EP2908802A1 - A solid oral pharmaceutical formulation containing ticagrelor - Google Patents

A solid oral pharmaceutical formulation containing ticagrelor

Info

Publication number
EP2908802A1
EP2908802A1 EP13792574.9A EP13792574A EP2908802A1 EP 2908802 A1 EP2908802 A1 EP 2908802A1 EP 13792574 A EP13792574 A EP 13792574A EP 2908802 A1 EP2908802 A1 EP 2908802A1
Authority
EP
European Patent Office
Prior art keywords
cellulose
formulation according
hygroscopic
formulation
binder
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.)
Withdrawn
Application number
EP13792574.9A
Other languages
German (de)
French (fr)
Inventor
Gregor Sedmak
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.)
Zentiva KS
Original Assignee
Zentiva KS
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 Zentiva KS filed Critical Zentiva KS
Publication of EP2908802A1 publication Critical patent/EP2908802A1/en
Withdrawn legal-status Critical Current

Links

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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—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
    • A61K9/2013—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
    • A61K9/205—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
    • A61K9/2095—Tabletting processes
    • 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
    • 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

Definitions

  • the present invention relates to a solid oral pharmaceutical formulation containing ticagrelor as the active pharmaceutical constituent and a preparation method of this formulation.
  • WO 1999/005143 was generically described in WO 1999/005143 and specifically mentioned in EP 1 135 391. This document also describes a method of its preparation, as well as the use of ticagrelor in treatment or prevention of myocardial infarction, stroke, diseases of peripheral vessels, etc.
  • WO 2001/092262 describes 4 polymorphous and an amorphous form of ticagrelor.
  • WO 2011/067571 describes cocrystals with various coformers such as glycolic, salicylic, succinic, malonic and 4-hydroxy-3-methoxybenzenecarboxylic acids.
  • WO 2008/024044 describes a solid formulation that comprises one or more fillers, one or more binders, preferably one or more disintegrants and preferably one or more lubricants.
  • the sodium salt of carboxymethylstarch was used as a disintegrant in the amount of 3 % by weight.
  • WO2008/024045 describes a very similar solid formulation that comprises one or more fillers, one or more binders, preferably one or more disintegrants and preferably one or more lubricants. This document indicates that the use of disintegrants is necessary. Particular examples mentioned in the document contain 2-6 % by weight of a disintegrant, which is the sodium salt of carboxymethylstarch.
  • WO 2011/076749 deals with the particle size of ticagrelor which was used in the formulation as ticagrelor is well-known as a poorly soluble compound.
  • disintegrants were used in amounts in the range of 4-6% by weight.
  • Ticagrelor is sold under the trade name Brilique for prevention of arteriothrombotic events in the form of coated tablets.
  • the marketed formulation also contains the sodium salt of carboxymethylstarch as the disintegrant. Disclosure of Invention
  • This invention relates to a solid oral pharmaceutical formulation containing ticagrelor with the chemical name (lS,2S,3R,5S)-3-[7-[[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]-5- (propylthio)-3H-l,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-l,2- cyclopentanediol, which further contains at least one non-hygroscopic filler and/or at least one non-hygroscopic binder that do not have a disintegrating effect.
  • the non-hygroscopic filler means a water-soluble filler, sugar alcohols being generally preferred, such as glucose, fructose, sucrose, lactose monohydrate, anhydrous lactose, raffinose, isomaltose, trehalose, dextrates, mannitol, erythritol, sorbitol, maltitol, xylitol, lactitol, compressible sugars. Hydroxypropyl cellulose or maltose, for example, can be used as the non-hygroscopic binder.
  • the composition in accordance with this invention preferably contains 0.5- 30% by weight of the binder, preferably 1-7% by weight of the binder and most preferably 2-4% by weight of the binder.
  • non-hygroscopic refers to a material that has a low capability of receiving and holding water. Or, put it in a better way, the term non-hygroscopic refers to a material that has an equilibrium moisture content lower than 6% by weight. This value is determined by Dynamic Vapour Sorption (DVS) at the relative humidity of 60% and temperature of 25 °C. The equilibrium moisture content is determined based on the sorption isothermal curve measured using the DVS method at the relative humidity of 60% and temperature of 25 °C.
  • DVS Dynamic Vapour Sorption
  • disintegrants in a formulation does not need to have an impact on increasing the biological availability of the active substance. This property is more influenced by sufficient humidification of the active substance present in the formulation. If such a composition can be prepared that will dissolve sufficiently quickly without the use of disintegrants, disintegrants only become a superfluous constituent that does not have any real effect.
  • Disintegrants represent a class of excipients that are generally considered as special excipients.
  • the price of special excipients i.e. disintegrants, is much higher than the price of commonly used excipients such as fillers.
  • the price of disintegrants such as the sodium salt of carboxymethylstarch or the sodium salt of croscarmellose may normally be several times higher than the price of general fillers as mannitol or calcium hydrogen phosphate.
  • disintegrants act is not clear so far. Mechanisms assumed in the past include, e.g., soaking with water, swelling, shape memory, repellency to the other constituents, heating during humidification.
  • the ability of disintegrants to bring water to the porous network of the tablet is essential for efficient disintegration. This explanation was provided by the Encyclopaedia of Pharmaceutical Technology, 3 rd issue, Informa Healthcare USA, Inc., 2007.
  • disintegrants are generally hygroscopic or very hygroscopic materials. According to the Handbook of Pharmaceutical Excipients, 6 th issue, Pharmaceutical Press, 2009 the sodium salt of croscarmellose and sodium salt of carboxymethylstarch exhibit the same characteristics.
