MX2015003866A - A solid oral pharmaceutical formulation containing ticagrelor. - Google Patents
A solid oral pharmaceutical formulation containing ticagrelor.Info
- Publication number
- MX2015003866A MX2015003866A MX2015003866A MX2015003866A MX2015003866A MX 2015003866 A MX2015003866 A MX 2015003866A MX 2015003866 A MX2015003866 A MX 2015003866A MX 2015003866 A MX2015003866 A MX 2015003866A MX 2015003866 A MX2015003866 A MX 2015003866A
- Authority
- MX
- Mexico
- Prior art keywords
- formulation according
- hygroscopic
- formulation
- binder
- starch
- Prior art date
Links
- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 title claims abstract description 33
- 239000007787 solid Substances 0.000 title claims abstract description 8
- 229960002528 ticagrelor Drugs 0.000 title abstract description 30
- 239000008203 oral pharmaceutical composition Substances 0.000 title abstract description 5
- 239000000203 mixture Substances 0.000 claims abstract description 52
- 238000009472 formulation Methods 0.000 claims abstract description 24
- 239000011230 binding agent Substances 0.000 claims abstract description 18
- 239000000945 filler Substances 0.000 claims abstract description 17
- 239000000126 substance Substances 0.000 claims abstract description 16
- 230000000694 effects Effects 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 238000007908 dry granulation Methods 0.000 claims abstract description 3
- 238000005550 wet granulation Methods 0.000 claims abstract description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 24
- 239000000463 material Substances 0.000 claims description 14
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 12
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 10
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- OKHHGHGGPDJQHR-YMOPUZKJSA-L calcium;(2s,3s,4s,5s,6r)-6-[(2r,3s,4r,5s,6r)-2-carboxy-6-[(2r,3s,4r,5s,6r)-2-carboxylato-4,5,6-trihydroxyoxan-3-yl]oxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylate Chemical compound [Ca+2].O[C@@H]1[C@H](O)[C@H](O)O[C@@H](C([O-])=O)[C@H]1O[C@H]1[C@@H](O)[C@@H](O)[C@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@H](O2)C([O-])=O)O)[C@H](C(O)=O)O1 OKHHGHGGPDJQHR-YMOPUZKJSA-L 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 229940045110 chitosan Drugs 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- FSBVERYRVPGNGG-UHFFFAOYSA-N dimagnesium dioxido-bis[[oxido(oxo)silyl]oxy]silane hydrate Chemical compound O.[Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O FSBVERYRVPGNGG-UHFFFAOYSA-N 0.000 description 1
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 229960000878 docusate sodium Drugs 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 229960004667 ethyl cellulose Drugs 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 238000005470 impregnation Methods 0.000 description 1
- 238000004898 kneading Methods 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 229960005455 polacrilin Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 229920003124 powdered cellulose Polymers 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- WKOLLVMJNQIZCI-UHFFFAOYSA-N vanillic acid Chemical compound COC1=CC(C(O)=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-N 0.000 description 1
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; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Heart & Thoracic Surgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (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-hyd roxyethoxy)-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 THAT CONTAINS
TICAGRELOR
Field of the Invention
The present invention relates to a solid oral pharmaceutical formulation containing ticagrelor as the active pharmaceutical constituent and a method of preparing this formulation.
Background of the Invention
The compound ticagrelor with the chemical name (1S, 2S, 3R, 5S) -3- [7 - [[(IR, 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, which is represented by the formula (I),
(I)
it was described generically in WO 1999/005143 and specifically mentioned in EP 1135 391. This document also describes a method for its preparation, as well as the use of ticagrelor in the
treatment or prevention of myocardial infarction, stroke, diseases of peripheral vessels, et cetera. WO 2001/092262 describes 4 polymorphs and an amorphous form of ticagrelor. WO 2011/067571 discloses co-crystals with various coforms such as glycolic, salicylic, succinic, malonic and 4-hydroxy-3-methoxybenzene carboxylic acid.
