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US20140147505A1 - Solid pharmaceutical dosage form of ticagrelor - Google Patents

Solid pharmaceutical dosage form of ticagrelor Download PDF

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Publication number
US20140147505A1
US20140147505A1 US14/167,490 US201414167490A US2014147505A1 US 20140147505 A1 US20140147505 A1 US 20140147505A1 US 201414167490 A US201414167490 A US 201414167490A US 2014147505 A1 US2014147505 A1 US 2014147505A1
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Prior art keywords
dosage form
ticagrelor
pharmaceutical dosage
solid pharmaceutical
cellulose
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US14/167,490
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Sandra Brueck
Dominique Meergans
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Ratiopharm GmbH
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Ratiopharm GmbH
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Priority to US14/167,490 priority Critical patent/US20140147505A1/en
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Publication of US20140147505A1 publication Critical patent/US20140147505A1/en
Abandoned legal-status Critical Current

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    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • 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
    • 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
    • A61K9/145—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 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
    • A61K9/141—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
    • A61K9/20—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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]

Definitions

  • the present invention relates to a solid pharmaceutical dosage form comprising ticagrelor as pharmaceutically active ingredient, to certain particles of ticagrelor and to a process of preparing the same.
  • Ticagrelor can be prepared according to the methods disclosed in WO 99/05143. This document also discloses that ticagrelor exhibits activity as P2Y ADP receptor antagonist.
  • ADP induced platelet aggregation is mediated by the P2Y ADP receptor subtype located on the platelet membrane.
  • the P2Y ADP an G-protein coupled receptor is primarily involved in mediating platelet aggregation/activation. The pharmacological characteristics of this receptor have been described by Humphries et al. in Br. J. Pharmacology (1994), 113, 1057-1063 and by Fagura et al. in Br. J. Pharmacology (1998), 124, 157-164.
  • Platelet adhesion and aggregation are initiating events in arterial thrombosis. Although the process of platelet adhesion to the sub-endothelial surface have an important role to play in the repair of damaged vessel walls, misdirected platelet aggregation can initiate acute thrombotic occlusion of vital vascular beds leading to events with high morbidity such as myocardial infarction and stable angina.
  • ticagrelor is indicated for use in the treatment of CNS disorders and prevention of the growth and spread of tumors.
  • ticagrelor exists in four different crystalline forms and an amorphous form.
  • any of these forms can be used.
  • compositions comprising ticagrelor are disclosed in WO 2008/024044 and WO 2008/024045. It is disclosed that the compositions which may contain up to 50% by weight of the active ingredient are suitable for oral administration and that they release substantially all of the active ingredient.
  • the preparations are prepared according to a conventional manner using a wet granulation process.
  • the particles of the pharmaceutically active ingredient, ticagrelor have a certain particle size. It was found that if at least 90% by volume of the ticagrelor particles have a particle size in the range of 1 ⁇ m to 150 ⁇ m, a solid pharmaceutical dosage form comprising these particles exhibits beneficial effects in particular with regard to improved dissolution rate. As a result thereof, the dosage form of the present invention provides a rapid achievement of maximum blood concentration of the P2Y ADP inhibitor and/or a rapid onset of the therapeutic P2Y ADP inhibitory effect.
  • the present invention relates to a solid pharmaceutical dosage form comprising ticagrelor or a pharmaceutically acceptable salt or ester thereof, characterized in that at least 90% by volume of the ticagrelor particles have a particle size in the range of 1 ⁇ m to 150 ⁇ m.
  • the ticagrelor particles can be amorphous or in any other polymorphic crystalline form.
  • the polymorphic forms include hydrates, solvates, co-crystals, etc.
  • the ticagrelor can be present in its free base form or in the form of any pharmaceutically acceptable salt or ester known to a person skilled in the art.
  • salts those of inorganic or organic acids can be exemplified, such as hydrochloride, sulfate, mesylate, tosylate, besylate, etc.
  • esters those of organic acids can be exemplified, such as acetate.
  • ticagrelor particles covers particles of ticagrelor free base as well as pharmaceutically acceptable salts or esters of ticagrelor.
  • At least 95% by volume, more preferable at least 98% by volume of the ticagrelor particles in the solid pharmaceutical dosage form of the present invention have a particle size in the range of 1 ⁇ m to 150 ⁇ m, preferably in the range of 3 ⁇ m to 130 ⁇ m, more preferable in the range of 5 ⁇ m to 120 ⁇ m, such as in the range of 10 ⁇ m to 100 ⁇ m, whereby any combinations of the lower and upper limits of these ranges are also intended to be covered by the present invention.
  • the ticagrelor particles have a mean particle size D 50 in the range of 30 ⁇ m to 70 ⁇ m, preferably in the range of 40 ⁇ m to 60 ⁇ m, more preferably of about 50 ⁇ m.
  • particle size of a certain particle refers to the diameter of an equivalent product being assumed to be spherical and showing the same light scattering pattern as the particle.
  • the particle size is measured via laser light diffraction technique.
  • the laser light diffraction technique used for the determination of particle size and its distribution is based on the analysis of the diffraction pattern produced when particles are exposed to a beam of monochromatic light.
  • the laser light diffraction uses the scattering of light caused by interaction of the laser light with the particles to determine the particle size.
  • particle size distribution refers to the statistical distribution of the volume share related of all particle sizes.
  • the particle size distribution of the particle size D 50 value is defined such that 50% by volume of the particles have a particle size smaller than the D 50 value and 50% by volume of the particles have a greater particle size greater than the D 50 -value.
  • a Mastersizer 2000 from Malvern Instruments is used for determining the particle size.
  • a wet measurement on a dispersion of the particles in a dispersing agent at 25° C., 2000 rpm, 30 sec ultrasound is preferred.
  • the analysis is carried out with assistance of the Mie method for particle D 50 smaller than 5.0 ⁇ m and the Fraunhofer method for particle D 50 greater than 5.0 ⁇ m.
  • the Fraunhofer diffraction theory is generally used for particle fractions which are significantly larger than the wavelength of the laser light (“Pharmaceutics The science of dosage form design”, 1998).
  • the Mie theory defines the secondary scattering caused by refraction of light within small particles as stated in the international norms of laser diffraction measurement (15013320-1 (1999)).
  • the particle size distribution according to the invention can be monomodal or bimodal.
  • the particle size distribution of the active agent is monomodal.
