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WO2015001489A1 - Pharmaceutical compositions of ticagrelor - Google Patents

Pharmaceutical compositions of ticagrelor Download PDF

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Publication number
WO2015001489A1
WO2015001489A1 PCT/IB2014/062773 IB2014062773W WO2015001489A1 WO 2015001489 A1 WO2015001489 A1 WO 2015001489A1 IB 2014062773 W IB2014062773 W IB 2014062773W WO 2015001489 A1 WO2015001489 A1 WO 2015001489A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
ticagrelor
composition according
tablets
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2014/062773
Other languages
French (fr)
Inventor
Radhanath Mandal
Mona Dhaliwal
Swati Agarwal
Mukesh Kumar Garg
Ajay Kumar Singla
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of WO2015001489A1 publication Critical patent/WO2015001489A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • the present invention relates to oral pharmaceutical compositions comprising amorphous ticagrelor and processes for their preparation. It further relates to a method of treating cardiovascular diseases using said pharmaceutical compositions.
  • Ticagrelor is a P2Yn platelet inhibitor. Chemically it is (l ⁇ S i ⁇ -S-f?- ⁇ [(li?,25)-2-(3,4-difluorophenyl)cyclopropyl]amino ⁇ -5-(propylthio)-3H-[l,2,3]- triazolo[4,5-£/]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol.
  • Ticagrelor is a crystalline powder with an aqueous solubility of approximately 10 ⁇ g/mL at room temperature.
  • 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
  • a pharmaceutical composition 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 compositions are prepared by using a 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.
  • 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 ⁇ to 150 ⁇ . It further discloses that ticagrelor, being poorly soluble, presents a significant problem in the design of pharmaceutical compositions. Further, in order to exhibit good bioavailability, it is desirable to formulate dosage forms showing fast dissolution of the drug. This can be achieved by reducing the particle size of the drug and by the use of hydrophilic polymers/emulsifiers in the dosage form. According to the Biopharmaceutics Classification System (BCS), ticagrelor is classified as a 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.
  • BCS Biopharmaceutics Classification System
  • the amorphous form of a drug has higher solubility as compared to the crystalline form.
  • the use of the amorphous form poses many challenges during formulation of the dosage form as the amorphous form is generally more hygroscopic and less stable than the crystalline form.
  • the present application discloses that the dissolution of ticagrelor can be improved by using the drug in its amorphous form.
  • the present invention provides an alternate pharmaceutical composition comprising ticagrelor in a stable and readily bioavailable form.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising amorphous ticagrelor and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition provides a desirable dissolution profile and enhanced bioavailability.
  • the pharmaceutically acceptable excipients further comprise diluents, binders, disintegrants, and lubricants.
  • the present invention also includes different processes for the preparation of said pharmaceutical composition and a method of treating cardiovascular diseases by administering said pharmaceutical composition.
  • pharmaceutically acceptable excipients includes diluents, binders, disintegrants, lubricants, glidants, stabilizers, surfactants, solubility enhancers, coloring agents, flavoring agents, plasticizers, opacifiers, or mixtures thereof.
  • solid dispersion refers to a group of solid products consisting of at least two different components, generally a hydrophilic matrix or a carrier/stabilizer and a hydrophobic drug.
  • the matrix can be either crystalline or amorphous.
  • the drug can be dispersed molecularly, in amorphous particles (clusters), or in crystalline particles,
  • a first aspect of the present invention provides a pharmaceutical composition comprising amorphous ticagrelor and one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition comprising amorphous ticagrelor and one or more pharmaceutically acceptable excipients selected from one or more diluents, binders, disintegrants, lubricants, glidants, stabilizers, surfactants, solubility enhancers, coloring agents, flavoring agents, plasticizers, opacifiers, or mixtures thereof.
  • a pharmaceutical composition comprising amorphous ticagrelor and one or more pharmaceutically acceptable excipients selected from diluents, binders, disintegrants, lubricants, or mixtures thereof.
  • a pharmaceutical composition comprising amorphous ticagrelor and one or more diluents, binders, disintegrants, and lubricants, wherein the diluent is not mannitol and/or dibasic calcium phosphate dihydrate.
  • the composition is free of mannitol and/or dibasic calcium phosphate dihydrate.
  • a pharmaceutical composition comprising amorphous ticagrelor and one or more diluents, binders, disintegrants, and lubricants, wherein the binder is not hydroxypropyl cellulose.
  • the composition is free of hydroxypropyl cellulose.
  • a pharmaceutical composition comprising amorphous ticagrelor and one or more diluents, binders, disintegrants, and lubricants, wherein the disintegrant is not sodium starch glycolate.