  • WO2008/024045 describes that the use of a composition that contains one or more fillers, one or more binders, preferably one or more disintegrants and preferably one or more lubricants is suitable for efficient releasing of at least 90% of ticagrelor. Contrary to the findings of the prior art we have found out that a ticagrelor composition with any known form of ticagrelor (crystalline, amorphous or in a cocrystal form) that contains at least one non-hygroscopic filler and/or at least one non-hygroscopic binder that do not feature the disintegration effect will achieve efficient release of at least 90% of ticagrelor.
  • disintegrant refers to any material that swells or soaks in contact with water.
  • the term disintegrant comprises, e.g., the group of compounds such as: povidone, crospovidone, starch, pregelatinized starch, sodium salt of carboxymethyl cellulose, hydroxypropyl starch, microcrystalline cellulose, calcium salt of carboxymethylcellulose, sodium salt of crosslinked carboxymethylcellulose, potassium salt of polacrilin, low- substituted hydroxypropyl cellulose, sodium or calcium alginate, sodium docusate, methyl cellulose, agar, guar gum, chitosan and alginic acid.
  • the composition of ticagrelor conveniently contains no or less than 2% of a disintegrant.
  • the pharmaceutical composition of ticagrelor contains substantially no disintegrant.
  • the composition of ticagrelor contains a non-hygroscopic filler.
  • a water-soluble filler is preferred.
  • Suitable fillers are, e.g., monosaccharides, oligosaccharides and sugar alcohols such as glucose, fructose, sucrose, lactose monohydrate, anhydrous lactose, raffinose, isomaltose, trehalose, dextrates, mannitol, erythritol, sorbitol, maltitol, xylitol and lactitol, compressible sugars, calcium hydrogen phosphate dihydrate and their mixtures. Lactose, mannitol and xylitol are preferred.
  • the composition of ticagrelor contains a non-hygroscopic binder.
  • Suitable binders are, e.g., povidone, copovidone, powdered, crystalline or microcrystalline cellulose, siliconized microcrystalline cellulose, cellulose derivatives such as hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropylmethyl cellulose, starch, pregelatinized starch, polymethacrylates and their mixtures.
  • the formulation of ticagrelor contains 0.5 to 30% by weight of the binder, preferably from 1 to 7%, and most conveniently from 2 to 4% by weight of the binder.
  • the composition of ticagrelor typically contains at least 1 surfactant.
  • Suitable surfactants are, e.g., anionic, cationic, ampholytic and/or non-ionic surfactants such as the sodium salt of lauryl sulphate, cetrimide, N-dodecyl-N,N-dimethyl betaine, polysorbates (e.g. T weens ® ), poloxamers and their mixtures.
  • the sodium salt of lauryl sulphate is the preferred compound.
  • the surfactant is used, in the formulation of ticagrelor, in an amount of from 0.1 to 4.0% by weight, most preferably in the range of from 0.5 to 2.0%.
  • composition of ticagrelor typically contains at least 1 lubricant and/or anti-adhesive compound selected, e.g., among magnesium stearate, stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, colloidal silicon dioxide, magnesium trisilicate and their mixtures.
  • lubricant and/or anti-adhesive compound selected, e.g., among magnesium stearate, stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, colloidal silicon dioxide, magnesium trisilicate and their mixtures.
  • Stearic acid, magnesium stearate, sodium stearyl fumarate and colloidal silicon dioxide are especially preferred.
  • the tablet of ticagrelor can be conveniently coated with any suitable coating.
  • a suitable coating agent for ticagrelor tablets is selected, e.g., from methyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polymers of acrylic acid, ethyl cellulose, cellulose acetate phtalate, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol, sodium salt of carboxymethyl cellulose, cellulose acetate, gelatine, copolymers of methacrylic acid, polyethylene glycol, shellac, sucrose, titanium dioxide and camauba wax. Polyethylene glycol, hydroxypropylmethyl cellulose and polyvinyl alcohol are preferred. Examples
  • Ticagrelor is granulated in wet conditions together with either lactose monohydrate or xylitol or mannitol or maltitol (either using granulation by kneading or with the use of a common granulator with a fluidized bed) with an aqueous solution of either hydroxypropyl cellulose or maltose.
  • Sodium lauryl sulphate is preferably added to the granulation solution.
  • the obtained granulate is dried and screened through a 1mm sieve.
  • the sieved granulate is then mixed with either lactose monohydrate or xylitol or mannitol or isomaltose or maltose in a suitable mixing device for 20 minutes. After this pre-mixing magnesium stearate is added to the mixture and the mixture is stirred for another 3 minutes so that a suitable tabletting mixture can be obtained. This mixture is then compressed into tablets in a rotary tabletting device.
  • Ticagrelor was granulated in dry conditions together with mannitol or lactose monohydrate or xylitol and preferably with sodium lauryl sulphate in a rotary compactor with a variable gap size.
  • the obtained granulate was screened through a 1mm sieve.
  • the sieved granulate is mixed with either lactose monohydrate or xylitol or mannitol or isomaltose or maltose or lactitol in a suitable mixing device for 20 minutes. After pre-mixing magnesium stearate is added to the mixture and the mixture is stirred for another 3 minutes so that a mixture ready for tabletting can be obtained. This mixture is then compressed into tablets in a rotary tabletting device.
  • Ticagrelor is mixed with lactose monohydrate or xylitol or mannitol or isomaltose or maltose or lactitol in a suitable mixing device for 20 minutes. After pre-mixing magnesium stearate is added to the mixture and the mixture is stirred for another 3 minutes so that a mixture ready for tabletting in a rotary tabletting device can be obtained.
  • Tablets obtained in accordance with Examples 1 to 3 are conveniently coated with a common coating material
  • Constituents of the coating mixture are dissolved or suspended in a sufficient quantity of water to provide the coating solution. Then, tablets are coated with this solution in a suitable device and finally they are dried.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Inorganic Chemistry (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)

