EP4208462A1 - Compositions de rivaroxaban - Google Patents
Compositions de rivaroxabanInfo
- Publication number
- EP4208462A1 EP4208462A1 EP21863854.2A EP21863854A EP4208462A1 EP 4208462 A1 EP4208462 A1 EP 4208462A1 EP 21863854 A EP21863854 A EP 21863854A EP 4208462 A1 EP4208462 A1 EP 4208462A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- rivaroxaban
- composition
- granulated
- compositions
- diluent
- 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.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 228
- 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 188
- 229960001148 rivaroxaban Drugs 0.000 title claims abstract description 183
- 238000004090 dissolution Methods 0.000 claims abstract description 22
- 239000003085 diluting agent Substances 0.000 claims description 60
- 239000003826 tablet Substances 0.000 claims description 56
- 239000000843 powder Substances 0.000 claims description 39
- 239000007891 compressed tablet Substances 0.000 claims description 24
- 239000007884 disintegrant Substances 0.000 claims description 17
- 239000002245 particle Substances 0.000 claims description 15
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 14
- 239000000314 lubricant Substances 0.000 claims description 12
- 239000002775 capsule Substances 0.000 claims description 10
- 239000002563 ionic surfactant Substances 0.000 claims description 8
- 238000009826 distribution Methods 0.000 claims description 5
- 238000007907 direct compression Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 16
- 238000003860 storage Methods 0.000 abstract description 14
- 238000002360 preparation method Methods 0.000 abstract description 5
- 239000004094 surface-active agent Substances 0.000 description 18
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 16
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 16
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 16
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 13
- 238000005469 granulation Methods 0.000 description 13
- 230000003179 granulation Effects 0.000 description 13
- 239000011230 binding agent Substances 0.000 description 11
- 238000007906 compression Methods 0.000 description 11
- 230000006835 compression Effects 0.000 description 11
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 11
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 11
- 238000005550 wet granulation Methods 0.000 description 11
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 229940016286 microcrystalline cellulose Drugs 0.000 description 10
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 10
- 239000008108 microcrystalline cellulose Substances 0.000 description 10
- 230000001186 cumulative effect Effects 0.000 description 9
- 239000008187 granular material Substances 0.000 description 9
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 9
- 239000012535 impurity Substances 0.000 description 9
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 8
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 8
- 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 description 7
- 229960003943 hypromellose Drugs 0.000 description 7
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical group [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 6
- 238000005056 compaction Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000008101 lactose Substances 0.000 description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 6
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 229920002785 Croscarmellose sodium Polymers 0.000 description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 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 description 5
- 229960001681 croscarmellose sodium Drugs 0.000 description 5
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 230000000737 periodic effect Effects 0.000 description 5
- 229940055725 xarelto Drugs 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 229960005191 ferric oxide Drugs 0.000 description 4
- 239000007888 film coating Substances 0.000 description 4
- 238000009501 film coating Methods 0.000 description 4
- 229960003511 macrogol Drugs 0.000 description 4
- 238000009481 moist granulation Methods 0.000 description 4
- 229940069328 povidone Drugs 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000004408 titanium dioxide Substances 0.000 description 4
- 229960005196 titanium dioxide Drugs 0.000 description 4
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 238000000975 co-precipitation Methods 0.000 description 3
- 238000001125 extrusion Methods 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 238000004811 liquid chromatography Methods 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 238000007909 melt granulation Methods 0.000 description 3
- 238000003801 milling Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229960000502 poloxamer Drugs 0.000 description 3
- 229920001983 poloxamer Polymers 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 229920002907 Guar gum Polymers 0.000 description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 2
- 235000019759 Maize starch Nutrition 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 239000004141 Sodium laurylsulphate Substances 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000002288 cocrystallisation Methods 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 229920001531 copovidone Polymers 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000007908 dry granulation Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 235000020937 fasting conditions Nutrition 0.000 description 2
- 238000009484 foam granulation Methods 0.000 description 2
- 238000009483 freeze granulation Methods 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000000665 guar gum Substances 0.000 description 2
- 235000010417 guar gum Nutrition 0.000 description 2
- 229960002154 guar gum Drugs 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 229920001477 hydrophilic polymer Polymers 0.000 description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 2
- 238000007561 laser diffraction method Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 238000009480 moisture-activated dry granulation Methods 0.000 description 2
- 239000002736 nonionic surfactant Substances 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 238000009486 pneumatic dry granulation Methods 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 238000000935 solvent evaporation Methods 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 229940032147 starch Drugs 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000009479 steam granulation Methods 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 238000009482 thermal adhesion granulation Methods 0.000 description 2
- 239000000230 xanthan gum Substances 0.000 description 2
- 235000010493 xanthan gum Nutrition 0.000 description 2
- 229920001285 xanthan gum Polymers 0.000 description 2
- 229940082509 xanthan gum Drugs 0.000 description 2
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound 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 GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 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 description 1
- 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 description 1
- 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 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 229920001328 Polyvinylidene chloride Polymers 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- XAAHAAMILDNBPS-UHFFFAOYSA-L calcium hydrogenphosphate dihydrate Chemical compound O.O.[Ca+2].OP([O-])([O-])=O XAAHAAMILDNBPS-UHFFFAOYSA-L 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- -1 glidants Substances 0.000 description 1
- 229940049654 glyceryl behenate Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000012052 hydrophilic carrier Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940127021 low-dose drug Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 239000005033 polyvinylidene chloride Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 239000000080 wetting agent Substances 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
- A61K9/2095—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
- 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
- A61K9/20—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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Definitions
- the present invention relates to non-granulated compositions comprising rivaroxaban.
