CA3028346A1 - Solid composition containing oral anticoagulant - Google Patents
Solid composition containing oral anticoagulant Download PDFInfo
- Publication number
- CA3028346A1 CA3028346A1 CA3028346A CA3028346A CA3028346A1 CA 3028346 A1 CA3028346 A1 CA 3028346A1 CA 3028346 A CA3028346 A CA 3028346A CA 3028346 A CA3028346 A CA 3028346A CA 3028346 A1 CA3028346 A1 CA 3028346A1
- Authority
- CA
- Canada
- Prior art keywords
- starch
- rivaroxaban
- sodium
- cellulose
- composition
- 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.)
- Abandoned
Links
- 239000003146 anticoagulant agent Substances 0.000 title abstract description 7
- 239000008247 solid mixture Substances 0.000 title description 3
- 239000000203 mixture Substances 0.000 claims abstract description 70
- 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 claims abstract description 55
- 229960001148 rivaroxaban Drugs 0.000 claims abstract description 55
- 238000000034 method Methods 0.000 claims abstract description 24
- 230000008569 process Effects 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 14
- 229940079593 drug Drugs 0.000 claims abstract description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 48
- -1 glidants Substances 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 239000006185 dispersion Substances 0.000 claims description 25
- 239000008213 purified water Substances 0.000 claims description 23
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 20
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 19
- 235000002639 sodium chloride Nutrition 0.000 claims description 19
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 18
- 150000004677 hydrates Chemical class 0.000 claims description 17
- 239000012453 solvate Substances 0.000 claims description 17
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 16
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 16
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 16
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 14
- 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 14
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 14
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 13
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 13
- 229920002472 Starch Chemical class 0.000 claims description 13
- 239000008187 granular material Substances 0.000 claims description 13
- 239000000463 material Substances 0.000 claims description 13
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 13
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 13
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 13
- 239000008203 oral pharmaceutical composition Substances 0.000 claims description 13
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 13
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 12
- 239000008188 pellet Substances 0.000 claims description 12
- 239000011230 binding agent Substances 0.000 claims description 11
- 235000019698 starch Nutrition 0.000 claims description 11
- 235000000346 sugar Nutrition 0.000 claims description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 10
- 235000019359 magnesium stearate Nutrition 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 229940032147 starch Drugs 0.000 claims description 10
- 239000008107 starch Chemical class 0.000 claims description 10
- 239000004094 surface-active agent Substances 0.000 claims description 10
- 239000011248 coating agent Substances 0.000 claims description 9
- 239000003085 diluting agent Substances 0.000 claims description 9
- 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 8
- 229920002678 cellulose Chemical class 0.000 claims description 8
- 235000010980 cellulose Nutrition 0.000 claims description 8
- 238000000576 coating method Methods 0.000 claims description 8
- 238000005507 spraying Methods 0.000 claims description 8
- 229930006000 Sucrose Natural products 0.000 claims description 7
- 239000007884 disintegrant Substances 0.000 claims description 7
- 239000000314 lubricant Substances 0.000 claims description 7
- 229960004793 sucrose Drugs 0.000 claims description 7
- 239000004359 castor oil Substances 0.000 claims description 6
- 235000019438 castor oil Nutrition 0.000 claims description 6
- 239000001913 cellulose Substances 0.000 claims description 6
- 239000012530 fluid Substances 0.000 claims description 6
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 6
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 5
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 5
- 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 claims description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 5
- 239000005720 sucrose Substances 0.000 claims description 5
- 239000005995 Aluminium silicate 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
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 4
- 229920002261 Corn starch Polymers 0.000 claims description 4
- 229920000881 Modified starch Polymers 0.000 claims description 4
- 235000021355 Stearic acid Nutrition 0.000 claims description 4
- 235000012211 aluminium silicate Nutrition 0.000 claims description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 4
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 4
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 4
- 229940105329 carboxymethylcellulose Drugs 0.000 claims description 4
- 238000007906 compression Methods 0.000 claims description 4
- 230000006835 compression Effects 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 4
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 4
- 229920000642 polymer Polymers 0.000 claims description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 4
- 229920001592 potato starch Polymers 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 239000008117 stearic acid Substances 0.000 claims description 4
- 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 3
- 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 3
- 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 3
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 3
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 3
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 claims description 3
- 229920001577 copolymer Polymers 0.000 claims description 3
- 238000005516 engineering process Methods 0.000 claims description 3
- 239000000945 filler Substances 0.000 claims description 3
- 229910021485 fumed silica Inorganic materials 0.000 claims description 3
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 229920000609 methyl cellulose Polymers 0.000 claims description 3
- 235000010981 methylcellulose Nutrition 0.000 claims description 3
- 239000001923 methylcellulose Substances 0.000 claims description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 3
- 235000010356 sorbitol Nutrition 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims 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 claims description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical class COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 2
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- 241000416162 Astragalus gummifer Species 0.000 claims description 2
- 229920002307 Dextran Polymers 0.000 claims description 2
- 229920000896 Ethulose Polymers 0.000 claims description 2
- 239000001856 Ethyl cellulose Substances 0.000 claims 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 claims description 2
- 239000001859 Ethyl hydroxyethyl cellulose Substances 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
- 239000001828 Gelatine Substances 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 229920002907 Guar gum Polymers 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 claims description 2
- 240000007472 Leucaena leucocephala Species 0.000 claims description 2
- 229920000161 Locust bean gum Polymers 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- 235000019759 Maize starch Nutrition 0.000 claims description 2
- 229920003110 Primojel Polymers 0.000 claims description 2
- 229920001615 Tragacanth Polymers 0.000 claims description 2
- 229920000615 alginic acid Polymers 0.000 claims description 2
- 235000010443 alginic acid Nutrition 0.000 claims description 2
- PZZYQPZGQPZBDN-UHFFFAOYSA-N aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 claims description 2
- 229910000323 aluminium silicate Inorganic materials 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 235000010216 calcium carbonate Nutrition 0.000 claims description 2
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 2
- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 claims description 2
- 239000001527 calcium lactate Substances 0.000 claims description 2
- 229960002401 calcium lactate Drugs 0.000 claims description 2
- 235000011086 calcium lactate Nutrition 0.000 claims description 2
- 235000013539 calcium stearate Nutrition 0.000 claims description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 2
- 239000008116 calcium stearate Substances 0.000 claims description 2
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 claims description 2
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 claims description 2
- 239000008120 corn starch Substances 0.000 claims description 2
- 229940099112 cornstarch Drugs 0.000 claims description 2
- 229960000913 crospovidone Drugs 0.000 claims description 2
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 claims description 2
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 2
- 235000013681 dietary sucrose Nutrition 0.000 claims description 2
- FSBVERYRVPGNGG-UHFFFAOYSA-N dimagnesium dioxido-bis[[oxido(oxo)silyl]oxy]silane hydrate Chemical compound O.[Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O FSBVERYRVPGNGG-UHFFFAOYSA-N 0.000 claims description 2
- 238000009826 distribution Methods 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
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- 235000019326 ethyl hydroxyethyl cellulose Nutrition 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 239000000665 guar gum Substances 0.000 claims description 2
- 235000010417 guar gum Nutrition 0.000 claims description 2
- 229960002154 guar gum Drugs 0.000 claims description 2
