“AN ORAL PHARMACEUTICAL COMPOSITION OF TICAGRELOR”
FIELD OF THE INVENTION
The present invention is related to a pharmaceutical composition of Ticagrelor or a pharmaceutically acceptable salt thereof wherein Hypromellose 5 CPS is used as binder in an amount of 1 to 2.9 % by weight of the composition. Further, the said pharmaceutical composition is useful for the treatment of reduction of the rate of cardiovascular death, myocardial infarction (MI), and stroke in people with acute coronary syndrome (ACS) or history of myocardial infarction.
BACKGROUND OF THE INVENTION
Ticagrelor is Chemically known as (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-
Difluorophenyl)cyclopropylamino]5(propylthio)3H[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2
hydroxyethoxy)cyclopentane-1,2-diol, it is an ADP receptor antagonist compound.
Ticagrelor is a crystalline powder with an aqueous solubility of approximately 10 pg/mL at room temperature. There are 4 non-solvated polymorphs (Polymorph I, II, III and IV). Polymorphic forms disclosed/claimed in US7, 265,124 (herein after used as ‘124)
According to Biopharmaceutics Classification System (BCS) Ticagrelor is classified as a class IV compound, exhibiting low solubility and low permeability. This property of Ticagrelor effects on bioavailability. The chemical structure of Ticagrelor is as follows.

Ticagrelor is currently approved for ASTRAZENECA PHARMS and marketed under brand name Brilinta Tablets. These are used for the treatment of reduction of the rate of cardiovascular death, myocardial infarction (MI), and stroke in people with acute coronary syndrome or history of myocardial infarction. BRILINTA also reduces the rate of stent thrombosis in patients who have been stented for treatment of ACS.
US 8,425,934 discloses a pharmaceutical composition comprising Ticagrelor (20-45 %), a filler (10-30 %) consisting essentially of a mixture of mannitol and dibasic calcium phosphate dihydrate, a binder (3-6 %) consisting essentially of hydroxypropyl cellulose, a disintegrant (2-6 %) consisting essentially of sodium starch glycolate, and one or more lubricants (0.5-3 %). The compositions are prepared by using a wet granulation technique. It is stated in the prosecution of the said patent that the manufacturing process resulted in disappointing yield, poor tablet compression properties poor stability of the formulated product and variable granule size distribution.
WO 2008024044 (here in after used as ‘044) discloses a pharmaceutical composition comprising Ticagrelor in an amount of 20 to 45% by weight; mannitol in an amount of 20 to 45% by weight; dibasic calcium phosphate dihydrate in an amount of 10 to 30% by weight; hydroxypropylcellulose in an amount of 3 to 6% by weight; sodium starch glycolate in an amount of 2 to 6% by weight; and one or more lubricants in an amount of 0.5 to 3% by weight.
IN1367/KOLNP/2015 discloses pharmaceutical composition comprising Ticagrelor, non-hygroscopic filler and one non-hygroscopic binder, composition is prepared by wet granulation/dry granulation/direct compression technique.
US 20170296666 (here in after used as ‘666) discloses pharmaceutical composition comprising amorphous Ticagrelor and colloidal silicon dioxide is present in intragranular and extra granular part of the composition by using wet granulation technique. The problem of using amorphous form of Ticagrelor in formulation that when amorphous Ticagrelor comes in contact with moisture, it forms a cohesive mass which prolongs the disintegration time as well as retards the dissolution of a formulation.

Hence in view of above, the present inventors has developed a composition with provide stable product as well as improved drug bioavailability. Moreover inventors here using simple method in comparison to above said methods, which is process friendly in commercial aspects to get a good yield with following advantages
• Hypromellose 5 CPS can dissolve in binder solvent to use as wet binder.
• Consistent granules shall manufactured with Hypromellose 5 CPS.
• Less probability of batch to batch variation.
• It is easy to extract the drug from HPMC granules when compared to HPC granules.
SUMMARY OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising a Ticagrelor as an active ingredient or a pharmaceutically acceptable salt thereof and a process of preparing the pharmaceutical composition.
In an aspect of the present invention relates to a stable pharmaceutical composition comprising Ticagrelor is P2Y12 platelet aggregation inhibitor and pharmaceutically acceptable excipients, specifically Hypromellose 5 CPS is used as binder in an amount of 1 to 2.9 % by weight of the composition.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising a Ticagrelor or a pharmaceutically acceptable salt thereof and a process of preparing the pharmaceutical composition.
In one embodiment of the present invention relates to a pharmaceutical composition comprising Ticagrelor or a pharmaceutically acceptable salt thereof, a one or more pharmaceutically acceptable excipients, and Hypromellose 5 CPS as a binder in an amount of 1 to 2.9 % by weight of the composition.