  • the term “monomodal” as used herein refers to only one peak observed in the histogram and/or a graph of the frequency distribution.
  • the present invention also relates to a solid pharmaceutical dosage form comprising more than 50% by weight of ticagrelor or a pharmaceutically acceptable salt or ester thereof, based on the total weight of the dosage form.
  • the improved fast dissolution rate of the pharmaceutical dosage form comprising more than 50% by weight of ticagrelor can for example be achieved by using either ticagrelor particles having the above defined certain particle size and/or by the addition of at least one hydrophilic polymer and/or emulsifier.
  • the solid pharmaceutical dosage form which comprises more than 50% by weight of ticagrelor or a pharmaceutically acceptable salt or ester thereof, based on the total weight of the dosage form, contains the active ingredient in a form such that at least 90% of the ticagrelor particles have a particle size in the range of 1 ⁇ m to 150 ⁇ m (wherein the preferred ranges are defined as above) and the dosage form additionally comprises at least one hydrophilic polymer and/or emulsifier.
  • the weight ratio of ticagrelor or a pharmaceutically acceptable salt or ester thereof to the hydrophilic polymer and/or emulsifier in the solid pharmaceutical dosage form is in the range of 100:1 to 1:1, preferably 100:1 to 2:1.
  • the hydrophilic polymer can be selected from known polymers having polar groups.
  • polar groups are hydroxy, amino, carboxy, carbonyl, ether, ester and sulfate. Polymers containing hydroxy groups are preferred.
  • hydrophilic polymers examples include cellulose derivatives, such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), preferably as sodium or calcium salt, hydroxyethyl cellulose (HEC), polyvinylpyrrolidone (PVP), preferable having a molecular weight in the range of 10.000 g/mol to 60.000 g/mol, copolymers of polyinylpyrrolidone, preferably copolymers comprising vinylpyrrolidone and vinylacetate units (e.g Povidon, VA64, BASF), preferably having a molecular weight in the range of 40.000 g/mol to 70.000 g/mol, polyoxyethylenalkyl ether, polyethylenglycol, co-block-polymers of ethylenoxide and propyleneoxide (poloxamer, pluronic), polymethacrylate derivatives, polyvinyl alcohol, polyvinyl
  • Emulsifiers which can be used in the solid pharmaceutical dosage form of the present invention are carboxylic acids and salts and ester thereof, sulfonic acids and salts thereof, alkylsulfate-alkylethersulfonic acids, phosphoric acid esters and salts thereof, acylamino acids and salts thereof, alkylamine salts, quaternary ammonium compounds and esters thereof, ethoxylated alkylamines and non-ionic tensides, e.g. fatty alcohols, ethylenoxids, alkanolamides, alkoxylated polysiloxanes, glycerol esters, etc.
  • the pharmaceutical dosage form according to the present invention can further comprise additional excipients and adjuvants, which are pharmaceutically acceptable, and general coating materials, which are preferably applied as a coating to the pharmaceutical dosage form of the present invention.
  • additional excipients and adjuvants are known to the person skilled in the art. In this regard it can be referred to the standard textbook by Fiedler (“Lexikon der Hilfsstoffe für Pharmazie, Kosmetik and angrenzende füre”, 5 th ed., 2002) and to the “Handbook of Exipients”, edited by the American Pharmaceutical Association and Dr. Arthur H. Kibbe, 3 rd ed., 2000.
  • the pharmaceutical dosage form according to the present invention comprises one or more diluents, binders, lubricants and/or coating materials and optionally colourants and/or surfactants, and in particular 0 to 40% by weight of a diluent, 0 to 30% by weight of a binder, 0 to 6% by weight of a disintegrant, 0 to 2% by weight of a lubricant, 0 to 3% by weight of a glidant, 0 to 3% by weight of a coating material, and optionally 0 to 6% by weight of a surfactant and 0 to 3% by weight of a colourant, each based on the total weight of the composition.
  • excipients and adjuvants and optionally coating materials or colourants are present in the pharmaceutical composition of the present invention, such that the total amount of the pharmaceutical composition results in 100% by weight. If not stated otherwise all % by weight figures herein are based on the total weight of the dosage form, including any shell or coating, if present.
  • diluent one or more components can be used, which contribute part of the dosage form to reach the necessary total mass of the dosage form.
  • diluents are inorganic phosphates, like dibasic calcium phosphate, or sugars or sugar analogues and derivatives thereof, in particular lactose, such as lactose monohydrate or water-free lactose, dextrose, sorbit, mannit, saccharose, maltodextrin, isomalt and tablettose.
  • Mannitol or cellulose like microcyrstalline cellulose or powdered celluloses are also preferable diluents according to the present invention.
  • the pharmaceutical dosage form according to the present invention comprises 5 to 40% by weight, more preferable 10 to 40% by weight, even more preferable 20-40% by weight, of a diluent.
  • Binders are compounds able to bind together active ingredient and excipients in a mixture.
  • polyvinylpyrrolidon (PVP) preferably having the molecular weight of 10.000 to 60.000 g/mol and copolymers of PVP preferably having a molecular weight of 40.000 to 70.000 g/mol and hydroxypropylmethyl cellulose are especially preferred.
  • the binder is usually present in an amount of 0 to 30% by weight, preferably 2 to 27% by weight, in particular 5 to 25% by weight, based on the total weight of the dosage form.
  • disintegrant one or more components can be used, which decompose the tablet in the gastrointestinal fluid.
  • Preferable disintegrants are alginates, pregelatinized starch, modified starch like croscarmellose and crosslinked PVP like collidone and crospovidon. Crospovidone and croscarmellose are preferable disintegrants according to the present invention.
  • the pharmaceutical dosage form according to the present invention comprises 1 to 10% by weight, more preferable 2 to 8% by weight, even more preferable 3 to 5% by weight, such as about 4% by weight of a disintegrant based on the total weight of the pharmaceutical dosage form.
  • Additional excipients to be used in the pharmaceutical dosage form of the present invention are glidants, such as silicium dioxide, which are added to a powder to improve its flowability; and/or amphipatic wetting agents, such as sodium lauryl sulfate (SDS), glycerol monostearate, triglycerides or glycerol behenate.
  • glidants such as silicium dioxide
  • amphipatic wetting agents such as sodium lauryl sulfate (SDS), glycerol monostearate, triglycerides or glycerol behenate.
  • lubricants can be used in the pharmaceutical dosage forms of the present invention fatty acids or fatty acid derivates, such as alkali and earth alkali salts of stearic, lauric and/or palmitic acid.
  • fatty acids or fatty acid derivates such as alkali and earth alkali salts of stearic, lauric and/or palmitic acid.
  • Sodium stearyl fumarate and magnesium stearate are preferred.
  • the lubricant is optionally present in an amount of 0 to 3% by weight, preferably 0.5 to 2.5% by weight, such as about 2% by weight, based on the total amount of the dosage form.
  • An advantage of the pharmaceutical dosage form of the present invention is that a lubricant is not necessarily required in its preparation. Therefore, in one embodiment the dosage form does not comprise any lubricant.
  • the solid pharmaceutical dosage form of the present invention preferably is an oral pharmaceutical dosage form, such as a tablet, capsule, granules, pellets or sachets.