- 239000008172 hydrogenated vegetable oil Substances 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
- 239000000832 lactitol Substances 0.000 claims description 2
- 235000010448 lactitol Nutrition 0.000 claims description 2
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol 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-JVCRWLNRSA-N 0.000 claims description 2
- 229960003451 lactitol Drugs 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 229960001375 lactose Drugs 0.000 claims description 2
- 235000010420 locust bean gum Nutrition 0.000 claims description 2
- 239000000711 locust bean gum Substances 0.000 claims description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 239000000391 magnesium silicate Substances 0.000 claims description 2
- 235000019793 magnesium trisilicate Nutrition 0.000 claims description 2
- 229940099273 magnesium trisilicate Drugs 0.000 claims description 2
- 229910000386 magnesium trisilicate Inorganic materials 0.000 claims description 2
- 229960001855 mannitol Drugs 0.000 claims description 2
- 150000004682 monohydrates Chemical class 0.000 claims description 2
- 239000002245 particle Substances 0.000 claims description 2
- 229920000193 polymethacrylate Polymers 0.000 claims description 2
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 claims description 2
- 229940116317 potato starch Drugs 0.000 claims description 2
- 229920003124 powdered cellulose Polymers 0.000 claims description 2
- 235000019814 powdered cellulose Nutrition 0.000 claims description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 2
- 229940100486 rice starch Drugs 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 229940023144 sodium glycolate Drugs 0.000 claims description 2
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 2
- 239000008109 sodium starch glycolate Substances 0.000 claims description 2
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 229960002920 sorbitol Drugs 0.000 claims description 2
- 150000008163 sugars Chemical class 0.000 claims description 2
- 239000000454 talc Substances 0.000 claims description 2
- 229910052623 talc Inorganic materials 0.000 claims description 2
- 235000010487 tragacanth Nutrition 0.000 claims description 2
- 239000000196 tragacanth Substances 0.000 claims description 2
- 229940116362 tragacanth Drugs 0.000 claims description 2
- JEJAMASKDTUEBZ-UHFFFAOYSA-N tris(1,1,3-tribromo-2,2-dimethylpropyl) phosphate Chemical compound BrCC(C)(C)C(Br)(Br)OP(=O)(OC(Br)(Br)C(C)(C)CBr)OC(Br)(Br)C(C)(C)CBr JEJAMASKDTUEBZ-UHFFFAOYSA-N 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 229940100445 wheat starch Drugs 0.000 claims description 2
- 229920001285 xanthan gum Polymers 0.000 claims description 2
- LQIAZOCLNBBZQK-UHFFFAOYSA-N 1-(1,2-Diphosphanylethyl)pyrrolidin-2-one Chemical compound PCC(P)N1CCCC1=O LQIAZOCLNBBZQK-UHFFFAOYSA-N 0.000 claims 2
- 229920003085 Kollidon® CL Polymers 0.000 claims 1
- 239000011575 calcium Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 11
- 239000007787 solid Substances 0.000 abstract description 6
- 239000007935 oral tablet Substances 0.000 abstract description 3
- 239000003826 tablet Substances 0.000 description 29
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 10
- 239000007888 film coating Substances 0.000 description 10
- 238000009501 film coating Methods 0.000 description 10
- 229960001021 lactose monohydrate Drugs 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 235000014113 dietary fatty acids Nutrition 0.000 description 8
- 239000000194 fatty acid Substances 0.000 description 8
- 229930195729 fatty acid Natural products 0.000 description 8
- 238000005469 granulation Methods 0.000 description 8
- 230000003179 granulation Effects 0.000 description 8
- 239000008194 pharmaceutical composition Substances 0.000 description 8
- 239000008389 polyethoxylated castor oil Substances 0.000 description 7
- 239000004615 ingredient Substances 0.000 description 6
- 239000002775 capsule Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 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 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 108010074860 Factor Xa Proteins 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 229920002556 Polyethylene Glycol 300 Polymers 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
- 229920003086 cellulose ether Polymers 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 235000010445 lecithin Nutrition 0.000 description 3
- 239000000787 lecithin Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 150000005846 sugar alcohols Polymers 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 description 2
- SERLAGPUMNYUCK-DCUALPFSSA-N 1-O-alpha-D-glucopyranosyl-D-mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O SERLAGPUMNYUCK-DCUALPFSSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- KMZHZAAOEWVPSE-UHFFFAOYSA-N 2,3-dihydroxypropyl acetate Chemical class CC(=O)OCC(O)CO KMZHZAAOEWVPSE-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- 229920001214 Polysorbate 60 Polymers 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 2
- 229960000878 docusate sodium Drugs 0.000 description 2
- 238000007908 dry granulation Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 239000000905 isomalt Substances 0.000 description 2
- 235000010439 isomalt Nutrition 0.000 description 2
- HPIGCVXMBGOWTF-UHFFFAOYSA-N isomaltol Natural products CC(=O)C=1OC=CC=1O HPIGCVXMBGOWTF-UHFFFAOYSA-N 0.000 description 2
- 238000007909 melt granulation Methods 0.000 description 2
- 238000003801 milling Methods 0.000 description 2
- 239000008185 minitablet Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 239000008184 oral solid dosage form Substances 0.000 description 2
- 239000004014 plasticizer Substances 0.000 description 2
- 229920000058 polyacrylate Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 235000004400 serine Nutrition 0.000 description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 229940035044 sorbitan monolaurate Drugs 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- 235000008521 threonine Nutrition 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- VXUOFDJKYGDUJI-UHFFFAOYSA-N (2-hydroxy-3-tetradecanoyloxypropyl) 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCC(=O)OCC(O)COP([O-])(=O)OCC[N+](C)(C)C VXUOFDJKYGDUJI-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- ASWBNKHCZGQVJV-UHFFFAOYSA-N (3-hexadecanoyloxy-2-hydroxypropyl) 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(O)COP([O-])(=O)OCC[N+](C)(C)C ASWBNKHCZGQVJV-UHFFFAOYSA-N 0.000 description 1
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 description 1
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- ZPDQFUYPBVXUKS-YADHBBJMSA-N 1-stearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)COP(O)(=O)OC[C@H](N)C(O)=O ZPDQFUYPBVXUKS-YADHBBJMSA-N 0.000 description 1
- LDGWQMRUWMSZIU-LQDDAWAPSA-M 2,3-bis[(z)-octadec-9-enoxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCCOCC(C[N+](C)(C)C)OCCCCCCCC\C=C/CCCCCCCC LDGWQMRUWMSZIU-LQDDAWAPSA-M 0.000 description 1
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 description 1
- CTXGTHVAWRBISV-UHFFFAOYSA-N 2-hydroxyethyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCCO CTXGTHVAWRBISV-UHFFFAOYSA-N 0.000 description 1
- BHIZVZJETFVJMJ-UHFFFAOYSA-N 2-hydroxypropyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCC(C)O BHIZVZJETFVJMJ-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- RZRNAYUHWVFMIP-GDCKJWNLSA-N 3-oleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-GDCKJWNLSA-N 0.000 description 1
- OCKGFTQIICXDQW-ZEQRLZLVSA-N 5-[(1r)-1-hydroxy-2-[4-[(2r)-2-hydroxy-2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-4-methyl-3h-2-benzofuran-1-one Chemical compound C1=C2C(=O)OCC2=C(C)C([C@@H](O)CN2CCN(CC2)C[C@H](O)C2=CC=C3C(=O)OCC3=C2C)=C1 OCKGFTQIICXDQW-ZEQRLZLVSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 102000004411 Antithrombin III Human genes 0.000 description 1
- 108090000935 Antithrombin III Proteins 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- 241000212384 Bifora Species 0.000 description 1
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- 206010051055 Deep vein thrombosis Diseases 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 229920005682 EO-PO block copolymer Polymers 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 108010014173 Factor X Proteins 0.000 description 1
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 1
- IECPWNUMDGFDKC-UHFFFAOYSA-N Fusicsaeure Natural products C12C(O)CC3C(=C(CCC=C(C)C)C(O)=O)C(OC(C)=O)CC3(C)C1(C)CCC1C2(C)CCC(O)C1C IECPWNUMDGFDKC-UHFFFAOYSA-N 0.000 description 1
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 1
- 239000004348 Glyceryl diacetate Substances 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 229920002507 Poloxamer 124 Polymers 0.000 description 1
- 229920002511 Poloxamer 237 Polymers 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 1
- 229920002690 Polyoxyl 40 HydrogenatedCastorOil Polymers 0.000 description 1
- 229920002700 Polyoxyl 60 hydrogenated castor oil Polymers 0.000 description 1
- 229920001219 Polysorbate 40 Polymers 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical class CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- ULUAUXLGCMPNKK-UHFFFAOYSA-N Sulfobutanedioic acid Chemical class OC(=O)CC(C(O)=O)S(O)(=O)=O ULUAUXLGCMPNKK-UHFFFAOYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- NWGKJDSIEKMTRX-BFWOXRRGSA-N [(2r)-2-[(3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)C1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-BFWOXRRGSA-N 0.000 description 1
- GCSPRLPXTPMSTL-IBDNADADSA-N [(2s,3r,4s,5s,6r)-2-[(2s,3s,4s,5r)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)O[C@@]1([C@]2(CO)[C@H]([C@H](O)[C@@H](CO)O2)O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O GCSPRLPXTPMSTL-IBDNADADSA-N 0.000 description 1
- ZPVGIKNDGJGLCO-VGAMQAOUSA-N [(2s,3r,4s,5s,6r)-2-[(2s,3s,4s,5r)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)O[C@@]1([C@]2(CO)[C@H]([C@H](O)[C@@H](CO)O2)O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O ZPVGIKNDGJGLCO-VGAMQAOUSA-N 0.000 description 1