- the present invention also provides a process for the preparation of such compositions.
- Rivaroxaban or 5-chloro-N-( ⁇ (5S)-2-oxo-3-4-(3-oxo-4-morpholinyl)-phenyl-1 ,3-oxazolidin -5-yl)-methyl-2-thiophenecarboxamide is a low molecular weight, orally administrable drug, which is employed for the prophylaxis and/or treatment of various thromboembolic diseases. It is a potent inhibitor of blood clotting factor Xa. It is commercially available as tablets (XARELTO®) in dose strengths of 2.5mg, 10mg, 15mg and 20mg.
- Rivaroxaban being a potent drug with relatively poor water solubility (about 7 mg/L), shows poor oral bioavailability and increased variability in the gastrointestinal absorption rate.
- Development of a dosage form comprising a potent, low dose, low solubility drug such as rivaroxaban needs to simultaneously address several factors such as solubility, dissolution, content uniformity oral bioavailability, and storage stability.
- Various processes and techniques have been used in prior art to increase the solubility, and dissolution, and improve oral bioavailability and stability of rivaroxaban.
- U.S. Patent No. 9,415,053 discloses wet/moist granulation of rivaroxaban and excipients, using a granulating liquid containing solvent, hydrophilic binding agent and wetting agent, to give a hydrophilized form of rivaroxaban. Hydrophilized form of rivaroxaban in the formulation leads to a significant increase in the bioavailability of rivaroxaban.
- Hydrophilic additives/binding agents used in the granulation are hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), ethylcellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), L-HPC (low-substituted HPC), polyvinylpyrrolidone, polyvinyl alcohol, polymers of acrylic acid and its salts, vinylpyrrolidone-vinyl acetate copolymers, gelatin, guar gum, partially hydrolysed starch, alginates and xanthan gum.
- HPMC hydroxypropyl methylcellulose
- CMC carboxymethylcellulose
- HPC hydroxypropyl cellulose
- L-HPC low-substituted HPC
- polyvinylpyrrolidone polyvinyl alcohol, polymers of acrylic acid and its salts, vinylpyrrolidone-vinyl acetate copolymers, gelatin, guar gum, partially hydrolysed
- 9,415,053 presents data that shows that tablets prepared by directly compressed tablet compositions (Tablet A) were found to be 35% less readily absorbed and less bioavailable than tablets prepared by moist granulation (Tablet B) where rivaroxaban is in the hydrophilized form.
- Tablet A tablets prepared by directly compressed tablet compositions
- Tablet B tablets prepared by moist granulation
- compositions comprising hydrophilized form of rivaroxaban prepared using processes like fluidized bed granulation, rapid mixer granulation, high-shear mixer granulation and centrifugal wet granulation.
- the said compositions use hydrophilic binding agents selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, maize starch, povidone, and pregelatinized starch.
- PCT Publication No. WO/2017/144071 relates to pharmaceutical compositions comprising rivaroxaban in the form of a tablet or a capsule, wherein rivaroxaban along with other excipients is wet granulated with a binder (hypromellose) and non-aqueous solvents using a high shear mixer granulator, and the granules dried using a fluidized bed dryer.
- a binder hyperromellose
- non-aqueous solvents using a high shear mixer granulator
- European Patent No. 2442799, U.S. Patent Publication No. 2017/0049782 and U.S. Patent Publication No. 2012/0231076 disclose a melt granulation process for the preparation of a solid compositions comprising rivaroxaban.
- the compositions use hydrophilic matrix formers (solubilizers), carriers or binders such as povidone, copovidone, polyethylene glycol, and poloxamer.
- U.S. Patent Publication No. 2016/0120870, Indian Patent Application No. 781/MUM/2014, Indian Patent Application No. 2777/MUM/2013, and Indian Patent Application No. 3370/CHE/2013 disclose co-milling/co-micronization of rivaroxaban with at least one hydrophilic binder or surfactant.
- U.S. Patent Publication No. 2017/0000799 relates to adsorption of a solubilizer on the surface of a poorly soluble drug like rivaroxaban.