  • the pharmaceutical dosage form can be prepared by methods known in the art, such as tabletting by melt granulation or direct compression.
  • the compression of the blend to tablet cores can be carried out using a conventional tabletting machine or a rotary compression machine.
  • the tablet cores may vary in shape and can be, for example, round, oval, oblong, cylindrical or any other suitable shape.
  • the cores may also vary in size depending on the concentration of the therapeutic agent.
  • the pharmaceutical dosage form according to the present invention comprising ticagrelor may be present in form of a tablet which is coated with one or more coating materials.
  • the coating materials are not particularly limited and are known to the person skilled in the art.
  • the dissolution profile is that of an uncoated tablet, if the tablet is not coated, and that of a coated tablet, if the tablet is coated.
  • the active ingredient in the pharmaceutical dosage form of the present invention is usually formulated in dose units.
  • the dose unit contains from 50 to 300 mg, advantageously from 70 to 240 mg, preferably from 90 to 180 mg of ticagrelor calculated as ticagrelor free base.
  • Such a dosage form is normally administered from 2 to 4 times daily, preferably 2 times daily.
  • the preferred unit dosage forms include tablets and capsules.
  • Another object of the present invention is to provide a solid oral dosage form containing ticagrelor in combination with an anti-thrombotic agent and a process of forming the same.
  • the anti-thrombotic compound is selected from anti-platelet agents, anticoagulant agents and fibrinolytic agents.
  • Anti-thrombotic agent selected from antiplatelet agents include ASA (acetylsalicylic acid), clopidogrel, ticlopidine, dipyridamole, GPIIb/IIIa antagonists; anti-coagulants such as thrombin inhibitors, warfarin, factor Xa inhibitors, heparin; and fibrinolytic agents including but not limited to, streptokinase and tenecteplase.
  • the subject of the present invention includes a solid oral dosage form containing ticagrelor in a combination with ASA.
  • Acetylsalicylic acid is often used as an analgesic, antipyretic and anti-inflammatory medication but also known as antiplatelet agent inhibiting the production of thromboxane and therefore as a result prevent heart attacks, strokes and blood clot formation.
  • ASA have an inhibition of the enzyme cyclooxygenase that is responsible for important biological mediators including thromboxane.
  • the present invention particularly relates to a solid oral dosage form, which contains a unit dose in the range of about 10 to 250 mg, preferably in the range of about 50 to 200 mg, particularly of 90 or 180 mg of the active ingredient ticagrelor and a unit dose in the range of about 6 to 60 mg, preferably in the range of about 30 to 500 mg, particularly of 50 or 100 mg of the active ingredient acetylsalicylic acid.
  • Respective formulations comprising ticagrelor and/or other antithrombotic agent may be administered, sequentially, separately and/or simultaneously, over the course of treating the relevant condition, which condition may be acute or chronic.
  • the present invention furthermore provides a process for the preparation of the above solid pharmaceutical dosage form which comprises the step of milling ticagrelor or a pharmaceutically acceptable salt or ester thereof in the presence of a polymer and/or emulsifier.
  • the polymer can be hydrophilic or amphiphilic. Hydrophilic polymers are preferred. Most preferred are those hydrophilic polymers which are exemplified above. Suitable amphiphilic polymers are for example gylcerol monostearat, triglyceride and glycerol behenate. Suitable emulsifiers are those as exemplified above.
  • the milling can be carried out as wet milling or dry milling. If necessary the milled particles after wet milling can be dried by drying methods known in the art, such as spray drying, vacuum drying and lyophilization.
  • the milled ticagrelor particles or mixture of particles can then be processed into solid pharmaceutical dosage forms by methods known in the art, such as direct compression, dry or wet granulation followed by compression or melt extrusion also followed by compression. Other known processing steps, such as spray coating, may also be employed.
  • Ticagrelor particles were prepared using a dry grinding process. A mixture of ticagrelor and part of the mannitol was ground in a ball mill. Subsequently the remaining excipients with the exception of magnesium stearate were added to the blend and mixed in a freefall mixer. The lubricant, magnesium stearate, was sifted and mixed with the blend. The final blend was then compressed into tablets using a suitable tablet press and then optionally coated with a coating material, e.g. Opadry.
  • a coating material e.g. Opadry.
  • the tablets were prepared using a process similar to the process described in example 1.
  • Ticagrelor particles were prepared using a dry grinding process. Ticagrelor was crushed using an air jet mill. Subsequently the diluent were added to the active agent and mixed in a freefall mixer. The lubricant, magnesium stearate was sifted and mixed with the blend. The final blend was then compressed into tablets using a suitable tablet press and then optionally coated with a coating material, e.g. Opadry.
  • a coating material e.g. Opadry.
  • Ticagrelor particles were prepared using a wet grinding process. The co-grinding was performed with ticagrelor together with HPMC and SDS within a dispersing agent using a wet mill. Subsequently the suspension was spray dried. Half of mannitol, croscarmellose and silicium dioxide were added to the dried intermediates, were blended and compacted. The compacted particles were sifted, afterwards the remaining excipients were added and blended. The final blend was then compressed into tablets using a suitable tablet press and then optionally coated with the coating material, e.g. Opadry.
  • the coating material e.g. Opadry.
  • Ticagrelor, povidone, SDS and half of croscarmellose and crystalline cellulose were mixed and heated forming melt granules using a heated high shear mixer.
  • the melt granules were sifted and mixed with the remaining excipients in exception of the lubricant in a freefall mixer. Subsequently the lubricant magnesium stearate was added.
  • Ticagrelor particles were prepared using a dry grinding process. The co-grinding was performed with ticagrelor together with mannitol using a ball mill for 1 hour. ASA was grinded separately and afterwards added to the mixture of grinded ticagrelor and mannitol. Subsequently, the remaining ingredients, except magnesium stearate, were added and mixed for 10 minutes in a free fall mixer. Magnesium stearate was added through a 0.5 mm sieve and the resulting mixture was mixed for further 3 minutes. The resulting material was directly compressed on a Korsch eccentric press.
  • Ticagrelor was milled together with HPMC and SDS in a dispersion medium for 1 hour in a Netsch microCer.
  • the obtained suspension was spray dried in a Büchi spray tower.
  • the resulting mixture was mixed for 10 minutes in a free fall mixer (Turbula TB10) together with the previously grinded ASA, half amount of the mannitol, croscarmellose and silica.
  • the mixture was then compacted.
  • the product was sieved using a coMill sieve (1000 ⁇ m), followed by adding the remaining excipients and the magnesium stearate being previously sieved through a 0.5 mm sieve.
  • the resulting mixture is mixed for further 3 minutes.
  • the final mixture was pressed into tablets using a Korsch eccentric press EK0.