- SZYSLWCAWVWFLT-UTGHZIEOSA-N [(2s,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)-2-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxolan-2-yl]methyl octadecanoate Chemical compound O([C@@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@]1(COC(=O)CCCCCCCCCCCCCCCCC)O[C@H](CO)[C@@H](O)[C@@H]1O SZYSLWCAWVWFLT-UTGHZIEOSA-N 0.000 description 1
- UGZICOVULPINFH-UHFFFAOYSA-N acetic acid;butanoic acid Chemical compound CC(O)=O.CCCC(O)=O UGZICOVULPINFH-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229920006243 acrylic copolymer Polymers 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229940064004 antiseptic throat preparations Drugs 0.000 description 1
- 229960005348 antithrombin iii Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000011021 bench scale process Methods 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- DWKPZOZZBLWFJX-UHFFFAOYSA-L calcium;1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate Chemical compound [Ca+2].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC.CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC DWKPZOZZBLWFJX-UHFFFAOYSA-L 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 229940106189 ceramide Drugs 0.000 description 1
- 150000001783 ceramides Chemical class 0.000 description 1
- 229960001927 cetylpyridinium chloride Drugs 0.000 description 1
- NFCRBQADEGXVDL-UHFFFAOYSA-M cetylpyridinium chloride monohydrate Chemical compound O.[Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 NFCRBQADEGXVDL-UHFFFAOYSA-M 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- YHAIUSTWZPMYGG-UHFFFAOYSA-L disodium;2,2-dioctyl-3-sulfobutanedioate Chemical compound [Na+].[Na+].CCCCCCCCC(C([O-])=O)(C(C([O-])=O)S(O)(=O)=O)CCCCCCCC YHAIUSTWZPMYGG-UHFFFAOYSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 229940018614 docusate calcium Drugs 0.000 description 1
- 229940018600 docusate potassium Drugs 0.000 description 1
- QBHFVMDLPTZDOI-UHFFFAOYSA-N dodecylphosphocholine Chemical compound CCCCCCCCCCCCOP([O-])(=O)OCC[N+](C)(C)C QBHFVMDLPTZDOI-UHFFFAOYSA-N 0.000 description 1
- 238000007580 dry-mixing Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940031098 ethanolamine Drugs 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- 230000006624 extrinsic pathway Effects 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000004088 foaming agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- IECPWNUMDGFDKC-MZJAQBGESA-N fusidic acid Chemical class O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C(O)=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C IECPWNUMDGFDKC-MZJAQBGESA-N 0.000 description 1
- 229960004675 fusidic acid Drugs 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 150000002270 gangliosides Chemical class 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 150000002327 glycerophospholipids Chemical class 0.000 description 1
- 235000019443 glyceryl diacetate Nutrition 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 238000009474 hot melt extrusion Methods 0.000 description 1
- 239000012943 hotmelt Substances 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 150000002462 imidazolines Chemical class 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 230000006623 intrinsic pathway Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 238000009481 moist granulation Methods 0.000 description 1
- RIEABXYBQSLTFR-UHFFFAOYSA-N monobutyrin Chemical compound CCCC(=O)OCC(O)CO RIEABXYBQSLTFR-UHFFFAOYSA-N 0.000 description 1
- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 description 1
- 125000001419 myristoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229960002446 octanoic acid Drugs 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 239000003605 opacifier Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 229940094335 peg-200 dilaurate Drugs 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 229940083254 peripheral vasodilators imidazoline derivative Drugs 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000008016 pharmaceutical coating Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229940093448 poloxamer 124 Drugs 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 229940044476 poloxamer 407 Drugs 0.000 description 1
- 229940113116 polyethylene glycol 1000 Drugs 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- CACRHRQTJDKAPJ-UHFFFAOYSA-M potassium;1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate Chemical compound [K+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC CACRHRQTJDKAPJ-UHFFFAOYSA-M 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 229940026235 propylene glycol monolaurate Drugs 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- GHBFNMLVSPCDGN-UHFFFAOYSA-N rac-1-monooctanoylglycerol Chemical compound CCCCCCCC(=O)OCC(O)CO GHBFNMLVSPCDGN-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 229960001153 serine Drugs 0.000 description 1
- 150000003355 serines Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229960005480 sodium caprylate Drugs 0.000 description 1
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 description 1
- FHHPUSMSKHSNKW-SMOYURAASA-M sodium deoxycholate Chemical compound [Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 FHHPUSMSKHSNKW-SMOYURAASA-M 0.000 description 1
- OABYVIYXWMZFFJ-ZUHYDKSRSA-M sodium glycocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 OABYVIYXWMZFFJ-ZUHYDKSRSA-M 0.000 description 1
- BYKRNSHANADUFY-UHFFFAOYSA-M sodium octanoate Chemical compound [Na+].CCCCCCCC([O-])=O BYKRNSHANADUFY-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 description 1
- FCZYGJBVLGLYQU-UHFFFAOYSA-M sodium;2-[2-[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethoxy]ethoxy]ethanesulfonate Chemical compound [Na+].CC(C)(C)CC(C)(C)C1=CC=C(OCCOCCOCCS([O-])(=O)=O)C=C1 FCZYGJBVLGLYQU-UHFFFAOYSA-M 0.000 description 1
- IWQPOPSAISBUAH-VOVMJQHHSA-M sodium;2-[[(2z)-2-[(3r,4s,5s,8s,9s,10s,11r,13r,14s,16s)-16-acetyl-3,11-dihydroxy-4,8,10,14-tetramethyl-2,3,4,5,6,7,9,11,12,13,15,16-dodecahydro-1h-cyclopenta[a]phenanthren-17-ylidene]-6-methylheptanoyl]amino]ethanesulfonate Chemical compound [Na+].C1C[C@@H](O)[C@@H](C)[C@@H]2CC[C@]3(C)[C@@]4(C)C[C@H](C(C)=O)/C(=C(C(=O)NCCS([O-])(=O)=O)/CCCC(C)C)[C@@H]4C[C@@H](O)[C@H]3[C@]21C IWQPOPSAISBUAH-VOVMJQHHSA-M 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 235000011071 sorbitan monopalmitate Nutrition 0.000 description 1
- 239000001570 sorbitan monopalmitate Substances 0.000 description 1
- 229940031953 sorbitan monopalmitate Drugs 0.000 description 1
- 229950011392 sorbitan stearate Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 229960002898 threonine Drugs 0.000 description 1
- 150000003588 threonines Chemical class 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 description 1
- 229960001661 ursodiol Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 235000008979 vitamin B4 Nutrition 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 239000002888 zwitterionic surfactant 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Abstract
The present invention relates to the field of Oral pharmaceuticals. The invention specifically relates to solid oral anticoagulant compositions and methods for the preparation of the same. The present invention more specifically relates to composition and process for preparation of Rivaroxaban Oral tablets prepared by drug layered spheres.
Description
SOLID COMPOSITION CONTAINING ORAL ANTICOAGULANT
FIELD OF INVENTION
The present invention relates to the field of Oral pharmaceuticals.
The invention specifically relates to solid oral anticoagulant compositions and methods for the preparation of the same.
The present invention more specifically relates to composition of Rivaroxaban Oral tablets and methods for the preparation of the same.
This invention also relates to the composition of Rivaroxaban Oral tablets prepared by drug layered spheres.
This invention also relates to the composition of Rivaroxaban tablets prepared by Non-aqueous granulation using Organic solvent and Hydroalcoholic granulation.
BACKGROUND OF INVENTION
The active ingredient in the present invention is Rivaroxaban chemically known as "5-Chloro-N-({(5S)-2-oxo-344-(3-oxo-4-morpholinyl) phenyl]-1, 3-oxazolidin-5-yll methyl)-2-thiophenecarboxamide" and has an empirical chemical formula C19H18C1N305S with a structural formula shown below:
s ci Rivaroxaban is a low molecular weight, orally administrable anticoagulant indicated for reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation and prophylaxis of deep vein thrombosis. It is an orally bioavailable factor Xa inhibitor that selectively blocks the active site of factor Xa and does not require a cofactor (such as Anti-thrombin III) for activity. Activation of factor X to factor Xa (FXa) via the intrinsic and extrinsic pathways plays a central role in the cascade of blood coagulation.
US 7157456 discloses rivaroxaban product with method of use as anticoagulant and different crystalline polymorphic forms of Rivaroxaban are disclosed in various patents and patent applications like US 8188270, US 20100168111, WO 2012004245 and W02013041651.
US 2008/0026057 disclose a solid, orally administrable pharmaceutical composition, comprising rivaroxaban in hydrophilized form. This application further discloses a process for the preparation of composition comprising Rivaroxaban in hydrophilized form, in which (a) first granules comprising the Rivaroxaban in hydrophilized form are prepared by moist granulation (b) and the granules are then converted into the pharmaceutical composition, if appropriate with addition of pharmaceutically suitable additives.
US 2010/0151011 disclose rapid release solid pharmaceutical dosage form of rivaroxaban containing drug in amorphous form or thermodynamically metastable crystal modification form. Use of these modified forms increases the solubility and the oral bioavailability of rivaroxaban.
US 2011/0300214 disclose pharmaceutical compositions of rivaroxaban comprising a solubilizer and a pseudo-emulsifier.
US 2012/0231076 disclose process for producing a pharmaceutical composition of rivaroxaban. The process involves mixing rivaroxaban, a matrix former, and a disintegrant, melting the mixture, and granulating the melted mixture.