- U.S. Patent Publication No. 2018/0214453 and European Patent Publication No. 3505160 disclose rivaroxaban immediate release tablet comprising a non-ionic surfactant like poloxamer, at least one hydrophilic binder like hydroxypropyl methylcellulose and hydroxypropyl cellulose, at least one filler, at least one disintegrant and at least one lubricant.
- the said compositions are prepared using a roll compaction, slug compaction or direct compression.
- hydrophilization of rivaroxaban with one or more hydrophilic polymers e.g. HPMC, HPC
- hydrophilic polymers e.g. HPMC, HPC
- wet I moist granulation, melt extrusion, co-milling, or co-precipitation techniques bringing hydrophilic polymers in close contact with the hydrophobic drugs to increase their solubility and dissolution rate
- hydrophilic binders like hydroxypropyl methylcellulose and hydroxypropyl cellulose, solubilizers, emulsifiers, hydrophilic matrix formers, or hydrophilic carriers
- rivaroxaban tablets In commercially available rivaroxaban tablets, the process of wet/moist granulation is used to hydrophilize rivaroxaban with hydrophilic polymer- hypromellose.
- compositions of the present invention do not use any of the above approaches, and yet achieve the desired dissolution, bioavailability and stability.
- compositions of the present invention are in the form of non-granulated compositions of rivaroxaban and yet achieve the desired dissolution, bioavailability and storage stability of rivaroxaban.
- the said compositions accomplish this by comprising rivaroxaban at low concentrations of about 20% or less (by weight of the composition), and diluent(s) at high concentrations of about 70% or more (by weight of the composition).
- the composition further comprises 1 % or less of surfactant (by weight of the composition).
- the compositions comprising a low dose drug like rivaroxaban in a low concentration they achieve the desired drug blend uniformity and content uniformity.
- the principal object of the present invention is to provide non-granulated, compositions of rivaroxaban for oral administration, wherein rivaroxaban is at a concentration of not more than 20% by weight of the composition.
- Yet another object of the present invention is to provide non-granulated compositions of rivaroxaban, wherein the dissolution of rivaroxaban from the said compositions is not less than 90% in 45 minutes.
- Yet another object of the present invention is to provide non-granulated compositions of rivaroxaban for oral administration, wherein the total impurities content in the said compositions, as determined by liquid chromatography, is not more than 3%.
- Yet another object of the present invention is to provide a process for preparation of the said non-granulated compositions of rivaroxaban.
- the present invention relates to non-granulated compositions of rivaroxaban, comprising rivaroxaban at a concentration of not more than 20% by weight of the composition.
- the present invention also provides a process for the preparation of such compositions.
- the present invention provides non-granulated compositions of rivaroxaban for oral administration.
- rivaroxaban is not subjected to processes of wet granulation, dry granulation, fluidized bed granulation, rapid mixer granulation, high-shear mixer granulation, centrifugal wet granulation, steam granulation, spray drying granulation, melt granulation, melt extrusion, freeze-granulation, thermal adhesion granulation, foam granulation, pneumatic dry granulation, moisture-activated dry granulation, roll compaction, slug compaction, comilling, co-crystallization, solvent evaporation, or co-precipitation.
- non-granulated composition refers to compositions that comprise rivaroxaban not in the form of granules or granulates, but in the form of a powder, or a powder blend with at least one excipient.
- non-granulated compositions rivaroxaban is not subjected to processes of wet granulation, dry granulation, fluidized bed granulation, rapid mixer granulation, high-shear mixer granulation, centrifugal wet granulation, steam granulation, spray drying granulation, melt granulation, melt extrusion, freeze-granulation, thermal adhesion granulation, foam granulation, pneumatic dry granulation, moisture-activated dry granulation, roll compaction, slug compaction, co-milling, co-crystallization, solvent evaporation, or coprecipitation.
- the ‘non-granulated composition’ can be in the form of powder, powder blend, tablet, directly compressed tablet, capsule, or combinations thereof.
- directly compressed refers to non-granulated compositions of rivaroxaban wherein rivaroxaban is in the form of powder or powder blends, which has been directly incorporated into tablets by compression.
- the present invention provides compositions of rivaroxaban, wherein rivaroxaban is nongranulated.
- compositions of the present invention may be in the form of powder blends, tablets, or capsules.
- the non-granulated compositions of rivaroxaban are in the form of directly compressed tablets and/or capsules.
- the non-granulated compositions of rivaroxaban are blended with inert excipient granules. The blend can be further compressed into tablets and/or filled into capsules.
- inert excipient granules refers to inactive and inert excipients in the form of granules or granulates, the said g ran ules/g ran ulates being free of rivaroxaban.
- non-granulated compositions of rivaroxaban provide rapid release, extended-release, sustained-release, controlled-release, prolonged release, delayed- release, enteric-release, timed-release, pulsed-release, or a combination thereof.
- Rivaroxaban as used herein includes rivaroxaban, and its pharmaceutically acceptable salts, hydrates, esters, derivatives or solvates thereof. Rivaroxaban can be in crystalline and/or amorphous form.