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Abstract

The present invention relates to a solid pharmaceutical dosage form comprising ticagrelor as pharmaceutically active ingredient, to certain particles of ticagrelor and to processes of preparing the same.

Description

    PRIORITY OF THE PRESENT INVENTION
  • This application is a continuation of U.S. patent application Ser. No. 13/518,450 filed Jul. 9, 2012, now U.S. Pat. No. ______, which corresponds to the national phase of International Application No. PCT/EP2010/070268 filed Dec. 20, 2010, which, in turn, claims priority to European Patent Application No. 09.180628.1 filed Dec. 23, 2009, the contents of which are incorporated by reference herein in their entirety.
    • FIELD OF THE PRESENT INVENTION
  • The present invention relates to a solid pharmaceutical dosage form comprising ticagrelor as pharmaceutically active ingredient, to certain particles of ticagrelor and to a process of preparing the same.
    • BACKGROUND OF THE PRESENT INVENTION
  • The compound, [1S-[1α,2α,3β(1S*,2R*),5β]]-3-[7-[[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 is known as ticagrelor and is represented by the formula (I) below:
  • Figure US20140147505A1-20140529-C00001
  • Ticagrelor can be prepared according to the methods disclosed in WO 99/05143. This document also discloses that ticagrelor exhibits activity as P2YADP receptor antagonist.
  • ADP induced platelet aggregation is mediated by the P2YADP receptor subtype located on the platelet membrane. The P2YADP, an G-protein coupled receptor is primarily involved in mediating platelet aggregation/activation. The pharmacological characteristics of this receptor have been described by Humphries et al. in Br. J. Pharmacology (1994), 113, 1057-1063 and by Fagura et al. in Br. J. Pharmacology (1998), 124, 157-164.
  • Platelet adhesion and aggregation are initiating events in arterial thrombosis. Although the process of platelet adhesion to the sub-endothelial surface have an important role to play in the repair of damaged vessel walls, misdirected platelet aggregation can initiate acute thrombotic occlusion of vital vascular beds leading to events with high morbidity such as myocardial infarction and stable angina.
  • Furthermore ticagrelor is indicated for use in the treatment of CNS disorders and prevention of the growth and spread of tumors.
  • According to WO 01/92262 ticagrelor exists in four different crystalline forms and an amorphous form. In the pharmaceutical dosage forms of the present invention any of these forms can be used.
  • Pharmaceutical compositions comprising ticagrelor are disclosed in WO 2008/024044 and WO 2008/024045. It is disclosed that the compositions which may contain up to 50% by weight of the active ingredient are suitable for oral administration and that they release substantially all of the active ingredient. The preparations are prepared according to a conventional manner using a wet granulation process.
  • For ticagrelor there still exists the problem that this pharmaceutically active compound exhibits only low solubility. The poor solubility of drug is a significant problem in the design of pharmaceutical formulations. Ticagrelor is hardly soluble in a neutral medium such as water. Consequently, water is the most suitable test medium for evaluating non-bioequivalence on conducting a dissolution test. In developing a solid oral dosage forms comprising ticagrelor as an active ingredient, it is desirable to find a formulation having a good dissolution property in water. Solid oral dosage forms comprising ticagrelor as an active ingredient are desired to show good dissolution properties in the first fluid, which is corresponding to gastric juice, in a dissolution test.
  • Therefore, it would be desirable to provide a pharmaceutical preparation which not only releases substantially all of the active ingredient but additionally provides a fast dissolution of the active ingredient. Moreover, in particular with respect to patient compliance, it would be desirable to provide a pharmaceutical composition having a high drug load but nevertheless being easily to be prepared and stable while maintaining the beneficial properties with respect to fast solubility and bioavailability. These and other problems are solved by the present invention.
    • SUMMARY OF THE PRESENT INVENTION
  • It has now been found that the above problems can be solved if the particles of the pharmaceutically active ingredient, ticagrelor, have a certain particle size. It was found that if at least 90% by volume of the ticagrelor particles have a particle size in the range of 1 μm to 150 μm, a solid pharmaceutical dosage form comprising these particles exhibits beneficial effects in particular with regard to improved dissolution rate. As a result thereof, the dosage form of the present invention provides a rapid achievement of maximum blood concentration of the P2YADP inhibitor and/or a rapid onset of the therapeutic P2YADP inhibitory effect.
  • Thus, the present invention relates to a solid pharmaceutical dosage form comprising ticagrelor or a pharmaceutically acceptable salt or ester thereof, characterized in that at least 90% by volume of the ticagrelor particles have a particle size in the range of 1 μm to 150 μm.
    • DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
  • The ticagrelor particles can be amorphous or in any other polymorphic crystalline form. The polymorphic forms include hydrates, solvates, co-crystals, etc. Moreover, the ticagrelor can be present in its free base form or in the form of any pharmaceutically acceptable salt or ester known to a person skilled in the art. As salts those of inorganic or organic acids can be exemplified, such as hydrochloride, sulfate, mesylate, tosylate, besylate, etc. As esters those of organic acids can be exemplified, such as acetate.
  • It is understood that any reference to “ticagrelor particles” covers particles of ticagrelor free base as well as pharmaceutically acceptable salts or esters of ticagrelor.
  • Preferably, at least 95% by volume, more preferable at least 98% by volume of the ticagrelor particles in the solid pharmaceutical dosage form of the present invention have a particle size in the range of 1 μm to 150 μm, preferably in the range of 3 μm to 130 μm, more preferable in the range of 5 μm to 120 μm, such as in the range of 10 μm to 100 μm, whereby any combinations of the lower and upper limits of these ranges are also intended to be covered by the present invention.
  • In a further embodiment of the present invention the ticagrelor particles have a mean particle size D50 in the range of 30 μm to 70 μm, preferably in the range of 40 μm to 60 μm, more preferably of about 50 μm.
  • The term “particle size” of a certain particle according to the invention refers to the diameter of an equivalent product being assumed to be spherical and showing the same light scattering pattern as the particle. According to the invention the particle size is measured via laser light diffraction technique. The laser light diffraction technique used for the determination of particle size and its distribution is based on the analysis of the diffraction pattern produced when particles are exposed to a beam of monochromatic light. The laser light diffraction uses the scattering of light caused by interaction of the laser light with the particles to determine the particle size.
  • The term “particle size distribution” as used herein assume refers to the statistical distribution of the volume share related of all particle sizes.
  • Herein the particle size distribution of the particle size D50 value is defined such that 50% by volume of the particles have a particle size smaller than the D50 value and 50% by volume of the particles have a greater particle size greater than the D50-value.
  • For determining the particle size a Mastersizer 2000 from Malvern Instruments is used. A wet measurement on a dispersion of the particles in a dispersing agent at 25° C., 2000 rpm, 30 sec ultrasound is preferred.
  • The analysis is carried out with assistance of the Mie method for particle D50 smaller than 5.0 μm and the Fraunhofer method for particle D50 greater than 5.0 μm. The Fraunhofer diffraction theory is generally used for particle fractions which are significantly larger than the wavelength of the laser light (“Pharmaceutics The science of dosage form design”, 1998). Furthermore the Mie theory defines the secondary scattering caused by refraction of light within small particles as stated in the international norms of laser diffraction measurement (15013320-1 (1999)).
