WO2021071444A1 - A unique granulation process for rivaroxaban containing granules - Google Patents
A unique granulation process for rivaroxaban containing granules Download PDFInfo
- Publication number
- WO2021071444A1 WO2021071444A1 PCT/TR2019/050850 TR2019050850W WO2021071444A1 WO 2021071444 A1 WO2021071444 A1 WO 2021071444A1 TR 2019050850 W TR2019050850 W TR 2019050850W WO 2021071444 A1 WO2021071444 A1 WO 2021071444A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- rivaroxaban
- oral pharmaceutical
- granulation
- pharmaceutical composition
- composition according
- Prior art date
Links
- KGFYHTZWPPHNLQ-AWEZNQCLSA-N rivaroxaban Chemical compound S1C(Cl)=CC=C1C(=O)NC[C@@H]1OC(=O)N(C=2C=CC(=CC=2)N2C(COCC2)=O)C1 KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 title claims abstract description 67
- 229960001148 rivaroxaban Drugs 0.000 title claims abstract description 65
- 238000005469 granulation Methods 0.000 title claims abstract description 51
- 230000003179 granulation Effects 0.000 title claims abstract description 51
- 238000000034 method Methods 0.000 title claims abstract description 45
- 239000008187 granular material Substances 0.000 title claims description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 24
- 239000008203 oral pharmaceutical composition Substances 0.000 claims abstract description 13
- 238000009478 high shear granulation Methods 0.000 claims abstract description 11
- 239000002552 dosage form Substances 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims description 51
- 239000011230 binding agent Substances 0.000 claims description 17
- 238000009472 formulation Methods 0.000 claims description 13
- 239000006186 oral dosage form Substances 0.000 claims description 11
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 10
- 229920002678 cellulose Polymers 0.000 claims description 8
- 239000001913 cellulose Substances 0.000 claims description 8
- 235000010980 cellulose Nutrition 0.000 claims description 8
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 8
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000002202 Polyethylene glycol Substances 0.000 claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- 239000004094 surface-active agent Substances 0.000 claims description 6
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 5
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 5
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 5
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 5
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 5
- -1 alkylbenzene sulfonates Chemical class 0.000 claims description 5
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 5
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 5
- 235000019359 magnesium stearate Nutrition 0.000 claims description 5
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 5
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 5
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 5
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 5
- 239000004135 Bone phosphate Substances 0.000 claims description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 4
- 229920000881 Modified starch Polymers 0.000 claims description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 4
- 229930006000 Sucrose Natural products 0.000 claims description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 4
- 239000001506 calcium phosphate Substances 0.000 claims description 4
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 4
- 235000011010 calcium phosphates Nutrition 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- 239000008107 starch Substances 0.000 claims description 4
- 229940032147 starch Drugs 0.000 claims description 4
- 235000019698 starch Nutrition 0.000 claims description 4
- 239000005720 sucrose Substances 0.000 claims description 4
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 4
- 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 claims description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- 239000007884 disintegrant Substances 0.000 claims description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 3
- 229960003943 hypromellose Drugs 0.000 claims description 3
- 229960001021 lactose monohydrate Drugs 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000007909 solid dosage form Substances 0.000 claims description 3
- 229960004793 sucrose Drugs 0.000 claims description 3
- 239000004408 titanium dioxide Substances 0.000 claims description 3
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 claims description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000005995 Aluminium silicate Substances 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- 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 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 239000004375 Dextrin Substances 0.000 claims description 2
- 229920001353 Dextrin Polymers 0.000 claims description 2
- 229930091371 Fructose Natural products 0.000 claims description 2
- 239000005715 Fructose Substances 0.000 claims description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 239000004368 Modified starch Substances 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- ULUAUXLGCMPNKK-UHFFFAOYSA-N Sulfobutanedioic acid Chemical compound OC(=O)CC(C(O)=O)S(O)(=O)=O ULUAUXLGCMPNKK-UHFFFAOYSA-N 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- 235000012211 aluminium silicate Nutrition 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 235000010216 calcium carbonate Nutrition 0.000 claims description 2
- ILWNTWRKKKGJCG-UHFFFAOYSA-L calcium;sulfate;trihydrate Chemical compound O.O.O.[Ca+2].[O-]S([O-])(=O)=O ILWNTWRKKKGJCG-UHFFFAOYSA-L 0.000 claims description 2
- 229960000913 crospovidone Drugs 0.000 claims description 2
- 229940096516 dextrates Drugs 0.000 claims description 2
- 235000019425 dextrin Nutrition 0.000 claims description 2
- 239000008121 dextrose Substances 0.000 claims description 2
- 150000004683 dihydrates Chemical class 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 235000001727 glucose Nutrition 0.000 claims description 2
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 229960001375 lactose Drugs 0.000 claims description 2
- 239000000845 maltitol Substances 0.000 claims description 2
- 235000010449 maltitol Nutrition 0.000 claims description 2
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims description 2
- 229940035436 maltitol Drugs 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- 235000019426 modified starch Nutrition 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
- 229940069328 povidone Drugs 0.000 claims description 2
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 2
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 2
- 239000008109 sodium starch glycolate Substances 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 235000010215 titanium dioxide Nutrition 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- 239000008367 deionised water Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 description 16
- 239000000843 powder Substances 0.000 description 14
- 230000002265 prevention Effects 0.000 description 11
- 238000011282 treatment Methods 0.000 description 9
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- 239000002245 particle Substances 0.000 description 7
- 206010051055 Deep vein thrombosis Diseases 0.000 description 6
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- 208000006011 Stroke Diseases 0.000 description 5
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- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 2
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- 229940126409 proton pump inhibitor Drugs 0.000 description 2
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- 238000005204 segregation Methods 0.000 description 2
- 208000004043 venous thromboembolism Diseases 0.000 description 2
- MHCRLDZZHOVFEE-UHFFFAOYSA-N 4-(4-aminophenyl)morpholin-3-one Chemical compound C1=CC(N)=CC=C1N1C(=O)COCC1 MHCRLDZZHOVFEE-UHFFFAOYSA-N 0.000 description 1
- BMPDCQVRKDNUAP-UHFFFAOYSA-N 5-chlorothiophene-2-carbonyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)S1 BMPDCQVRKDNUAP-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
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- ZQTNQVWKHCQYLQ-UHFFFAOYSA-N dronedarone Chemical compound C1=CC(OCCCN(CCCC)CCCC)=CC=C1C(=O)C1=C(CCCC)OC2=CC=C(NS(C)(=O)=O)C=C12 ZQTNQVWKHCQYLQ-UHFFFAOYSA-N 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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- DENPQNAWGQXKCU-UHFFFAOYSA-N thiophene-2-carboxamide Chemical compound NC(=O)C1=CC=CS1 DENPQNAWGQXKCU-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—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
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
Definitions
- the present invention relates to a pharmaceutical composition, comprising non-hydrophilized rivaroxaban or a pharmaceutically acceptable salt thereof, wherein the composition is in an oral solid dosage form with good flowability and drug release profile.