  • the composition is free of sodium starch glycolate.
  • a pharmaceutical composition comprising amorphous ticagrelor and one or more diluents, binders, disintegrants, and lubricants, wherein the diluent is not mannitol and/or dibasic calcium phosphate dihydrate, the binder is not hydroxypropyl cellulose, and the disintegrant is not sodium starch glycolate.
  • the composition is free of mannitol, dibasic calcium phosphate dehydrate, hydroxypropyl cellulose and sodium starch glycolate.
  • a pharmaceutical composition comprising amorphous ticagrelor and one or more diluents, binders, disintegrants, and lubricants, wherein the binder is povidone and the disintegrant is croscarmellose sodium.
  • a pharmaceutical composition comprising a solid dispersion of amorphous ticagrelor, one or more hydrophilic polymers, and optionally one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition comprising amorphous ticagrelor and one or more pharmaceutically acceptable excipients, wherein the composition further comprises one or more other anti -thrombotic agents.
  • the water content of the final composition of the present invention is not more than 5.0% w/w.
  • a pharmaceutical composition comprising amorphous ticagrelor and one or more diluents, binders, disintegrants, and lubricants, wherein the composition is prepared by direct compression or dry granulation.
  • a pharmaceutical composition comprising amorphous ticagrelor and one or more diluents, binders, disintegrants, and lubricants, wherein the composition is prepared by hot melt extrusion.
  • a second aspect of the present invention provides a process for the preparation of a pharmaceutical composition of the present invention, wherein the process comprises the steps of:
  • a third aspect of the present invention provides a process for the preparation of the pharmaceutical composition of the present invention, wherein the process comprises the steps of:
  • diluents binders, disintegrants, and/or lubricants can also be added extragranularly.
  • a fourth aspect of the present invention provides a process for the preparation of a pharmaceutical composition of the present invention, wherein the process comprises the steps of:
  • a surfactant in a rapid mixer granulator optionally a surfactant in a rapid mixer granulator
  • step (b) loading the granules obtained in step (a) into a hot melt extruder to form a solid dispersion in the form of extrudates;
  • a fifth aspect of the present invention provides a method of treating cardiovascular diseases by administering a pharmaceutical composition comprising amorphous ticagrelor and one or more pharmaceutically acceptable excipients.
  • cardiovascular diseases refers to thrombotic cardiovascular events selected from unstable angina, myocardial infarction, stroke, transient ischaemic attacks, or peripheral vascular disease.
  • ACS acute coronary syndrome
  • the method of treatment further comprises administration of an additional anti-thrombotic agent.
  • Suitable diluents are selected from the group consisting of lactose, microcrystalline cellulose, co-processed microcrystalline cellulose, powdered cellulose, crospovidone, co- povidone, mannitol, sorbitol, xylitol, erythritol, dibasic calcium phosphate, dibasic calcium phosphate anhydrate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, calcium sulfate, calcium carbonate, pregelatinized starch, maize starch, corn starch, or mixtures thereof.
  • the present invention comprises one or more diluents in an amount of from about 5% to about 90% by weight of the composition.
  • Suitable binders are selected from the group consisting of povidone, co-povidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, carboxymethyl cellulose sodium, xanthan gum, gum acacia, gum arabic, tragacanth, sorbitol, dextrose, sucrose, mannitol, gelatin, pullulan, sodium alginate, propylene glycol, polyvinyl alcohol, corn starch, maize starch, pregelatinized starch, methacrylates, carboxyvinyl polymers like carbomers, or mixtures thereof.
  • the present invention comprises one or more binders in an amount of from about 0.5% to about 30% by weight of the composition.
  • Suitable disintegrants are selected from the group consisting of hydroxypropyl cellulose, crospovidone, croscarmellose sodium, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, sodium starch glycolate, gums, alginic acid or alginates, starch, corn starch, modified starch, carboxymethyl starch, polyacrylates, or mixtures thereof.
  • the present invention comprises one or more disintegrants in an amount of from about 0.5% to about 30% by weight of the composition.
  • Suitable lubricants are selected from the group consisting of stearic acid, polyethylene glycol, magnesium stearate, calcium stearate, talc, zinc stearate,
  • Suitable glidants are selected from the group consisting of colloidal silicon dioxide, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, or mixtures thereof.
  • Suitable stabilizers are selected from the group consisting of cellulose derivatives such as hydroxypropyl methylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose phthalate, carboxymethylcellulose sodium, and carboxymethylcellulose calcium; polyvinylpyrrolidone and/or derivatives thereof, such as co-povidone; polyvinyl alcohol; polyethylene glycol; block copolymers of ethylene oxide and/or propylene oxide; gums such as xanthan gum, pectins, alginates, tragacanth and/or derivatives thereof, and gum arabic and/or derivatives thereof; carrageenans, agar and/or derivatives thereof; polysaccharides from microbiological sources; acacia; starch;
  • the stabilizers may also act as crystallization inhibitors.