US 2013/0064888 disclose pharmaceutical dosage forms of rivaroxaban having a compressed inert core, an optional subcoat over the compressed inert core, a drug layer over the compressed core.
WO 2010/146179 disclose solid pharmaceutical compositions of rivaroxaban, prepared by dry mixing or dry granulation of the rivaroxaban with at least one
FIELD OF INVENTION
The present invention relates to the field of Oral pharmaceuticals.
The invention specifically relates to solid oral anticoagulant compositions and methods for the preparation of the same.
The present invention more specifically relates to composition of Rivaroxaban Oral tablets and methods for the preparation of the same.
This invention also relates to the composition of Rivaroxaban Oral tablets prepared by drug layered spheres.
This invention also relates to the composition of Rivaroxaban tablets prepared by Non-aqueous granulation using Organic solvent and Hydroalcoholic granulation.
BACKGROUND OF INVENTION
The active ingredient in the present invention is Rivaroxaban chemically known as "5-Chloro-N-({(5S)-2-oxo-344-(3-oxo-4-morpholinyl) phenyl]-1, 3-oxazolidin-5-yll methyl)-2-thiophenecarboxamide" and has an empirical chemical formula C19H18C1N305S with a structural formula shown below:
s ci Rivaroxaban is a low molecular weight, orally administrable anticoagulant indicated for reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation and prophylaxis of deep vein thrombosis. It is an orally bioavailable factor Xa inhibitor that selectively blocks the active site of factor Xa and does not require a cofactor (such as Anti-thrombin III) for activity. Activation of factor X to factor Xa (FXa) via the intrinsic and extrinsic pathways plays a central role in the cascade of blood coagulation.
US 7157456 discloses rivaroxaban product with method of use as anticoagulant and different crystalline polymorphic forms of Rivaroxaban are disclosed in various patents and patent applications like US 8188270, US 20100168111, WO 2012004245 and W02013041651.
US 2008/0026057 disclose a solid, orally administrable pharmaceutical composition, comprising rivaroxaban in hydrophilized form. This application further discloses a process for the preparation of composition comprising Rivaroxaban in hydrophilized form, in which (a) first granules comprising the Rivaroxaban in hydrophilized form are prepared by moist granulation (b) and the granules are then converted into the pharmaceutical composition, if appropriate with addition of pharmaceutically suitable additives.
US 2010/0151011 disclose rapid release solid pharmaceutical dosage form of rivaroxaban containing drug in amorphous form or thermodynamically metastable crystal modification form. Use of these modified forms increases the solubility and the oral bioavailability of rivaroxaban.
US 2011/0300214 disclose pharmaceutical compositions of rivaroxaban comprising a solubilizer and a pseudo-emulsifier.
US 2012/0231076 disclose process for producing a pharmaceutical composition of rivaroxaban. The process involves mixing rivaroxaban, a matrix former, and a disintegrant, melting the mixture, and granulating the melted mixture.
US 2013/0064888 disclose pharmaceutical dosage forms of rivaroxaban having a compressed inert core, an optional subcoat over the compressed inert core, a drug layer over the compressed core.
WO 2010/146179 disclose solid pharmaceutical compositions of rivaroxaban, prepared by dry mixing or dry granulation of the rivaroxaban with at least one
2 excipient, co-milling rivaroxaban with the excipients, hot melt granulation with a molten excipient, or hot melt extrusion with an excipient. The mixture may then be agglomerated, granulated with a granulation liquid, or milled before compressing to form a tablet.
WO 2015/124995 Al disclose an oral solid dosage form of rivaroxaban, prepared by a process, comprising the steps of blending, granulation, drying, milling and formulating the blend obtained into solid dosage form.
The above prior art references discloses different process for the preparation of solid oral dosage form of rivaroxaban. However, the inventors of the present invention have formulated a simple formulation with simple process which will provide enhanced dissolution and bioavailability of drug.
OBJECTIVE OF INVENTION
The main objective of the present invention is to provide an oral solid dosage form of rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients.
Another objective of the present invention is to provide a process for the Preparation of solid dosage form of rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts.
Another objective of the invention is to provide an alternative pharmaceutical composition of rivaroxaban and its method of preparation which will enhance the dissolution and oral bioavailability of the drug.
SUMMARY OF INVENTION
One embodiment of the present invention provides an oral pharmaceutical composition comprising Rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts prepared by drug layering technology.
WO 2015/124995 Al disclose an oral solid dosage form of rivaroxaban, prepared by a process, comprising the steps of blending, granulation, drying, milling and formulating the blend obtained into solid dosage form.
The above prior art references discloses different process for the preparation of solid oral dosage form of rivaroxaban. However, the inventors of the present invention have formulated a simple formulation with simple process which will provide enhanced dissolution and bioavailability of drug.
OBJECTIVE OF INVENTION
The main objective of the present invention is to provide an oral solid dosage form of rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients.
Another objective of the present invention is to provide a process for the Preparation of solid dosage form of rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts.
Another objective of the invention is to provide an alternative pharmaceutical composition of rivaroxaban and its method of preparation which will enhance the dissolution and oral bioavailability of the drug.
SUMMARY OF INVENTION
One embodiment of the present invention provides an oral pharmaceutical composition comprising Rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts prepared by drug layering technology.
3 In another embodiment of the present invention provides an oral pharmaceutical composition comprising Rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts prepared by non-aqueous granulation and hydroalcoholic granulation.
In another embodiment of the present invention provides an oral pharmaceutical composition comprising Rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts prepared by non-aqueous granulation/
Hydroalcoholic granulation containing cremophore.
In another embodiment of the present invention provides an oral pharmaceutical composition comprising Rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, diluents/fillers, binders, disintegrants, glidants, lubricants, surfactants, solubilizers and other excipients.
In another embodiment of the present invention provides an oral pharmaceutical composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, prepared by a process comprising steps of:
a) Dissolving excipients in mixture of ethanol and Purified water, b) Dispersing drug in step 1 solution until smooth dispersion forms, c) Spraying step 2 dispersion on to sugar pellets, and d) Adding extragranular materials to step 3 pellets and blend followed by compression and optional coating.
In another embodiment of the present invention provides an oral pharmaceutical composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, prepared by a process comprising steps of:
a) Dissolving Hydroxypropyl cellulose, Croscarmellose sodium and Sodium lauryl sulphate in mixture of ethanol and Purified water, b) Dispersing Rivaroxaban in step 1 solution until smooth dispersion forms, c) Spraying step 2 dispersion on to sugar pellets in Fluid bed dryer, d) Adding extragranular materials to step 3 pellets and blend,
In another embodiment of the present invention provides an oral pharmaceutical composition comprising Rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts prepared by non-aqueous granulation/
Hydroalcoholic granulation containing cremophore.
In another embodiment of the present invention provides an oral pharmaceutical composition comprising Rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, diluents/fillers, binders, disintegrants, glidants, lubricants, surfactants, solubilizers and other excipients.
In another embodiment of the present invention provides an oral pharmaceutical composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, prepared by a process comprising steps of:
a) Dissolving excipients in mixture of ethanol and Purified water, b) Dispersing drug in step 1 solution until smooth dispersion forms, c) Spraying step 2 dispersion on to sugar pellets, and d) Adding extragranular materials to step 3 pellets and blend followed by compression and optional coating.
In another embodiment of the present invention provides an oral pharmaceutical composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, prepared by a process comprising steps of:
a) Dissolving Hydroxypropyl cellulose, Croscarmellose sodium and Sodium lauryl sulphate in mixture of ethanol and Purified water, b) Dispersing Rivaroxaban in step 1 solution until smooth dispersion forms, c) Spraying step 2 dispersion on to sugar pellets in Fluid bed dryer, d) Adding extragranular materials to step 3 pellets and blend,
4
5 PCT/IB2017/054031 e) Compressing the tablets using step 4 blend, f) Dispersing Opadry brown in Purified water, and g) Coating the tablets of step 5 with step 6 dispersion.
In another embodiment of the present invention provides an oral pharmaceutical composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, prepared by a process comprising steps of:
a) Preparing binder solution, b) Dispersing Drug in step 1 solution until smooth dispersion forms, c) Sifting and blending the excipients, d) Spraying step 2 dispersion on to step 3 blend until proper granules obtains, and e) Adding extragranular materials and compression with optional coating.
In another embodiment of the present invention provides an oral pharmaceutical composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, prepared by a process comprising steps of:
a) Dissolving Hydroxypropyl cellulose and Cremophor in ethanol or mixture of Ethanol and Purified water, b) Dispersing Rivaroxaban in step 1 solution until smooth dispersion forms, c) Sifting Croscarmellose sodium, Lactose monohydrate and microcrystalline cellulose, d) Spraying step 2 dispersion on to step 3 blend in Fluid bed dryer until proper granules obtained, e) Adding extragranular materials to step 4 granules and blend, and f) Compressing the tablets using step 5 blend.