  • The particle size distribution according to the invention can be monomodal or bimodal. In the preferred embodiment of the invention the particle size distribution of the active agent is monomodal. The term “monomodal” as used herein refers to only one peak observed in the histogram and/or a graph of the frequency distribution.
  • Furthermore, it has surprisingly been found that contrary to the teaching of WO 2008/024045 it is possible to provide solid pharmaceutical dosage forms having a high drug load and nevertheless exhibiting an improved dissolution rate. Therefore, the present invention also relates to a solid pharmaceutical dosage form comprising more than 50% by weight of ticagrelor or a pharmaceutically acceptable salt or ester thereof, based on the total weight of the dosage form.
  • The improved fast dissolution rate of the pharmaceutical dosage form comprising more than 50% by weight of ticagrelor can for example be achieved by using either ticagrelor particles having the above defined certain particle size and/or by the addition of at least one hydrophilic polymer and/or emulsifier.
  • Preferably, the solid pharmaceutical dosage form which comprises more than 50% by weight of ticagrelor or a pharmaceutically acceptable salt or ester thereof, based on the total weight of the dosage form, contains the active ingredient in a form such that at least 90% of the ticagrelor particles have a particle size in the range of 1 μm to 150 μm (wherein the preferred ranges are defined as above) and the dosage form additionally comprises at least one hydrophilic polymer and/or emulsifier.
  • In one embodiment of the present invention the weight ratio of ticagrelor or a pharmaceutically acceptable salt or ester thereof to the hydrophilic polymer and/or emulsifier in the solid pharmaceutical dosage form is in the range of 100:1 to 1:1, preferably 100:1 to 2:1.
  • The hydrophilic polymer can be selected from known polymers having polar groups. Examples of polar groups are hydroxy, amino, carboxy, carbonyl, ether, ester and sulfate. Polymers containing hydroxy groups are preferred.
  • Examples of suitable hydrophilic polymers are cellulose derivatives, such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), preferably as sodium or calcium salt, hydroxyethyl cellulose (HEC), polyvinylpyrrolidone (PVP), preferable having a molecular weight in the range of 10.000 g/mol to 60.000 g/mol, copolymers of polyinylpyrrolidone, preferably copolymers comprising vinylpyrrolidone and vinylacetate units (e.g Povidon, VA64, BASF), preferably having a molecular weight in the range of 40.000 g/mol to 70.000 g/mol, polyoxyethylenalkyl ether, polyethylenglycol, co-block-polymers of ethylenoxide and propyleneoxide (poloxamer, pluronic), polymethacrylate derivatives, polyvinyl alcohol, polyvinyl alcohol derivatives and polyethylenglycol derivatives. Preferred hydrophilic polymers are polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone and hydroxypropylmethyl cellulose.
  • Emulsifiers which can be used in the solid pharmaceutical dosage form of the present invention are carboxylic acids and salts and ester thereof, sulfonic acids and salts thereof, alkylsulfate-alkylethersulfonic acids, phosphoric acid esters and salts thereof, acylamino acids and salts thereof, alkylamine salts, quaternary ammonium compounds and esters thereof, ethoxylated alkylamines and non-ionic tensides, e.g. fatty alcohols, ethylenoxids, alkanolamides, alkoxylated polysiloxanes, glycerol esters, etc.
  • The pharmaceutical dosage form according to the present invention can further comprise additional excipients and adjuvants, which are pharmaceutically acceptable, and general coating materials, which are preferably applied as a coating to the pharmaceutical dosage form of the present invention. Such further excipients and adjuvants are known to the person skilled in the art. In this regard it can be referred to the standard textbook by Fiedler (“Lexikon der Hilfsstoffe für Pharmazie, Kosmetik and angrenzende Gebiete”, 5th ed., 2002) and to the “Handbook of Exipients”, edited by the American Pharmaceutical Association and Dr. Arthur H. Kibbe, 3rd ed., 2000.
  • In particular the pharmaceutical dosage form according to the present invention comprises one or more diluents, binders, lubricants and/or coating materials and optionally colourants and/or surfactants, and in particular 0 to 40% by weight of a diluent, 0 to 30% by weight of a binder, 0 to 6% by weight of a disintegrant, 0 to 2% by weight of a lubricant, 0 to 3% by weight of a glidant, 0 to 3% by weight of a coating material, and optionally 0 to 6% by weight of a surfactant and 0 to 3% by weight of a colourant, each based on the total weight of the composition. The excipients and adjuvants and optionally coating materials or colourants are present in the pharmaceutical composition of the present invention, such that the total amount of the pharmaceutical composition results in 100% by weight. If not stated otherwise all % by weight figures herein are based on the total weight of the dosage form, including any shell or coating, if present.
  • As diluent one or more components can be used, which contribute part of the dosage form to reach the necessary total mass of the dosage form. Preferable diluents are inorganic phosphates, like dibasic calcium phosphate, or sugars or sugar analogues and derivatives thereof, in particular lactose, such as lactose monohydrate or water-free lactose, dextrose, sorbit, mannit, saccharose, maltodextrin, isomalt and tablettose. Mannitol or cellulose like microcyrstalline cellulose or powdered celluloses are also preferable diluents according to the present invention. Preferably the pharmaceutical dosage form according to the present invention comprises 5 to 40% by weight, more preferable 10 to 40% by weight, even more preferable 20-40% by weight, of a diluent.
  • Binders are compounds able to bind together active ingredient and excipients in a mixture. As binder to be used in the pharmaceutical dosage form of the present invention polyvinylpyrrolidon (PVP) preferably having the molecular weight of 10.000 to 60.000 g/mol and copolymers of PVP preferably having a molecular weight of 40.000 to 70.000 g/mol and hydroxypropylmethyl cellulose are especially preferred. The binder is usually present in an amount of 0 to 30% by weight, preferably 2 to 27% by weight, in particular 5 to 25% by weight, based on the total weight of the dosage form.
  • As disintegrant one or more components can be used, which decompose the tablet in the gastrointestinal fluid. Preferable disintegrants are alginates, pregelatinized starch, modified starch like croscarmellose and crosslinked PVP like collidone and crospovidon. Crospovidone and croscarmellose are preferable disintegrants according to the present invention. Preferably the pharmaceutical dosage form according to the present invention comprises 1 to 10% by weight, more preferable 2 to 8% by weight, even more preferable 3 to 5% by weight, such as about 4% by weight of a disintegrant based on the total weight of the pharmaceutical dosage form.
  • Additional excipients to be used in the pharmaceutical dosage form of the present invention are glidants, such as silicium dioxide, which are added to a powder to improve its flowability; and/or amphipatic wetting agents, such as sodium lauryl sulfate (SDS), glycerol monostearate, triglycerides or glycerol behenate.
  • Optionally, as lubricants can be used in the pharmaceutical dosage forms of the present invention fatty acids or fatty acid derivates, such as alkali and earth alkali salts of stearic, lauric and/or palmitic acid. Sodium stearyl fumarate and magnesium stearate are preferred. The lubricant is optionally present in an amount of 0 to 3% by weight, preferably 0.5 to 2.5% by weight, such as about 2% by weight, based on the total amount of the dosage form.
  • An advantage of the pharmaceutical dosage form of the present invention is that a lubricant is not necessarily required in its preparation. Therefore, in one embodiment the dosage form does not comprise any lubricant.
  • The solid pharmaceutical dosage form of the present invention preferably is an oral pharmaceutical dosage form, such as a tablet, capsule, granules, pellets or sachets. The pharmaceutical dosage form can be prepared by methods known in the art, such as tabletting by melt granulation or direct compression.
  • The compression of the blend to tablet cores can be carried out using a conventional tabletting machine or a rotary compression machine. The tablet cores may vary in shape and can be, for example, round, oval, oblong, cylindrical or any other suitable shape. The cores may also vary in size depending on the concentration of the therapeutic agent.