  • Suitable surfactants are selected from the group consisting of 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 (PVA), 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 (Span ® 20 or Span ® 80),
  • polysorbates polyoxyethylene sorbitan fatty acid ester (polysorbates), or mixtures thereof.
  • Suitable solubility enhancers are selected from the group consisting of sodium lauryl sulfate, polyethylene glycol, propylene glycol, glycerol, glycerol monostearate, glycerol behenate, triglycerides, mono-alcohols, higher alcohols, dimethylsulfoxide, dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-(2- hydroxyethyl) pyrrolidone, 2-pyrrolidone, or mixtures thereof.
  • Suitable coloring agents and flavoring agents are selected from any FDA approved colors and flavors for oral use.
  • Suitable plasticizers are selected from the group consisting of triethyl citrate, dibutyl sebacate, acetylated triacetin, tributyl citrate, glyceryl tributyrate, sorbitol monolaurate (Span ® 20), monoglyceride, rapeseed oil, olive oil, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, glycerin sorbitol, diethyl oxalate, diethyl phthalate, diethyl malate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, or mixtures thereof.
  • Suitable opacifiers are selected from the group consisting of titanium dioxide, manganese dioxide, iron oxide, silicon dioxide, or mixtures thereof.
  • Suitable hydrophilic polymers are selected from the group consisting of polyvinyl alcohol (PVA), polyvinylpyrrolidone, co-povidone, vinyl acetate polymer, polyalkylene oxide, polyoxyethylene stearates, polyacrylate, polymethacrylate, pluronics,
  • polyacrylamide a polyvinyl alcohol-polyethylene glycol graft copolymer, a block copolymer of polyoxyethylene and polyoxypropylene, homopolymer of N-vinyl lactam, copolymer of N-vinyl lactam, oligosaccharide, polysaccharide, cellulose such as cellulose ester, cellulose ether, or mixtures thereof.
  • the pharmaceutical composition of the present invention can be obtained by using known conventional methods, i.e., granulation or direct compression.
  • the granulation process includes, but is not limited to, wet granulation, dry granulation, hot melt granulation, hot melt extrusion, or solvent evaporation.
  • composition of the present invention may be in the form of minitablets, granules, pellets, tablets, or capsules.
  • the pharmaceutical composition of the present invention may further be film-coated using techniques well known in the art such as spray coating in a conventional coating pan or a fluidized bed processor or dip coating.
  • coating may also be performed using the hot melt technique.
  • the film coat comprises film-forming polymers and one or more pharmaceutically acceptable excipients.
  • 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.
  • 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 are selected from methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water, or mixtures thereof.
  • 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).
  • 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).
  • ACS acute coronary syndrome
  • the pharmaceutical composition of the present invention may be administered along with an additional anti-thrombotic agent.
  • the other anti-thrombotic agent is selected from anti-platelet agents such as ASA (acetylsalicylic acid), clopidogrel, ticlopidine, dipyridamole, and GPIIb/llla antagonists; anticoagulant agents such as thrombin inhibitors, warfarin, factor Xa inhibitors, and heparin; and fibrinolytic agent such as streptokinase and tenecteplase.
  • anti-platelet agents such as ASA (acetylsalicylic acid), clopidogrel, ticlopidine, dipyridamole, and GPIIb/llla antagonists
  • anticoagulant agents such as thrombin inhibitors, warfarin, factor Xa inhibitors, and heparin
  • fibrinolytic agent such as streptokinase and tenecteplase.
  • Ticagrelor, crospovidone, povidone, and croscarmellose sodium are blended in a blender.
  • step 1 The blend of step 1 is lubricated with magnesium stearate and compressed into tablets.
  • step 2 The tablets of step 2 are coated with an Opadry ® dispersion.
  • Example 2
  • Ticagrelor, lactose monohydrate, povidone, and croscarmellose sodium are blended in a blender.
  • step 1 The blend of step 1 is lubricated with magnesium stearate and compressed into tablets.
  • step 2 The tablets of step 2 are coated with an Opadry ® dispersion.
  • Ticagrelor, microcrystalline cellulose, povidone, and croscarmellose sodium are blended in a blender.
  • step 1 The blend of step 1 is lubricated with magnesium stearate and compressed into tablets.
  • step 2 The tablets of step 2 are coated with an Opadry ® dispersion.
  • Example 4
  • Ticagrelor, mannitol, dibasic calcium phosphate dihydrate, sodium starch glycolate, hydroxypropyl methylcellulose, and a part of magnesium stearate are blended in a blender.