The pharmaceutical formulations have been described in 2 applications of the company Astra Zeneca, WO 2008/024044 and WO 2008/024045. WO 2008/024044 discloses a solid formulation comprising one or more fillers, one or more binder substances, preferably one or more disintegrating agents and preferably one or more lubricants. According to Example 1 of WO 2008/024044 the sodium salt of carboxymethyl starch was used as a disintegrating agent in the amount of 3% by weight. The document does not mention any example where a disintegrating agent would not be used. WO 2008/024045 discloses a very similar solid formulation comprising one or more fillers, one or more binder substances, preferably one or more disintegrating agents and preferably one or more lubricants. This document indicates that the use of disintegrating agents is necessary. The particular examples mentioned in the document
they contain 2-6% by weight of a disintegrating agent, which is the sodium salt of carboxymethyl-starch.
WO 2011/076749 deals with the particle size of ticagrelor which was used in the formulation since ticagrelor is well known as a poorly soluble compound. In the cited examples of this application, disintegrating agents were used in amounts in the range of 4-6% by weight.
Ticagrelor is sold under the brand name Brilique for the prevention of arteriotrombotic events in the form of coated tablets. The commercialized formulation also contains the sodium salt of carboxymethyl starch as the disintegrating agent.
Detailed description of the invention
This invention relates to a solid oral pharmaceutical formulation containing ticagrelor with the chemical name (1S, 2S, 3R, 5S) -3- [7 - [[(IR, 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, which contains in addition at least one non-hygroscopic filler material and / or at least one non-hygroscopic binder substance which does not have a disintegrating effect.
Non-hygroscopic filler means
a water-soluble filler material, sugar alcohols are generally preferred, such as glucose, fructose, sucrose, lactose monohydrate, lactose anhydrous, raffinose, isomaltose, trehalose, dextrates, mannitol, erythritol, sorbitol, maltitol, xylitol, lactitol , compressible sugars. Hydroxypropylcellulose or maltose, for example, can be used as the non-hygroscopic binder substance. The composition according to this invention preferably contains 0.5-30% by weight of the binder, preferably 1-7% by weight of the binder and more preferably 2-4% by weight of the binder.
The term non-hygroscopic, used in this invention, refers to a material that has a low capacity to receive and retain water. Or, rather, the term non-hygroscopic refers to a material having an equilibrium moisture content of less than 6% by weight. This value is determined by Dynamic Vapor Sorption (DVS) at a relative humidity of 60% and a temperature of 25 ° C. The equilibrium moisture content is determined based on the isothermal sorption curve measured using the DVS method at 60% relative humidity and 25 ° C temperature.
An expert in the field knows that the use of agents
Disintegrants in a formulation need not have an impact on the increase of biological availability of the active substance. This property is more influenced by sufficient humidification of the active substance that is present in the formulation. If a composition can be prepared in such a way that it will dissolve quickly enough without the use of disintegrating agents, the disintegrating agents only become a superfluous constituent that has no real effect.
The disintegrating agents represent a class of excipients that are generally considered as special excipients. The price of special excipients, i.e. disintegrating agents, is much higher than the price of commonly used excipients such as fillers. The price of the disintegrating agents such as the sodium salt of carboxymethyl starch or the sodium salt of croscarmellose can normally be several times higher than the price of general fillers such as mannitol or calcium acid phosphate.
The manner in which the disintegrating agents act is not clear until now. The mechanisms assumed in the past include, for example, impregnation with water, swelling, shape memory,
repellency to other constituents, heating during humidification. The ability of the disintegrating agents to carry water to the porous network of the tablet is essential for efficient disintegration. This explanation was provided by the Encyclopaedia of Pharmaceutical Technology, 3rd edition, Informa Healthcare USA, Inc., 2007. As a natural consequence of the ability to carry water to tablets, the disintegrating agents are generally hygroscopic or very hygroscopic materials. According to the Handbook of Pharmaceutical Excipients, 6th edition, Pharmaceutical Press, 2009, the sodium salt of croscarmellose and the sodium salt of carboxymethyl starch exhibit the same characteristics.