Abstract

The present solution provides a solid oral pharmaceutical formulation containing ticagrelor, in the chemical name (1S,2S,3R,5S)-3-[7-[[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]- 5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1,2- cyclopentanediol, comprising at least one non-hygroscopic filler and/or at least one non- hygroscopic binder, wherein neither the filler, nor the binder have any disintegration effect. Preparation of the formulation is possible by wet granulation or dry granulation or direct

Description

A solid oral pharmaceutical formulation containing ticagrelor
Technical Field
The present invention relates to a solid oral pharmaceutical formulation containing ticagrelor as the active pharmaceutical constituent and a preparation method of this formulation.
Background Art
The compound ticagrelor with the chemical name (lS,2S,3R,5S)-3-[7-[[(lR,2S)-2-(3,4- difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-l,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5- (2-h droxyethoxy)-l,2-cyclopentanediol, which is represented by formula (I),
was generically described in WO 1999/005143 and specifically mentioned in EP 1 135 391. This document also describes a method of its preparation, as well as the use of ticagrelor in treatment or prevention of myocardial infarction, stroke, diseases of peripheral vessels, etc. WO 2001/092262 describes 4 polymorphous and an amorphous form of ticagrelor. WO 2011/067571 describes cocrystals with various coformers such as glycolic, salicylic, succinic, malonic and 4-hydroxy-3-methoxybenzenecarboxylic acids.
Pharmaceutical formulations have been described in 2 applications of the company Astra Zeneca, WO 2008/024044 and WO 2008/024045. WO 2008/024044 describes a solid formulation that comprises one or more fillers, one or more binders, preferably one or more disintegrants and preferably one or more lubricants. According to Example 1 of WO 2008/024044 the sodium salt of carboxymethylstarch was used as a disintegrant in the amount of 3 % by weight. The document does not mention any example where no disintegrant would be used. WO2008/024045 describes a very similar solid formulation that comprises one or more fillers, one or more binders, preferably one or more disintegrants and preferably one or more lubricants. This document indicates that the use of disintegrants is necessary. Particular examples mentioned in the document contain 2-6 % by weight of a disintegrant, which is the sodium salt of carboxymethylstarch.
WO 2011/076749 deals with the particle size of ticagrelor which was used in the formulation as ticagrelor is well-known as a poorly soluble compound. In the quoted examples of this application disintegrants were used in amounts in the range of 4-6% by weight.
Ticagrelor is sold under the trade name Brilique for prevention of arteriothrombotic events in the form of coated tablets. The marketed formulation also contains the sodium salt of carboxymethylstarch as the disintegrant. Disclosure of Invention
This invention relates to a solid oral pharmaceutical formulation containing ticagrelor with the chemical name (lS,2S,3R,5S)-3-[7-[[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]-5- (propylthio)-3H-l,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-l,2- cyclopentanediol, which further contains at least one non-hygroscopic filler and/or at least one non-hygroscopic binder that do not have a disintegrating effect.
The non-hygroscopic filler means a water-soluble filler, sugar alcohols being generally preferred, such as glucose, fructose, sucrose, lactose monohydrate, anhydrous lactose, raffinose, isomaltose, trehalose, dextrates, mannitol, erythritol, sorbitol, maltitol, xylitol, lactitol, compressible sugars. Hydroxypropyl cellulose or maltose, for example, can be used as the non-hygroscopic binder. The composition in accordance with this invention preferably contains 0.5- 30% by weight of the binder, preferably 1-7% by weight of the binder and most preferably 2-4% by weight of the binder.
The term non-hygroscopic, as used in this invention, refers to a material that has a low capability of receiving and holding water. Or, put it in a better way, the term non-hygroscopic refers to a material that has an equilibrium moisture content lower than 6% by weight. This value is determined by Dynamic Vapour Sorption (DVS) at the relative humidity of 60% and temperature of 25 °C. The equilibrium moisture content is determined based on the sorption isothermal curve measured using the DVS method at the relative humidity of 60% and temperature of 25 °C.
