CLIAMS:1. A solid oral pharmaceutical composition comprising ticagrelor or salts thereof with one or more pharmaceutically acceptable excipients, wherein the composition is free of water-insoluble fillers.

2. The solid oral pharmaceutical composition of claim 1, wherein the composition comprises of water-soluble fillers.

3. The solid oral pharmaceutical composition of claim 1 or 2, wherein the water-soluble fillers are selected from dextrose, fructose, lactitol, lactose, L-hydroxypropyl- cellulose (low substituted), starches or modified starches (including potato starch, wheat starch, corn starch, rice starch, pregelatinized maize starch), maltitol, maltodextrins, maltose, sorbitol, starch, sucrose, sugar, and xylitol, erythritol, mixtures thereof.

4. The solid oral pharmaceutical composition of claim 1, wherein the composition is devoid of pH modifying filler.

5. The solid oral pharmaceutical composition of claim 2, wherein the ratio of amount of ticagrelor to water-soluble fillers is 1:1.5 to 1:5.

6. The solid oral pharmaceutical composition of claim 1, wherein ticagrelor or salts thereof present in an amount less than 20% by weight of the total composition.

7. The solid oral pharmaceutical composition of claim 1, wherein the composition is in the form of a tablet.

8. The solid oral pharmaceutical composition of claim 1, wherein the composition retains at least 90% by weight of the total content of ticagrelor when stored at 40°C and 75% relative humidity over a period of at least 3 months.

9. A method of treating acute coronary syndrome in a patient in need thereof, which method comprises of administering the solid oral pharmaceutical composition of claim 1 comprising ticagrelor or salts.
,TagSPECI:4. DESCRIPTION

The present invention relates to solid oral pharmaceutical compositions comprising ticagrelor or salts thereof. In particular, the present invention relates to solid oral pharmaceutical compositions comprising ticagrelor or salts thereof and at least one pharmaceutically acceptable excipient other than water-insoluble fillers. There is also provided a method of reducing the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) by using the solid oral pharmaceutical composition ticagrelor or salts thereof.

Ticagrelor is a P2Y12 platelet inhibitor that is used 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). It is an inhibitor of platelet activation and aggregation mediated by the P2Y12 ADP-receptor.

Chemically it is (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl) cyclopropyl] amino} -5-(propylthio) -3H- [1,2,3] –triazolo [4,5-d] pyrimidin-3-yl] -5- (2-hydroxyethoxy) cyclopentane -1,2-diol. The empirical formula of ticagrelor is C23H28F2N6O4S and its molecular weight is 522.57. The chemical structure of ticagrelor is:

It appears as a white or off-white to pale pink crystalline powder which does not exhibit pH dependent solubility (aqueous solubility approx. 10 µg/mL at RT) and is defined as ‘low solubility’ under the Biopharmaceutics Classification System (BCS). Having also a low permeability, ticagrelor is a BCS class IV compound. Ticagrelor and its major metabolite reversibly interact with the platelet P2Y12 ADP-receptor to prevent signal transduction and platelet activation. Ticagrelor and its active metabolite are approximately equipotent.

Currently, ticagrelor is marketed in the US with a brand name Brilinta® as an immediate release tablet. It is indicated for reduction in the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS).

PCT Application No. WO 2005/113006 discloses ticagrelor compositions in a general way, without specifying the excipients comprised therein.

PCT Application No. WO 2000/34283 discloses processes for the preparation of ticagrelor and related compounds, as well as their formulation in general terms with different pharmaceutical excipients.

PCT Application Nos. WO 2004/024127 and WO 2004/037263 and U.S. Patent Application No. 2004/001885 disclose fillers, binders, disintegrants and lubricants as excipients in pharmaceutical compositions comprising active agents different than ticagrelor.

U.S. Patent Application No. 2013/0131087 discloses composition of 90 mg ticagrelor and a means of releasing the said amount.