  • step 1 The blend of step 1 is dry granulated by compaction to obtain a 60:40 ratio of granules: fines.
  • step 2 The blend of step 2 is lubricated with the remaining part of magnesium stearate and compressed into tablets.
  • step 3 The tablets of step 3 are coated with an Opadry ® dispersion.
  • Ticagrelor, mannitol, dibasic calcium phosphate dihydrate, sodium starch glycolate, hydroxypropyl cellulose, and a part of magnesium stearate are blended in a blender.
  • the blend of step 1 is dry granulated by compaction to obtain a 60:40 ratio of granules: fines.
  • step 2 The blend of step 2 is lubricated with the remaining part of magnesium stearate and compressed into tablets.
  • step 3 The tablets of step 3 are coated with an Opadry ® dispersion.
  • Ticagrelor and co-povidone are mixed together.
  • Sorbitol monolaurate is added to the blend of step 1 and the blend is loaded into a rapid mixer granulator to obtain granules.
  • step 2 The granules obtained from step 2 are loaded into a hot melt extruder and the extrudate/sheet obtained is milled.
  • step 4 Sodium starch glycolate, hydroxypropyl cellulose, microcrystalline cellulose, and magnesium stearate are added to the milled extrudates of step 3 and blended. The blend of step 4 is compressed into tablets.
  • step 5 The tablets of step 5 are coated with an Opadry ® dispersion.
  • Example 7 The tablets of step 5 are coated with an Opadry ® dispersion.
  • Ticagrelor, mannitol, dibasic calcium phosphate dihydrate, croscarmellose sodium, and hydroxypropyl cellulose were blended in a blender.
  • step 1 The blend of step 1 was lubricated with magnesium stearate and compressed into tablets.
  • step 2 The tablets of step 2 were coated with an Opadry ® dispersion.
  • Ticagrelor, mannitol, 2/3 of the croscarmellose sodium, hydroxypropyl cellulose, and 4/7 of the magnesium stearate were blended in a blender.
  • step 2 The blend of step 1 was dry granulated by compaction to obtain a 60:40 ratio of granules: fines.
  • step 3 Dibasic calcium phosphate dihydrate and the remaining part of croscarmellose sodium were sifted and blended with the blend of step 2. 4. The blend of step 3 was lubricated with the remaining part of magnesium stearate and compressed into tablets.
  • step 4 The tablets of step 4 were coated with an Opadry ® dispersion.
  • Ticagrelor, mannitol, dibasic calcium phosphate dihydrate/ anhydrous, povidone, croscarmellose sodium, and pregelatinized starch were blended in a blender.
  • step 1 The blend of step 1 was lubricated with magnesium stearate and compressed into tablets.
  • step 2 The tablets of step 2 were coated with an Opadry ® dispersion.
  • Ticagrelor, mannitol, half of the croscarmellose sodium and 4/7 of the magnesium stearate were blended in a blender.
  • step 2 The blend of step 1 was dry granulated by compaction to obtain a 60:40 ratio of granules: fines.
  • step 3 The blend of step 3 was lubricated with the remaining part of magnesium stearate and compressed into tablets.
  • step 4 The tablets of step 4 were coated with an Opadry ® dispersion.

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Abstract

The present invention relates to oral pharmaceutical compositions comprising amorphous ticagrelor and processes for their preparation. It further relates to a method of treating cardiovascular diseases using said pharmaceutical compositions.

Description

PHARMACEUTICAL COMPOSITIONS OF TICAGRELOR
Field of the Invention
The present invention relates to oral pharmaceutical compositions comprising amorphous ticagrelor and processes for their preparation. It further relates to a method of treating cardiovascular diseases using said pharmaceutical compositions.
Background of the Invention
Ticagrelor is a P2Yn platelet inhibitor. Chemically it is (l^^^S i^^-S-f?- {[(li?,25)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]- triazolo[4,5-£/]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol. Ticagrelor is a crystalline powder with an aqueous solubility of approximately 10 μg/mL at room temperature.
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 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 compositions are prepared by using a 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 μπι to 150 μπι. It further discloses that ticagrelor, being poorly soluble, presents a significant problem in the design of pharmaceutical compositions. Further, in order to exhibit good bioavailability, it is desirable to formulate dosage forms showing fast dissolution of the drug. This can be achieved by reducing the particle size of the drug and by the use of hydrophilic polymers/emulsifiers in the dosage form. According to the Biopharmaceutics Classification System (BCS), ticagrelor is classified as a 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.