The term “Cohesive mass” refers to a mass capable of adhering or sticking or having a tendency to unite and to resist separation especially in the presence of moisture.
According to embodiment of the present invention, the pharmaceutical composition is in a solid dosage form, such as a tablet or capsule.
In another embodiment of the present invention relates to a pharmaceutical composition prepared by a high shear or rapid mixer granulator by wet granulation process comprising the Ticagrelor and one or more pharmaceutical acceptable excipients and Hypromellose 5 CPS.
Additionally, the pharmaceutical composition of the present invention may contain Hypromellose 5 CPS present in binder solution in an amount of 1 to 2.9 % by weight of the composition.
According to embodiment of the present invention, there is provided a pharmaceutical composition of Ticagrelor or a pharmaceutically acceptable salt thereof, wherein the active pharmaceutical ingredient (API) or pharmaceutically acceptable salt thereof may present in amount from about 20% to about 30% by weight of composition.
In yet another embodiment of the present invention provides process for the preparation of stable oral pharmaceutical compositions, wherein the process comprises of the following steps.
i. Sifting Ticagrelor with at least one or more pharmaceutically acceptable
excipients.
ii. Dissolve Hypromellose 5 CPS as a binder in an amount 1 to 2.9 % by weight of
the composition in solvent under continues stirring. Continue stirring until it forms clear solution.
iii. Load step (i) material in rapid mixture granulator and mix for 10 minutes with
impeller at slow speed and chopper off.

iv. Granulate the step (iii) material by using step (ii) binder solution with impeller at
slow speed and chopper off.
v. Mill the wet mass by using mobile cone will with suitable screen and drying the
material at 60o±5o C and check the Loss of drying (LOD) at 105o C. Sift the dried granules through sieve #30 ASTM and mill the retained granules of sieve # 30 ASTM with mobile cone mill fitted with 40 G screen at 500-1000 RPM.
vi. Sift sodium starch glycolate through sieve # 40 ASTM and mix with step (v)
material in bin blender for 10 minutes at slow speed. Sift magnesium stearate through sieve # 40 ASTM and add to pre lubricated blend and mix for 5 minutes at slow speed.
vii. Finally compress the lubricated blend into tablets using suitable punches and coat
the tablets with Opadry yellow by using automatic coating pan.
According to another embodiment of the present invention, there is provided a pharmaceutical composition of Ticagrelor or a pharmaceutically acceptable salt thereof, a one or more pharmaceutically acceptable excipients, and Hypromellose 5 CPS, wherein a one or more pharmaceutically acceptable excipients selected from diluents, binders, disintegrants, glidants, lubricants, and mixtures thereof.
The pharmaceutical composition of the present invention can be obtained by a known conventional methods like dry granulation, wet granulation, direct compression, roller compaction, fluidized bed granulation, rapid mixture granulation, solvent evaporation, hot-melt extrusion or a like that. And preferably used wet granulation by using rapid mixture granulator.
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, or the like. These are generally safe, nontoxic. Reference to an excipient includes both one and more than one such excipient.
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.
Diluents/fillers includes, but are not limited to, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, dextrates, dextrin, dextrose, kaolin, magnesium carbonate, magnesium oxide, sugars such as sucrose; sugar alcohols such as mannitol, sorbitol, erythritol; and mixtures thereof.
Binders includes, but are not limited to, binder is hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose E3 LV, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, Povidone, hydroxypropyl cellulose, carbomers, carboxymethylcellulose sodium, dextrin, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, or combinations thereof.
Disintegrant includes, but are not limited to, croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, sodium alginate and mixtures thereof.
Lubricant includes, but are not limited to, anti-tacking agent, sodium lauryl sulphate, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glycerylpalmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearylfumarate, sodium benzoate, mineral oil, and mixtures thereof ; solvents includes, but are not limited to acetone, isopropyl alcohol and purified water.

In particularly, the present invention provides a pharmaceutical composition comprising about API (active pharmaceutical ingredient), filler (mannitol and di basic calcium phosphate anhydrous), binder (Hypromellose 5 CPS), Disintegrant (SSG-sodium starch glycolate) and lubricants (Magnesium stearate). These composition are prepared by wet granulation technique.
According to another embodiment of the present invention, provides a pharmaceutical composition comprising Ticagrelor in an amount of 20-30%; mannitol in an amount of 40-45%; dibasic calcium phosphate dihydrate in an amount of 20-25%; Hypromellose 5 CPS in an amount of 1 to 2.9 %; sodium starch glycolate in an amount of 2- 4.5 %; and one or more lubricants in an amount of 1 to 2% by weight of the composition.
According to another embodiment of the present invention, provides a pharmaceutical composition consisting Hypromellose (HPMC) used as binder in an amount of 1 to 2.9 % by weight of the composition., more preferably 1.5- 2 % and Magnesium stearate is used as Lubricant in an amount of 1 to 2 % by weight of the composition, more preferably 1.33%.
Specifically, the inventors have used Hypromellose 5 CPS in an amount of 1 to 2.9 % by weight of the composition. This is due to advantage of present invention is as follows
• Hypromellose 5 CPS can dissolve in binder solvent to use as wet binder.
• Consistent granules shall manufactured with Hypromellose 5 CPS.
• Less probability of batch to batch variation.
• It is easy to extract the drug from HPMC granules when compared to HPC granules.

