FIELD OF THE INVENTION

The invention relates to oral pharmaceutical compositions comprising Ticagrelor and pharmaceutically acceptable polymer in a ratio of 1:0.1 to 1 : 1 in the form of solid dispersion and process for the preparation of such compositions.

BACKGROUND OF THE INVENTION

Ticagrelor, a cyclopentyltriazolopyrimidine, inhibitor of platelet activation and aggregation mediated by the P2Y12 ADP-receptor. Chemically it is (lS,2S,3R,5S)-3- [7-{ [(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5(propylth io)-3H-[l,2,3]- triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopenta ne-l,2-diol. The structural formula is:

TICAGRELOR

PCT Publication No. WO 00/34283 discloses ticagrelor as a compound and U.S. Patent No. 7,265,124 discloses various polymorphs of ticagrelor.

U.S. Patent No. 8,425,934 discloses a pharmaceutical composition comprising ticagrelor, a filler consisting essentially of a mixture of mannitol and di basic calcium phosphate dihydrate, a binder consisting essentially of hydroxypropyl cellulose, a disintegrant consisting essentially of sodium starch glycolate, and one or more lubricants. The compositions are prepared by using a wet granulation process or a high shear wet granulation process.

U.S. Publication No. 2008/0045548 discloses a pharmaceutical composition of ticagrelor suitable for oral administration that releases substantially all of the drug substance.

PCT Publication No. WO 2011/076749 discloses solid dosage forms comprising ticagrelor, characterized in that at least 90% by volume of ticagrelor particles have a particle size in the range of 1 μιτι to 150 μιτι.

PCT Publication No. WO 2015/110952 discloses process of preparing solid oral pharmaceutical composition of ticag

Ticagrelor is classified as BCS class IV compound, exhibiting low solubility and low permeability. This property leads to an undesirable dissolution profile and hence poor bioavailability. It also leads to high intra-subject and inter-subject variability following oral administration.

In general, amorphous form of drug substance has higher solubility as compared to the crystalline form and more hygroscopic and less stable than the crystalline form. This makes formulating amorphous form is challenging. The present application discloses that the dissolution of ticagrelor can be improved by using the drug in its amorphous form.

Thus, there exists a need to prepare alternate ticagrelor compositions that are stable and provide the desired dissolution and bioavailability. SUMMARY OF THE INVENTION

In one general aspect, there is provided a pharmaceutical composition comprising Ticagrelor and pharmaceutically acceptable polymer in a ratio of 1:0.1 to 1: 1 in the form of solid dispersion.

Embodiments of the present invention may include one or more of the following features for example the pharmaceutical composition may further include one or more pharmaceutical acceptable excipients. The pharmaceutical acceptable excipients may include diluents, binders, disintegrants, surfactants, lubricants, glidants and the like.

The details of one or more embodiments of the present invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides provided a pharmaceutical composition comprising Ticagrelor and pharmaceutically acceptable polymer in a ratio of 1:0.1 to 1: 1 in the form of solid dispersion.

In an embodiment, the pharmaceutical composition comprising Ticagrelor and pharmaceutically acceptable polymer in a ratio of 1:0.1 to 1 : 1 in the form of solid dispersion and one or more pharmaceutically acceptable excipients include diluents, binders, disintegrants, surfactants, lubricants, glidants and the like.

In another embodiment, the ratio of Ticagrelor to polymer is 1:0.2 to 1:0.8. Preferably, 1 :0.5.

In another embodiment, the Ticagrelor is molecularly dispersed in polymer matrix. In another embodiment, the pharmaceutical composition comprises Ticagrelor in crystalline or amorphous form.

In another embodiment, the pharmaceutical composition comprises crystalline form N of Ticagrelor.

In another embodiment, the pharmaceutical composition comprises amorphous Ticagrelor.

In another embodiment, the pharmaceutically acceptable polymer is water soluble polymer.

Water soluble polymers include, but not limited to polyvinylpyrrolidone, copovidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol and polyethylene oxide. Preferably, povidone.

The solid dispersion is prepared by methods known to the art for the manufacture of solid dispersions, such as fusion/melt technology, hot melt extrusion, hot melt coating, prilling, congealing, solvent evaporation (e.g. freeze drying, spray drying, vacuum drying, layering of powders, granules or pellets and fluid bed granulation), coprecipitation, supercritical fluid technology and electrostatic spinning method. Preferably, solvent evaporation or hot melt extrusion.

Solvent suitable for manufacture of solid dispersion by solvent evaporation processes include, but not limited to methanol, ethanol, n-propanol, isopropanol, butanol, acetone, methyl ethyl ketone and methyl isobutyl ketone, ethyl acetate, propyl acetate, acetonitrile, methylene chloride, chloroform, hexane, toluene, tetrahydrofuran, cyclic ethers, 1, 1,1-trichloroethane, dimethyl acetamide, dimethyl sulfoxide or mixtures thereof. Preferably, methanol, ethanol, isopropanol or acetone. More preferably, ethanol or acetone.

In another embodiment, the pharmaceutical composition is in the form of powder, granules, pellets, tablets, capsules, dragees, chewable tablets, effervescent tablets, dispersible tablets, troches, lozenges, melts, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions.