An expert in the art knows that the use of disintegrants in a formulation does not need to have an impact on increasing the biological availability of the active substance. This property is more influenced by sufficient humidification of the active substance present in the formulation. If such a composition can be prepared that will dissolve sufficiently quickly without the use of disintegrants, disintegrants only become a superfluous constituent that does not have any real effect.
Disintegrants represent a class of excipients that are generally considered as special excipients. The price of special excipients, i.e. disintegrants, is much higher than the price of commonly used excipients such as fillers. The price of disintegrants such as the sodium salt of carboxymethylstarch or the sodium salt of croscarmellose may normally be several times higher than the price of general fillers as mannitol or calcium hydrogen phosphate.
The way disintegrants act is not clear so far. Mechanisms assumed in the past include, e.g., soaking with water, swelling, shape memory, repellency to the other constituents, heating during humidification. The ability of disintegrants to bring water to the porous network of the tablet is essential for efficient disintegration. This explanation was provided by the Encyclopaedia of Pharmaceutical Technology, 3rd issue, Informa Healthcare USA, Inc., 2007. As a natural consequence of the ability to bring water to tablets disintegrants are generally hygroscopic or very hygroscopic materials. According to the Handbook of Pharmaceutical Excipients, 6th issue, Pharmaceutical Press, 2009 the sodium salt of croscarmellose and sodium salt of carboxymethylstarch exhibit the same characteristics.
Due to the hygroscopic character of the excipients it is necessary to pack the ticagrelor formulation in PVC/PVDC blisters. The use of non-hygroscopic blister packs makes it possible to replace expensive PVS/PVDC with more affordable PVC blisters. With regard to lower costs of excipients and lower packing costs it is desirable to prepare a formulation that contains non-hygroscopic excipients that do not have any disintegration effect.
WO2008/024045 describes that the use of a composition that contains one or more fillers, one or more binders, preferably one or more disintegrants and preferably one or more lubricants is suitable for efficient releasing of at least 90% of ticagrelor. Contrary to the findings of the prior art we have found out that a ticagrelor composition with any known form of ticagrelor (crystalline, amorphous or in a cocrystal form) that contains at least one non-hygroscopic filler and/or at least one non-hygroscopic binder that do not feature the disintegration effect will achieve efficient release of at least 90% of ticagrelor.
The term "disintegrant", used here, refers to any material that swells or soaks in contact with water. The term disintegrant comprises, e.g., the group of compounds such as: povidone, crospovidone, starch, pregelatinized starch, sodium salt of carboxymethyl cellulose, hydroxypropyl starch, microcrystalline cellulose, calcium salt of carboxymethylcellulose, sodium salt of crosslinked carboxymethylcellulose, potassium salt of polacrilin, low- substituted hydroxypropyl cellulose, sodium or calcium alginate, sodium docusate, methyl cellulose, agar, guar gum, chitosan and alginic acid. The composition of ticagrelor conveniently contains no or less than 2% of a disintegrant.
In the most preferable embodiment the pharmaceutical composition of ticagrelor contains substantially no disintegrant.
The composition of ticagrelor contains a non-hygroscopic filler. Generally, a water-soluble filler is preferred. Suitable fillers are, e.g., monosaccharides, oligosaccharides and sugar alcohols such as glucose, fructose, sucrose, lactose monohydrate, anhydrous lactose, raffinose, isomaltose, trehalose, dextrates, mannitol, erythritol, sorbitol, maltitol, xylitol and lactitol, compressible sugars, calcium hydrogen phosphate dihydrate and their mixtures. Lactose, mannitol and xylitol are preferred.
The composition of ticagrelor contains a non-hygroscopic binder. Suitable binders are, e.g., povidone, copovidone, powdered, crystalline or microcrystalline cellulose, siliconized microcrystalline cellulose, cellulose derivatives such as hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropylmethyl cellulose, starch, pregelatinized starch, polymethacrylates and their mixtures. In a preferred composition the formulation of ticagrelor contains 0.5 to 30% by weight of the binder, preferably from 1 to 7%, and most conveniently from 2 to 4% by weight of the binder.