DETAILED DESCRIPTION OF THE INVENTION
The invention specifically relates to oral anticoagulant compositions and methods for the preparation of the same.
One embodiment of the present invention provides an oral pharmaceutical composition comprising Rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, diluents, binders, disintegrants, glidants, lubricants, surfactants, solubilizers and other excipients.
In another embodiment of the present invention provides process for the preparation of oral solid composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, diluents, binders, disintegrants, glidants, lubricants, surfactants and other excipients.
The term "rivaroxaban" includes various forms of rivaroxaban such as hydrates, solvates, polymorphs, isomers, stereoisomers, enantiomers, racemates, esters, prodrugs, complexes or mixture thereof and all other forms known in the art.
Rivaroxaban can be present in different physical forms, e.g. in an amorphous form, in one or several crystal form (s) (e.g. anhydrous, solvated or hydrated forms), in the form of mixture of different crystal forms (e.g. anhydrous, solvated or hydrated forms) or as a mixture of an amorphous form and crystal form (s) (e.g. anhydrous, solvated or hydrated forms). Each of these forms is included in the term "rivaroxaban" as used in the present invention.
The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.
The composition according to the invention comprise diluents such as microcrystalline cellulose, powdered cellulose, lactose (anhydrous or monohydrate), compressible sugar, fructose, dextranes, other sugars such as mannitol, sorbitol, lactitol, saccharose or a mixture thereof, siliconised microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, calcium lactate or mixtures thereof.
A preferred further diluent that also causes reduced sticking properties of tablets to the equipment used for tabletting is silica, preferably colloidal or fumed silica.
Preferably,
In another embodiment of the present invention provides an oral pharmaceutical composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, prepared by a process comprising steps of:
a) Preparing binder solution, b) Dispersing Drug in step 1 solution until smooth dispersion forms, c) Sifting and blending the excipients, d) Spraying step 2 dispersion on to step 3 blend until proper granules obtains, and e) Adding extragranular materials and compression with optional coating.
In another embodiment of the present invention provides an oral pharmaceutical composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, prepared by a process comprising steps of:
a) Dissolving Hydroxypropyl cellulose and Cremophor in ethanol or mixture of Ethanol and Purified water, b) Dispersing Rivaroxaban in step 1 solution until smooth dispersion forms, c) Sifting Croscarmellose sodium, Lactose monohydrate and microcrystalline cellulose, d) Spraying step 2 dispersion on to step 3 blend in Fluid bed dryer until proper granules obtained, e) Adding extragranular materials to step 4 granules and blend, and f) Compressing the tablets using step 5 blend.
DETAILED DESCRIPTION OF THE INVENTION
The invention specifically relates to oral anticoagulant compositions and methods for the preparation of the same.
One embodiment of the present invention provides an oral pharmaceutical composition comprising Rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, diluents, binders, disintegrants, glidants, lubricants, surfactants, solubilizers and other excipients.
In another embodiment of the present invention provides process for the preparation of oral solid composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, diluents, binders, disintegrants, glidants, lubricants, surfactants and other excipients.
The term "rivaroxaban" includes various forms of rivaroxaban such as hydrates, solvates, polymorphs, isomers, stereoisomers, enantiomers, racemates, esters, prodrugs, complexes or mixture thereof and all other forms known in the art.
Rivaroxaban can be present in different physical forms, e.g. in an amorphous form, in one or several crystal form (s) (e.g. anhydrous, solvated or hydrated forms), in the form of mixture of different crystal forms (e.g. anhydrous, solvated or hydrated forms) or as a mixture of an amorphous form and crystal form (s) (e.g. anhydrous, solvated or hydrated forms). Each of these forms is included in the term "rivaroxaban" as used in the present invention.
The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.
The composition according to the invention comprise diluents such as microcrystalline cellulose, powdered cellulose, lactose (anhydrous or monohydrate), compressible sugar, fructose, dextranes, other sugars such as mannitol, sorbitol, lactitol, saccharose or a mixture thereof, siliconised microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, calcium lactate or mixtures thereof.
A preferred further diluent that also causes reduced sticking properties of tablets to the equipment used for tabletting is silica, preferably colloidal or fumed silica.
Preferably,
6 the excipients include at least one diluent selected from microcrystalline cellulose and lactose monohydrate.
The composition according to the invention comprise binders, such as polyvinyl pyrollidone, polyvinylpyrrolidone/vinyl acetate copolymer, polyvinyl alcohol, polymers of acrylic acid and its salts, starch, celluloses and celluloses derivatives like methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyl propyl cellulose, ethylhydroxyethylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose etc., maltrin, sucrose solution, dextrose solution, acacia, tragacanth, locust bean gum, gelatine, guar gum, starch, pregelatinised starch, partially hydrolysed starch, alginates, xanthan or polymethacrylate, or mixtures thereof. It is preferable to use a binder with good water solubility. In a preferred embodiment of the invention the excipients include at least one binder selected from hydroxypropyl cellulose and povidone.
The composition according to the invention comprise disintegrants, such as is carboxymethylcellulose, carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC-Na), crosslinked sodium carboxymethyl cellulose as e.g. Ac-Di-Sol , PrimeHose , Pharmacelt XL, Explocel , and Nymcel ZSX having a molecular weight of 90 000-700 000, sodium starch glycolate e.g. ExplosolO, ExplotabO, Glycolys , Primojel , Tablo , Vivastar0 P, in particular having molecular weight is 500000-11000000, crosslinked polyvinylpolypyrrolidone (Plasone-XL , Polyplasdone XL and KolEdon CL) in particular having a molecular weight in excess of 1000000, more particularly having a particle size distribution of less than 400 microns or less than 74 microns, microcrystalline cellulose, L-HPC (low-substituted hydroxypropylcellulose), sodium carboxymethyl starch, sodium glycolate of potato starch, partially hydrolysed starch, wheat starch, maize starch, rice starch or potato starch, cornstarch, pregelatinized starch, crospovidone, for example, POLYPLASDONE XL (International Specialty Products), magnesium aluminium silicate or mixtures thereof.
The composition according to the invention comprise binders, such as polyvinyl pyrollidone, polyvinylpyrrolidone/vinyl acetate copolymer, polyvinyl alcohol, polymers of acrylic acid and its salts, starch, celluloses and celluloses derivatives like methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyl propyl cellulose, ethylhydroxyethylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose etc., maltrin, sucrose solution, dextrose solution, acacia, tragacanth, locust bean gum, gelatine, guar gum, starch, pregelatinised starch, partially hydrolysed starch, alginates, xanthan or polymethacrylate, or mixtures thereof. It is preferable to use a binder with good water solubility. In a preferred embodiment of the invention the excipients include at least one binder selected from hydroxypropyl cellulose and povidone.
The composition according to the invention comprise disintegrants, such as is carboxymethylcellulose, carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC-Na), crosslinked sodium carboxymethyl cellulose as e.g. Ac-Di-Sol , PrimeHose , Pharmacelt XL, Explocel , and Nymcel ZSX having a molecular weight of 90 000-700 000, sodium starch glycolate e.g. ExplosolO, ExplotabO, Glycolys , Primojel , Tablo , Vivastar0 P, in particular having molecular weight is 500000-11000000, crosslinked polyvinylpolypyrrolidone (Plasone-XL , Polyplasdone XL and KolEdon CL) in particular having a molecular weight in excess of 1000000, more particularly having a particle size distribution of less than 400 microns or less than 74 microns, microcrystalline cellulose, L-HPC (low-substituted hydroxypropylcellulose), sodium carboxymethyl starch, sodium glycolate of potato starch, partially hydrolysed starch, wheat starch, maize starch, rice starch or potato starch, cornstarch, pregelatinized starch, crospovidone, for example, POLYPLASDONE XL (International Specialty Products), magnesium aluminium silicate or mixtures thereof.
7 The composition according to the invention also comprise lubricants, such as stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, macrogols, or mixtures thereof.
The composition according to the invention also comprise glidants, such as talc, fumed silica, magnesium stearate, stearic acid, kaolin, magnesium trisilicate either alone or in combination thereof.