Generally, the amorphous form of a drug has higher solubility as compared to the crystalline form. However, the use of the amorphous form poses many challenges during formulation of the dosage form as the amorphous form is generally more hygroscopic and less stable than the crystalline form. The present application discloses that the dissolution of ticagrelor can be improved by using the drug in its amorphous form.
The present invention provides an alternate pharmaceutical composition comprising ticagrelor in a stable and readily bioavailable form.
Summary of the Invention
The present invention relates to a pharmaceutical composition comprising amorphous ticagrelor and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition provides a desirable dissolution profile and enhanced bioavailability. The pharmaceutically acceptable excipients further comprise diluents, binders, disintegrants, and lubricants.
The present invention also includes different processes for the preparation of said pharmaceutical composition and a method of treating cardiovascular diseases by administering said pharmaceutical composition.
Detailed Description of the Invention
The term "pharmaceutically acceptable excipients", as used herein, includes diluents, binders, disintegrants, lubricants, glidants, stabilizers, surfactants, solubility enhancers, coloring agents, flavoring agents, plasticizers, opacifiers, or mixtures thereof.
The term "about", as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.
The term "solid dispersion", as used herein, refers to a group of solid products consisting of at least two different components, generally a hydrophilic matrix or a carrier/stabilizer and a hydrophobic drug. The matrix can be either crystalline or amorphous. The drug can be dispersed molecularly, in amorphous particles (clusters), or in crystalline particles, A first aspect of the present invention provides a pharmaceutical composition comprising amorphous ticagrelor and one or more pharmaceutically acceptable excipients.
According to one embodiment of the present invention, there is provided a pharmaceutical composition comprising amorphous ticagrelor and one or more pharmaceutically acceptable excipients selected from one or more diluents, binders, disintegrants, lubricants, glidants, stabilizers, surfactants, solubility enhancers, coloring agents, flavoring agents, plasticizers, opacifiers, or mixtures thereof.
According to a particular embodiment of the present invention, there is provided a pharmaceutical composition comprising amorphous ticagrelor and one or more pharmaceutically acceptable excipients selected from diluents, binders, disintegrants, lubricants, or mixtures thereof.
According to another embodiment of the present invention, there is provided a pharmaceutical composition comprising amorphous ticagrelor and one or more diluents, binders, disintegrants, and lubricants, wherein the diluent is not mannitol and/or dibasic calcium phosphate dihydrate. As such, the composition is free of mannitol and/or dibasic calcium phosphate dihydrate.
According to another embodiment of the present invention, there is provided a pharmaceutical composition comprising amorphous ticagrelor and one or more diluents, binders, disintegrants, and lubricants, wherein the binder is not hydroxypropyl cellulose. As such, the composition is free of hydroxypropyl cellulose.
According to another embodiment of the present invention, there is provided a pharmaceutical composition comprising amorphous ticagrelor and one or more diluents, binders, disintegrants, and lubricants, wherein the disintegrant is not sodium starch glycolate. As such, the composition is free of sodium starch glycolate.
According to another embodiment of the present invention, there is provided a pharmaceutical composition comprising amorphous ticagrelor and one or more diluents, binders, disintegrants, and lubricants, wherein the diluent is not mannitol and/or dibasic calcium phosphate dihydrate, the binder is not hydroxypropyl cellulose, and the disintegrant is not sodium starch glycolate. The composition is free of mannitol, dibasic calcium phosphate dehydrate, hydroxypropyl cellulose and sodium starch glycolate. According to another embodiment of the present invention, there is provided a pharmaceutical composition comprising amorphous ticagrelor and one or more diluents, binders, disintegrants, and lubricants, wherein the binder is povidone and the disintegrant is croscarmellose sodium.
According to another embodiment of the present invention, there is provided a pharmaceutical composition comprising a solid dispersion of amorphous ticagrelor, one or more hydrophilic polymers, and optionally one or more pharmaceutically acceptable excipients.
According to another embodiment of the present invention, there is provided a pharmaceutical composition comprising amorphous ticagrelor and one or more pharmaceutically acceptable excipients, wherein the composition further comprises one or more other anti -thrombotic agents.
According to another embodiment, the water content of the final composition of the present invention is not more than 5.0% w/w.
According to another embodiment of the present invention, there is provided a pharmaceutical composition comprising amorphous ticagrelor and one or more diluents, binders, disintegrants, and lubricants, wherein the composition is prepared by direct compression or dry granulation.
According to another embodiment of the present invention, there is provided a pharmaceutical composition comprising amorphous ticagrelor and one or more diluents, binders, disintegrants, and lubricants, wherein the composition is prepared by hot melt extrusion.