Due to the hygroscopic nature of the excipients it is necessary to pack the formulation of ticagrelor in PVC / PVDC bubble type packaging. The use of non-hygroscopic bubble-type packaging makes it possible to replace expensive PVS / PVDC with more affordable PVC bubble-type packaging. With regard to lower excipient costs and lower packaging costs it is desirable to prepare a formulation containing non-hygroscopic excipients that have no disintegration effect.
The document W02008 / 024045 describes that the use of a composition containing one or more materials of
filler, one or more binder substances, preferably one or more disintegrating agents and preferably one or more lubricants is suitable for the efficient release of at least 90% ticagrelor. Contrary to the findings of the foregoing, it has been found that a ticagrelor composition with any known form of ticagrelor (crystalline, amorphous or in a co-crystal form) containing at least one non-hygroscopic filler material and / or at least a non-hygroscopic binder that does not exhibit the disintegration effect will achieve an efficient release of at least 90% ticagrelor.
The term "disintegrating agent", used in this document, refers to any material that swells or soaks in contact with water. The term disintegrating agent comprises, for example, the group of compounds such as: povidone, crospovidone, starch, pregelatinized starch, sodium salt of carboxymethylcellulose, 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, docusate sodium, methylcellulose, agar, guar gum, chitosan and alginic acid. The composition of ticagrelor conveniently contains nothing
or less than 2% of a disintegrating agent.
In the most preferred embodiment the pharmaceutical composition of ticagrelor does not substantially contain disintegrating agent.
The ticagrelor composition contains a non-hygroscopic filler material. Generally, a water-soluble filler material is preferred. Suitable fillers are, for example, monosaccharides, oligosaccharides and sugar alcohols such as glucose, fructose, sucrose, lactose monohydrate, lactose anhydrous, raffinose, isomaltose, trehalose, dextrates, mannitol, erythritol, sorbitol, maltitol, xylitol and lactitol, compressible sugars, calcium acid phosphate dihydrate and their mixtures. Lactose, mannitol and xylitol are preferred.
The composition of ticagrelor contains a non-hygroscopic binder substance. Suitable binding substances are, for example, povidone, copovidone, powdered cellulose, crystalline or microcrystalline, silicone microcrystalline cellulose, cellulose derivatives such as hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylmethylcellulose, starch, pregelatinized starch, polymethacrylates and mixtures thereof. In a preferred composition, the ticagrelor formulation contains from 0.5 to 30% by weight of the binder substance, preferably from 1 to 7% and more conveniently from 2 to 4%
by weight of the binder substance.
The ticagrelor composition typically contains at least one surfactant. Suitable surfactants are, for example, anionic, cationic, ampholytic and / or nonionic surfactants such as the sodium salt of lauryl sulfate, cetrimide, N-dodecyl-N, N-dimethyl-betaine, polysorbates (for example, Tweens ™). , poloxamers and their mixtures. The sodium salt of lauryl sulfate is the preferred compound. The surfactant is used, in the ticagrelor formulation, in an amount of 0.1 to 4.0% by weight, more preferably in the range of 0.5 to 2.0%.
The ticagrelor composition typically contains at least 1 lubricant and / or an antiadhesive compound selected, for example, from magnesium stearate, stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, silicon dioxide. colloidal, magnesium trisilicate and their mixtures. Especially preferred are stearic acid, magnesium stearate, sodium stearyl fumarate and colloidal silicon dioxide.
The ticagrelor tablet can be conveniently coated with any suitable coating. A suitable coating agent for ticagrelor tablets is selected, for example, from methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose,
polymers of acrylic acid, ethylcellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl alcohol, sodium salt of carboxymethylcellulose, cellulose acetate, gelatin, methacrylic acid copolymers, polyethylene glycol, shellac, sucrose, dioxide titanium and carnauba wax. Polyethylene glycol, hydroxypropylmethylcellulose and polyvinyl alcohol are preferred.