- Rivaroxaban (5-chloro-N- ⁇ [(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxazolidin-5- yl] methyl ⁇ thiophene-2-carboxamide) is a low molecular weight, orally administrable anticoagulant drug. Rivaroxaban is an anticoagulant and the first orally active direct factor Xa inhibitor. The pharmaceutical directly inhibits the active form of serine protease Factor Xa (FXa).
- Rivaroxaban can be used for the prevention and treatment of various thromboembolic diseases, in particular of deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infract, angina pectoris, re-occlusions and recurrence of stenosis after angioplasty or aortocoronary bypass, cerebral stroke, transitory ischemic attacks, and peripheral arterial occlusive diseases.
- DVT deep vein thrombosis
- PE pulmonary embolism
- myocardial infract myocardial infract
- angina pectoris re-occlusions and recurrence of stenosis after angioplasty or aortocoronary bypass
- cerebral stroke CAD
- transitory ischemic attacks and peripheral arterial occlusive diseases.
- Rivaroxaban was first disclosed in WO0147919, has the systematic name 5-chloro-N-( ⁇ (5S)-2- oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-l ,3-oxazolidin-5-yl ⁇ methyl) thiophene-2-carboxamide and the following chemical structure:
- US2007/0149522 relates to a synthesis method of 5-chloro-N-( ⁇ 5S)-2-oxo-3-[4-(3-oxo-4- morpholinyl)-phenyl]-l,3-oxazolidin-5-yl ⁇ -methyl)-2-thiophene carboxamide using from 5- chlorothiophene-2-carbonyl chloride and (2S)-3-amino-propane-l,2-diol and 4-(4-aminophenyl)- 3-morpholinone as starting materials.
- W02009023233 relates to novel compounds that are substituted oxazolidinones derivatives and pharmaceutically acceptable salts thereof. More specifically, this invention relates to novel oxazolidinone compounds that are derivatives of Rivaroxaban.
- the invention also provides pyrogen-free compositions comprising one or more compounds of the invention and a carrier, along with the use of the disclosed compounds and compositions in methods of treating diseases and condition that are beneficially treated by administering a selective inhibitor of factor Xa, such as Rivaroxaban.
- WO2015155307 relates to a novel pharmaceutical composition
- a novel pharmaceutical composition comprising rivaroxaban or a pharmaceutically acceptable salt thereof in combination with a proton pump inhibitor for use in the anticoagulant treatment with preventing or reducing the risk of a gastrointestinal disorder.
- WO2015169957 relates to a novel pharmaceutical composition
- a novel pharmaceutical composition comprising rivaroxaban or a pharmaceutically acceptable salt thereof in combination with a proton pump inhibitor for use in the anticoagulant treatment with preventing or reducing the risk of a gastrointestinal disorder.
- WO2016131896 relates to a pharmaceutical combination comprising dronedarone or a pharmaceutically acceptable salt thereof in combination with rivaroxaban and at least one pharmaceutically acceptable excipient.
- W007039122 relates to rivaroxaban formulations comprising rivaroxaban in amorphous form or thermodynamically metastable crystal modification.
- W009049820 relates to rivaroxaban formulations comprising at least one solid substance at room temperature, the thermodynamically preferred crystalline form of rivaroxaban, cellulose and/or cellulose derivatives, as well as optionally a surface-active substance, wherein more than 50% of rivaroxaban in the formulation is in amorphous mixed phase as determined by X-ray diffractometer.
- EP3505160 relates to a manufacturing process of a tablet comprising rivaroxaban wherein it comprises of preparing a powder mixture comprising rivaroxaban, surfactant and pharmaceutically acceptable excipients and subjecting the powder mixture obtained previous to compress tablet by direct compression method.
- TR2017/13325 and TR2017/13326 disclose a process for manufacturing a formulation comprising the step of granulating the solid mixture comprising the active ingredient rivaroxaban, at least one water-soluble binder and at least one water-soluble filler with a suitable granulation solution.
- WO2017146709 relates to the rivaroxaban containing granules wherein process steps are; dry mixing rivaroxaban and a pharmaceutically acceptable excipient in a high-shear mixer to form a dry mix blend, adding a binder solution to the dry mix blend to form a granulating mixture and finally mixing, drying and milling the rivaroxaban-containing granules.
- the final granulating mixture has water content of less than 30% and the high shear granulation time is carried out between three to five minutes.
- WO20 15124995 relates to an oral solid dosage form comprising rivaroxaban and one or more pharmaceutically acceptable excipients manufactured by a wet granulation process wherein the ratio of rivaroxaban to excipient is in the range of 1:2 to 1:8 and obtaining solid dosage form.