U.S. Patent No. 8,425,934 discloses compositions of ticagrelor comprising mixture of mannitol and dibasic calcium phosphate dihydrate, hydroxypropyl cellulose, sodium starch glycolate, and one or more lubricants.

As ticagrelor is a low soluble drug substance (not ionised in the physiological pH range) and exhibits a moderate intrinsic permeability, there is potentially a higher risk that changes in formulation such as nature and amount of excipients and processing parameters can affect drug release from the dosage form thereby may affect its clinical performance. This has to be taken into account during formulation development of BCS class IV drugs. Also, it is desirable ensure uniform and complete release of ticagrelor or salts thereof from the composition to avoid any variability in clinical performance.

Thus there exists an enduring need to provide an improved formulation of ticagrelor or salts thereof having lower total weight which can address the aforesaid objective i.e. uniform and complete release as well as may exhibit excellent storage stability.

As ticagrelor is BCS class IV drug, inventors of the present invention tried to incorporate mostly water-soluble excipients to ensure immediate and complete release of ticagrelor. As fillers constitute major portion of the tablet composition, any water-insoluble filler in the composition is avoided. Moreover, as solubility of ticagrelor is not pH dependent, inventors of the present invention have avoided use of any pH modifying filler in the formulation.

The inventors of the present invention prepared a solid oral pharmaceutical composition comprising ticagrelor or salts thereof free of any water-insoluble filler.

Inventors of the present invention have surprisingly found it is possible to formulate a solid oral pharmaceutical composition free of water-insoluble fillers.

In one general aspect, there is provided a solid oral pharmaceutical composition comprising ticagrelor or salts thereof with one or more pharmaceutically acceptable excipients, wherein the solid oral pharmaceutical composition is free of water-insoluble fillers.

In another general aspect, there is provided a solid oral pharmaceutical composition comprising ticagrelor or salts thereof, which composition is in the form of a tablet.

In another general aspect, there is provided a solid oral pharmaceutical composition comprising ticagrelor or salts thereof, which composition is in the form of a capsule.

In another general aspect, there is provided a tablet or capsule comprising ticagrelor or salts thereof intended for oral administration.

The present invention also provides a tablet comprising:
(a) a pharmacologically effective amount of ticagrelor or salts thereof; and
(b) at least one pharmaceutically acceptable excipient suitable for the preparation of tablets;
wherein the tablet is free of water-insoluble fillers.

In another general aspect, there is provided a solid oral pharmaceutical composition of ticagrelor or salts thereof, wherein the ratio of amount of ticagrelor to water-soluble fillers is 1:1.5 to 1:5.

In another aspect, there is provided a solid oral pharmaceutical composition comprising ticagrelor or salts thereof with one or more pharmaceutically acceptable excipients, wherein all the excipients are water-soluble in nature.

In another general aspect, there is provided a solid oral pharmaceutical composition comprising ticagrelor or salts thereof with one or more pharmaceutically acceptable excipients, wherein ticagrelor comprises less than 20% by weight of the composition.

One or more pharmaceutically acceptable excipients may be present in the tablets, e.g. at least one filler, at least one binder, at least one disintegrant, at least one glidant, and at least one lubricant, and optionally a coating comprising film forming polymer.

The amount of water-soluble filler may vary within a range of from about 5 to 90%, e.g. 10 to 30% in weight based on the total weight of the solid oral pharmaceutical composition.

According to the present invention, the amount of binder may vary within a range of from about 1 to 30%, preferably 1 to 20%, in particular 1 to 10% in weight based on the total weight of the solid oral pharmaceutical composition.

The amount of disintegrant may vary within a range of from about 5 to 20%, e.g. 10 to 15% in weight based on the total weight of the tablet.

The amount of lubricant may vary within a range of from about 0.1 to 5%, e.g. 0.5 to 2% in weight based on the total weight of the tablet.

The amount of basic coating may vary from about 1 to 10%, preferably from 1.5 to 2.5% in weight based on the total weight of the tablet.