The composition according to the invention also comprise surfactants, such as sodium salts of fatty alcohol sulphates such as sodium lauryl sulphate; or sulphosuccinates such as sodium dioctyl sulphosuccinate; or partial fatty acid esters of polyhydric alcohols such as glycerol monostearate, glyceryl monooleate, glyceryl monobutyrate; or block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene block copolymers or polyoxyethylene polypropyleneglycol, such as Poloxamer 124, Poloxamer 188, Poloxamer 237, Poloxamer 388, Poloxamer 407 (BASF Wyandotte Corp.); or fatty acid esters of sorbitan such as sorbitan mono laurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan stearate, sorbitan monolaurate etc. such as Span or Arlacel , Emsorb@, Capmul , or Sorbester , Triton X-200 etc.; or a fatty acid esters of polyhydroxyethylene sorbitan such as polyoxyethylene (20) sorbitan, e.g.
polyoxyethylene (20) sorbitan monooleate (Tween 80), polyoxyethylene (20) sorbitan monostearate (Tween 60), polyoxyethylene (20) sorbitan monopalmitate (Tween 40), polyoxyethylene (20) sorbitan monolaurate (Tween 20); or polyethylene glycol fatty acid esters, e.g. PEG-200 monolaurate, PEG-200 dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate, PEG-300 dioleate;
alkylene glycol fatty acid mono esters, e.g. propylene glycol monolaurate (Lauroglycol ); or hydrogenated castor oil and polyoxyethylene castor oil derivates, e.g. polyoxyethyleneglycerol triricinoleate or polyoxyl 35 castor oil (Cremophor@ EL;
BASF Corp.); or polyoxyethyleneglycerol oxystearate such as polyethylenglycol hydrogenated castor oil (Cremophor RH 40) or polyethylenglycol 60 hydrogenated
The composition according to the invention also comprise glidants, such as talc, fumed silica, magnesium stearate, stearic acid, kaolin, magnesium trisilicate either alone or in combination thereof.
The composition according to the invention also comprise surfactants, such as sodium salts of fatty alcohol sulphates such as sodium lauryl sulphate; or sulphosuccinates such as sodium dioctyl sulphosuccinate; or partial fatty acid esters of polyhydric alcohols such as glycerol monostearate, glyceryl monooleate, glyceryl monobutyrate; or block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene block copolymers or polyoxyethylene polypropyleneglycol, such as Poloxamer 124, Poloxamer 188, Poloxamer 237, Poloxamer 388, Poloxamer 407 (BASF Wyandotte Corp.); or fatty acid esters of sorbitan such as sorbitan mono laurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan stearate, sorbitan monolaurate etc. such as Span or Arlacel , Emsorb@, Capmul , or Sorbester , Triton X-200 etc.; or a fatty acid esters of polyhydroxyethylene sorbitan such as polyoxyethylene (20) sorbitan, e.g.
polyoxyethylene (20) sorbitan monooleate (Tween 80), polyoxyethylene (20) sorbitan monostearate (Tween 60), polyoxyethylene (20) sorbitan monopalmitate (Tween 40), polyoxyethylene (20) sorbitan monolaurate (Tween 20); or polyethylene glycol fatty acid esters, e.g. PEG-200 monolaurate, PEG-200 dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate, PEG-300 dioleate;
alkylene glycol fatty acid mono esters, e.g. propylene glycol monolaurate (Lauroglycol ); or hydrogenated castor oil and polyoxyethylene castor oil derivates, e.g. polyoxyethyleneglycerol triricinoleate or polyoxyl 35 castor oil (Cremophor@ EL;
BASF Corp.); or polyoxyethyleneglycerol oxystearate such as polyethylenglycol hydrogenated castor oil (Cremophor RH 40) or polyethylenglycol 60 hydrogenated
8 castor oil (Cremophor RH 60); or sucrose fatty acid esters, such as sucrose stearate, sucrose oleate, sucrose palmitate, sucrose laurate, and sucrose acetate butyrate; or vitamin E and its derivatives such as Vitamin E-TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate); or phospholipids, glycerophospholipids (lecithins, kephalins, phosphatidyl serine), glyceroglycolipids (galactopyransoide), sphingophospholipids (sphingomyelin), and sphingoglycolipids (ceramides, gangliosides), DSS (docusate sodium), docusate calcium, docusate potassium, SDS
(sodium dodecyl sulfate or sodium lauryl sulfate), dipalmitoyl phosphatidic acid, sodium caprylate; or bile acids and salts thereof; or ethoxylated triglyceiides; or quaternary ammonium salts such as cetyl-trimethylammonium bromide, cetylpyridinium chloride; or glycerol acetates such as acetin, diacetin and triacetin; or triethanolamine, lecithin, monohydric alcohol esters such as trialkyl citrates, lactones and lower alcohol fatty acid esters, nitrogen-containing solvents, glycerol fatty acid esters such as mono-, di- and triglycerides and a cetylated mono- and di-glycerides;
propylene glycol esters, ethylene glycol esters, glycerol, cholic acid or derivatives thereof, lecithins, alcohols and glycine or taurine conjugates, ursodeoxycholic acid, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, N-Hexadecyl-N, N-dimeth y1-3- ammonio- 1 -propanesulfonate, anionic (alkyl-arylsulphonates) monovalent surfactants, palmitoyl lysophosphatidyl-L-serine, lysophospholipids (e.g. 1-acyl-sn-glycero-3-phosphate esters of ethanolamine, choline, serine or threonine), alkyl, alkoxyl (alkyl ester), alkoxy (alkyl ether)-derivatives of lysophosphatidyl and phosphatidylcholines, e.g. lauroyl and myristoyl derivatives of lysophosphatidylcholine, dipalmitoylphosphatidylcholine, and modifications of the polar head group, that is cholines, ethanolamines, phosphatidic acid, serines, threonines, glycerol, inositol, and the postively charged DODAC, DOTMA, DCP, BISHOP, lysophosphatidylserine and lysophosphatidylthreonine, zwitterionic surfactants (e.g. N- alkyl-N, N-dimethylammonio-1 -propanesulfonates, 3-cholamido-l-propyldimethylammonio-1 -propanesulfonate, dodecylphosphocholine, myristoyl lysophosphatidylcholine, hen egg lysolecithin), cationic surfactants (quarternary ammonium bases), fusidic acid derivatives-(e.g. sodium tauro-dihydrofusidate etc.),
(sodium dodecyl sulfate or sodium lauryl sulfate), dipalmitoyl phosphatidic acid, sodium caprylate; or bile acids and salts thereof; or ethoxylated triglyceiides; or quaternary ammonium salts such as cetyl-trimethylammonium bromide, cetylpyridinium chloride; or glycerol acetates such as acetin, diacetin and triacetin; or triethanolamine, lecithin, monohydric alcohol esters such as trialkyl citrates, lactones and lower alcohol fatty acid esters, nitrogen-containing solvents, glycerol fatty acid esters such as mono-, di- and triglycerides and a cetylated mono- and di-glycerides;
propylene glycol esters, ethylene glycol esters, glycerol, cholic acid or derivatives thereof, lecithins, alcohols and glycine or taurine conjugates, ursodeoxycholic acid, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, N-Hexadecyl-N, N-dimeth y1-3- ammonio- 1 -propanesulfonate, anionic (alkyl-arylsulphonates) monovalent surfactants, palmitoyl lysophosphatidyl-L-serine, lysophospholipids (e.g. 1-acyl-sn-glycero-3-phosphate esters of ethanolamine, choline, serine or threonine), alkyl, alkoxyl (alkyl ester), alkoxy (alkyl ether)-derivatives of lysophosphatidyl and phosphatidylcholines, e.g. lauroyl and myristoyl derivatives of lysophosphatidylcholine, dipalmitoylphosphatidylcholine, and modifications of the polar head group, that is cholines, ethanolamines, phosphatidic acid, serines, threonines, glycerol, inositol, and the postively charged DODAC, DOTMA, DCP, BISHOP, lysophosphatidylserine and lysophosphatidylthreonine, zwitterionic surfactants (e.g. N- alkyl-N, N-dimethylammonio-1 -propanesulfonates, 3-cholamido-l-propyldimethylammonio-1 -propanesulfonate, dodecylphosphocholine, myristoyl lysophosphatidylcholine, hen egg lysolecithin), cationic surfactants (quarternary ammonium bases), fusidic acid derivatives-(e.g. sodium tauro-dihydrofusidate etc.),
9 long-chain falty acids and salts thereof C6-C2 (eg. oleic acid and caprylic acid), acylcarnitines and derivatives, N-a-acylated derivatives of lysine, arginine or histidine, or side-chain acylated derivatives of lysine or arginine, N-a-acylated derivatives of dipeptides comprising any combination of lysine, arginine or histidine and a neutral or acidic amino acid, N-a-acylated derivative of a tripeptide comprising any combination of a neutral amino acid and two charged amino acids, or the surfactant may be selected from the group of imidazoline derivatives, or mixtures thereof. Each one of these specific surface-active agent constitutes an alternative embodiment of the invention.
The composition according to the invention also comprise solubilizers such as .. sugar alcohols like isomalt, sorbitol, xylitol or mannitol, cellulose derivatives (especially hydroxypropylmethyl cellulose (HPMC) and/or hydroxypropyl cellulose (HPC)), sugar alcohols (especially isomalt), polyethoxylated castor oil (Cremophor), polyvinylpyrrolidone and copolymers of polyvinylpyrrolidone are used as solubilizer.
The composition according to the invention also comprise solvents such as methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and the like and mixtures thereof.