A second aspect of the present invention provides a process for the preparation of a pharmaceutical composition of the present invention, wherein the process comprises the steps of:
(a) blending amorphous ticagrelor and one or more pharmaceutically acceptable excipients;
(b) lubricating the blend; and
(c) directly compressing the lubricated blend into tablets. A third aspect of the present invention provides a process for the preparation of the pharmaceutical composition of the present invention, wherein the process comprises the steps of:
(a) blending amorphous ticagrelor, one or more diluents, binders, and
disintegrants, and lubricants;
(b) compacting the blend to obtain granules;
(c) lubricating the granules using the additional lubricants; and
(d) compressing the lubricated granules into tablets or filling into capsules.
Alternatively, additional diluents, binders, disintegrants, and/or lubricants can also be added extragranularly.
A fourth aspect of the present invention provides a process for the preparation of a pharmaceutical composition of the present invention, wherein the process comprises the steps of:
(a) blending amorphous ticagrelor, one or more hydrophilic polymers, and
optionally a surfactant in a rapid mixer granulator;
(b) loading the granules obtained in step (a) into a hot melt extruder to form a solid dispersion in the form of extrudates;
(c) milling the extrudates and adding one or more diluents, binders,
disintegrants, and lubricants; and
(d) compressing the granules into tablets or filling into capsules.
A fifth aspect of the present invention provides a method of treating cardiovascular diseases by administering a pharmaceutical composition comprising amorphous ticagrelor and one or more pharmaceutically acceptable excipients.
The term "cardiovascular diseases", as used herein, refers to thrombotic cardiovascular events selected from unstable angina, myocardial infarction, stroke, transient ischaemic attacks, or peripheral vascular disease.
According to one embodiment of the present invention, there is provided a method of treating cardiovascular diseases in patients with acute coronary syndrome (ACS). According to another embodiment of the present invention, the method of treatment further comprises administration of an additional anti-thrombotic agent.
Suitable diluents are selected from the group consisting of lactose, microcrystalline cellulose, co-processed microcrystalline cellulose, powdered cellulose, crospovidone, co- povidone, mannitol, sorbitol, xylitol, erythritol, dibasic calcium phosphate, dibasic calcium phosphate anhydrate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, calcium sulfate, calcium carbonate, pregelatinized starch, maize starch, corn starch, or mixtures thereof. The present invention comprises one or more diluents in an amount of from about 5% to about 90% by weight of the composition.
Suitable binders are selected from the group consisting of povidone, co-povidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, carboxymethyl cellulose sodium, xanthan gum, gum acacia, gum arabic, tragacanth, sorbitol, dextrose, sucrose, mannitol, gelatin, pullulan, sodium alginate, propylene glycol, polyvinyl alcohol, corn starch, maize starch, pregelatinized starch, methacrylates, carboxyvinyl polymers like carbomers, or mixtures thereof. The present invention comprises one or more binders in an amount of from about 0.5% to about 30% by weight of the composition.
Suitable disintegrants are selected from the group consisting of hydroxypropyl cellulose, crospovidone, croscarmellose sodium, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, sodium starch glycolate, gums, alginic acid or alginates, starch, corn starch, modified starch, carboxymethyl starch, polyacrylates, or mixtures thereof. The present invention comprises one or more disintegrants in an amount of from about 0.5% to about 30% by weight of the composition.
Suitable lubricants are selected from the group consisting of stearic acid, polyethylene glycol, magnesium stearate, calcium stearate, talc, zinc stearate,
hydrogenated castor oil, silica, colloidal silica, cornstarch, calcium silicate, magnesium silicate, silicon hydrogel, or mixtures thereof.
Suitable glidants are selected from the group consisting of colloidal silicon dioxide, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, or mixtures thereof.
Suitable stabilizers are selected from the group consisting of cellulose derivatives such as hydroxypropyl methylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose phthalate, carboxymethylcellulose sodium, and carboxymethylcellulose calcium; polyvinylpyrrolidone and/or derivatives thereof, such as co-povidone; polyvinyl alcohol; polyethylene glycol; block copolymers of ethylene oxide and/or propylene oxide; gums such as xanthan gum, pectins, alginates, tragacanth and/or derivatives thereof, and gum arabic and/or derivatives thereof; carrageenans, agar and/or derivatives thereof; polysaccharides from microbiological sources; acacia; starch;
arabinogalactanes; galactomannans; dextrans; or mixtures thereof. The stabilizers may also act as crystallization inhibitors.
Suitable surfactants are selected from the group consisting of 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 (PVA), 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 (Span® 20 or Span® 80),
polyoxyethylene sorbitan fatty acid ester (polysorbates), or mixtures thereof.
