified water, iii) The blend of step (i) was granulated with binder solution of step (ii) and dried, iv) The granules of step (iii) were lubricated with zinc stearate. v) The lubricated granules of. step (iv) compressed into a tablet by a suitable compression machine.

EXAMPLE 3: The manufacturing process followed is similar to Example 2. The excipients at each of the process steps of Example 2 are substituted with equivalent excipients as stated in the composition of Example 3. 12 Opadry® coating 3 3 3 *Lost in processing

Manufacturing process (Example 4): i) Ticagrelor, sucrose, microcrystalline cellulose and carmellose sodium were sifted together, ii) Binder solution was prepared by dissolving hydroxypropyl methylcellulose in purified water, iii) The blend of step (i) was granulated with binder solution of step (ii) and dried, iv) The granules of step (iii) were lubricated with glyceryl behenate. v) The lubricated granules of step (iv) are compressed into tablets by a suitable compression machine, vi) The tablets obtained from step (v) were coated with opadry coating solution for obtaining the desired weight gain.

EXAMPLES 5 & 6: The manufacturing process followed is similar to Example 4. The excipients at each of the process steps of Example 4 are substituted with equivalent excipients as stated in the compositions of Example 5 and Example 6.

Manufacturing process (Example 7):

i) Ticagrelor, sucrose, microcrystalline cellulose and carmellose sodium were sifted together, ii) Binder solution was prepared by dissolving hydroxypropyl methylcellulose in purified water, iii) The blend of step (i) was granulated with binder solution of step (ii) and dried, iv) The dried granules of step (iii) were mixed with powdered cellulose and colloidal silicon dioxide, v) The material of step (iv) was lubricated with glyceryl behenate. vi) The lubricated material of step (v) compressed into tablets by a suitable compression machine. vii)The tablets obtained from step (vi) were coated with opadry coating solution with desired weight gain.

EXAMPLE 8: The manufacturing process followed is similar to Example 7. The excipients at each of the process steps of Example 7 are substituted with equivalent excipients as stated in the composition of Example 8. Manufacturing process: i) Ticagrelor, microcrystalline cellulose, lactose monohydrate, and methyl cellulose were sifted together, ii) The blend of step (i) was slugged/compacted and milled, iii) The granules obtained in step (ii) were blended with sodium starch glycollate. iv) The material of step (iii) was lubricated with zinc stearate. v) The lubricated material of step (iv) was compressed to tablets.

Manufacturing process: i) Ticagrelor, acetyl salicylic acid, microcrystalline cellulose, and methyl cellulose were sifted together, ii) The blend of step (i) was slugged/compacted and milled, iii) The granules obtained in step (ii) were blended with sodium starch glycollate. iv) The materia] of step (iii) was lubricated with magnesium stearate. v) The lubricated material of step (iv) was compressed to tablets.

claim:

1. Pharmaceutical compositions comprising ticagrelor as an active agent(s), atleast one excipient(s) which is not a sugar alcohol, optionally with one or more other pharmaceutically acceptable excipient(s).

2. The composition according to claim 1, wherein atleast one excipient(s) which is not a sugar alcohol is selected from a group comprising saccharides, celluloses, cellulose derivatives, dicalcium phosphate, tribasic calcium phosphate, dihydrogen sodium phosphate, carbonates or bicarbonates or oxides or hydroxides of metals such as alkali or alkaline earth metals, alginates, carboxyalkyl celluloses, gums, amido group containing polymers, amino group containing polymers, sugars, hydrophobic compounds and mixtures thereof.

3. The composition according to claim 2, wherein a saccharide is selected from group comprising monosaccharides, disaccharides, oligosaccharides and polysaccharides, and mixtures thereof.

4. The composition according to claim 3, wherein the monosaccharide(s) is selected from a group Comprising xylose, glucose, dextrose, fructose, mannose and maltose; disaccharide(s) js selected from a group comprising glucose, maltose, lactose, cellobiose, trehalose, and galactose; oligosaccharide(s) is selected from a group comprising raffinose, dextrates, cyclodextrins and maltodextrins; polysaccharide(s) is selected from ^ group comprising xanthan gum, guar gum, gum arabic, carrageenan gum, karaya gum, locust bean gum, acacia gum, tragacanth gum, agar, pectin, furcellaran, zein, casein; and starches are selected from group comprising corn, waxy corn, high amylose corn, potato, tapioca, rice, sago, wheat or waxy sorghum starch.

5. The composition according to claim 2, comprising ticagrelor as an active agent(s) or pharmaceutically acceptable salts, esters, hydrates and solvates thereof from about 0.1% w/w to about 99% w/w of the composition, saccharide(s) from about 0.1% to about 99% wAv of the composition, optionally with one or more pharmaceutically acceptable excipients, from about 0.9% to about 97% w/w of the composition.

6. The composition according to claim 1, wherein the composition further comprises acetyl salicylic acid as another active agent(s).

7. The composition according to claim 1, wherein the pharmaceutically acceptable excipient(s) i$ selected from a group comprising diluents/fillers, binders, disintegrants, lubricants, glidants, compression aids, colors, sweeteners, preservatives, surfactants, suspending agents, dispersing agents, film formers, flavors, printing inks, used either alone or in combination thereof.

8. The composition according to any of the preceding claims 1 to 7, wherein the ratio of active agent(s) to saccharide(s) is from about 0.1:100 to about 100:0.1.

9. A process for the preparation of stable oral pharmaceutical composition according to claim 1, wherein the process comprises of the following steps:

i) treating ticagrelor with atleast one excipient other than sugar alcohol,

ii) optionally adding one or more other pharmaceutically acceptable excipients, and iii) formulating the material of step (i) and (ii) into a suitable dosage form.

10. A process for the preparation of stable oral pharmaceutical composition according to claim 9, wherein the process comprises of the following steps:

i) treating ticagrelor with one or more saccharide(s), ii) treating acetyl salicylic acid with pharmaceutically acceptable excipients, iii) optionally adding one or more pharmaceutically acceptable excipients, and iv) formulating the material of step (i), (ii) and (iii) into a suitable dosage form.