In another embodiment, the pharmaceutical composition is in the form of tablet. In another embodiment, the tablet is film coated.

The film coat comprises film-forming polymers and one or more pharmaceutically acceptable excipients.

In another embodiment, the process for the preparation of the pharmaceutical composition comprises the steps of:

i. preparing solid dispersion containing ticagrelor and pharmaceutically acceptable water soluble polymer in a ratio of 1:0.5 by hot melt extrusion. ii. milling the extrudes to obtain granules.

iii. blending granules with one or more pharmaceutically acceptable excipients. iv. lubricating the granules

v. compressing the lubricated granules into tablets.

In another embodiment, the process for the preparation of the pharmaceutical composition comprises the steps of: i. preparing solid dispersion containing ticagrelor and pharmaceutically acceptable water soluble polymer in a ratio of 1 :0.5 in a suitable solvent by solvent evaporation process.

ii. blending solid dispersion of step 1 and one or more pharmaceutically acceptable excipients.

iii. lubricating the blend

iv. compacting the blend to obtain granules

v. lubricating the granules

vi. compressing the lubricated granules into tablets.

In another embodiment, the solid dispersion comprising ticagrelor in substantially amorphous form.

The pharmaceutically acceptable excipients diluents, binders, disintegrants, surfactants, lubricants, glidants and the like.

Diluent 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.

Binder includes, but are not limited to, carrageenan, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, carboxymethylcellulose sodium, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, pregelatinized starch, sodium alginate, gums, synthetic resins and the like. 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.

Surfactant includes, but are not limited to, sodium lauryl sulfate, sodium dodecyl sulfate, ammonium lauryl sulfate, benzalkonium chloride, alkyl poly (ethylene oxide), copolymers of poly (ethylene oxide) and poly (propylene oxide) commercially called as poloxamers or poloxamines, polyvinyl alcohol, fatty alcohols, polyoxyethylene alkyl ether, polyoxyethylene alkylaryl ether, polyethylene glycol fatty acid ester, alkylene glycol fatty acid mono ester, sucrose fatty acid ester, and sorbitan fatty acid mono ester, sorbitol monolaurate or mixtures thereof.

Lubricant includes, but are not limited to, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, and mixtures thereof.

Glidant includes, but are not limited to, colloidal silicon dioxide, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, or mixtures thereof.

Film-forming agents include, but are not limited to, cellulose derivatives such as methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethyl ethylcellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, and ethyl cellulose; waxes; fat substances; or mixtures thereof. Alternatively, commercially available coating compositions comprising film forming polymers marketed under various trade names, such as Opadry®, may be used for coating. Solvents used for preparing the coating solution include, but not limited to methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water, or mixtures thereof.

In another embodiment, the pharmaceutical composition of the present invention is useful for the treatment of cardiovascular diseases such as thrombotic cardiovascular events selected from unstable angina, myocardial infarction, stroke, transient ischaemic attacks, or peripheral vascular disease in patients with acute coronary syndrome (ACS).

The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Examples

Example -1

Table 1

7 Microcrystalline cellulose PHI 02 84.00

8 Magnesium stearate 2.00

Extra granular

9 Croscarmellose sodium 40.00

10 Microcrystalline cellulose PHI 02 100.00

11 Magnesium stearate 4.00

Coating

12 Opadry 13.8

13 Purified water q.s

Manufacturing process: i. Ticagrelor and copovidone are dissolved in sufficient quantity of ethanol. ii. solution of step-i is spray dried using spray dryer followed by tray drying to obtain amorphous ticagrelor.

iii. solid dispersion of step-ii is blended with mannitol, calcium hydrogen phosphate anhydrous, microcrystalline cellulose PH102 and croscarmellose sodium for 10 min.

iv. blend is lubricated with magnesium stearate for 2 min.

v. lubricated blend is subjected to roller compaction followed by milling to obtain the granules.

vi. granules of step-v are blended microcrystalline cellulose PHI 02 and croscarmellose sodium.

vii. blend of step-vi is lubricated with magnesium stearate.

viii. compressing the lubricated blend into tablets,

ix. Coating the tablets with opadry solution. Film coated tablets of Ticagrelor are packed in Alu-Alu Blisters and HDPE bottles and stored at the accelerated stability testing conditions of 40°C and 75% RH. The impurity content is analyzed by HPLC at intervals and results are show below:

Example -2

Table 2

Manufacturing process:

i. Ticagrelor and copovidone are extruded through hot melt extruder followed by milling to obtain granules.

ii. Granules containing amorphous ticagrelor is blended with mannitol, calcium hydrogen phosphate anhydrous, microcrystalline cellulose phi 02 and croscarmellose sodium for 10 min. iii. The blend is lubricated with magnesium stearate for 2 min.

iv. compressing the lubricated blend into tablets.

v. Coating the tablets with opadry solution.

Dissolution Data

The following table depicts the dissolution profile of examples 1 and 2 in comparison with Brillianta (USP Type II apparatus, 0.2 % w/v Polysorbate 80 in water, 900 ml, 75 rpm).

Table 3