  • The pharmaceutical dosage form according to the present invention comprising ticagrelor may be present in form of a tablet which is coated with one or more coating materials. The coating materials are not particularly limited and are known to the person skilled in the art.
  • As far as it is herein referred to a dissolution profile, the dissolution profile is that of an uncoated tablet, if the tablet is not coated, and that of a coated tablet, if the tablet is coated.
  • In the pharmaceutical dosage form of the present invention the active ingredient, ticagrelor, is usually formulated in dose units. The dose unit contains from 50 to 300 mg, advantageously from 70 to 240 mg, preferably from 90 to 180 mg of ticagrelor calculated as ticagrelor free base. Such a dosage form is normally administered from 2 to 4 times daily, preferably 2 times daily. The preferred unit dosage forms include tablets and capsules.
  • Another object of the present invention is to provide a solid oral dosage form containing ticagrelor in combination with an anti-thrombotic agent and a process of forming the same. The anti-thrombotic compound is selected from anti-platelet agents, anticoagulant agents and fibrinolytic agents. Anti-thrombotic agent selected from antiplatelet agents include ASA (acetylsalicylic acid), clopidogrel, ticlopidine, dipyridamole, GPIIb/IIIa antagonists; anti-coagulants such as thrombin inhibitors, warfarin, factor Xa inhibitors, heparin; and fibrinolytic agents including but not limited to, streptokinase and tenecteplase.
  • Particularly the subject of the present invention includes a solid oral dosage form containing ticagrelor in a combination with ASA.
  • Acetylsalicylic acid is often used as an analgesic, antipyretic and anti-inflammatory medication but also known as antiplatelet agent inhibiting the production of thromboxane and therefore as a result prevent heart attacks, strokes and blood clot formation. ASA have an inhibition of the enzyme cyclooxygenase that is responsible for important biological mediators including thromboxane.
  • The present invention particularly relates to a solid oral dosage form, which contains a unit dose in the range of about 10 to 250 mg, preferably in the range of about 50 to 200 mg, particularly of 90 or 180 mg of the active ingredient ticagrelor and a unit dose in the range of about 6 to 60 mg, preferably in the range of about 30 to 500 mg, particularly of 50 or 100 mg of the active ingredient acetylsalicylic acid.
  • Respective formulations comprising ticagrelor and/or other antithrombotic agent may be administered, sequentially, separately and/or simultaneously, over the course of treating the relevant condition, which condition may be acute or chronic.
  • The present invention furthermore provides a process for the preparation of the above solid pharmaceutical dosage form which comprises the step of milling ticagrelor or a pharmaceutically acceptable salt or ester thereof in the presence of a polymer and/or emulsifier. In this process, the polymer can be hydrophilic or amphiphilic. Hydrophilic polymers are preferred. Most preferred are those hydrophilic polymers which are exemplified above. Suitable amphiphilic polymers are for example gylcerol monostearat, triglyceride and glycerol behenate. Suitable emulsifiers are those as exemplified above.
  • The milling can be carried out as wet milling or dry milling. If necessary the milled particles after wet milling can be dried by drying methods known in the art, such as spray drying, vacuum drying and lyophilization.
  • The milled ticagrelor particles or mixture of particles can then be processed into solid pharmaceutical dosage forms by methods known in the art, such as direct compression, dry or wet granulation followed by compression or melt extrusion also followed by compression. Other known processing steps, such as spray coating, may also be employed.
  • The invention will now be further explained by way of examples which are not construed to be limiting.
    • EXAMPLES Example 1
  • Ingredients Function mg/Tab % w/w
    Ticagrelor Active 90.0 50.0
    Mannitol Diluent 72.0 40.0
    Povidon Binder 9.0 5.0
    Crospovidon Disintegrant 7.2 4.0
    Magnesium stearate Lubricant 1.8 1.0
    Total Weight 180.0 100.0
  • Ticagrelor particles were prepared using a dry grinding process. A mixture of ticagrelor and part of the mannitol was ground in a ball mill. Subsequently the remaining excipients with the exception of magnesium stearate were added to the blend and mixed in a freefall mixer. The lubricant, magnesium stearate, was sifted and mixed with the blend. The final blend was then compressed into tablets using a suitable tablet press and then optionally coated with a coating material, e.g. Opadry.
    • Example 2
  • Ingredients Function mg/Tab % w/w
    Ticagrelor Active 90.0 52.0
    Lactose Diluent 72.0 41.6
    Maize starch Disintegrant 11.0 6.4
    Total Weight 173.0 100.0
  • The tablets were prepared using a process similar to the process described in example 1.
    • Example 3
  • Ingredients Function mg/Tab % w/w
    Ticagrelor Active 90.0 54.9
    Isomalt Diluent 72.0 43.9
    Magnesium stearate Lubricant 2.0 1.2
    Total Weight 164.0 100.0
  • Ticagrelor particles were prepared using a dry grinding process. Ticagrelor was crushed using an air jet mill. Subsequently the diluent were added to the active agent and mixed in a freefall mixer. The lubricant, magnesium stearate was sifted and mixed with the blend. The final blend was then compressed into tablets using a suitable tablet press and then optionally coated with a coating material, e.g. Opadry.
    • Example 4
  • Ingredients Function mg/Tab % w/w
    Ticagrelor Active 90.0 48.3
    Hydroxy propyl methyl cellulose Binder 18.0 9.7
    (HPMC)
    SDS Wetting agent 4.5 2.4
    Mannitol Diluent 64 34.3
    Croscarmellose Disintegrant 7.2 3.9
    Silica Glidant 0.9 0.5
    Magnesium stearate Lubricant 1.8 1.0
    Total Weight 186.4 100.0
  • Ticagrelor particles were prepared using a wet grinding process. The co-grinding was performed with ticagrelor together with HPMC and SDS within a dispersing agent using a wet mill. Subsequently the suspension was spray dried. Half of mannitol, croscarmellose and silicium dioxide were added to the dried intermediates, were blended and compacted. The compacted particles were sifted, afterwards the remaining excipients were added and blended. The final blend was then compressed into tablets using a suitable tablet press and then optionally coated with the coating material, e.g. Opadry.
    • Example 5
  • Ingredients Function mg/Tab % w/w
    Ticagrelor Active 90.0 46.7
    Povidone Binder 45.0 23.4
    SDS Wetting agent 1.0 0.5
    Microcrystalline cellulose Diluent 45.0 23.4
    Croscarmellose Disintegrant 9.0 4.7
    Silica Glidant 0.9 0.5
    Magnesium stearate Lubricant 1.8 0.9
    Total Weight 192.7 100.0
  • Ticagrelor, povidone, SDS and half of croscarmellose and crystalline cellulose were mixed and heated forming melt granules using a heated high shear mixer. The melt granules were sifted and mixed with the remaining excipients in exception of the lubricant in a freefall mixer. Subsequently the lubricant magnesium stearate was added.
    • Example 6
  • Ingredients mg/Tab
    Ticagrelor 90
    ASA 37.5-100
    Mannitol 72
    Povidon 25 9.0
    Crospovidon 7.2
    Magnesium stearate 1.8
  • Ticagrelor particles were prepared using a dry grinding process. The co-grinding was performed with ticagrelor together with mannitol using a ball mill for 1 hour. ASA was grinded separately and afterwards added to the mixture of grinded ticagrelor and mannitol. Subsequently, the remaining ingredients, except magnesium stearate, were added and mixed for 10 minutes in a free fall mixer. Magnesium stearate was added through a 0.5 mm sieve and the resulting mixture was mixed for further 3 minutes. The resulting material was directly compressed on a Korsch eccentric press.
    • Example 7
  • Ingredients mg/Tab
    Ticagrelor 90
    ASA 37.5-100
    HPMC 18
    SDS 4.5
    Mannitol 32 + 32
    Croscarmellose 7.2
    Silica 0.9
    Magnesium stearate 1.8
  • Ticagrelor was milled together with HPMC and SDS in a dispersion medium for 1 hour in a Netsch microCer. The obtained suspension was spray dried in a Büchi spray tower. The resulting mixture was mixed for 10 minutes in a free fall mixer (Turbula TB10) together with the previously grinded ASA, half amount of the mannitol, croscarmellose and silica. The mixture was then compacted. The product was sieved using a coMill sieve (1000 μm), followed by adding the remaining excipients and the magnesium stearate being previously sieved through a 0.5 mm sieve. The resulting mixture is mixed for further 3 minutes. The final mixture was pressed into tablets using a Korsch eccentric press EK0.

