CLIAMS:1. A process for preparing the solid oral pharmaceutical composition comprising ticagrelor or salts thereof, which process comprises steps of:
(a) mixing ticagrelor or salts thereof in an amount less than 20% by weight of the total composition with one or more pharmaceutically acceptable excipients to form a dry powder blend;
(b) granulating the dry powder blend of step (a) with aqueous solution or dispersion of polymer to form granules;
(c) compressing the granules obtained in step (b) to form core.

2. A solid oral pharmaceutical composition prepared by the process of claim 1, wherein the composition is in the form of a tablet.

3. A process for preparing the solid oral pharmaceutical composition comprising ticagrelor or salts thereof, which process comprises steps of:
(a) mixing ticagrelor or salts thereof in an amount less than 20% by weight of the total composition with one or more pharmaceutically acceptable excipients to form a dry powder blend;
(b) granulating the dry powder blend of step (a) with aqueous solution or dispersion of polymer to form granules;
(c) compressing the granules obtained in step (b) to form a tablet, and
(d) optionally, coating the tablet prepared in step (c) with one or more film forming polymers.

4. A tablet prepared by the process of claim 1, wherein ticagrelor or salt thereof is present in an amount less than 10% by weight based on the total weight of the composition.

5. A solid oral pharmaceutical composition prepared by the process of claim 1, wherein the composition is free of water-insoluble fillers.

6. A tablet prepared by the process of claim 3, wherein the weight of the tablet is more than 450 mg.

7. A tablet prepared by the process of claim 4, wherein the weight of the tablet is more than 1000 mg.

8. A composition prepared by the process of claim 1, wherein the composition retains at least 90% by weight of the total content of ticagrelor or salt thereof 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.

Dated this 20th day of January 2014 For Wockhardt Limited
(Dr. Mandar Kodgule)
Authorized Signatory
,TagSPECI:DESCRIPTION

The present invention relates to process for preparing solid oral pharmaceutical compositions comprising ticagrelor or salts thereof. In particular, the present invention relates to a process for preparing solid oral pharmaceutical composition comprising ticagrelor or salts thereof in an amount less than 20 % of the weight of total composition and at least one pharmaceutically acceptable excipient. The invention further relates to method of reducing the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) by using the 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 used to reduce 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 low drug load which can address the aforesaid objective i.e. uniform and complete release as well as may exhibit excellent storage stability.

To formulate a composition having low drug load, the inventors of the present invention have prepared a composition comprising low drug (ticagrelor or salts thereof) load i.e. less than 20 % of total weight of composition. In other words, as the dose of ticagrelor is 90 mg, a composition with a total weight more than 450 mg is prepared.

The high excipient load may enable the production of solid oral pharmaceutical composition that releases its content completely and more uniformly. The total amount of excipients in a given unit dosage may be about 80% or more by weight based on the total weight of the tablet.

Inventors of the present invention have surprisingly found it is possible to formulate a ticagrelor solid oral pharmaceutical composition having low drug load (less than 20%) that exhibits desired release profile.

Accordingly, the present invention provides a solid oral pharmaceutical composition with low drug load comprising a pharmacologically effective amount of ticagrelor or salts thereof present in an amount of less than about 20%.

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 ticagrelor comprises less than 20% by weight of the composition. Preferably ticagrelor comprises less than 10% by weight of the composition.

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.

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 amount of ticagrelor or salts thereof is less than 20% when calculated as the percentage of the content in weight of the active moiety based on the total the tablet,

One or more pharmaceutically acceptable excipients may be present in the tablets, e.g. at least one diluent, 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.

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 the composition comprises at least 80% pharmaceutically acceptable excipients by weight of the composition.

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

The amount of diluent may vary within a range of from to 5 to 90%, e.g. 10 to 80% and particularly 40 to 70% in weight based on the total weight of the 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 composition.

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

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

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

In another aspect of the invention, the tablet comprises the following excipients, one or more diluent 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 composition.

The absolute amounts of each excipient and the amounts relative to other excipients are similarly dependent on the desired properties of the tablet and may also be chosen by routine experimentation. For example, the solid oral pharmaceutical composition 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 solid oral pharmaceutical composition is chosen to exhibit immediate release of the ticagrelor.

The solid oral pharmaceutical composition in accordance with the present invention may be in the form of a tablet.

In accordance with the present invention, it has now unexpectedly been found that stable and convenient tablets comprising low load of ticagrelor are obtainable. Specifically, the tablets of the invention may be prepared by granulation, preferably wet-granulation, followed by compression methods.

It is a characteristic of the tablet according to the invention that it contains a low content of ticagrelor given the relatively high amount of excipients. This enables the production of tablets that releases its content completely and more uniformly. The total amount of excipients in a given unit dosage may be about 80% or more by weight based on the total weight of the tablet.

In another general aspect, 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 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; and
(d) filling one or more cores prepared in step (c) in a hard gelatin capsule shell.

In another general aspect, there is provided a process of preparing the 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 prepared in step (c) with one or more film forming polymers.

Thus, inventors of the present invention have formulated a solid oral pharmaceutical composition having low drug load (less than 20%) to produce sufficiently small, and therefore, convenient to administer dosage form. A particular advantage of the composition is that it exhibits similar dissolution properties as compared to currently marketed ticagrelor tablets.

In an embodiment, the 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.

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 capsule.

In another embodiment, the solid oral pharmaceutical composition comprises:
(a) a pharmacologically effective amount of ticagrelor or salts thereof; and
(b) at least one pharmaceutically acceptable excipient;
wherein the amount of ticagrelor or salts thereof, calculated as the percentage of the content in weight of the active moiety based on the total the composition, is less than 20%.