- Rivaroxaban is used herein in concentrations ranging from about 0.25% to about 20%, preferably from about 0.5% to about 15%, more preferably from about 0.75% to about 10%, and most preferably from about 1 % to about 10% by weight of the composition.
- Rivaroxaban used in the non-granulated compositions has a particle size distribution wherein 90% by volume (d (0.9)) of rivaroxaban particles have a particle size of not more than 100 microns, preferably not more than 50 microns, more preferably not more than 25 microns, and most preferably not more than 20 microns, as determined by the laser diffraction method (Malvern Master Sizer) using the water dispersion method.
- Rivaroxaban used in the non-granulated compositions has a particle size distribution wherein 50% by volume (d (0.5)) of rivaroxaban particles have a particle size of not more than 50 microns, preferably not more than 30 microns, more preferably not more than 20 microns, and most preferably not more than 10 microns, as determined by the laser diffraction method (Malvern Master Sizer) using the water dispersion method.
- the non-granulated compositions comprise a powder blend of rivaroxaban and at least one diluent.
- Diluent in the non-granulated compositions is selected from water-soluble diluents, waterinsoluble diluents, and mixtures thereof.
- Water-soluble diluents are selected from mannitol, sorbitol, and lactose. The preferred water-soluble diluent is lactose.
- Waterinsoluble diluents are selected from microcrystalline cellulose and dibasic calcium phosphate. The preferred water-insoluble diluent is microcrystalline cellulose.
- the non-granulated compositions comprise diluent(s) in concentrations ranging from about 70% to about 99%, preferably from about 75% to about 99%, and more preferably from about 80% to about 99% by weight of the composition.
- concentration of diluent(s) is not less than 70% by weight of the composition.
- concentration of diluent(s) is not less than 75% by weight of the composition.
- concentration of diluent(s) is not less than 80% by weight of the composition.
- the non-granulated compositions of rivaroxaban comprise at least two diluents.
- the weight ratio of the diluents can range from about 1 :0.25 to about 1 :2.5.
- the non-granulated compositions of rivaroxaban comprise at least two diluents, wherein the first diluent is a water-insoluble diluent, and the second diluent is a water-soluble diluent.
- the weight ratio of water-insoluble diluent to water-soluble diluent, in the non-granulated compositions of rivaroxaban can range from about 1 :1 to 1 :2.5, preferably from about 1 :1 to 1 :2.
- the non-granulated rivaroxaban composition comprises rivaroxaban and at least two diluents, wherein rivaroxaban is not more than 20% by weight of the composition, and wherein the weight ratio of the diluents range from 1 : 0.25 to 1 : 2.5
- non-granulated compositions of the present invention comprise at least one surfactant.
- the non-granulated compositions comprise rivaroxaban, at least one diluent, and at least one surfactant.
- the surfactant(s) is selected from ionic surfactants known in the art.
- the ionic surfactant is sodium lauryl sulphate.
- non-granulated compositions are free of non-ionic surfactants.
- the non-granulated compositions comprise surfactant(s) in concentrations ranging from about 0.05% to about 1 % by weight of the composition.
- concentration of the surfactant(s) ranges from about 0.1 % to about 0.75% by weight of the composition.
- the concentration of the surfactant(s) is not more than about 1 %, preferably not more than about 0.75% and more preferably not more than about 0.5% by weight of the composition.
- the non-granulated compositions comprise surfactant(s) in concentrations of about 1% to about 50% by weight of rivaroxaban.
- the non-granulated compositions comprise rivaroxaban and surfactant in a weight ratio ranging from 1 :0.01 to 1 :0.5.
- non-granulated compositions comprise at least one disintegrant.
- non-granulated compositions are in the form of rapid release compositions and comprise rivaroxaban, at least one diluent, and at least one disintegrant.
- Disintegrant(s) may be present in concentrations from about 1 % to about 20% by weight of the composition, and are selected from those known in the art such as sodium starch glycolate, crospovidone, and croscarmellose sodium.
- Lubricant(s) may be present in concentrations from about 0.25% to about 5% by weight of the composition, and are selected from those known in the art such as magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, palmitic acid, talc, and glyceryl behenate.
- Glidant(s) may be present in concentrations from about 0.1 % to about 10% by weight of the composition, and are selected from those known in the art such as colloidal silicon dioxide, hydrated silicon dioxide, light anhydrous silicic acid, aluminum silicate, stearic acid, and talc.
- the non-granulated compositions may optionally be film coated with a film-coating layer comprising film-coating materials and optionally one or more pharmaceutically acceptable excipients selected from plasticizers, colorants, pigments, glidants, lubricants or mixtures thereof.
- the film coating materials are selected from those known in the art.
- the non-granulated compositions of rivaroxaban comprise rivaroxaban in the non-hydrophilized form.