In a preferred aspect of the invention, there is provided a tablet comprises of one or more fillers in a total amount of about 5% to 90%, one or more binders in a total amount of about 1% to 20% in weight based on the total weight of the tablet, one or more disintegrants in a total amount of about 10% to 20% in weight based on the total weight of the tablet, and one or more lubricants in a total amount of about 0.5% to 2% in weight based on the total weight of the tablet, wherein the tablet is free of water-insoluble filler.

In another general aspect, there is provided a solid oral pharmaceutical composition retains at least 90% by weight of the total content of ticagrelor or salts thereof when stored at 40°C and 75% relative humidity over a period of at least 3 months.

In another general aspect, there is provided a process of preparing the solid oral pharmaceutical composition of ticagrelor or salts thereof, which process comprises steps of:
(a) mixing ticagrelor or salts thereof with one or more pharmaceutically acceptable excipients to form a dry powder blend;
(b) granulating the dry powder blend of step (a) to form granules;
(c) compressing granules obtained in step (b) to form a core comprising ticagrelor or salts thereof, and
(d) filling cores of step (c) in a hard gelatin capsule shell.

In another general aspect, there is provided a process of preparing the solid oral pharmaceutical composition of ticagrelor or salts thereof, which process comprises steps of:
(a) mixing ticagrelor or salts thereof with one or more pharmaceutically acceptable excipients to form a dry powder blend;
(b) granulating the dry powder blend of step (a) to form granules;
(c) compressing granules obtained in step (b) to form tablet, and
(d) optionally, coating the tablet of step (c) with one or more film forming polymers.

The absolute amounts of each excipient and the amounts relative to other excipients are dependent on the desired properties of the tablet and may also be chosen by routine experimentation. For example, the tablet may be chosen to exhibit accelerated and/or delayed release of ticagrelor with or without quantitative control of the release of active agent. Preferably the tablet is chosen to exhibit immediate release of the ticagrelor.

In accordance with the present invention, it has now unexpectedly been found that stable and convenient tablets free of water-insoluble fillers are obtainable. Further, the tablets of the present invention may ensure complete release of ticagrelor or salts thereof. Specifically, the tablets of the invention may be prepared by granulation, preferably wet-granulation, followed by compression methods.

Thus, according to the present invention, an improved formulation of ticagrelor or salts thereof is prepared with one or more pharmaceutically acceptable excipients other than water-insoluble fillers. A particular advantage of the solid oral pharmaceutical composition is feasibility of using only water-soluble fillers and avoiding any water-insoluble filler.

In an embodiment, the solid oral pharmaceutical composition comprising ticagrelor or salts thereof with one or more pharmaceutically acceptable excipients, wherein the composition is free of water-insoluble fillers.

In another embodiment, the filler in the solid oral pharmaceutical composition is water-soluble filler such as mannitol.

In another embodiment, the solid oral pharmaceutical composition of ticagrelor or salts thereof, wherein the ratio of amount of ticagrelor to water-soluble fillers is 1:1.5 to 1:5.

In another embodiment, the solid oral pharmaceutical composition comprising ticagrelor or salts thereof, which composition is in the form of tablet.

In another embodiment, the solid oral pharmaceutical composition comprising ticagrelor or salts thereof, which composition is in the form of tablet.

In another embodiment, the tablet or capsule comprising ticagrelor or salts thereof intended for oral administration.

In another embodiment, the tablet prepared by a process comprising steps of:
(a) a pharmacologically effective amount of ticagrelor or salts thereof; and
(b) at least one pharmaceutically acceptable excipient suitable for the preparation of tablets;
wherein the tablet is free of water-insoluble fillers.

In another embodiment, the solid oral pharmaceutical composition comprising ticagrelor or salts thereof, wherein ticagrelor or salts thereof is present in an amount less than 20% by weight of the total composition.

In an embodiment, the solid oral pharmaceutical composition comprising ticagrelor or salts thereof with one or more pharmaceutically acceptable excipients, wherein all the excipients are water-soluble in nature.