The composition of ticagrelor typically contains at least 1 surfactant. Suitable surfactants are, e.g., anionic, cationic, ampholytic and/or non-ionic surfactants such as the sodium salt of lauryl sulphate, cetrimide, N-dodecyl-N,N-dimethyl betaine, polysorbates (e.g. T weens®), poloxamers and their mixtures. The sodium salt of lauryl sulphate is the preferred compound. The surfactant is used, in the formulation of ticagrelor, in an amount of from 0.1 to 4.0% by weight, most preferably in the range of from 0.5 to 2.0%. The composition of ticagrelor typically contains at least 1 lubricant and/or anti-adhesive compound selected, e.g., among magnesium stearate, stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, colloidal silicon dioxide, magnesium trisilicate and their mixtures. Stearic acid, magnesium stearate, sodium stearyl fumarate and colloidal silicon dioxide are especially preferred.
The tablet of ticagrelor can be conveniently coated with any suitable coating. A suitable coating agent for ticagrelor tablets is selected, e.g., from methyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polymers of acrylic acid, ethyl cellulose, cellulose acetate phtalate, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol, sodium salt of carboxymethyl cellulose, cellulose acetate, gelatine, copolymers of methacrylic acid, polyethylene glycol, shellac, sucrose, titanium dioxide and camauba wax. Polyethylene glycol, hydroxypropylmethyl cellulose and polyvinyl alcohol are preferred. Examples
Example 1
Wet granulation
1 A 1 B 1 C 1 D 1 E 1 F 1 G 1 H
Active
Ticagrelor 90.0 90.0 90.0 90.0 90.0 90.0 90.0 90.0 substance
Lactose Filler
90.0 150.0
monohydrate
Xylitol Filler 90.0 150.0
Mannitol Filler 150.0 90.0
Maltitol Filler 150.0 90.0
Hydroxypropyl Binder
3.6 3.6 3.6 3.6
cellulose Maltose Binder 3.6 3.6 3.6 3.6
Sodium lauryl Surfactant
3.0 3.0 3.0 3.0 sulphate
Lactose Filler
107.4 50.4
monohydrate
Xylitol Filler 110.4 107.4
Mannitol Filler 47.4 110.4
Isomaltose Filler 50.4
Maltose Filler 47.4
Magnesium Lubricant
6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 stearate
Total (mg) 300.0 300.0 300.0 300.0 300.0 300.0 300.0 300.0
Ticagrelor is granulated in wet conditions together with either lactose monohydrate or xylitol or mannitol or maltitol (either using granulation by kneading or with the use of a common granulator with a fluidized bed) with an aqueous solution of either hydroxypropyl cellulose or maltose. Sodium lauryl sulphate is preferably added to the granulation solution. The obtained granulate is dried and screened through a 1mm sieve. The sieved granulate is then mixed with either lactose monohydrate or xylitol or mannitol or isomaltose or maltose in a suitable mixing device for 20 minutes. After this pre-mixing magnesium stearate is added to the mixture and the mixture is stirred for another 3 minutes so that a suitable tabletting mixture can be obtained. This mixture is then compressed into tablets in a rotary tabletting device.
Example 2
Dry granulation
Lactose monohydrate Filler 81.0
Xylitol Filler 84.0
Mannitol Filler 81.0
Isomaltose Filler 44.0
Maltose Filler 41.0
Lactitol Filler 44.0
Magnesium stearate Lubricant 6.0 6.0 6.0 6.0 6.0 6.0
Total (mg) 300.0 300.0 300.0 300.0 300.0 300.0
Ticagrelor was granulated in dry conditions together with mannitol or lactose monohydrate or xylitol and preferably with sodium lauryl sulphate in a rotary compactor with a variable gap size. The obtained granulate was screened through a 1mm sieve. The sieved granulate is mixed with either lactose monohydrate or xylitol or mannitol or isomaltose or maltose or lactitol in a suitable mixing device for 20 minutes. After pre-mixing magnesium stearate is added to the mixture and the mixture is stirred for another 3 minutes so that a mixture ready for tabletting can be obtained. This mixture is then compressed into tablets in a rotary tabletting device. Example 3
Direct compression
Ticagrelor is mixed with lactose monohydrate or xylitol or mannitol or isomaltose or maltose or lactitol in a suitable mixing device for 20 minutes. After pre-mixing magnesium stearate is added to the mixture and the mixture is stirred for another 3 minutes so that a mixture ready for tabletting in a rotary tabletting device can be obtained.
Example 4 Tablet coating
Tablets obtained in accordance with Examples 1 to 3 are conveniently coated with a common coating material
Constituents of the coating mixture are dissolved or suspended in a sufficient quantity of water to provide the coating solution. Then, tablets are coated with this solution in a suitable device and finally they are dried.