Other excipients commonly used in pharmaceutical composition may be used and reference is made to the extensive literature on suitable substances [see in particular "Handbook of Pharmaceutical Excipients" edited by Raymond C Rowe, .. Paul J Sheskey & Sian C Owen (2006)1 the content of which is incorporated herein by reference.
The pharmaceutical composition of the present invention can be present in the form of a tablet, a capsule, powder, a disc, a caplet, granules, pellets, granules in a capsule, minitablets, minitablets in a capsule, pellets in a capsule, a sachet and other dosage forms suitable for oral administration.
The granules may be prepared by methods such as, but not limited to, wet granulation, melt granulation, dry granulation or roll compaction or the like.
Optionally, cores/tablets can be coated with conventional materials used for film coating, i. e. as described in "Pharmaceutical Coating Technology", 1995, edited by Graham Cole. Film coating formulations usually contain the following components: polymer (s), plasticizer (s), colourant (s) /opacifier (s), vehicle (s). In film coating suspension the minor quantities of flavours, surfactants and waxes can be used. The majority of the polymers used in film coating are either cellulose derivatives, such as the cellulose ethers, or acrylic polymers and copolymers.
Occasionally encountered are high molecular weight polyethylene glycols, polyvinyl pyrrolidone, polyvinyl alcohol and waxy materials. Typical cellulose ethers are hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and methylcellulose. Acrylic polymers comprise a group of synthetic polymers with diverse functionalities. Some of them can be further modified to enhance swelling and permeability by the incorporation of materials such as water soluble cellulose ethers and starches in order to ensure complete disintegration/ dissolution of the film.
is Other additives used in the preparations to the compositions of this invention, the following can be used and there were no limitations: stabilizer, surfactant, plasticizer, lubricant, reducing agent, buffer agent, sweetening agent, base, adsorbent, corrigent, binder, suspending agent, antioxidant, polish, coating, wetting agent, wet modifier, filler, antifoaming agent, refrigerative agent, coloring matter, flavoring agent, perfume, sugar coating agent, isotonizing agent, softener, emulsifying agent, foaming agent, pH modifier, anti-frothing agents, diluent, excipient, dispersing agent, disintegrator, fragrance, desiccant, antiseptics, preservative, solubilizing agent, solubilizer The following examples describes the nature of the invention and are given only for the purpose of illustrating the present invention in more detail and are not limitative and relate to solutions which have been particularly effective on a bench scale.
Example 1 S.No Ingredients Quantity in mg per tablet Example 1A Example 1B
1. Sugar Spheres (#60/80) 33.0 33.0 2. Rivaroxaban 20.0 20.0 3. Croscarmellose sodium 7.0 4. Hydroxy propyl cellulose 2.5 2.5 5. Sodium lauryl sulphate 0.5 0.5 6. Lactose monohydrate 55.0 62.0 7. Colloidal silicon dioxide 1.0 1.0 8. Magnesium Stearate 1.0 1.0 9. Ethanol QS QS
The composition according to the invention also comprise solubilizers such as .. sugar alcohols like isomalt, sorbitol, xylitol or mannitol, cellulose derivatives (especially hydroxypropylmethyl cellulose (HPMC) and/or hydroxypropyl cellulose (HPC)), sugar alcohols (especially isomalt), polyethoxylated castor oil (Cremophor), polyvinylpyrrolidone and copolymers of polyvinylpyrrolidone are used as solubilizer.
The composition according to the invention also comprise solvents such as methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and the like and mixtures thereof.
Other excipients commonly used in pharmaceutical composition may be used and reference is made to the extensive literature on suitable substances [see in particular "Handbook of Pharmaceutical Excipients" edited by Raymond C Rowe, .. Paul J Sheskey & Sian C Owen (2006)1 the content of which is incorporated herein by reference.
The pharmaceutical composition of the present invention can be present in the form of a tablet, a capsule, powder, a disc, a caplet, granules, pellets, granules in a capsule, minitablets, minitablets in a capsule, pellets in a capsule, a sachet and other dosage forms suitable for oral administration.
The granules may be prepared by methods such as, but not limited to, wet granulation, melt granulation, dry granulation or roll compaction or the like.
Optionally, cores/tablets can be coated with conventional materials used for film coating, i. e. as described in "Pharmaceutical Coating Technology", 1995, edited by Graham Cole. Film coating formulations usually contain the following components: polymer (s), plasticizer (s), colourant (s) /opacifier (s), vehicle (s). In film coating suspension the minor quantities of flavours, surfactants and waxes can be used. The majority of the polymers used in film coating are either cellulose derivatives, such as the cellulose ethers, or acrylic polymers and copolymers.
Occasionally encountered are high molecular weight polyethylene glycols, polyvinyl pyrrolidone, polyvinyl alcohol and waxy materials. Typical cellulose ethers are hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and methylcellulose. Acrylic polymers comprise a group of synthetic polymers with diverse functionalities. Some of them can be further modified to enhance swelling and permeability by the incorporation of materials such as water soluble cellulose ethers and starches in order to ensure complete disintegration/ dissolution of the film.
is Other additives used in the preparations to the compositions of this invention, the following can be used and there were no limitations: stabilizer, surfactant, plasticizer, lubricant, reducing agent, buffer agent, sweetening agent, base, adsorbent, corrigent, binder, suspending agent, antioxidant, polish, coating, wetting agent, wet modifier, filler, antifoaming agent, refrigerative agent, coloring matter, flavoring agent, perfume, sugar coating agent, isotonizing agent, softener, emulsifying agent, foaming agent, pH modifier, anti-frothing agents, diluent, excipient, dispersing agent, disintegrator, fragrance, desiccant, antiseptics, preservative, solubilizing agent, solubilizer The following examples describes the nature of the invention and are given only for the purpose of illustrating the present invention in more detail and are not limitative and relate to solutions which have been particularly effective on a bench scale.
Example 1 S.No Ingredients Quantity in mg per tablet Example 1A Example 1B
1. Sugar Spheres (#60/80) 33.0 33.0 2. Rivaroxaban 20.0 20.0 3. Croscarmellose sodium 7.0 4. Hydroxy propyl cellulose 2.5 2.5 5. Sodium lauryl sulphate 0.5 0.5 6. Lactose monohydrate 55.0 62.0 7. Colloidal silicon dioxide 1.0 1.0 8. Magnesium Stearate 1.0 1.0 9. Ethanol QS QS
10. Purified Water QS QS
Core tablet weight 120.0 120.0 Film Coating
Core tablet weight 120.0 120.0 Film Coating
11. Opadry brown 3.0 3.0
12. Purified Water QS QS
Total Weight (mg) 123.0 123.0 Example 2 S.No Ingredients Quantity in mg per tablet Example 2A Example 2B
1. Sugar Spheres (#60/80) 33.0 33.0 2. Rivaroxaban 10.0 10.0 3. Croscarmellose sodium 6.4 6.4 4. Hydroxy propyl cellulose 4.0 4.0 5. Sodium lauryl sulphate 0.5 0.2 6. Lactose monohydrate 37.1 37.4 7. Colloidal silicon dioxide 1.0 1.0 8. Magnesium Stearate 1.0 1.0 9. Ethanol QS QS
10. Purified Water QS QS
Core tablet weight 85.0 85.0 Film Coating 11. Opadry brown 2.5 2.5 12. Purified Water QS QS
Total Weight (mg) 87.5 87.5 Example 3 S.No Ingredients Quantity in mg per tablet Example 3A Example 3B
1. Sugar Spheres (#60/80) 34.0 34.0 2. Rivaroxaban 20.0 20.0 3. Croscarmellose sodium 7.0 7.0 4. Hydroxy propyl cellulose 2.0 4.0 5. Sodium lauryl sulphate 0.5 0.5 6. Lactose monohydrate 54.5 52.5 7. Colloidal silicon dioxide 1.0 1.0 8. Magnesium Stearate 1.0 1.0 9. Ethanol QS QS
10. Purified Water QS QS
Core tablet weight 120.0 120.0 Film Coating 11. Opadry brown 3.0 3.0 12. Purified Water QS QS
Total Weight (mg) 123.0 123.0 Example 4
Total Weight (mg) 123.0 123.0 Example 2 S.No Ingredients Quantity in mg per tablet Example 2A Example 2B
1. Sugar Spheres (#60/80) 33.0 33.0 2. Rivaroxaban 10.0 10.0 3. Croscarmellose sodium 6.4 6.4 4. Hydroxy propyl cellulose 4.0 4.0 5. Sodium lauryl sulphate 0.5 0.2 6. Lactose monohydrate 37.1 37.4 7. Colloidal silicon dioxide 1.0 1.0 8. Magnesium Stearate 1.0 1.0 9. Ethanol QS QS
10. Purified Water QS QS
Core tablet weight 85.0 85.0 Film Coating 11. Opadry brown 2.5 2.5 12. Purified Water QS QS
Total Weight (mg) 87.5 87.5 Example 3 S.No Ingredients Quantity in mg per tablet Example 3A Example 3B
1. Sugar Spheres (#60/80) 34.0 34.0 2. Rivaroxaban 20.0 20.0 3. Croscarmellose sodium 7.0 7.0 4. Hydroxy propyl cellulose 2.0 4.0 5. Sodium lauryl sulphate 0.5 0.5 6. Lactose monohydrate 54.5 52.5 7. Colloidal silicon dioxide 1.0 1.0 8. Magnesium Stearate 1.0 1.0 9. Ethanol QS QS
10. Purified Water QS QS
Core tablet weight 120.0 120.0 Film Coating 11. Opadry brown 3.0 3.0 12. Purified Water QS QS
Total Weight (mg) 123.0 123.0 Example 4
13 S.No Quantity/ tablet in mg Name of the ingredients 20 mg 15 mg 10 mg 2.5 mg strength strength strength strength Intra-granular 1. Sugar Spheres (#60/80) 34.0 39.0 44.0 51.5 2. Rivaroxaban 20.0 15.0 10.0 2.5 3. Croscarmellose sodium 7.0 7.0 7.0 7.0 4. Hydroxy propyl cellulose 2.0 2.0 2.0 2.0 5. Sodium lauryl sulphate 0.5 0.5 0.5 0.5 6.