Suitable solubility enhancers are selected from the group consisting of sodium lauryl sulfate, polyethylene glycol, propylene glycol, glycerol, glycerol monostearate, glycerol behenate, triglycerides, mono-alcohols, higher alcohols, dimethylsulfoxide, dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-(2- hydroxyethyl) pyrrolidone, 2-pyrrolidone, or mixtures thereof.
Suitable coloring agents and flavoring agents are selected from any FDA approved colors and flavors for oral use.
Suitable plasticizers are selected from the group consisting of triethyl citrate, dibutyl sebacate, acetylated triacetin, tributyl citrate, glyceryl tributyrate, sorbitol monolaurate (Span® 20), monoglyceride, rapeseed oil, olive oil, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, glycerin sorbitol, diethyl oxalate, diethyl phthalate, diethyl malate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, or mixtures thereof.
Suitable opacifiers are selected from the group consisting of titanium dioxide, manganese dioxide, iron oxide, silicon dioxide, or mixtures thereof. Suitable hydrophilic polymers are selected from the group consisting of polyvinyl alcohol (PVA), polyvinylpyrrolidone, co-povidone, vinyl acetate polymer, polyalkylene oxide, polyoxyethylene stearates, polyacrylate, polymethacrylate, pluronics,
polyacrylamidea polyvinyl alcohol-polyethylene glycol graft copolymer, a block copolymer of polyoxyethylene and polyoxypropylene, homopolymer of N-vinyl lactam, copolymer of N-vinyl lactam, oligosaccharide, polysaccharide, cellulose such as cellulose ester, cellulose ether, or mixtures thereof.
The pharmaceutical composition of the present invention can be obtained by using known conventional methods, i.e., granulation or direct compression. The granulation process includes, but is not limited to, wet granulation, dry granulation, hot melt granulation, hot melt extrusion, or solvent evaporation.
The composition of the present invention may be in the form of minitablets, granules, pellets, tablets, or capsules. The pharmaceutical composition of the present invention may further be film-coated using techniques well known in the art such as spray coating in a conventional coating pan or a fluidized bed processor or dip coating.
Alternatively, coating may also be performed using the hot melt technique. The film coat comprises film-forming polymers and one or more pharmaceutically acceptable excipients.
Examples of 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.
Examples of solvents used for preparing the coating solution are selected from methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water, or mixtures thereof.
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 pharmaceutical composition of the present invention may be administered along with an additional anti-thrombotic agent.
The other anti-thrombotic agent is selected from anti-platelet agents such as ASA (acetylsalicylic acid), clopidogrel, ticlopidine, dipyridamole, and GPIIb/llla antagonists; anticoagulant agents such as thrombin inhibitors, warfarin, factor Xa inhibitors, and heparin; and fibrinolytic agent such as streptokinase and tenecteplase.
The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
EXAMPLES
Example 1
Figure imgf000010_0001
Procedure:
1. Ticagrelor, crospovidone, povidone, and croscarmellose sodium are blended in a blender.
2. The blend of step 1 is lubricated with magnesium stearate and compressed into tablets.
3. The tablets of step 2 are coated with an Opadry® dispersion. Example 2
Figure imgf000011_0001
Procedure:
1. Ticagrelor, lactose monohydrate, povidone, and croscarmellose sodium are blended in a blender.
2. The blend of step 1 is lubricated with magnesium stearate and compressed into tablets.
3. The tablets of step 2 are coated with an Opadry® dispersion.
Example 3
Figure imgf000011_0002
Procedure:
1. Ticagrelor, microcrystalline cellulose, povidone, and croscarmellose sodium are blended in a blender.
2. The blend of step 1 is lubricated with magnesium stearate and compressed into tablets.
3. The tablets of step 2 are coated with an Opadry® dispersion. Example 4
Figure imgf000012_0001
Procedure:
Ticagrelor, mannitol, dibasic calcium phosphate dihydrate, sodium starch glycolate, hydroxypropyl methylcellulose, and a part of magnesium stearate are blended in a blender.
The blend of step 1 is dry granulated by compaction to obtain a 60:40 ratio of granules: fines.
The blend of step 2 is lubricated with the remaining part of magnesium stearate and compressed into tablets.
The tablets of step 3 are coated with an Opadry® dispersion.
Example 5
Figure imgf000012_0002
Procedure:
Ticagrelor, mannitol, dibasic calcium phosphate dihydrate, sodium starch glycolate, hydroxypropyl cellulose, and a part of magnesium stearate are blended in a blender. The blend of step 1 is dry granulated by compaction to obtain a 60:40 ratio of granules: fines.
The blend of step 2 is lubricated with the remaining part of magnesium stearate and compressed into tablets.
The tablets of step 3 are coated with an Opadry® dispersion.