Claims

Claims
1) A solid pharmaceutical composition, containing ticagrelor having the chemical name (lS,2S,3R,5S)-3-[7-[[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]-5- (propylthio)-3H-l,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-l,2- cyclopentanediol, characterized in that it contains at least one non-hygroscopic filler and/or at least one non-hygroscopic binder.
2) The formulation according to claim 1 , characterized in that the non-hygroscopic filler and the non-hygroscopic binder do not have any disintegration effect.
3) The formulation according to claim 2, characterized in that the non-hygroscopic filler is selected from the group that consists of sugar alcohols such as glucose, fructose, sucrose, lactose monohydrate, anhydrous lactose, raffinose, isomaltose, trehalose, dextrates, mannitol, erythritol, sorbitol, maltitol, xylitol, lactitol and compressible sugars.
4) The formulation according to claim 2, characterized in that the non-hygroscopic binder is selected from hydroxypropyl cellulose and maltose.
5) The formulation according to claims 1-4, characterized in that the composition further contains at least one lubricant, optionally at least one surfactant, and preferably at least one disintegrant in an amount in the range of 0 to 2% by weight.
6) The formulation according to claim 5, characterized in that a further binder is selected from the group comprising povidone, copovidone, powdered, crystalline or microcrystalline cellulose, siliconized microcrystalline cellulose, cellulose derivatives such as hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropylmethyl cellulose, starch, pregelatinized starch, polymethacrylates and their mixtures.
7) The formulation according to claim 5, characterized in that the lubricant is selected from stearic acid, magnesium stearate or sodium stearyl fumarate. 8) The formulation according to claim 5, characterized in that the surfactant is selected from the group comprising anionic, cationic, ampholytic or non-ionic surfactants such as the sodium salt of lauryl sulphate, cetrimide, N-dodecyl-N,N-dimethyl betaine, polysorbates, poloxamers and their mixtures.
9) The formulation according to claim 5, characterized in that a further disintegrant is selected from the group comprising povidone, crospovidone, starch, pregelatinized starch, sodium salt of carboxymethyl cellulose, hydroxypropyl starch, microcrystalline cellulose, calcium salt of carboxymethylcellulose, sodium salt of crosslinked carboxymethylcellulose and low substituted hydroxypropyl cellulose.
10) The formulation according to claims 1-9, characterized in that the composition is provided with a coating.
11) A method of preparing the formulation defined in claims 1-10, characterized in that it is prepared by wet granulation.
12) A method of preparing the formulation defined in claims 1-10, characterized in that it is prepared by dry granulation.
13) A method of preparing the formulation defined in claims 1-10, characterized in that it is prepared by direct compression.
EP13792574.9A 2012-10-16 2013-10-15 A solid oral pharmaceutical formulation containing ticagrelor Withdrawn EP2908802A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ2012-705A CZ2012705A3 (en) 2012-10-16 2012-10-16 Solid oral pharmaceutical formulation containing ticagrelor
PCT/CZ2013/000130 WO2014059955A1 (en) 2012-10-16 2013-10-15 A solid oral pharmaceutical formulation containing ticagrelor