- the non-granulated compositions are free of hydrophilic components such as hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), ethylcellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), L-HPC (low-substituted HPC), polyvinylpyrrolidone, polyvinyl alcohol, polymers of acrylic acid and its salts, vinylpyrrolidone-vinyl acetate copolymers, gelatin, guar gum, partially hydrolysed starch, alginates and xanthan gum.
- HPMC hydroxypropyl methylcellulose
- CMC carboxymethylcellulose
- HPC hydroxypropyl cellulose
- L-HPC low-substituted HPC
- polyvinylpyrrolidone polyvinyl alcohol
- non-granulated compositions are free of binders such as hydrophilic binding agents selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, maize starch, povidone, and pregelatinized starch.
- binders such as hydrophilic binding agents selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, maize starch, povidone, and pregelatinized starch.
- non-granulated compositions are free of hydrophilic matrix formers (solubilizers), carriers or binders such as povidone, copovidone, polyethylene glycol, and poloxamer.
- hydrophilic matrix formers solubilizers
- carriers or binders such as povidone, copovidone, polyethylene glycol, and poloxamer.
- the non-granulated compositions comprise rivaroxaban, at least one diluent, at least one surfactant and at least one disintegrant.
- non-granulated compositions comprise rivaroxaban, at least two diluents, at least one surfactant, and at least one disintegrant. In another embodiment, the non-granulated compositions comprise rivaroxaban, at least two diluents, at least one ionic surfactant, and at least one disintegrant.
- non-granulated compositions comprise rivaroxaban, at least one water-insoluble diluent, at least one water-soluble diluent, at least one surfactant, and at least one disintegrant.
- the non-granulated compositions consist essentially of rivaroxaban, two diluents, a surfactant, a disintegrant, and a lubricant.
- the non-granulated, rapid release compositions consist essentially of rivaroxaban, two diluents, a surfactant, a disintegrant, and a lubricant.
- the non-granulated compositions consist essentially of rivaroxaban, a water-insoluble diluent, a water-soluble diluent, a surfactant, a disintegrant, and a lubricant.
- the non-granulated, rapid release compositions consist essentially of rivaroxaban, a water-insoluble diluent, a water-soluble diluent, a surfactant, a disintegrant, and a lubricant.
- the non-granulated compositions consist essentially of rivaroxaban, a water-insoluble diluent, a water-soluble diluent, an ionic surfactant, a disintegrant, and a lubricant.
- the non-granulated, rapid-release compositions consist essentially of rivaroxaban, a water-insoluble diluent, a water-soluble diluent, an ionic surfactant, a disintegrant, and a lubricant.
- the process for preparing the non-granulated compositions comprises one or more of the following steps: a) sifting rivaroxaban, diluent(s) and optionally other excipients; b) co-sifting rivaroxaban with at least one surfactant and optionally at least one diluent to obtain a powder blend; c) sequentially blending rivaroxaban of step a) or the mixture of step b) with sifted diluent(s), and optionally other sifted excipients to obtain a powder blend ; d) optionally re-sifting and re-blending powder blends after a sequential blending process to obtain a powder blend; e) optionally directly compressing the powder blend from step b), c) or d) into tablets; f) optionally film-coating and/or seal-coating the tablets of step e) g) optionally filling the powder blend from step b), c) or d
- the non-granulated compositions comprise powder blends with a compressibility index of not more than 31 %, preferably not more than 25%, and more preferably not more than 15%.
- the non-granulated compositions comprise powder blends with a Hausner ratio of not more than 1 .45, preferably not more than 1 .34, and most preferably not more than 1 .25.
- the non-granulated compositions comprise powder blends with an angle of repose of not more than 45°, preferably not more than 40°, and most preferably not more than 35°.
- compositions comprising a powder blend can further be compressed into tablets, or filled into capsules.
- the compressibility of the non-granulated compositions was evaluated by determining the hardness and friability of the compressed tablets.
- Hardness of the non-granulated, compressed tablets of the present invention was evaluated at periodic time intervals of the compression cycle (initial, middle and end), and at various compression speeds (low speed, optimum speed, high speed).
- the hardness of the said tablets was in the range of about 3 kilopond (kp) to about 9 kilopond (kp), preferably from about 4 kilopond (kp) to about 8 kilopond (kp).
- Friability testing of the non-granulated, compressed tablets was evaluated in accordance to United States Pharmacopeia (USPNF-2021 -Issue 1 , (1216) Tablet Friability). Friability was determined using the Drum Friability Tester. 20 tablets were carefully dusted before testing, and weighed.
- the tablets were placed in the drum of friability tester and rotated at the speed of 25 ⁇ 1 rotations per minute for 4 minutes (100 rotations). After 100 rotations the tablets were de-dusted and re-weighed, and the friability percentage calculated. Acceptance criteria is that the loss in weight of the tablets, at the end of the test, should be not more that 1 %.
- the non-granulated compositions are evaluated in terms of rivaroxaban content, total impurities, blend uniformity, content uniformity, average cumulative % dissolution of rivaroxaban, and oral bioavailability.