Claims (19)

1. A solid pharmaceutical dosage form comprising particles of ticagrelor or a pharmaceutically acceptable salt or ester thereof, characterized in that at least 90% by volume of the ticagrelor particles have a particle size in the range of 1 μm to 150 μm.
2. A solid pharmaceutical dosage form comprising more than 50% by weight of ticagrelor or salt or ester thereof in particle form, based on the total weight of the dosage form.
3. The solid pharmaceutical dosage form according to claim 2, wherein at least 90% by volume of the ticagrelor particles have a particle size in the range of 1 μm to 150 μm.
4. The solid pharmaceutical dosage form according to claim 1, further comprising at least one hydrophilic polymer and/or emulsifier.
5. The solid pharmaceutical dosage form according to claim 4, wherein the weight ratio of ticagrelor or salt or ester thereof to the hydrophilic polymer and/or emulsifier ranges from 100:1 to 1:1.
6. The solid pharmaceutical dosage form according to claim 4, wherein the hydrophilic polymer is selected from the group consisting of cellulose derivatives, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone, polyoxyethylenealkyl ether, polyethylenglycol, co-block-polymers of ethylenoxide and propylenoxide, polymethacrylate derivatives, polyvinylalcohol, polyvinylalcohol derivatives and polyethylenglycol derivatives.
7. The solid pharmaceutical dosage form according to claim 1, which does not comprise any lubricant.
8. The solid pharmaceutical dosage form according to claim 1, which further comprises an anti-thrombotic agent, in particular acetylsalicylic acid.
9. A process for the preparation of a solid pharmaceutical dosage form according to claim 1, comprising the step of milling ticagrelor or a pharmaceutically acceptable salt or ester thereof in the presence of a polymer and/or emulsifier.
10. The process according to claim 9, wherein the milling step is carried out as wet milling or dry milling.
11. The process according to claim 9, wherein the polymer is a hydrophilic polymer.
12. The process according to claim 11, wherein the hydrophilic polymer is selected from the group consisting of cellulose derivatives, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone, polyoxyethylenealkyl ether, polyethylenglycol, co-block-polymers of ethylenoxide and propylenoxide, polymethacrylate derivatives, polyvinylalcohol, polyvinylalcohol derivatives and polyethylenglycol derivatives.
13. A solid composition comprising particles of ticagrelor or a pharmaceutically acceptable salt or ester thereof, wherein at least 90% by volume of the ticagrelor particles have a particle size in the range of 1 μm to 150 μm.
14. The solid pharmaceutical dosage form according to claim 4, wherein the weight ratio of ticagrelor or salt or ester thereof to hydrophilic polymer and/or emulsifier ranges from 100:1 to 2:1.
15. The solid pharmaceutical dosage form according to claim 6, wherein the hydrophilic polymer is a cellulose derivative selected from the group consisting of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, and hydroxyethyl cellulose.
16. The solid pharmaceutical dosage form according to claim 16, wherein the cellulose derivative is in the form of a sodium or calcium salt.
17. The solid pharmaceutical dosage form according to claim 6, wherein the hydrophilic polymer is a copolymer of polyvinylpyrrolidone comprising vinylpyrrolidone and vinylacetate units.
18. The process according to claim 12, wherein the hydrophilic polymer is a cellulose derivative selected from the group consisting of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, and hydroxyethyl cellulose.
19. The process according to claim 12, wherein the cellulose derivative is in the form of a sodium or calcium salt.
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Cited By (2)

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WO2016013795A1 (en) * 2014-07-25 2016-01-28 동아에스티 주식회사 Slow release preparation
GR1010621B (en) * 2022-12-19 2024-01-30 Elpen Ανωνυμος Εταιρεια Φαρμακευτικη Βιομηχανια, Solid pharmacotechnical forms of ticagrelor

Families Citing this family (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102657629B (en) * 2012-05-14 2014-04-02 深圳市华力康生物医药有限公司 Ticagrelor sustained-release tablet system and preparation method thereof
CZ2012705A3 (en) 2012-10-16 2014-04-23 Zentiva, K.S. Solid oral pharmaceutical formulation containing ticagrelor
WO2014118808A2 (en) * 2013-02-04 2014-08-07 Hetero Research Foundation Ticagrelor solid dispersion
EP2813216A1 (en) 2013-06-10 2014-12-17 Zentiva, a.s. Stabilized amorphous ticagrelor
WO2014170026A1 (en) 2013-04-18 2014-10-23 Zentiva, K.S. Stabilized amorphous ticagrelor
EP3003276A1 (en) * 2013-05-29 2016-04-13 ratiopharm GmbH Solid pharmaceutical dosage form
EP2813212A1 (en) * 2013-06-10 2014-12-17 Zentiva, a.s. Drug formulation using API in nanofibers
EP2816043A1 (en) * 2013-06-21 2014-12-24 LEK Pharmaceuticals d.d. Spherical ticagrelor particles
WO2015001489A1 (en) 2013-07-01 2015-01-08 Ranbaxy Laboratories Limited Pharmaceutical compositions of ticagrelor
CN104414989B (en) * 2013-09-10 2019-02-22 四川海思科制药有限公司 A kind of Ticagrelor pharmaceutical composition and preparation method thereof
CN104434805B (en) * 2013-09-22 2017-09-29 成都盛迪医药有限公司 A kind of ticagrelor solid dispersions and preparation method thereof
CZ2013866A3 (en) 2013-11-08 2015-05-20 Zentiva, K.S. Novel crystalline form of ticagrelor synthesis intermediate and process for preparing thereof
CN104644604A (en) * 2013-11-23 2015-05-27 天津市汉康医药生物技术有限公司 Ticagrelor sesquihydrate capsule and preparation method thereof
CN103751109A (en) * 2013-12-31 2014-04-30 北京万全德众医药生物技术有限公司 Ticagrelor dry suspension and preparation method thereof
WO2015110952A1 (en) * 2014-01-21 2015-07-30 Wockhardt Limited Solid oral pharmaceutical compositions comprising ticagrelor or salt thereof
CN104971042B (en) * 2014-04-04 2018-01-05 中国医学科学院医药生物技术研究所 The oral self-emulsion composition of ticagrelor
CN104523640B (en) * 2014-12-19 2017-02-22 河南润弘制药股份有限公司 Ticagrelor tablets and preparation method thereof
JP6451310B2 (en) * 2014-12-24 2019-01-16 ライオン株式会社 Solid pharmaceutical composition and method for producing the same
CN105832683A (en) * 2015-01-15 2016-08-10 成都国弘医药有限公司 Tablet containing ticagrelor
CN105998026B (en) * 2015-03-26 2020-07-14 四川海思科制药有限公司 Ticagrelor medicine composition and preparation method thereof
TR201601835A2 (en) 2016-02-12 2017-08-21 Ali Raif Ilac Sanayi Ve Ticaret Anonim Sirketi PRODUCTION METHOD FOR FORMULATIONS CONTAINING TIKAGRELOR
US20170296666A1 (en) 2016-04-18 2017-10-19 Amneal Pharmaceuticals Company Gmbh Stable Pharmaceutical Composition Of Amorphous Ticagrelor
CN105943515A (en) * 2016-06-24 2016-09-21 山东鲁抗医药股份有限公司 Ticagrelor orally disintegrating tablets and preparation method thereof
TR201617983A2 (en) 2016-12-07 2018-06-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi SOLID ORAL PHARMACEUTICAL COMPOSITIONS OF TICAGRELOR
CN106727378A (en) * 2016-12-28 2017-05-31 江苏飞马药业有限公司 A kind of tablet composition containing ticagrelor main ingredient and preparation method thereof
EP3761965A1 (en) 2018-03-08 2021-01-13 Pharmaceutical Oriented Services Ltd Ticagrelor-containing tablet formulation
EP3829547A1 (en) 2018-07-27 2021-06-09 KRKA, d.d., Novo mesto Pharmaceutical composition of ticagrelor
CN110327305A (en) * 2019-06-26 2019-10-15 慧生医学科技(徐州)有限公司 A kind of ticagrelor piece and preparation method thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070003615A1 (en) * 2005-06-13 2007-01-04 Elan Pharma International Limited Nanoparticulate clopidogrel and aspirin combination formulations
WO2008024044A1 (en) * 2006-08-21 2008-02-28 Astrazeneca Ab Compositions, suitable for oral administration, comprising a triazolo [4, 5] pyrimidin derivate
US20080254036A1 (en) * 2007-04-13 2008-10-16 Millennium Pharmaceuticals, Inc. Combination anticoagulant therapy with a compound that acts as a factor xa inhibitor
US20080279845A1 (en) * 2007-05-02 2008-11-13 Portola Pharmaceuticals, Inc. Combination therapy with a compound acting as a platelet adp receptor inhibitor
WO2009007675A2 (en) * 2007-07-11 2009-01-15 Cardoz Ab Combination for use in the treatment of atherosclerosis comprising a mast cell inhibitor and a p2 gamma 12 antagonist
US20090048216A1 (en) * 2007-05-02 2009-02-19 Portola Pharmaceuticals, Inc. Intravenous and oral dosing of a direct-acting and reversible p2y12 inhibitor