In another embodiment, the solid oral pharmaceutical composition comprises of a core comprising ticagrelor or salts thereof and at least one filler, at least one binder, at least one disintegrant, at least one glidant, and at least one lubricant, and optionally a coating over the core comprising film forming polymer.

In another embodiment, the solid oral pharmaceutical composition of ticagrelor or salts thereof, wherein the amount of filler may vary within a range of from to 5 to 90%, particularly 10 to 30% in weight based on the total weight of the composition.

In another embodiment, the tablet comprises one or more fillers in a total amount of about 5% to 90%, one or more binders in a total amount of about 1% to 20% in weight based on the total weight of the tablet, one or more disintegrants in a total amount of about 10% to 20% in weight based on the total weight of the tablet, and one or more lubricants in a total amount of about 0.5% to 2% in weight based on the total weight of the tablet, wherein the tablet is free of water-insoluble filler.

In another embodiment, the solid oral pharmaceutical composition comprising 30% of ticagrelor or salts thereof, 63% of water-soluble filler, 3% of disintegrant and 1% of lubricant of total amount of uncoated consumption.

In another embodiment, the solid oral pharmaceutical composition comprising 30% of ticagrelor or salts thereof, 63% of mannitol, 3% of sodium starch glycollate and 1% of magnesium stearate of total amount of uncoated consumption.

In another embodiment, the solid oral pharmaceutical composition of ticagrelor or salts thereof, wherein the composition is chosen to exhibit immediate release of the ticagrelor.

In another embodiment, the solid oral pharmaceutical composition retains at least 90% by weight of the total content of ticagrelor or salts thereof when stored at 40°C and 75% relative humidity over a period of at least 3 months.

In another embodiment, the process of preparing the solid oral pharmaceutical composition of ticagrelor or salts thereof, which process comprises steps of:
(a) mixing ticagrelor or salts thereof with one or more pharmaceutically acceptable excipients to form a dry powder blend;
(b) granulating the dry powder blend of step (a) to form granules;
(c) compressing granules obtained in step (b) to form a core comprising ticagrelor or salts thereof, and
(d) filling cores of step (c) in a hard gelatin capsule shell.

In another embodiment, the process of preparing the solid oral pharmaceutical composition of ticagrelor or salts thereof, which process comprises steps of:
(a) mixing ticagrelor or salts thereof with one or more pharmaceutically acceptable excipients to form a dry powder blend;
(b) granulating the dry powder blend of step (a) to form granules;
(c) compressing granules obtained in step (b) to form tablet, and
(d) optionally, coating the tablet of step (c) with one or more film forming polymers.

In another embodiment, the process of preparing the solid oral pharmaceutical composition of ticagrelor or salts thereof, which process comprises steps of:
(a) mixing ticagrelor and mannitol and granulating with aqueous solution of hydroxypropylmethyl cellulose to form granules,
(b) compressing formed granules of step (a) to form a tablet, and
(c) coating the tablet of step (b) with one or more layers comprising hydroxypropylmethyl.

In another embodiment, the process of preparing the solid oral pharmaceutical composition of ticagrelor or salts thereof, which process comprises steps of:
(a) mixing ticagrelor and mannitol and granulated with aqueous solution of povidone to form granules,
(b) compressing formed granules of step (a) to form a tablet, and
(c) coating the tablet with one or more layers comprising hydroxypropylmethyl.

The term “ticagrelor” as used herein refers to ticagrelor base or its salts, solvates, prodrugs, hydrates, enantiomers or polymorphs thereof. Particularly, preferred salt of ticagrelor is ticagrelor base.