- Blend analysis was conducted on the powder blend by sampling (in triplicate) from three different locations of the blender using a unit dose sampler. Acceptance criteria is that average % rivaroxaban content of individual sample at all locations is within 90%-110% of the target content, and the relative standard deviation of all samples is not more than 5%.
- Dissolution of rivaroxaban from the non-granulated compositions was studied in 900ml of acetate buffer pH 4.5 (with 0.2%-0.4% sodium lauryl sulphate) using USP - Type II (Paddle) apparatus at 75rpm, and calculated in terms of average cumulative percentage dissolution of rivaroxaban at various time-points.
- Dissolution of rivaroxaban from the non-granulated compositions, for rapid release is not less than 90% in 45 minutes, preferably not less than 90% in 30 minutes, preferably not less than 85% in 20 minutes, more preferably not less than 85% in 15 minutes and most preferably not less than 80% in 10 minutes.
- Total impurities content in the non-granulated compositions is not more than 3%, preferably not more than 2.5%, more preferably not more than 2%, and most preferably not more than 1 .5%.
- the total impurities in the non-granulated compositions is not more than 1 %, preferably not more than 0.8%, more preferably not more than 0.5%, and most preferably not more than 0.25%.
- the total impurities in the non-granulated compositions is not more than 0.2%.
- Accelerated Storage Conditions i) 40°C ⁇ 2°C and 75% ⁇ 5 % relative humidity (40°C/75%RH)
- compositions were analyzed for % rivaroxaban content, % total impurities and average cumulative % dissolution of rivaroxaban.
- Magnesium stearate (0.48%w/w) was sifted through 60 mesh ASTM and mixed with the second blend for about 2 minutes to give the lubricated powder blend.
- the powder blend was directly compressed into tablets using 7.8 mm, round, standard concave punch tooling.
- the compressed tablets were film-coated to 2.39% by weight of the composition using Opadry® solutions (containing hypromellose, titanium dioxide, macrogol, iron oxide yellow).
- Flow Properties of the lubricated powder blend was evaluated, and was found to have a compressibility index of 25%, a Hausner ratio of 1 .33 and an angle of repose of 39 s .
- Blend uniformity analysis of 3 batches manufactured according to Example 1 was conducted on the lubricated blend.
- ‘Average % rivaroxaban content’ met the acceptance criteria.
- the relative standard deviation calculated for the batches met the acceptance criteria and was in the range of 0.20% to 1 .10%.
- Friability of the non-granulated, directly compressed tablets of Example 1 when evaluated at periodic time intervals of the compression cycle, was found to be not more than 0.32%.
- Hardness of the non-granulated, directly compressed tablets of Example 1 when evaluated at periodic time intervals of the compression cycle, and at different compression speeds (low speed of 12 rpm; optimum speed of 15 rpm; high speed of 18 rpm), was found to be in the range of about 3 kp to about 9 kp.
- Average cumulative % dissolution of rivaroxaban from non-granulated, directly compressed tablets prepared according to Example 1 was 94% in 10 minutes.
- Rivaroxaban (d(0.5) of 4 microns, d(0.9) of 9 microns) (4.78%w/w) and sodium lauryl sulfate (0.48%w/w) were co-sifted through 60 mesh ASTM, and the sieve was rinsed with microcrystalline cellulose (10.0%w/w) to give a first blend.
- Microcrystalline cellulose (17.75%w/w), lactose (52.63%w/w) and croscarmellose sodium (1 1 ,48%w/w) were sifted through 40 mesh ASTM and sequentially mixed with first blend for about 5 minutes to give a second blend. The second blend was sifted through 24 mesh ASTM and blended again for about 20 minutes.
- Magnesium stearate (0.48%w/w) was sifted through 60 mesh ASTM and mixed with the second blend for about 2 minutes to give the lubricated powder blend.
- the lubricated powder blend was directly compressed into tablets using 7.8 mm, round, standard concave punch tooling.
- the compressed tablets were film-coated to 2.39% by weight of the composition using Opadry® solutions (containing hypromellose, titanium dioxide, macrogol, iron oxide red).
- Flow Properties of the lubricated powder blend of Example 2 was evaluated, and was found to have a compressibility index of 23.5%, a Hausner ratio of 1 .3 and an angle of repose of 42 s .
- Friability of the non-granulated, directly compressed tablets of Example 2 when evaluated at periodic time intervals of the compression cycle, was found to be not more than 0.23%.
- Hardness of the non-granulated, directly compressed tablets of Example 1 when evaluated at periodic time intervals of the compression cycle, and at different compression speeds (low speed of 12 rpm; optimum speed of 15 rpm; high speed of 18 rpm), was found to be in the range of about 3 kp to about 9 kp.
- Average cumulative % dissolution of rivaroxaban from non-granulated, directly compressed tablets prepared according to Example 2 was 96% in 15 minutes.