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.

Manufacturing Process:
1. Sifting:
1.1 Co-Sift Ticagrelor, mannitol, Dibasic Calcium Phosphate Anhydrous and Sodium Starch Glycolate through sieve # 20ASTM.
2. Binder solution:
2.1 Dissolve Hypromellose 5 CPS in purified ware under continues stirring. Continue stirring until it forms clear solution.
3. Wet granulation:
3.1 Load step 1.1material in rapid mixer granulator and mix for 10 with impeller at slow speed and chopper off.
3.2 Granulate the step 3.1 material by using step 2.1 binder solution with impeller at slow speed and chopper off.
3.3 Mill the wet mass by using mobile cone mill with suitable screen.
4. Drying
4.1 Dry step 3.3 material at 60° ± 5° C and check the LOD at 105°C. Continue drying until it reaches desired LOD.
5. Sifting and Milling
5.1 Sift the dried granules through sieve #30 ASTM.
5.2 Mill the retained granules of sieve #30ASTM with mobile cone mill fitted with 40G
screen at 500-1000 RPM. Continue milling until all the material passes through sieve
#30ASTM.
6. Blending
6.1 Sift Sodium Starch Glycolate through sieve #40ASTM and mix with step 5.2 material in bin blender for 10 at slow speed.
6.2 Sift magnesium stearate through sieve #40ASTM and add to above pre-lubricated blend and mix for 5 minutes at slow speed.
7. Compression and Film coating:
7.1 Compress the lubricated blend in to tablets using suitable punches.
Coat the tablets with Opadry yellow (03B520157) by using automatic coating pan.

We Claim:
1. An oral pharmaceutical composition consisting of Ticagrelor in an amount of about 20 to 30%, mannitol in an amount of 40 to 45 %, dibasic calcium phosphate dihydrate in an amount of 20 to 25 %, Hypromellose 5 CPS in an amount of 1 to 2.9 %, sodium starch glycolate in an amount of 2-4.5%, and one or more lubricants in an amount of 1 to 2 % by weight of the pharmaceutical composition.
2. A pharmaceutical composition according to claim 1 wherein a pharmaceutical composition of Ticagrelor or a pharmaceutically acceptable salt thereof, wherein Ticagrelor or pharmaceutically acceptable salt thereof may present in amount from about 25 to 30% by weight of composition.
3. A pharmaceutical composition according to claim 1 wherein a pharmaceutical composition consisting Hypromellose (HPMC) used as binder in an amount of 1.5 to 2.0% by weight of the composition.
4. A pharmaceutical composition according to claim 1 wherein a pharmaceutical composition consisting magnesium Stearate used as lubricant in an amount of 1.33% by weight of the composition.
5. A pharmaceutical composition according to claim 1 which has been prepared by a wet granulation process, which has been prepared by a high shear wet granulation process.
6. The pharmaceutical composition according to claim 1, wherein said pharmaceutical composition is prepared by a process comprising the following steps
i. Sifting Ticagrelor with at least one or more pharmaceutically acceptable
excipients.
ii. Dissolve Hypromellose 5 CPS as a binder in an amount of 1 to 2.9 % by weight of
the composition in solvent under continues stirring. Continue stirring until it forms clear solution.

iii. Load step (i) material in rapid mixture granulator and mix for 10 minutes with
impeller at slow speed and chopper off.
iv. Granulate the step (iii) material by using step (ii) binder solution with impeller at
slow speed and chopper off.
v. Mill the wet mass by using mobile cone will with suitable screen. And drying the
material at 60o ± 5o and check the LOD at 105o C. Sift the dried granules through sieve #3 ASTM and mill the retained granules of sieve # 30 ASTM with mobile cone mill fitted with 40 G screen at 500-1000 RPM.
vi. Sift sodium starch glycolate through sieve # 40 ASTM and mix with step (v)
material in bin blender for 10 minutes at slow speed. Sift magnesium stearate through sieve # 40 ASTM and add to pre lubricated blend and mix for 5 minutes at slow speed.
vii. Finally compress the lubricated blend into tablets using suitable punches and coat
the tablets with Opadry yellow by using automatic coating pan.
7. A pharmaceutical composition according to claim 1 wherein the composition is a form of tablet.