- WO20 18007945 relates to an oral pharmaceutical composition
- an oral pharmaceutical composition comprising rivaroxaban, its solvates, hydrates and/or pharmaceutically acceptable salts prepared by non-aqueous granulation and hydroalcoholic granulation.
- W02005060940 relates to a method for production of a solid, orally administrable pharmaceutical composition comprising rivaroxaban in hydrophilized form.
- the wet granulation manufacturing method is disclosed by using fluidized-bed granulation. In the manufacturing method, first rivaroxaban is introduced into the wet granulation suspended in the granulation liquid.
- rivaroxaban is a poor-water soluble drug, it should be dissolved in a suitable solvent for further processing and get a dosage form with good pharmaceutical properties.
- WO2016166733 related to a process for preparing an oral pharmaceutical composition of Rivaroxaban in non-hydrophilized form, wherein rivaroxaban is incorporated in a dry mix with other pharmaceutically acceptable excipients which is granulated with non-aqueous solvents using high shear mixer granulator and dried using fluidized bed dryer.
- WO20 17021482 relates to an immediate release tablet comprising; rivaroxaban, a non-ionic surfactant and optionally one or more pharmaceutically acceptable excipients obtainable by using a dry process wherein the particle size is not reduced during the process of manufacturing the tablets.
- W02006072367 relates a process comprising hot melt extrusion of rivaroxaban and an excipient, performed a temperature exceeding 150°C, wherein 80% of rivaroxaban is released in a period of from 4 to 20 hours by using the USP release method with apparatus 2.
- W010146179 or W011042156 disclose hot melt rivaroxaban formulations.
- the use of hot melt process, coated granules, milling with excipients or microspheres formulations imply complex, lengthy and costly processes; therefore, they are not desirable.
- Rivaroxaban is a pharmaceutical agent that is used to reduce stroke risk in nonvalvular atrial fibrillation. It helps reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. It is also indicated for treating deep vein thrombosis and pulmonary embolism. It also reduces in the risk of recurrence of the same. Specifically, rivaroxaban is used for the prophylaxis of deep vein thrombosis after knee or hip replacement surgery which may lead to pulmonary embolism.
- Rivaroxaban is an orally active factor Xa inhibitor marketed for the treatment or prevention of atherothrombotic events, prevention of venous thromboembolism, prevention of stroke and systemic embolism, treatment and prevention of deep vein thrombosis or treatment and prevention of pulmonary embolism.
- Rivaroxaban is marketed in 2.5, 10, 15 and 20 mg strengths immediate release tablets.
- Rivaroxaban has poor water solubility (7 mg/L) and is thus difficult to incorporate into oral dosage forms that provide sufficient bioavailability of rivaroxaban following oral administration. There is thus a need to provide an improved process for the preparation of dosage forms of rivaroxaban with improved bioavailability of the rivaroxaban active ingredient.
- a high-shear granulator consists of a cylindrical or conical mixing bowl, a three bladed impeller, a chopper, an auxiliary chopper, a motor to drive the blades and a discharge pot.
- the mixing bowl is jacketed for heating or cooling the contents of the bowl as the case may be.
- the present invention is an oral dosage form comprising non-hydrophilized rivaroxaban with improved physicochemical and pharmaceutical characteristics manufactured by using high-shear granulation process as a part of wet granulation method.
- the present invention relates to an immediate release solid oral composition comprising rivaroxaban and one or more acceptable excipients manufactured by using conventional manufacturing methods with characteristic process parameters.
- Another object of the invention is the oral dosage form of the present invention for the treatment or prevention of atherothrombotic events, prevention of venous thromboembolism, prevention of stroke and systemic embolism, treatment and prevention of deep vein thrombosis or treatment and prevention of pulmonary embolism.
- An advantage of high-shear granulation is that the process is completed within a short period of time. It does, however, need to be carefully controlled as the formulation can quickly progress from under- to over-granulated.
- Another object of the invention is to obtain a rivaroxaban containing granules with good flowability and dissolution profile.
- process parameters of water content in granulation solution and the time to give the solvent to the powder blend before granulation process should be characterized.
- the purpose is to obtain homogeneous granules to improve the flow, content uniformity, compression characteristics, and drug release profile; and to reduce the potential for segregation and dusting.
- Granules that possess ideal properties result in efficient processing and high throughput of solid dose units with desired critical quality attributes (CQAs).
- solid oral dosage forms comprising non-hydrophilized rivaroxaban manufactured by using high-shear granulation process has improved pharmaceutical properties through a specified time to give the solvent and mix before granulation step.
- the present invention provides an improved process for the preparation of granules of rivaroxaban together with one or more pharmaceutically acceptable excipients.
- the rivaroxaban- containing particles of the present invention may be incorporated into pharmaceutical dosage forms for oral administration to patients in need thereof.
- the present invention provides a solid oral dosage form comprising non-hydrophilized rivaroxaban and pharmaceutically acceptable excipients manufactured by using a high-shear granulation process with a specified time to give the solvent and mix before granulation step.
- the rivaroxaban-containing particles of the present invention is easily incorporated into pharmaceutical dosage forms for oral administration to patients in need thereof.
- the granules are prepared using a high-moisture, high-shear granulation process with a minimized mixing time. This process minimizes segregation, dust and improves flowability.
- these properties may result in enhanced granule consistency, improved workability of the final blend prior to tablet formation, and may also enhance the dissolution of the final dosage form.
- these granules provide good flowability and dissolution profile when compared to tablets formulated with granules prepared using conventional, prior-art high-shear granulation techniques.
- Granule uniformity is therefore influenced by the composition of the powder blend, where ideally an even distribution of all excipients and active substance should be incorporated into the granule.
- rivaroxaban is considered to be mixed with pharmaceutically acceptable excipients without a solvent which means it is in non-hydrophilized form.
- a formulation and manufacturing method design is set considering rivaroxaban chemical structure and the most convenient pharmaceutically acceptable excipients to be used with.