The term “filler” as used herein refers to any pharmaceutically acceptable inert material or composition added to a formulation to add bulk. Suitable filler includes, but are not limited, to dextrose, fructose, lactitol, lactose (e.g. spray-dried lactose, a-lactose, [beta]-lactose, Tablettose®, various grades of Pharmatose®, Microtose® or Fast-Floe®), L-hydroxypropyl- cellulose (low substituted), and other water-soluble cellulose derivatives, starches or modified starches (including potato starch, wheat starch, corn starch, rice starch, pregelatinized maize starch), maltitol, maltodextrins, maltose, sorbitol, starch, sucrose, sugar, and xylitol, erythritol, mixtures thereof and the like.

In an embodiment, the solid oral pharmaceutical composition of the present invention is devoid of any pH modifying filler, such as dibasic calcium phosphate.

Suitable binders include, but not limited to, microcrystalline cellulose, hydroxypropylcellulose, starch (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, lactose, and sorbitol), waxes, polyethylene glycol, natural and synthetic gums (e.g. acacia, tragacanth sodium alginate, celluloses, and Veegum),and synthetic water-soluble polymers, mixtures thereof and the like.

Suitable disintegrants include, but not limited to, cross linked polyvinylpyrolidone (crospovidone, polyplyplasdone XL(R), kollidon CL(R)); starches such as maize starch and dried sodium starch glycolate; gums such as maize starch and dried sodium starch glycolate; gums such as alginic acid, sodium alginate, guar gum; croscarmellose sodium; cellulose products such as microcrystalline cellulose and its salts, low-substituted hydroxypropylcellulose, mixtures thereof and the like.

Suitable lubricants include, but not limited to stearic acid, sodium stearyl fumarate, calcium stearate, magnesium stearate, magnesium lauryl sulfate, sodium stearyl fumarate, sucrose esters or fatty acid, zinc, polyethylene glycol, talc, mixtures thereof and the like.

The invention further provides a method of treating multiple sclerosis by administering a solid oral pharmaceutical dosage form comprising ticagrelor or salts thereof of administering the solid oral pharmaceutical solid oral pharmaceutical composition of ticagrelor or salts thereof in accordance with the present invention.

The invention now will be described in particularity with the following illustrative examples; however, the scope of the present invention is not intended to be, and shall not be, limited to the exemplified embodiments below.

Example 1:
Table 1
Sr. No. Ingredients Strategy I
Intragranular mg/tab
1 Ticagrelor 90.0
2 Mannitol 189.0
3 Povidone 9.0
Binder
4 Purified water q.s.
Extragranular
5 Sodium Starch Glycollate 9.0
6 Magnesium Stearate 3.0
Core tab Total wt. 300.0
Coating
7 Opadry 6.0
Total 306.0
Process:
Intragranular materials were sifted through # 40 sieve and dry mixed in RMG. The dry blend was granulated using purified water to form wet mass. Thus formed wet mass was dries in fluidized bed dryer at 60°C till LOD of less than 2 % is achieved. Granules were sized through # 20 sieve. Dried and sized granules were mix for 2 min with extragranular material and lubricated with magnesium stearate in a blender. This lubricated blend was compressed using suitable tooling on compression machine to form tablets. The compressed tablets were coated using opadry dispersion in water using coating pan.

Example 2:
Table 2
Sr. No. Ingredients Strategy I
Intragranular mg/tab
1 Ticagrelor 90.0
2 Mannitol 379.0
3 Povidone 19.0
Binder
4 Purified water q.s.
Extragranular
5 Sodium Starch Glycollate 9.0
6 Magnesium Stearate 3.0
Core tab Total wt. 500.0
Coating
7 Opadry 10.0
Total 510.0

Process:
Intragranular materials were sifted through # 40 sieve and dry mixed in RMG. The dry blend was granulated using purified water to form wet mass. Thus formed wet mass was dries in fluidized bed dryer at 60°C till LOD of less than 2 % is achieved. Granules were sized through # 20 sieve. Dried and sized granules were mix for 2 min with extragranular material and lubricated with magnesium stearate in a blender. This lubricated blend was compressed using suitable tooling on compression machine to form tablets. The compressed tablets were coated using opadry dispersion in water using coating pan.