Examples
Example 1
Wet granulation
Ticagrelor is granulated in wet conditions together with either lactose or xylitol monohydrate or mannitol or maltitol (either using granulation by means of kneading or with the use of a common granulator with a fluidized bed) with an aqueous solution of either hydroxypropylcellulose or maltose. The sodium lauryl sulfate is preferably added to the granulation solution. He
The granulated material obtained is dried and sieved through a 1 mm mesh. The screened granulate material 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 premixing, magnesium stearate is added to the mixture and the mixture is stirred for another 3 minutes so that a suitable tablet manufacturing mixture can be obtained. This mixture is then compressed into tablets in a rotary tablet manufacturing device.
Example 2
Dry granulation
The ticagrelor was granulated under dry conditions together with mannitol or lactose monohydrate or xylitol and preferably with sodium lauryl sulfate in a rotary compactor with a variable aperture size. The granulated material obtained was sieved through a 1 mm mesh. The screened granulate material 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 the premixing, magnesium stearate is added to the mixture and the mixture is stirred for another 3 minutes so that a mixture ready for the manufacture of tablets can be obtained. This
The mixture is then compressed into tablets in a rotary tablet making 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 the premixing, magnesium stearate is added to the mixture and the mixture is stirred for another 3 minutes so that a ready mix for the manufacture of tablets can be obtained in a rotary tablet manufacturing device.
Example 4
Coating of the tablets
The tablets obtained according to Examples 1 to 3 are conveniently coated with a common coating material
The constituents of the coating mixture are dissolved or suspended in a sufficient amount of
water to provide the coating solution Then, the tablets are coated with this solution in a suitable device and finally dried.
Claims (13)
1. A solid pharmaceutical formulation, containing ticagr that has 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, characterized in that it contains at least one non-hygroscopic filler material and / or at least one substance non-hygroscopic binder.
2. The formulation according to claim 1, characterized in that the non-hygroscopic filler material and the non-hygroscopic binder have no disintegration effect.
3. The formulation according to claim 2, characterized in that the non-hygroscopic filler material is selected from the group consisting of sugar alcohols such as glucose, fructose, sucrose, lactose monohydrate, lactose anhydrous, 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 substance is selected from hydroxypropyl cellulose and maltose.
5. The formulation according to claims 1-4, characterized in that it also contains at least one lubricant, optionally at least one surfactant and preferably at least one disintegrating agent 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 substance is selected from the group comprising povidone, copovidone, powdery cellulose, crystalline or microcrystalline, silicone microcrystalline cellulose, cellulose derivatives such as hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylmethylcellulose, 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 nonionic surfactants such as the sodium salt of lauryl sulfate, cetrimide, N-dodecyl-N, N-dimethyl- betaine, polysorbates, poloxamers and their mixtures.
9. The formulation in accordance with the claim 5, characterized in that a further disintegrating agent is selected from the group - comprising povidone, crospovidone, starch, pregelatinized starch, sodium salt of carboxymethylcellulose, hydroxypropyl starch, microcrystalline cellulose, calcium salt of carboxymethylcellulose, sodium salt of crosslinked carboxymethylcellulose and substituted hydroxypropylcellulose low.
10. The formulation according to claims 1-9, characterized in that it is provided with a coating.
11. A method for preparing the formulation according to claims 1-10, characterized in that it comprises a preparation step by means of wet granulation.
12. A method for preparing the formulation according to claims 1-10, characterized in that it comprises a preparation step by means of dry granulation.
13. A method for preparing the formulation according to claims 1-10, characterized in that it comprises a preparation step by means of direct compression.