- the amounts of pharmaceutically acceptable excipients are determined based on Handbook of Pharmaceutical Excipients.
- step 2 Specified amount of rivaroxaban, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium and the remaining part of HPMC are stirred in a separate bowl. 3. The granulation solution prepared in step 1 is added on the intragranular phase obtained in step
- the water content of granulation solution in step 1 and the process of giving granulation solution at a specified duration to powder blend (intragranular phase) in step 3 are the critical parameters for the formulation design and manufacturing process stated above. Many experiments were performed to optimize key parameters of manufacturing process by using high-shear granulation techniques. The water content of granulation solution used to granulate the intragranular phase comprising non-hydrophilized rivaroxaban and pharmaceutically acceptable excipients is investigated.
- the workability range of water content of granulation solution is determined as 45- 55% w/w.
- the particle size of granule was used as a tool for initial characterization of the powder binder couple by carrying out the multiple binder addition test.
- Granule properties such as particle size, Carr index (compressibility index) should be specified. Thereby, flowability properties will be optimized. Analysis were performed on the granules obtained.
- Particle Size Distribution (PSD) analysis were performed using light-scattering method, in particular Malvern Mastersizer.
- Carr index is one of the most popular method of predicting powder flow characteristics.
- the compressibility index has been proposed as an indirect measure of bulk density, size and shape, surface area, moisture content and cohesiveness of materials because all of these can influence the observed compressibility index.
- the second variation to be optimized with a constant water content of granulation solution between 45-55% w/w is the duration to give the granulation solution on intragranular phase.
- the granulation solution comprising binder and surfactant was given to intragranular phase by strring.
- Binders or “granulating agents” are a critical formulation component in wet granulation, ensuring appropriate surface wetting ability to ensure adhesion and cohesion between inter-particulate surfaces in the wet state, as well as excellent plasticity, compactibility and binding ability. Binder effect has a strong impact on granule formation and granule size.
- the granule size affects disintegration and dissolution profile of the product directly.
- the duration for mixing during the meeting of intragranular phase with granulation solution was investigated through performing many experiments.
- the granules may then be dried and milled.
- the drying step may be achieved by well-known methods, for example, by oven tray drying, or by fluid bed drying. Milling may also be carried out by methods well known in the art, for example, by using a Fitzmill or a Comil.
- a binder solution is added to the intragranular phase of rivaroxaban and one or more pharmaceutically acceptable excipients, resulting in a granulation blend.
- the granulation solution at defined concentration range is added to the powder with a certain duration range to give granulation solution by using high shear granulation.
- the binder may be, for example, hypromellose, cellulose or cellulose derivatives, povidone, starch, sucrose, polyethylene glycol, or mixtures thereof.
- the binder is dissolved in a solvent, for instance, water, an alcohol, or mixtures thereof.
- the binder solution is hypromellose dissolved in water.
- the filler is selected from the group consisting of lactose, microcrystalline cellulose, starch, pregelatinized starch, modified starch, calcium phosphate (dibasic and / or tribasic), calcium sulphate trihydrate or dihydrate, calcium carbonate, kaolin, cellulose, dextrose, dextrates, dextrin, sucrose, maltose, fructose, glucose, mannitol, maltitol, sorbitol, xylitol, titanium dioxide (Ti02) or the mixture thereof.
- the disintegrant is selected from the group consisting of calcium phosphate (dibasic and/or tribasic), sodium starch glycolate, crospovidone, croscarmellose sodium and the mixture thereof.
- the surfactant is selected from the group consisting of alkylbenzene sulfonates, sodium lauryl sulphate, dialkyl sulfosuccinate, polyethylene glycol, sorbitan monoester, glycerol diester and the mixture thereof.
- the lubricant is selected from the group consisting of magnesium stearate, stearic acid, polyethylene glycol, sodium stearyl fumarate and the mixture thereof.
- step 1 The critical steps in the process of the present invention are the step 1 and step 3, preparing granulation solution with defined concentration range and granulating the intragranular phase with a specified duration to give this granulation solution.
- Step 1 is optimized above with a specification range of 45-55% w/w.
- the duration time to give granulation solution in step 3 is investigated by performing in-vitro dissolution test.
- PK parameters (AUC t and C max ) are in line with the specifications based on Guideline on the Investigation on Bioequivalence.
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Abstract
An oral pharmaceutical formulation comprising rivaroxaban and pharmaceutically acceptable excipients wherein rivaroxaban is in non-hydrophilized form and the dosage form is manufactured by using high-shear granulation method in which the granulation solution comprising water content between 45% to 55% is given in a duration time range between 30 seconds to 2 minutes to the intragranular phase.
Description
A UNIQUE GRANULATION PROCESS FOR RIVAROXABAN CONTAINING
GRANULES
FIELD OF INVENTION
The present invention relates to a pharmaceutical composition, comprising non-hydrophilized rivaroxaban or a pharmaceutically acceptable salt thereof, wherein the composition is in an oral solid dosage form with good flowability and drug release profile.
STATE OF ART
Rivaroxaban (5-chloro-N-{[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxazolidin-5- yl] methyl }thiophene-2-carboxamide) is a low molecular weight, orally administrable anticoagulant drug. Rivaroxaban is an anticoagulant and the first orally active direct factor Xa inhibitor. The pharmaceutical directly inhibits the active form of serine protease Factor Xa (FXa). Rivaroxaban can be used for the prevention and treatment of various thromboembolic diseases, in particular of deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infract, angina pectoris, re-occlusions and recurrence of stenosis after angioplasty or aortocoronary bypass, cerebral stroke, transitory ischemic attacks, and peripheral arterial occlusive diseases.
Rivaroxaban was first disclosed in WO0147919, has the systematic name 5-chloro-N-({(5S)-2- oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-l ,3-oxazolidin-5-yl}methyl) thiophene-2-carboxamide and the following chemical structure:
Formula
Three different polymorphic forms of rivaroxaban have been described in W007039132.