Publications (1)

Publication Number Publication Date
EP2908802A1 true EP2908802A1 (en) 2015-08-26

Family

ID=49619770

Family Applications (1)

Application Number Title Priority Date Filing Date
EP13792574.9A Withdrawn EP2908802A1 (en) 2012-10-16 2013-10-15 A solid oral pharmaceutical formulation containing ticagrelor

Country Status (13)

Country Link
EP (1) EP2908802A1 (en)
JP (1) JP6301934B2 (en)
KR (1) KR20150067153A (en)
CN (1) CN104661649A (en)
BR (1) BR112015008076A2 (en)
CZ (1) CZ2012705A3 (en)
EA (1) EA201590745A1 (en)
HK (1) HK1205456A1 (en)
IL (1) IL238036B (en)
MX (1) MX2015003866A (en)
UA (1) UA116784C2 (en)
WO (1) WO2014059955A1 (en)
ZA (1) ZA201501954B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020021110A1 (en) 2018-07-27 2020-01-30 Krka, D.D., Novo Mesto Pharmaceutical composition of ticagrelor

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20160012706A (en) * 2014-07-25 2016-02-03 동아에스티 주식회사 Sustained release formulations
CN111588702B (en) * 2015-04-29 2023-01-20 江苏恒瑞医药股份有限公司 Ticagrelor preparation of pharmaceutically acceptable salt thereof
CN105193759B (en) * 2015-09-18 2018-07-03 乐普药业股份有限公司 A kind of ticagrelor piece and preparation method thereof
CN106667926B (en) * 2015-11-09 2020-01-17 石药集团中奇制药技术（石家庄）有限公司 Favipiravir tablet 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
KR102488486B1 (en) * 2016-04-21 2023-01-12 아스트라제네카 아베 Orally disintegrating tablets
TR201617983A2 (en) * 2016-12-07 2018-06-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi SOLID ORAL PHARMACEUTICAL COMPOSITIONS OF TICAGRELOR
KR102610876B1 (en) * 2018-03-05 2023-12-06 주식회사 파마코스텍 Crystal form I of Ticagrelor Fumarateand its preparing method
WO2019170244A1 (en) 2018-03-08 2019-09-12 Pharmaceutical Oriented Services Ltd. Ticagrelor—containing tablet formulation
CN111450067A (en) * 2019-01-18 2020-07-28 北京万全德众医药生物技术有限公司 Ticagrelor dispersible tablet and preparation method thereof
CN116370423B (en) * 2023-02-28 2024-11-12 天津力生制药股份有限公司 A kind of ticagrelor orally disintegrating tablet and preparation method thereof