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 |
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| Publication Number | Publication Date |
|---|---|
| MX2015003866A true MX2015003866A (en) | 2015-07-17 |
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| MX2015003866A MX2015003866A (en) | 2012-10-16 | 2013-10-15 | A solid oral pharmaceutical formulation containing ticagrelor. |
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| 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) |
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| KR20160012706A (en) * | 2014-07-25 | 2016-02-03 | 동아에스티 주식회사 | Sustained release formulations |
| CN106074357B (en) * | 2015-04-29 | 2021-07-02 | 江苏恒瑞医药股份有限公司 | A preparation of ticagrelor or a 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 |
| LT3445338T (en) * | 2016-04-21 | 2025-02-25 | Astrazeneca Ab | 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 |
| EP3761965A1 (en) | 2018-03-08 | 2021-01-13 | Pharmaceutical Oriented Services Ltd | Ticagrelor-containing tablet formulation |
| EA202190328A1 (en) | 2018-07-27 | 2021-07-01 | КРКА, д.д., НОВО МЕСТО | PHARMACEUTICAL COMPOSITION CONTAINING TICAGRELOR |
| 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)
| 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 |
| US20080045548A1 (en) | 2006-08-21 | 2008-02-21 | Astrazeneca Ab | Pharmaceutical Compositions |
| TWI482772B (en) * | 2006-08-21 | 2015-05-01 | Astrazeneca Ab | Compositions, suitable for oral administration, comprising a triazolo(4,5-d)pyrimidin derivate |
| KR20120123659A (en) | 2009-12-03 | 2012-11-09 | 아스트라제네카 아베 | Co-crystals of a triazolo[4,5-d]pyrimidine platelet aggregation inhibitor |
| EP2633857B1 (en) * | 2009-12-23 | 2015-08-12 | ratiopharm GmbH | Solid pharmaceutical dosage form of ticagrelor and acetylsalicylic acid |
-
2012
- 2012-10-16 CZ CZ2012-705A patent/CZ2012705A3/en unknown
-
2013
- 2013-10-15 EA EA201590745A patent/EA201590745A1/en unknown
- 2013-10-15 HK HK15106027.7A patent/HK1205456A1/en unknown
- 2013-10-15 UA UAA201504754A patent/UA116784C2/en unknown
- 2013-10-15 EP EP13792574.9A patent/EP2908802A1/en not_active Withdrawn
- 2013-10-15 WO PCT/CZ2013/000130 patent/WO2014059955A1/en not_active Ceased
- 2013-10-15 BR BR112015008076A patent/BR112015008076A2/en not_active IP Right Cessation
- 2013-10-15 CN CN201380050404.5A patent/CN104661649A/en active Pending
- 2013-10-15 MX MX2015003866A patent/MX2015003866A/en unknown
- 2013-10-15 JP JP2015535983A patent/JP6301934B2/en not_active Expired - Fee Related
- 2013-10-15 KR KR1020157007818A patent/KR20150067153A/en not_active Withdrawn
-
2015
- 2015-03-20 ZA ZA2015/01954A patent/ZA201501954B/en unknown
- 2015-03-30 IL IL238036A patent/IL238036B/en not_active IP Right Cessation
Also Published As
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|---|---|
| WO2014059955A1 (en) | 2014-04-24 |
| JP6301934B2 (en) | 2018-03-28 |
| HK1205456A1 (en) | 2015-12-18 |
| ZA201501954B (en) | 2017-04-26 |
| IL238036B (en) | 2019-05-30 |
| CZ2012705A3 (en) | 2014-04-23 |
| BR112015008076A2 (en) | 2017-07-04 |
| JP2015533129A (en) | 2015-11-19 |
| KR20150067153A (en) | 2015-06-17 |
| EA201590745A1 (en) | 2015-08-31 |
| CN104661649A (en) | 2015-05-27 |
| UA116784C2 (en) | 2018-05-10 |
| EP2908802A1 (en) | 2015-08-26 |
| IL238036A0 (en) | 2015-05-31 |
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