- Rivaroxaban (d(0.5) of 4 microns, d(0.9) of 11 microns) (9.57%w/w) and sodium lauryl sulfate (0.48%w/w) were co-sifted through 60 mesh ASTM, and the sieve was rinsed with microcrystalline cellulose (10.0%w/w) to give a first blend.
- Microcrystalline cellulose (17.75%w/w), lactose (47.85%w/w) and croscarmellose sodium (1 1 ,48%w/w) were sifted through 40 mesh ASTM and sequentially mixed with first blend for about 5 minutes to give a second blend.
- the second blend was sifted through 24 mesh ASTM and blended again for about 20 minutes.
- Magnesium stearate (0.48%w/w) was sifted through 60 mesh ASTM and mixed with the second blend for about 2 minutes to give the lubricated powder blend.
- the lubricated powder blend was directly compressed into tablets using 7.8 mm, round, standard concave punch tooling.
- the compressed tablets were film-coated to 2.39% by weight of the composition using Opadry® solutions (containing hypromellose, titanium dioxide, macrogol, iron oxide red).
- Blend uniformity analysis of 3 batches manufactured according to Example 3 was conducted on the lubricated blend.
- ‘Average % rivaroxaban content’ met the acceptance criteria.
- the relative standard deviation calculated for the batches met the acceptance criteria and was in the range of 0.63 to 0.96%.
- Rivaroxaban (d(0.5) of 4 microns, d(0.9) of 9 microns) (9.55%w/w) and sodium lauryl sulfate (0.48%w/w) were co-sifted through 60 mesh ASTM, and the sieve was rinsed with microcrystalline cellulose (10.0%w/w) to give a first blend.
- Microcrystalline cellulose (17.71%w/w), lactose (47.77%w/w) and croscarmellose sodium (1 1 ,46%w/w) were sifted through 40 mesh ASTM and sequentially mixed with first blend for about 5 minutes to give a second blend.
- the second blend was sifted through 24 mesh ASTM and blended again for about 20 minutes.
- Magnesium stearate (0.48%w/w) was sifted through 60 mesh ASTM and mixed with the second blend for about 2 minutes to give the lubricated powder blend.
- the lubricated powder blend was directly compressed into using 7.0 mm, round, standard concave punch tooling.
- the compressed tablets were film-coated to 2.55% by weight of the composition using Opadry® solutions (containing hypromellose, titanium dioxide, macrogol, iron oxide red).
- Flow Properties of the lubricated powder blend of Example 4 was evaluated, and was found to have a compressibility index of 25%, a Hausner ratio of 1 .33 and an angle of repose of 38 s .
- Blend uniformity analysis of 3 batches manufactured according to Example 4 was conducted on the lubricated blend.
- ‘Average % rivaroxaban content’ met the acceptance criteria.
- the relative standard deviation calculated for the batches met the acceptance criteria and was in the range of 0.63% to 0.96%.
- the non-granulated and directly compressed rivaroxaban tablets 10 mg of example 2 of the present invention was found to be bioequivalent to the commercially available rivaroxaban tablets 10mg (XARELTO®) (comprising granulated, hydrophilized rivaroxaban prepared by wet granulation) in a fasting bioequivalence study.
- XARELTO® commercially available rivaroxaban tablets 10mg
- the non-granulated and directly compressed rivaroxaban tablets 20 mg of example 2 of the present invention was found to be bioequivalent to the commercially available rivaroxaban tablets 20 mg (XARELTO®) (comprising granulated, hydrophilized rivaroxaban prepared by wet granulation) in a fed bioequivalence study.
- XARELTO® commercially available rivaroxaban tablets 20 mg
- the tablets of examples 1 , 2, 3 and 4 were packed in PVC-PVDC blister packs and subjected to storage stability studies. After specified time intervals, the tablets were analyzed for rivaroxaban content, total impurities and dissolution.
- Table 3 provides the % rivaroxaban content, % total impurities, and average cumulative % dissolution of rivaroxaban at 30 minutes, of the non-granulated and directly compressed tablets of examples 1 , 2, 3 and 4, after 6 months of storage.
- Table 4 provides the % rivaroxaban content, % total impurities and average cumulative % dissolution of rivaroxaban at 30 minutes, of the non-granulated and directly compressed tablets of examples 1 , 2, 3 and 4, after 24 months of storage at room temperature conditions.
- Table 3 Stability of non-granulated tablets of examples 1 , 2, 3 and 4 after 6 months of storage
- Table 4 Stability of non-granulated tablets of Examples 1 , 2, 3 and 4 after 24 months of storage
- non-granulated compositions of the present invention comprising rivaroxaban at low concentrations and diluents at high concentrations, were found to provide the desired flow properties, blend uniformity, content uniformity, dissolution, and storage stability.
- the non-granulated compositions of the present invention are bioequivalent to the commercially available rivaroxaban compositions (prepared by granulation).