In another embodiment, the tablet comprises:
(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 amount of ticagrelor or salts thereof, calculated as the percentage of the content in weight of the active moiety based on the total the tablet, is less than 20%.

In another embodiment, the solid oral pharmaceutical composition comprises of one or more diluent 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 composition.

In another embodiment, the solid oral pharmaceutical composition comprises the following excipients, mannitol, dibasic calcium phosphate dihydrate, povidone, sodium starch glycollate and magnesium stearate.

A solid bulk of granulate mass, which is necessary for manufacturing tablets, can be manufactured using two main processes, wet granulation or dry granulation. Tablets may also be manufactured using direct compression. Direct compression relates to the tabletting process itself rather than preparation of the starting material.

In wet granulation, components are typically mixed and granulated using a wet binder. The wet granulates are then sieved, dried and optionally ground prior to compressing into tablets. Wet granulation is used extensively in the pharmaceutical industry although it has proven to be a difficult method, mainly because the liquids needed in the granule and tablet manufacturing process often have an adverse effect on the characteristics of the active pharmaceutical ingredients (APIs) and/or on the end product such as a tablet.

Dry granulation is usually described as a method of controlled crushing of precompacted powders densified by either slugging or passing the material between two counter-rotating rolls.

More specifically, powdered components that may contain very fine particles are typically mixed prior to being compacted to yield hard slugs which are then ground and sieved before the addition of other ingredients and final compression to form tablets. Because substantially no liquids are used in the dry granulation process, the issues related to wet granulation are avoided. Although dry granulation would in many cases appear to be the best way to produce products such as tablets containing APIs, it has been relatively little used because of the challenges in producing the desired kind of granules as well as managing the granulated material in the manufacturing process. Known dry granulation methods, as well as the known issues related to them are well described in scientific articles, such as the review article "Roll compaction / dry granulation: pharmaceutical applications" written by Peter Kleinebudde and published in European Journal of Pharmaceutics and Biopharmaceutics 58 (2004) at pages 317-326.

Direct compression is generally considered to be the simplest and the most economical process for producing tablets. However, it may only be applied to materials that do not need to be granulated before tableting. Direct compression requires only two principal steps; i.e., the mixing of all the ingredients and the compression of this mixture. However, direct compression is applicable to only a relatively small number of substances as the ingredients of the tablets often need to be processed by some granulation technique to make them compressible and/or for improving their homogeneity and flow-ability.

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.

It is also well known in the art that in order to get uniform tablets the bulk to be tableted should be homogeneous and should have good flow characteristics.

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; and
(d) filling one or more cores prepared in step (c) in a hard gelatin capsule shell.

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

In another embodiment, the process of preparing the composition of ticagrelor or salts thereof, which process comprises steps of:
(a) mixing ticagrelor, mannitol and dibasic calcium phosphate dihydrate 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 cellulose.

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' or ‘diluent’ and the term 'diluent' are herein used interchangeably. Suitable filler/diluent includes, but are not limited, to calcium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate, calcium carboxymethylcellulose, cellulose, dextrin derivatives, dextrin, dextrose, fructose, lactitol, lactose (e.g. spray-dried lactose, a-lactose, [beta]-lactose, Tablettose®, various grades of Pharmatose®, Microtose® or Fast-Floe®), methyl cellulose polymers such as, e.g., Methocel A®, Methocel A4C®, Methocel A15C®, Metocel A4M®), hydroxyethylcellulose, hydroxypropylcellulose, L-hydroxypropyl- cellulose (low substituted), hydroxypropyl methylcellulose (HPMC) (e.g. Methocel E®, F and K, Metolose SH® of Shin-Etsu, grades of Methocel F® and Metolose 65 SH®, the 4,000, 15,000 and 100,000 cps grades of Methocel K®; and the 4,000, 15,000, 39,000 and 100,000 grades of Metolose 90 SH®), sodium carboxymethyl cellulose, carboxymethylene, carboxy methyl hydroxyethyl cellulose and other cellulose derivatives, starches or modified starches (including potato starch, wheat starch, corn starch, rice starch, pregelatinized maize starch), magnesium carbonate, magnesium oxide, maltitol, maltodextrins, maltose, sorbitol, starch, sucrose, sugar, and xylitol, erythritol and the like.

Suitable binders include, but not limited to, microcrystalline cellulose, hydroxymethyl 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 polymers such as polymetacrylates and polyvinylpyrrolidone (povidone), ethylcellulose, hydroxyethyl cellulose, polyethylene oxide, 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, microfine cellulose, low-substituted hydroxypropylcellulose, mixtures thereof and the like.

Suitable lubricants include, but not limited to sodium oleate, sodium stearate, sodium benzoate, sodium stearate, sodium chloride, 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 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 226.0
3 Dibasic calcium phosphate dihydrate 153.0
4 Hydroxypropylmethyl cellulose 19.0
Binder
5 Purified water q.s.
Extragranular
6 Sodium Starch Glycollate 9.0
7 Magnesium Stearate 3.0
Core tab Total wt. 500.0
Coating
8 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.

Example 2:
Table 2
Sr. No. Ingredients Strategy I
Intragranular mg/tab
1 Ticagrelor 90.0
2 Mannitol 645.0
3 Dibasic calcium phosphate dihydrate 206.0
4 Povidone 38.0
Binder
5 Purified water q.s.
Extragranular
6 Sodium Starch Glycollate 18.0
7 Magnesium Stearate 3.0
Core tab Total wt. 1000.0
Coating
8 Opadry 20.0
Total 1020.0

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.