US2007/0149522 relates to a synthesis method of 5-chloro-N-({5S)-2-oxo-3-[4-(3-oxo-4- morpholinyl)-phenyl]-l,3-oxazolidin-5-yl}-methyl)-2-thiophene carboxamide using from 5- chlorothiophene-2-carbonyl chloride and (2S)-3-amino-propane-l,2-diol and 4-(4-aminophenyl)- 3-morpholinone as starting materials.
W02009023233 relates to novel compounds that are substituted oxazolidinones derivatives and pharmaceutically acceptable salts thereof. More specifically, this invention relates to novel oxazolidinone compounds that are derivatives of Rivaroxaban. The invention also provides pyrogen-free compositions comprising one or more compounds of the invention and a carrier, along with the use of the disclosed compounds and compositions in methods of treating diseases and condition that are beneficially treated by administering a selective inhibitor of factor Xa, such as Rivaroxaban.
WO2015155307 relates to a novel pharmaceutical composition comprising rivaroxaban or a pharmaceutically acceptable salt thereof in combination with a proton pump inhibitor for use in the anticoagulant treatment with preventing or reducing the risk of a gastrointestinal disorder.
WO2015169957 relates to a novel pharmaceutical composition comprising rivaroxaban or a pharmaceutically acceptable salt thereof in combination with a proton pump inhibitor for use in the anticoagulant treatment with preventing or reducing the risk of a gastrointestinal disorder.
WO2016131896 relates to a pharmaceutical combination comprising dronedarone or a pharmaceutically acceptable salt thereof in combination with rivaroxaban and at least one pharmaceutically acceptable excipient.
W007039122 relates to rivaroxaban formulations comprising rivaroxaban in amorphous form or thermodynamically metastable crystal modification.
W009049820 relates to rivaroxaban formulations comprising at least one solid substance at room temperature, the thermodynamically preferred crystalline form of rivaroxaban, cellulose and/or cellulose derivatives, as well as optionally a surface-active substance, wherein more than 50% of
rivaroxaban in the formulation is in amorphous mixed phase as determined by X-ray diffractometer.
EP3505160 relates to a manufacturing process of a tablet comprising rivaroxaban wherein it comprises of preparing a powder mixture comprising rivaroxaban, surfactant and pharmaceutically acceptable excipients and subjecting the powder mixture obtained previous to compress tablet by direct compression method.
TR2017/13325 and TR2017/13326 disclose a process for manufacturing a formulation comprising the step of granulating the solid mixture comprising the active ingredient rivaroxaban, at least one water-soluble binder and at least one water-soluble filler with a suitable granulation solution.
WO2017146709 relates to the rivaroxaban containing granules wherein process steps are; dry mixing rivaroxaban and a pharmaceutically acceptable excipient in a high-shear mixer to form a dry mix blend, adding a binder solution to the dry mix blend to form a granulating mixture and finally mixing, drying and milling the rivaroxaban-containing granules. The final granulating mixture has water content of less than 30% and the high shear granulation time is carried out between three to five minutes.
WO20 15124995 relates to an oral solid dosage form comprising rivaroxaban and one or more pharmaceutically acceptable excipients manufactured by a wet granulation process wherein the ratio of rivaroxaban to excipient is in the range of 1:2 to 1:8 and obtaining solid dosage form.
WO20 18007945 relates to an oral pharmaceutical composition comprising rivaroxaban, its solvates, hydrates and/or pharmaceutically acceptable salts prepared by non-aqueous granulation and hydroalcoholic granulation.
W02005060940 relates to a method for production of a solid, orally administrable pharmaceutical composition comprising rivaroxaban in hydrophilized form. The wet granulation manufacturing method is disclosed by using fluidized-bed granulation. In the manufacturing method, first rivaroxaban is introduced into the wet granulation suspended in the granulation liquid. In the description part of the patent document it is discussed that since rivaroxaban is a
poor-water soluble drug, it should be dissolved in a suitable solvent for further processing and get a dosage form with good pharmaceutical properties.
WO2016166733 related to a process for preparing an oral pharmaceutical composition of Rivaroxaban in non-hydrophilized form, wherein rivaroxaban is incorporated in a dry mix with other pharmaceutically acceptable excipients which is granulated with non-aqueous solvents using high shear mixer granulator and dried using fluidized bed dryer.
WO20 17021482 relates to an immediate release tablet comprising; rivaroxaban, a non-ionic surfactant and optionally one or more pharmaceutically acceptable excipients obtainable by using a dry process wherein the particle size is not reduced during the process of manufacturing the tablets.
W02006072367 relates a process comprising hot melt extrusion of rivaroxaban and an excipient, performed a temperature exceeding 150°C, wherein 80% of rivaroxaban is released in a period of from 4 to 20 hours by using the USP release method with apparatus 2.
W010146179 or W011042156 disclose hot melt rivaroxaban formulations. The use of hot melt process, coated granules, milling with excipients or microspheres formulations imply complex, lengthy and costly processes; therefore, they are not desirable.
Rivaroxaban is a pharmaceutical agent that is used to reduce stroke risk in nonvalvular atrial fibrillation. It helps reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. It is also indicated for treating deep vein thrombosis and pulmonary embolism. It also reduces in the risk of recurrence of the same. Specifically, rivaroxaban is used for the prophylaxis of deep vein thrombosis after knee or hip replacement surgery which may lead to pulmonary embolism.
Rivaroxaban is an orally active factor Xa inhibitor marketed for the treatment or prevention of atherothrombotic events, prevention of venous thromboembolism, prevention of stroke and systemic embolism, treatment and prevention of deep vein thrombosis or treatment and prevention of pulmonary embolism. Rivaroxaban is marketed in 2.5, 10, 15 and 20 mg strengths immediate release tablets.