Example 6
Figure imgf000013_0001
Procedure:
Ticagrelor and co-povidone are mixed together.
Sorbitol monolaurate is added to the blend of step 1 and the blend is loaded into a rapid mixer granulator to obtain granules.
The granules obtained from step 2 are loaded into a hot melt extruder and the extrudate/sheet obtained is milled.
Sodium starch glycolate, hydroxypropyl cellulose, microcrystalline cellulose, and magnesium stearate are added to the milled extrudates of step 3 and blended. The blend of step 4 is compressed into tablets.
The tablets of step 5 are coated with an Opadry® dispersion. Example 7
Figure imgf000014_0001
Procedure:
Ticagrelor, mannitol, dibasic calcium phosphate dihydrate, croscarmellose sodium, and hydroxypropyl cellulose were blended in a blender.
The blend of step 1 was lubricated with magnesium stearate and compressed into tablets.
The tablets of step 2 were coated with an Opadry® dispersion.
Example 8
Figure imgf000014_0002
Procedure:
1. Ticagrelor, mannitol, 2/3 of the croscarmellose sodium, hydroxypropyl cellulose, and 4/7 of the magnesium stearate were blended in a blender.
2. The blend of step 1 was dry granulated by compaction to obtain a 60:40 ratio of granules: fines.
3. Dibasic calcium phosphate dihydrate and the remaining part of croscarmellose sodium were sifted and blended with the blend of step 2. 4. The blend of step 3 was lubricated with the remaining part of magnesium stearate and compressed into tablets.
5. The tablets of step 4 were coated with an Opadry® dispersion.
Example 9 and Example 10
Figure imgf000015_0001
Procedure:
Ticagrelor, mannitol, dibasic calcium phosphate dihydrate/ anhydrous, povidone, croscarmellose sodium, and pregelatinized starch were blended in a blender.
The blend of step 1 was lubricated with magnesium stearate and compressed into tablets.
The tablets of step 2 were coated with an Opadry® dispersion.
Example 11
Figure imgf000015_0002
Procedure:
1. Ticagrelor, mannitol, half of the croscarmellose sodium and 4/7 of the magnesium stearate were blended in a blender.
2. The blend of step 1 was dry granulated by compaction to obtain a 60:40 ratio of granules: fines.
3. Dibasic calcium phosphate anhydrous and the remaining part of croscarmellose sodium were sifted and blended with the blend of step 2.
4. The blend of step 3 was lubricated with the remaining part of magnesium stearate and compressed into tablets.
5. The tablets of step 4 were coated with an Opadry® dispersion.

Claims

Claims:
1. A pharmaceutical composition comprising amorphous ticagrelor and one or more pharmaceutically acceptable excipients.
2. The pharmaceutical composition according to claim 1, wherein the
pharmaceutically acceptable excipients are selected from diluents, binders, disintegrants, lubricants, and mixtures thereof.
3. The pharmaceutical composition according to claim 2, wherein the binder is povidone and the disintegrant is croscarmellose sodium.
4. The pharmaceutical composition according to claim 1, wherein the composition is prepared by direct compression or dry granulation.
5. The pharmaceutical composition according to claim 1, wherein the composition is prepared by hot melt extrusion.
6. The pharmaceutical composition according to claim 1, wherein the composition comprises a solid dispersion of amorphous ticagrelor, hydrophilic polymers, and optionally one or more pharmaceutically acceptable excipients.
7. A process for the preparation of a pharmaceutical composition according to claim 1, wherein the process comprises the steps of:
(a) blending amorphous ticagrelor and one or more pharmaceutically acceptable excipients;
(b) lubricating the blend; and
(c) directly compressing the lubricated blend into tablets.
8. A process for the preparation of a pharmaceutical composition according to claim 1, wherein the process comprises the steps of:
(a) blending amorphous ticagrelor, one or more diluents, binders, disintegrants, and lubricants;
(b) compacting the blend to obtain granules;
(c) lubricating the granules using additional lubricants; and
(d) compressing the lubricated granules into tablets or filling into capsules.
9. A process for the preparation of a pharmaceutical composition according to claim 1, wherein the process comprises the steps of:
(a) blending amorphous ticagrelor, one or more hydrophilic polymers, and optionally a surfactant in a rapid mixer granulator;
(b) loading the granules obtained in step (a) into a hot melt extruder to form a solid dispersion in the form of extrudates;
(c) milling the extrudates and adding one or more diluents, binders,
disintegrants, and lubricants; and
(d) compressing the granules into tablets or filling into capsules.
10. A method of treating cardiovascular diseases by administering a pharmaceutical composition comprising amorphous ticagrelor and one or more pharmaceutically acceptable excipients.
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