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Obesity (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
Abstract
La présente invention concerne des compositions non granulaires comprenant du rivaroxaban pour une administration orale, le rivaroxaban étant à une concentration ne dépassant pas 20 % en poids de la composition. Lesdites compositions non granulaires fournissent la dissolution souhaitée, et la stabilité au stockage du rivaroxaban, et sont bioéquivalentes à des compositions granulaires disponibles dans le commerce de rivaroxaban. La présente invention concerne également un procédé de préparation de telles compositions.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN202021038382 | 2020-09-05 | ||
PCT/IN2021/050855 WO2022049602A1 (fr) | 2020-09-05 | 2021-09-04 | Compositions de rivaroxaban |
Publications (1)
Publication Number | Publication Date |
---|---|
EP4208462A1 true EP4208462A1 (fr) | 2023-07-12 |
Family
ID=80491661
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP21863854.2A Pending EP4208462A1 (fr) | 2020-09-05 | 2021-09-04 | Compositions de rivaroxaban |
Country Status (2)
Country | Link |
---|---|
EP (1) | EP4208462A1 (fr) |
WO (1) | WO2022049602A1 (fr) |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10355461A1 (de) * | 2003-11-27 | 2005-06-23 | Bayer Healthcare Ag | Verfahren zur Herstellung einer festen, oral applizierbaren pharmazeutischen Zusammensetzung |
DE102004062475A1 (de) * | 2004-12-24 | 2006-07-06 | Bayer Healthcare Ag | Feste, oral applizierbare pharmazeutische Darreichungsformen mit modifizierter Freisetzung |
HUE031177T2 (hu) * | 2009-06-18 | 2017-07-28 | Krka Tovarna Zdravil D D Novo Mesto | Rivaroxabant tartalmazó szilárd gyógyszerkészítmény |
US20130064888A1 (en) * | 2011-08-08 | 2013-03-14 | Roey Solomonovich | Pharmaceutical formulations |
WO2015124995A1 (fr) * | 2014-02-19 | 2015-08-27 | Aurobindo Pharma Ltd | Formes galéniques solides de rivaroxaban |
-
2021
- 2021-09-04 WO PCT/IN2021/050855 patent/WO2022049602A1/fr unknown
- 2021-09-04 EP EP21863854.2A patent/EP4208462A1/fr active Pending
Also Published As
Publication number | Publication date |
---|---|
WO2022049602A1 (fr) | 2022-03-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8778398B2 (en) | Immediate release formulations and dosage forms of gamma-hydroxybutyrate | |
AU2007242984B2 (en) | Controlled released preparations of oxcarbazepine having sigmoidal release profile | |
JP2009542647A (ja) | メマンチン医薬組成物 | |
JP2005517690A (ja) | 固体薬物分散物を含有する即時放出剤形 | |
WO2017170858A1 (fr) | Préparation orale présentant une exceptionnelle aptitude à l'élution | |
JP2017507928A (ja) | アンドロゲン受容体アンタゴニストの固体医薬組成物 | |
WO2008064202A2 (fr) | Formulations à libération modifiée de composés actifs vis-à-vis du récepteur de calcium | |
EP2068835A2 (fr) | Compositions d'imatinib | |
JP2008524317A (ja) | 腸溶コーティングされたアジスロマイシン多粒子 | |
TW201705944A (zh) | 含藥物之立即釋放錠劑及形成該錠劑的方法 | |
WO2016209787A1 (fr) | Formulation à libération prolongée et comprimés préparés à partir de celle-ci | |
US20220362235A1 (en) | Pharmaceutical compositions of cabozantinib | |
JP2016512845A (ja) | ソバプレビル錠剤 | |
CA3104695A1 (fr) | Formules d'ag10 | |
WO2015136329A1 (fr) | Composition pharmaceutique de cinacalcet | |
WO2017006290A1 (fr) | Compositions de nicergoline à libération modifiée | |
US20240131018A1 (en) | Pharmaceutical compositions of cabozantinib | |
WO2021074808A1 (fr) | Composition pharmaceutique comprenant du sacubitril et du valsartan et son procédé de préparation | |
US11679105B1 (en) | Pharmaceutical compositions of cabozantinib | |
WO2022049602A1 (fr) | Compositions de rivaroxaban | |
EP2925306A1 (fr) | Composition pharmaceutique de fébuxostat | |
EP2461801A2 (fr) | Compositions pharmaceutiques de milnacipran à libération contrôlée | |
JP2021518422A (ja) | レナリドミドを含む医薬組成物 | |
US20120121700A1 (en) | Pharmaceutical formulations comprising valganciclovir | |
EP4279075A1 (fr) | Composition pharmaceutique contenant de l'elagolix |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
17P | Request for examination filed |
Effective date: 20230317 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
RAP3 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: INVENTIA HEALTHCARE LIMITED |
|
DAV | Request for validation of the european patent (deleted) | ||
DAX | Request for extension of the european patent (deleted) |