Rivaroxaban has poor water solubility (7 mg/L) and is thus difficult to incorporate into oral dosage forms that provide sufficient bioavailability of rivaroxaban following oral administration. There is thus a need to provide an improved process for the preparation of dosage forms of rivaroxaban with improved bioavailability of the rivaroxaban active ingredient.
Based on the information about the solubility of rivaroxaban wet granulation method is the preferred manufacturing method to achieve a solid dosage form with good pharmaceutical characteristics.
One process in wet granulation method is performed with high-shear granulator. A high-shear granulator consists of a cylindrical or conical mixing bowl, a three bladed impeller, a chopper, an auxiliary chopper, a motor to drive the blades and a discharge pot. By either circulating hot or cool liquid or steam through the jacket, the mixing bowl is jacketed for heating or cooling the contents of the bowl as the case may be.
The present invention is an oral dosage form comprising non-hydrophilized rivaroxaban with improved physicochemical and pharmaceutical characteristics manufactured by using high-shear granulation process as a part of wet granulation method.
SUMMARY OF THE INVENTION
The present invention relates to an immediate release solid oral composition comprising rivaroxaban and one or more acceptable excipients manufactured by using conventional manufacturing methods with characteristic process parameters.
Another object of the invention is the oral dosage form of the present invention for the treatment or prevention of atherothrombotic events, prevention of venous thromboembolism, prevention of stroke and systemic embolism, treatment and prevention of deep vein thrombosis or treatment and prevention of pulmonary embolism.
Another object of the invention is to develop an oral dosage form with improved physicochemical properties. However, since the water-solubility of rivaroxaban is very low it is difficult to have an oral dosage form with improved dissolution profile and flowability properties. Thus, critical manufacturing processes are improved.
Another object of the invention is the oral dosage form comprising rivaroxaban in non- hydrophilized form mixed with convenient pharmaceutically acceptable excipients prior to introduce solvent and continue manufacturing by using high-shear technique which is one of the wet granulation processes.
An advantage of high-shear granulation is that the process is completed within a short period of time. It does, however, need to be carefully controlled as the formulation can quickly progress from under- to over-granulated.
The properties of the granules, such as porosity, hygroscopicity, hardness, size, shape, texture, surface area, density, elasticity, and plasticity, can be controlled through manipulation of several processing parameters and material attributes. It is of paramount significance to understand how material attributes and process parameters/conditions influence the quality attributes of granules.
Another object of the invention is to obtain a rivaroxaban containing granules with good flowability and dissolution profile. Thus, process parameters of water content in granulation solution and the time to give the solvent to the powder blend before granulation process should be characterized. The purpose is to obtain homogeneous granules to improve the flow, content uniformity, compression characteristics, and drug release profile; and to reduce the potential for segregation and dusting. Granules that possess ideal properties result in efficient processing and high throughput of solid dose units with desired critical quality attributes (CQAs).
It is surprisingly found that solid oral dosage forms comprising non-hydrophilized rivaroxaban manufactured by using high-shear granulation process has improved pharmaceutical properties through a specified time to give the solvent and mix before granulation step.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of granules of rivaroxaban together with one or more pharmaceutically acceptable excipients. The rivaroxaban- containing particles of the present invention may be incorporated into pharmaceutical dosage forms for oral administration to patients in need thereof.
The present invention provides a solid oral dosage form comprising non-hydrophilized rivaroxaban and pharmaceutically acceptable excipients manufactured by using a high-shear granulation process with a specified time to give the solvent and mix before granulation step. The rivaroxaban-containing particles of the present invention is easily incorporated into pharmaceutical dosage forms for oral administration to patients in need thereof.
In one embodiment of the present invention, the granules are prepared using a high-moisture, high-shear granulation process with a minimized mixing time. This process minimizes segregation, dust and improves flowability.
These properties may result in enhanced granule consistency, improved workability of the final blend prior to tablet formation, and may also enhance the dissolution of the final dosage form. Surprisingly, when incorporated into oral dosage forms, these granules provide good flowability and dissolution profile when compared to tablets formulated with granules prepared using conventional, prior-art high-shear granulation techniques.
When liquid binder is introduced to the dry powder mix to promote granule growth, the liquid spray initially contacts the powder blend. Granule uniformity is therefore influenced by the composition of the powder blend, where ideally an even distribution of all excipients and active substance should be incorporated into the granule.
In an embodiment to improve granule characteristics, rivaroxaban is considered to be mixed with pharmaceutically acceptable excipients without a solvent which means it is in non-hydrophilized form.
A formulation and manufacturing method design is set considering rivaroxaban chemical structure and the most convenient pharmaceutically acceptable excipients to be used with. The amounts of pharmaceutically acceptable excipients are determined based on Handbook of Pharmaceutical Excipients.
Formulation Design:
Manufacturing process:
1. Sodium lauryl sulphate and a specified amount of HPMC are dissolved in water and mixed to obtain uniform solution (granulation solution).
2. Specified amount of rivaroxaban, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium and the remaining part of HPMC are stirred in a separate bowl. 3. The granulation solution prepared in step 1 is added on the intragranular phase obtained in step
2 and granulation process is performed by using high-shear granulator.
4. Wet granules are dried to a specified moisture value and shifted through a proper sieve.
5. Pharmaceutically acceptable amount of magnesium stearate is added on the granules obtained in step 4 and stirred to obtain a uniform final blend. 6. Granules are used to get a pharmaceutically acceptable solid oral dosage forms.
According to the present invention, the water content of granulation solution in step 1 and the process of giving granulation solution at a specified duration to powder blend (intragranular phase) in step 3 are the critical parameters for the formulation design and manufacturing process stated above. Many experiments were performed to optimize key parameters of manufacturing process by using high-shear granulation techniques.
The water content of granulation solution used to granulate the intragranular phase comprising non-hydrophilized rivaroxaban and pharmaceutically acceptable excipients is investigated.
