EP2603288A1 - Granulat pharmaceutique comprenant de l'imatinib mésylate - Google Patents
Granulat pharmaceutique comprenant de l'imatinib mésylateInfo
- Publication number
- EP2603288A1 EP2603288A1 EP10747433.0A EP10747433A EP2603288A1 EP 2603288 A1 EP2603288 A1 EP 2603288A1 EP 10747433 A EP10747433 A EP 10747433A EP 2603288 A1 EP2603288 A1 EP 2603288A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- imatinib mesylate
- granulate
- imatinib
- composition
- mesylate
- 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- Withdrawn
Links
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 title claims abstract description 81
- 239000008187 granular material Substances 0.000 title claims abstract description 79
- 229960003685 imatinib mesylate Drugs 0.000 title claims abstract description 76
- 238000000034 method Methods 0.000 claims abstract description 33
- 239000000203 mixture Substances 0.000 claims abstract description 32
- 239000007788 liquid Substances 0.000 claims abstract description 20
- 238000005469 granulation Methods 0.000 claims abstract description 17
- 230000003179 granulation Effects 0.000 claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 15
- 238000001035 drying Methods 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 6
- 238000003801 milling Methods 0.000 claims abstract description 6
- 238000007873 sieving Methods 0.000 claims abstract description 5
- 238000009736 wetting Methods 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 19
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 18
- 239000005517 L01XE01 - Imatinib Substances 0.000 claims description 17
- 229960002411 imatinib Drugs 0.000 claims description 16
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 239000013078 crystal Substances 0.000 claims description 5
- 239000012530 fluid Substances 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 239000012458 free base Substances 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 description 9
- 239000011248 coating agent Substances 0.000 description 9
- 238000000576 coating method Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 239000002245 particle Substances 0.000 description 8
- 238000005550 wet granulation Methods 0.000 description 8
- 238000002156 mixing Methods 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 4
- 239000004372 Polyvinyl alcohol Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 229960000913 crospovidone Drugs 0.000 description 4
- 239000000945 filler Substances 0.000 description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 229920002451 polyvinyl alcohol Polymers 0.000 description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 4
- -1 4- methyl-piperazino- methyl Chemical group 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 238000007907 direct compression Methods 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 3
- 239000003039 volatile agent Substances 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- UHZZMRAGKVHANO-UHFFFAOYSA-M chlormequat chloride Chemical class [Cl-].C[N+](C)(C)CCCl UHZZMRAGKVHANO-UHFFFAOYSA-M 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229960003943 hypromellose Drugs 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 238000005029 sieve analysis Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 238000007580 dry-mixing Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000007909 melt granulation Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000000979 retarding effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000010963 scalable process Methods 0.000 description 1
- 238000005204 segregation Methods 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- 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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
-
- 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
- A61P35/00—Antineoplastic agents
Definitions
- WO 2006/121941 discloses a melt granulation process which comprises the steps of (a) forming a mixture of imatinib mesylate with at least one release retardant, e.g., a release retarding polymer, a plasticizer or a release modifier; (b) granulating the mixture using an extruder and (c) cooling the granules.
- a release retardant e.g., a release retarding polymer, a plasticizer or a release modifier
- US 2007/0036850 discloses a dry granulation (by compaction) process for the preparation of imatinib Form a or ⁇ granules prior to the tabletting process.
- the imatinib granule cores contain between 25 and 80% of imatinib together with filler-binder additives , e.g. with microcrystalline cellulose and crospovidone.
- the population of granules has an average size of between 250-800 ⁇ , as determined by sieve analysis.
- the invention provides a process for making a granulate comprising imatinib mesylate, which process comprises wetting imatinib mesylate with a granulation liquid, which is preferably water, ethanol and/or isopropanol and most preferably in an amount of 5 - 50 weight %, in respect to the mass of imatinib mesylate, and granulating the mixture in a suitable granulator, e.g. high shear or fluid bed granulator, followed by drying, and optionally sieving and/or milling of the produced population of granules.
- a suitable granulator e.g. high shear or fluid bed granulator
- the last aspect deals with the use of the pharmaceutical imatinib mesylate granulate of the present invention and/or a composition comprising it for making a medicament.
- compositions comprising imatinib mesylate and useful for making compressed dosage forms, such as tablets, comprises the step of granulation of imatinib with filler-binders excipients to yield a "composite" granulate, i.e. a granulate comprising imatinib and at least one granulate-forming excipient.
- the "wet granulation” as used herein is a process, which itself is well known in the art and comprises, within many technological variants, moistening a solid component or a mixture of solid components with a liquid, and vigorous mixing of the composition, whereby the wet particles of solids adhere together by cohesive forces to form larger, sometimes essentially spherical, agglomerates (a granulate).
- the excess of the granulation liquid may be removed from the raw granulate by drying and the suitable size range of particles is obtained by sieving and/or milling the population of granules.
- imatinib mesylate can be wet granulated without using any granulate-forming excipient, such as a filler and/or binder , to form a free flowing solid granulate material comprising ,based on a solvent-free basis, only imatinib (small amounts of used granulation liquid may be present).