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR017014A1 (en) 1997-07-22 2001-08-22 Astrazeneca Ab TRIAZOL COMPOUNDS [4,5-D] PYRIMIDINE, PHARMACEUTICAL COMPOSITIONS, USE OF THE SAME TO PREPARE MEDICATIONS AND PROCESSES FOR THE PREPARATION OF SUCH COMPOUNDS
JPH11199517A (en) * 1997-10-31 1999-07-27 Meiji Seika Kaisha Ltd Intraoral fast disintegrable tablet
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
GB0013407D0 (en) 2000-06-02 2000-07-26 Astrazeneca Ab Forms of a chemical compound
WO2007018057A1 (en) * 2005-08-05 2007-02-15 Freund Corporation Tablet rapidly disintegrating in the oral cavity and method of producing the same
TWI482772B (en) * 2006-08-21 2015-05-01 Astrazeneca Ab Compositions, suitable for oral administration, comprising a triazolo(4,5-d)pyrimidin derivate
US20080045548A1 (en) * 2006-08-21 2008-02-21 Astrazeneca Ab Pharmaceutical Compositions
CN104230936A (en) 2009-12-03 2014-12-24 阿斯利康(瑞典)有限公司 Co-Crystals Of A Triazolo [4,5-D] Pyrimide Platelet Aggregation Inhibitor
EP2633857B1 (en) * 2009-12-23 2015-08-12 ratiopharm GmbH Solid pharmaceutical dosage form of ticagrelor and acetylsalicylic acid

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None *
See also references of WO2014059955A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020021110A1 (en) 2018-07-27 2020-01-30 Krka, D.D., Novo Mesto Pharmaceutical composition of ticagrelor

Also Published As

Publication number Publication date
HK1205456A1 (en) 2015-12-18
ZA201501954B (en) 2017-04-26
KR20150067153A (en) 2015-06-17
IL238036A0 (en) 2015-05-31
UA116784C2 (en) 2018-05-10
IL238036B (en) 2019-05-30
MX2015003866A (en) 2015-07-17
CN104661649A (en) 2015-05-27
EA201590745A1 (en) 2015-08-31
WO2014059955A1 (en) 2014-04-24
JP2015533129A (en) 2015-11-19
JP6301934B2 (en) 2018-03-28
BR112015008076A2 (en) 2017-07-04
CZ2012705A3 (en) 2014-04-23

Similar Documents

Publication Publication Date Title
WO2014059955A1 (en) A solid oral pharmaceutical formulation containing ticagrelor
TWI583384B (en) Pharmaceutical compositions comprising 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1h-benzi midazol-2-yl]-1h-quinolin-2-one lactate monohydrate
MXPA05006802A (en) Non-hygroscopic formulation comprising a hydroscopic drug.
WO2012164578A1 (en) Compositions and methods for preparing immediate release formulations of nilotinib
WO2017182455A1 (en) Stable pharmaceutical composition of amorphous ticagrelor
WO2015110952A1 (en) Solid oral pharmaceutical compositions comprising ticagrelor or salt thereof
EP2620140A1 (en) Crizotinib containing compositions
US20160120870A1 (en) The process for the preparation of a pharmaceutical composition comprising rivaroxaban
KR101171375B1 (en) Oral solid dosage form comprising poorly soluble drugs
HU231036B1 (en) Pharmaceutical composition comprising a cholesterol biosynthesis inhibitor and a cholesterol absorption inhibitor
WO2019073062A1 (en) Tablet containing valsartan and sacubitril
WO2012055941A1 (en) Multilayer pharmaceutical composition comprising telmisartan and amlodipine
JP2019535696A (en) Pharmaceutical composition of pyridone derivative and method for producing the same
WO2011080706A1 (en) Enhanced solubility of ziprasidone
JP2017520619A (en) Ceritinib formulation
WO2020021110A1 (en) Pharmaceutical composition of ticagrelor
WO2014091263A1 (en) Telmisartan containing pharmaceutical composition
CZ30477U1 (en) A solid oral pharmaceutical formulation comprising ticagrelor
WO2014122671A2 (en) Solid oral compositions of saxagliptin
WO2024084496A1 (en) Pharmaceutical compositions comprising acalabrutinib maleate
CZ26356U1 (en) Stabilized composition containing amorphous ticagrelor
EP4321154A1 (en) A tablet of tolvaptan and at least one binder processed with spray granulation
WO2024030098A1 (en) A tablet of tolvaptan and at least one binder processed with spray granulation
JP6086520B2 (en) Drug-rich solid preparation
EA047149B1 (en) PHARMACEUTICAL COMPOSITION CONTAINING TICAGRELOR

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20150430

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

17Q First examination report despatched

Effective date: 20170601

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20201114