Different water contents of granulation solutions were used in granulation of intragranular phase in step 3. It directly affects granule uniformity which is important in pharmaceutical manufacturing, as the tablet must contain a uniform distribution of active substance and excipients in the product to ensure product efficacy. Increasing the water content of granulation solution more than 55% w/w decreased the binder properties of the binder solution. It is due to hygroscopicity of a powder refers to its ability to absorb moisture from its surroundings. For granules to form, a critical amount of liquid must be available at the surface of the particles to form the required liquid bridges between the particles. Optimized amount of binder is therefore required to ensure a critical amount at the surface for the liquid bridges and granule formation. The binder is added to the intragranular phase in a certain duration range via granulation solution. This step is repeated a certain number of times usually taking the powder from the dry state to a suspension.
When the water content of granulation solution is under or equal to 20% w/w, granulation process is not achieved because the granules obtained were very fine like powder, not granule and also the granule formation is very bad. No further process was able to be performed.
When the water content of granulation solution is 30% w/w, obtained granule represents the same characteristics with 20% w/w level experiment.
When the water content of granulation solution is 40% w/w, it was observed that the flowability was improved but not enough. Thus, the experiments were performed for further levels of solvent.
When the water content of granulation solution is 45% w/w, it was observed that flowability of granule was good for the next step.
Optimization processes were performed to set out the upper limit water content of granulation solution for workability.
It was found that higher water content of granulation solution than 55% w/w, it was observed that flowability of granule was good for the next step.
It was found that higher water content of granulation solution than 60% w/w, obtained granule was not able to be compressed into tablets. The physical appearance of the granule seems like a slurry.
The physico-chemical properties of granule were changed when different water contents of granulation solutions were used.
As a result, the workability range of water content of granulation solution is determined as 45- 55% w/w. The particle size of granule was used as a tool for initial characterization of the powder binder couple by carrying out the multiple binder addition test.
Optimization processes conducted due to different water contents of granulation solution were analyzed. Granule properties, such as particle size, Carr index (compressibility index) should be specified. Thereby, flowability properties will be optimized. Analysis were performed on the granules obtained.
Particle Size Distribution (PSD) analysis were performed using light-scattering method, in particular Malvern Mastersizer.
Carr index is one of the most popular method of predicting powder flow characteristics. The compressibility index has been proposed as an indirect measure of bulk density, size and shape, surface area, moisture content and cohesiveness of materials because all of these can influence the observed compressibility index. These calculations were done according United States Pharmacopeia <1174> Powder Flow test.
The second variation to be optimized with a constant water content of granulation solution between 45-55% w/w is the duration to give the granulation solution on intragranular phase. The granulation solution comprising binder and surfactant was given to intragranular phase by strring. Binders or “granulating agents” are a critical formulation component in wet granulation, ensuring appropriate surface wetting ability to ensure adhesion and cohesion between inter-particulate surfaces in the wet state, as well as excellent plasticity, compactibility and binding ability. Binder effect has a strong impact on granule formation and granule size.
The granule size affects disintegration and dissolution profile of the product directly. The duration for mixing during the meeting of intragranular phase with granulation solution was investigated through performing many experiments.
Different durations to give granulation solution were investigated: from 30 seconds to 3 minutes. Between these range, 1st minute, 1.5th minute, 2nd minute and 3rd minute intervals were applied.
According to the present invention, the granules may then be dried and milled.
Within the context of the present, the drying step may be achieved by well-known methods, for example, by oven tray drying, or by fluid bed drying. Milling may also be carried out by methods well known in the art, for example, by using a Fitzmill or a Comil.
According to the present invention, a binder solution is added to the intragranular phase of rivaroxaban and one or more pharmaceutically acceptable excipients, resulting in a granulation blend. In particularly advantageous embodiments of the present invention, the granulation solution at defined concentration range is added to the powder with a certain duration range to give granulation solution by using high shear granulation.
Within the context of the present invention, the binder may be, for example, hypromellose, cellulose or cellulose derivatives, povidone, starch, sucrose, polyethylene glycol, or mixtures thereof. The binder is dissolved in a solvent, for instance, water, an alcohol, or mixtures thereof.
In particularly advantageous embodiments of the present invention, the binder solution is hypromellose dissolved in water.
In a preferred embodiment of the invention the filler is selected from the group consisting of lactose, microcrystalline cellulose, starch, pregelatinized starch, modified starch, calcium phosphate (dibasic and / or tribasic), calcium sulphate trihydrate or dihydrate, calcium carbonate, kaolin, cellulose, dextrose, dextrates, dextrin, sucrose, maltose, fructose, glucose, mannitol, maltitol, sorbitol, xylitol, titanium dioxide (Ti02) or the mixture thereof.
In a preferred embodiment of the invention the disintegrant is selected from the group consisting of calcium phosphate (dibasic and/or tribasic), sodium starch glycolate, crospovidone, croscarmellose sodium and the mixture thereof.
In a preferred embodiment of the invention the surfactant is selected from the group consisting of alkylbenzene sulfonates, sodium lauryl sulphate, dialkyl sulfosuccinate, polyethylene glycol, sorbitan monoester, glycerol diester and the mixture thereof.
In a preferred embodiment of the invention the lubricant is selected from the group consisting of magnesium stearate, stearic acid, polyethylene glycol, sodium stearyl fumarate and the mixture thereof.
The critical steps in the process of the present invention are the step 1 and step 3, preparing granulation solution with defined concentration range and granulating the intragranular phase with a specified duration to give this granulation solution. Step 1 is optimized above with a specification range of 45-55% w/w. Furthermore, the duration time to give granulation solution in step 3 is investigated by performing in-vitro dissolution test.
Table 3: Results of In-vitro Analysis obtained with duration interval range to give granulation solution which is at certain range of 45-55 %
Most proper dissolution results are obtained with a duration range to give granulation solution from 30 seconds to 2 minutes.