- a granulation liquid which is preferably water and/or an alcohol, e.g. ethanol or isopropanol, and processing the mixture in a suitable granulator results in a stable free flowing granulate form of imatinib mesylate with suitable characteristics for further processing.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
La présente invention concerne un granulat contenant entre 95 et 99 % d'imatinib mésylate et entre 1 et 5 % d'un liquide volatil. L'invention porte en outre sur un procédé de fabrication d'un granulat d'imatinib mésylate. Ledit procédé comprend le mouillage d'imatinib mésylate avec un liquide de granulation, et la granulation du mélange dans un granulateur, suivie du séchage, et éventuellement du tamisage et/ou du broyage de la population produite de granules, en vue d'obtenir une composition pharmaceutique pour administration orale destinée à être utilisée en médecine.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/EP2010/005214 WO2012019633A1 (fr) | 2010-08-11 | 2010-08-11 | Granulat pharmaceutique comprenant de l'imatinib mésylate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP2603288A1 true EP2603288A1 (fr) | 2013-06-19 |
Family
ID=44065563
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP10747433.0A Withdrawn EP2603288A1 (fr) | 2010-08-11 | 2010-08-11 | Granulat pharmaceutique comprenant de l'imatinib mésylate |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP2603288A1 (fr) |
| MX (1) | MX2013001653A (fr) |
| RU (1) | RU2013110058A (fr) |
| WO (1) | WO2012019633A1 (fr) |
| ZA (1) | ZA201300872B (fr) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9750700B2 (en) * | 2011-06-22 | 2017-09-05 | Natco Pharma Limited | Imatinib mesylate oral pharmaceutical composition and process for preparation thereof |
| IN2014DN07898A (fr) * | 2012-02-21 | 2015-04-24 | Ranbaxy Lab Ltd | |
| EP2749271A1 (fr) * | 2012-12-31 | 2014-07-02 | Deva Holding Anonim Sirketi | Procédé optimisée de fabrication et formulation pharmaceutique de l'imatinib |
| EP2803353B1 (fr) | 2013-05-14 | 2018-05-23 | Hetero Research Foundation | Compositions d'imatinib |
| WO2015004556A1 (fr) * | 2013-07-09 | 2015-01-15 | Shilpa Medicare Limited | Compositions pharmaceutiques orales comprenant du mésylate d'imatinib |
| EP3257499A1 (fr) | 2016-06-17 | 2017-12-20 | Vipharm S.A. | Procédé pour la préparation de capsules de méthanesulfonate d'imatinib |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW225528B (fr) | 1992-04-03 | 1994-06-21 | Ciba Geigy Ag | |
| US5521184A (en) | 1992-04-03 | 1996-05-28 | Ciba-Geigy Corporation | Pyrimidine derivatives and processes for the preparation thereof |
| CO4940418A1 (es) | 1997-07-18 | 2000-07-24 | Novartis Ag | Modificacion de cristal de un derivado de n-fenil-2- pirimidinamina, procesos para su fabricacion y su uso |
| GB0209265D0 (en) | 2002-04-23 | 2002-06-05 | Novartis Ag | Organic compounds |
| WO2006040779A2 (fr) | 2004-10-11 | 2006-04-20 | Natco Pharma Limited | Formule à matrice flottante gastrique à libération contrôlée contenant la substance imatinib |
| MY148074A (en) | 2005-05-10 | 2013-02-28 | Novartis Ag | Pharmaceutical compositions comprising imatinib and a release retardant |
| DE502006005084D1 (de) | 2005-08-15 | 2009-11-26 | Siegfried Generics Int Ag | Filmtablette oder Granulat enthaltend ein Pyridylpyrimidin |
| PL390611A1 (pl) * | 2010-03-04 | 2011-09-12 | Tomasz Koźluk | Sposób otrzymywania polimorficznej formy alfa i nowa forma polimorficzna mesylanu imatinibu |
| CA2789307A1 (fr) * | 2010-03-29 | 2011-10-06 | Hetero Research Foundation | Composition pharmaceutique stable d'imatinib |
-
2010
- 2010-08-11 EP EP10747433.0A patent/EP2603288A1/fr not_active Withdrawn
- 2010-08-11 RU RU2013110058/15A patent/RU2013110058A/ru unknown
- 2010-08-11 MX MX2013001653A patent/MX2013001653A/es unknown
- 2010-08-11 WO PCT/EP2010/005214 patent/WO2012019633A1/fr active Application Filing
-
2013
- 2013-02-01 ZA ZA2013/00872A patent/ZA201300872B/en unknown
Non-Patent Citations (2)
| Title |
|---|
| None * |
| See also references of WO2012019633A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA201300872B (en) | 2014-04-30 |
| MX2013001653A (es) | 2013-05-22 |
| RU2013110058A (ru) | 2014-09-20 |
| WO2012019633A1 (fr) | 2012-02-16 |
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