Family Cites Families (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US118410A (en) 1871-08-22 Improvement in combined hay and manure-forks
US4721709A (en) 1984-07-26 1988-01-26 Pyare Seth Novel pharmaceutical compositions containing hydrophobic practically water-insoluble drugs adsorbed on pharmaceutical excipients as carrier; process for their preparation and the use of said compositions
TW530058B (en) 1997-07-22 2003-05-01 Astra Pharma Prod Triazolo [4,5-d]pyrimidine compounos and their use and process for preparation
TWI229674B (en) 1998-12-04 2005-03-21 Astra Pharma Prod Novel triazolo[4,5-d]pyrimidine compounds, pharmaceutical composition containing the same, their process for preparation and uses
UA74141C2 (en) 1998-12-09 2005-11-15 Дж.Д. Сірл Енд Ко. Oral pharmaceutical compositions comprising micronized eplerenone (variants), method for its production and method for treating aldosterone-mediated states (variants)
GB0013407D0 (en) 2000-06-02 2000-07-26 Astrazeneca Ab Forms of a chemical compound
JP4969761B2 (en) * 2000-08-31 2012-07-04 オバン・エナジー・リミテッド Method for producing a synergistic mixture comprising small particles of a solid substrate having a desired particle size and small particles of a first material
SE0101932D0 (en) 2001-05-31 2001-05-31 Astrazeneca Ab Pharmaceutical combinations
UA80991C2 (en) 2002-10-07 2007-11-26 Solid preparation containing an insulin resistance improving drug and an active ingredient useful as a remedy for diabetes
WO2005067976A2 (en) 2004-01-20 2005-07-28 Novartis Ag Direct compression formulation and process
US20080214599A1 (en) * 2005-08-19 2008-09-04 John Thomas Brandt Use of Par-1/Par-4 Inhibitors for Treating or Preventing Vascular Diseases
WO2007146712A2 (en) * 2006-06-09 2007-12-21 Kemia, Inc. Therapy using cytokine inhibitors
TWI482772B (en) 2006-08-21 2015-05-01 Astrazeneca Ab Compositions, suitable for oral administration, comprising a triazolo(4,5-d)pyrimidin derivate
AP2010005341A0 (en) * 2008-01-11 2010-08-31 Cipla Ltd Solid pharmaceutical dosage form
CA2712282A1 (en) 2008-01-25 2009-07-30 Alphapharm Pty Ltd Delayed release pharmaceutical composition of duloxetine
TR200801178A2 (en) 2008-02-22 2009-09-23 Bi̇li̇m İlaç Sanayi̇ Ti̇caret A.Ş. Oral tablet compositions containing nateglinide and surfactant-ph regulating system
DE102008037324A1 (en) 2008-08-11 2010-02-18 Ratiopharm Gmbh Pharmaceutical formulation for pulmonary reduction of blood pressure
WO2010056910A2 (en) * 2008-11-12 2010-05-20 Carolus Therapeutics, Inc. Methods of treating cardiovascular disorders
WO2011160768A1 (en) * 2010-06-23 2011-12-29 Stefan Kralev Medical device for self-administration of patients with acute coronary events
CN102657629B (en) * 2012-05-14 2014-04-02 深圳市华力康生物医药有限公司 Ticagrelor sustained-release tablet system and preparation method thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070003615A1 (en) * 2005-06-13 2007-01-04 Elan Pharma International Limited Nanoparticulate clopidogrel and aspirin combination formulations
WO2008024044A1 (en) * 2006-08-21 2008-02-28 Astrazeneca Ab Compositions, suitable for oral administration, comprising a triazolo [4, 5] pyrimidin derivate
US20080254036A1 (en) * 2007-04-13 2008-10-16 Millennium Pharmaceuticals, Inc. Combination anticoagulant therapy with a compound that acts as a factor xa inhibitor
US20080279845A1 (en) * 2007-05-02 2008-11-13 Portola Pharmaceuticals, Inc. Combination therapy with a compound acting as a platelet adp receptor inhibitor
US20090048216A1 (en) * 2007-05-02 2009-02-19 Portola Pharmaceuticals, Inc. Intravenous and oral dosing of a direct-acting and reversible p2y12 inhibitor
WO2009007675A2 (en) * 2007-07-11 2009-01-15 Cardoz Ab Combination for use in the treatment of atherosclerosis comprising a mast cell inhibitor and a p2 gamma 12 antagonist

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016013795A1 (en) * 2014-07-25 2016-01-28 동아에스티 주식회사 Slow release preparation
GR1010621B (en) * 2022-12-19 2024-01-30 Elpen Ανωνυμος Εταιρεια Φαρμακευτικη Βιομηχανια, Solid pharmacotechnical forms of ticagrelor

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