Furthermore, formulation obtained with optimized duration time to give granulation solution in which the water content level lies between 45-55% is subjected to bioequivalence study.
According to “Guideline on the Investigation on Bioequivalence” published by EMA, to establish bioequivalence of the test product with that of reference product, 90% Confidence Interval (Cl) for the ratio (Test/Reference) of Least Square Means of the Ln transformed PK parameters (AUCt and Cmax) must fall between 80.00% to 125.00%.
PK parameters (AUCt and Cmax) are in line with the specifications based on Guideline on the Investigation on Bioequivalence.
Both in-vitro and in-vivo release profile of the drug comprising non-hydrophilized rivaroxaban and manufactured by wet granulation method in which high-shear granulator is used.
While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.
Claims
1. An oral pharmaceutical formulation comprising rivaroxaban and pharmaceutically acceptable excipients wherein rivaroxaban is in non-hydrophilized form and the dosage form is manufactured by using high-shear granulation method in which the granulation solution comprising water content between 45% to 55% is given in a duration time range between 30 seconds to 2 minutes to the intragranular phase.
2. An oral pharmaceutical composition according to claim 1, the composition is in the form of solid dosage form.
3. An oral pharmaceutical composition according to any of the preceding claims, wherein the pharmaceutically acceptable excipient is selected from the group consisting of a lubricant, a binder, a disintegrant, a filler, a surfactant, lubricant and mixtures thereof.
4. An oral pharmaceutical composition according to claim 3, wherein binder is selected from the group comprising hypromellose, cellulose or cellulose derivatives, povidone, starch, sucrose, polyethylene glycol, or mixtures thereof.
5. An oral pharmaceutical composition according to claim 3, wherein disintegrant is selected from the group comprising calcium phosphate (dibasic and / or tribasic), sodium starch glycolate, crospovidone, croscarmellose sodium and the mixture thereof.
6. An oral pharmaceutical composition according to claim 3, wherein filler is selected from the group comprising lactose, microcrystalline cellulose, starch, pregelatinized starch, modified starch, calcium phosphate (dibasic and / or tribasic), calcium sulphate trihydrate or dihydrate, calcium carbonate, kaolin, cellulose, dextrose, dextrates, dextrin, sucrose, maltose, fructose, glucose, mannitol, maltitol, sorbitol, xylitol, titanium dioxide (T1O2) or the mixture thereof.
7. An oral pharmaceutical composition according to claim 3, wherein surfactant is selected from the group comprising alkylbenzene sulfonates, sodium lauryl sulphate, dialkyl sulfosuccinate, polyethylene glycol, sorbitan monoester, glycerol diester and the mixture thereof.
8. An oral pharmaceutical composition according to claim 3, wherein lubricant is selected from the group comprising magnesium stearate, stearic acid, polyethylene glycol, sodium stearyl fumarate and the mixture thereof.
9. An oral pharmaceutical composition according to any of the preceding claims wherein the formulation in w/w % is as stated below:
Rivaroxaban 20.0 - 25.0 Lactose monohydrate 20.0 - 30.0 Microcrystalline cellulose 35.0 - 45.0 Croscarmellose sodium 1.0 - 5.0 HPMC 1.0 - 5.0
Sodium lauryl sulphate 0.2 - 1.5 Magnesium stearate 0.2 2.0 Deionised water Quantity sufficient
10. An oral pharmaceutical composition according to any of the preceding claims wherein the process for the preparation comprises the steps of: a. Sodium lauryl sulphate and a specified amount of HPMC are dissolved in water and mixed to obtain uniform solution (granulation solution). b. Specified amount of rivaroxaban, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium and the remaining part of HPMC are stirred in a separate bowl. c. The granulation solution prepared in step a is added on the intragranular phase obtained in step b and granulation process is performed by using high-shear granulator. d. Wet granules are dried to a specified moisture value and shifted through a proper sieve. e. Pharmaceutically acceptable amount of magnesium stearate is added on the granules obtained in step d and stirred to obtain a uniform final blend. f. Granules are used to get a pharmaceutically acceptable solid oral dosage forms.
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CN113425729A (en) * | 2021-06-24 | 2021-09-24 | 上海奥全生物医药科技有限公司 | Rivaroxaban-containing pharmaceutical composition and application thereof |
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KR20160004483A (en) * | 2014-07-02 | 2016-01-13 | 한미약품 주식회사 | Pharmaceutical Composition for Oral Administration Comprising Rivaroxaban And Method of Preparing the Same |
WO2016166733A1 (en) * | 2015-04-17 | 2016-10-20 | Micro Labs Limited | A process for preparing a pharmaceutical composition comprising rivaroxaban |
US20190046449A1 (en) * | 2016-02-25 | 2019-02-14 | Mylan Inc. | A unique high-shear granulation process for improved bioavailability of rivaroxaban |
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2019
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KR20160004483A (en) * | 2014-07-02 | 2016-01-13 | 한미약품 주식회사 | Pharmaceutical Composition for Oral Administration Comprising Rivaroxaban And Method of Preparing the Same |
WO2016166733A1 (en) * | 2015-04-17 | 2016-10-20 | Micro Labs Limited | A process for preparing a pharmaceutical composition comprising rivaroxaban |
US20190046449A1 (en) * | 2016-02-25 | 2019-02-14 | Mylan Inc. | A unique high-shear granulation process for improved bioavailability of rivaroxaban |
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CN113425729A (en) * | 2021-06-24 | 2021-09-24 | 上海奥全生物医药科技有限公司 | Rivaroxaban-containing pharmaceutical composition and application thereof |
WO2022267169A1 (en) * | 2021-06-24 | 2022-12-29 | 上海奥全生物医药科技有限公司 | Pharmaceutical composition containing rivaroxaban, and application thereof |
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