7. Lactose monohydrate 54.5 54.5 54.5 54.5 8. Colloidal silicon dioxide 1.0 1.0 1.0 1.0 9. Magnesium Stearate 1.0 1.0 1.0 1.0 10. Ethanol QS QS QS QS
11. Purified Water QS QS QS
QS
Core tablet weight 120.0 120.0 120.0 120.0 Film coating 12. Opadry brown 3.0 3.0 3.0 3.0 13. Purified Water QS QS QS
QS
Coated Tablet Weight 123.0 123.0 123.0 123.0 Manufacturing Process:
1. Dissolving Hydroxypropyl cellulose, Croscarmellose sodium and Sodium lauryl sulphate in mixture of ethanol and Purified water, 2. Dispersing Rivaroxaban in step 1 solution until smooth dispersion forms, 3. Spraying step 2 dispersion on to sugar pellets in Fluid bed dryer, 4. Adding extragranular materials to step 3 pellets and blend, 5. Compressing the tablets using step 4 blend,
7. Lactose monohydrate 54.5 54.5 54.5 54.5 8. Colloidal silicon dioxide 1.0 1.0 1.0 1.0 9. Magnesium Stearate 1.0 1.0 1.0 1.0 10. Ethanol QS QS QS QS
11. Purified Water QS QS QS
QS
Core tablet weight 120.0 120.0 120.0 120.0 Film coating 12. Opadry brown 3.0 3.0 3.0 3.0 13. Purified Water QS QS QS
QS
Coated Tablet Weight 123.0 123.0 123.0 123.0 Manufacturing Process:
1. Dissolving Hydroxypropyl cellulose, Croscarmellose sodium and Sodium lauryl sulphate in mixture of ethanol and Purified water, 2. Dispersing Rivaroxaban in step 1 solution until smooth dispersion forms, 3. Spraying step 2 dispersion on to sugar pellets in Fluid bed dryer, 4. Adding extragranular materials to step 3 pellets and blend, 5. Compressing the tablets using step 4 blend,
14 6. Dispersing Opadry brown in Purified water, and 7. Coating the tablets of step 5 with step 6 dispersion.
Example 5 S.No. Ingredients Quantity/ tablet in mg 1. Rivaroxaban 20.0 20.0 20.0 2. Microcrystalline cellulose 28.0 35.0 37.0 3. Lactose monohydrate 22.9 22.9 22.9 4. Croscarmellose sodium 2.0 3.0 2.0 5. Hydroxy propyl cellulose 1.0 3.0 2.0 6. Cremophor 0.5 0.5 0.5 7. Ethanol QS QS QS
8. Microcrystalline cellulose 10.0 9. Magnesium Stearate 0.6 0.6 0.6 Core tablet weight 85.0 85.0 85.0 Film Coating 10. Opadry brown 2.5 2.5 2.5 11. Purified Water QS QS
QS
Coated Tablet Weight (mg) 87.5 87.5 87.5 Manufacturing process:
1. Dissolving Hydroxypropyl cellulose and Cremophor in ethanol, 2. Disperse Rivaroxaban in step 1 solution until smooth dispersion forms, 3. Sift together Croscarmellose sodium, Lactose monohydrate and Microcrystalline cellulose, 4. Spray step 2 dispersion on to step 3 blend in Fluid bed dryer until proper granules obtains, 5. Add extragranular materials to step 4 granules and blend, 6. Compress the tablets using step 5 blend, 7. Disperse Opadry brown in Purified water, ad 8. Coat the tablets of step 6 with step 7 dispersion.
Example 6 S.No. Ingredients Quantity/ tablet in mg 1.
Rivaroxaban 20.0 20.0 2.
Microcrystalline cellulose 35.0 35.0 3. Lactose monohydrate 22.9 22.9 4. Croscarmellose sodium 3.0 5. Hydroxy propyl cellulose 3.0 6.0 6.
Cremophor 0.5 0.5 7. Ethanol & Purified Water QS QS
8.
Magnesium Stearate 0.6 0.6 Core tablet weight 85.0 85.0 Film Coating 9. Opadry brown 2.5 2.5 10. Purified Water QS QS
Coated Tablet Weight (mg) 87.5 87.5 Manufacturing process:
1. Dissolve Hydroxypropyl cellulose and Cremophor in mixture of ethanol and Purified water, 2. Disperse Rivaroxaban in step 1 solution until smooth dispersion forms, 3. Sift together Croscarmellose sodium, Lactose monohydrate and microcrystalline cellulose, 4. Spray step 2 dispersion on to step 3 blend in Fluid bed dryer until proper granules obtains, 5. Add extragranular materials to step 4 granules and blend, 6. Compress the tablets using step 5 blend, 7. Disperse Opadry brown in Purified water, and 8. Coat the tablets of step 6 with step 7 dispersion.
Example 5 S.No. Ingredients Quantity/ tablet in mg 1. Rivaroxaban 20.0 20.0 20.0 2. Microcrystalline cellulose 28.0 35.0 37.0 3. Lactose monohydrate 22.9 22.9 22.9 4. Croscarmellose sodium 2.0 3.0 2.0 5. Hydroxy propyl cellulose 1.0 3.0 2.0 6. Cremophor 0.5 0.5 0.5 7. Ethanol QS QS QS
8. Microcrystalline cellulose 10.0 9. Magnesium Stearate 0.6 0.6 0.6 Core tablet weight 85.0 85.0 85.0 Film Coating 10. Opadry brown 2.5 2.5 2.5 11. Purified Water QS QS
QS
Coated Tablet Weight (mg) 87.5 87.5 87.5 Manufacturing process:
1. Dissolving Hydroxypropyl cellulose and Cremophor in ethanol, 2. Disperse Rivaroxaban in step 1 solution until smooth dispersion forms, 3. Sift together Croscarmellose sodium, Lactose monohydrate and Microcrystalline cellulose, 4. Spray step 2 dispersion on to step 3 blend in Fluid bed dryer until proper granules obtains, 5. Add extragranular materials to step 4 granules and blend, 6. Compress the tablets using step 5 blend, 7. Disperse Opadry brown in Purified water, ad 8. Coat the tablets of step 6 with step 7 dispersion.
Example 6 S.No. Ingredients Quantity/ tablet in mg 1.
Rivaroxaban 20.0 20.0 2.
Microcrystalline cellulose 35.0 35.0 3. Lactose monohydrate 22.9 22.9 4. Croscarmellose sodium 3.0 5. Hydroxy propyl cellulose 3.0 6.0 6.
Cremophor 0.5 0.5 7. Ethanol & Purified Water QS QS
8.
Magnesium Stearate 0.6 0.6 Core tablet weight 85.0 85.0 Film Coating 9. Opadry brown 2.5 2.5 10. Purified Water QS QS
Coated Tablet Weight (mg) 87.5 87.5 Manufacturing process:
1. Dissolve Hydroxypropyl cellulose and Cremophor in mixture of ethanol and Purified water, 2. Disperse Rivaroxaban in step 1 solution until smooth dispersion forms, 3. Sift together Croscarmellose sodium, Lactose monohydrate and microcrystalline cellulose, 4. Spray step 2 dispersion on to step 3 blend in Fluid bed dryer until proper granules obtains, 5. Add extragranular materials to step 4 granules and blend, 6. Compress the tablets using step 5 blend, 7. Disperse Opadry brown in Purified water, and 8. Coat the tablets of step 6 with step 7 dispersion.
Claims (10)
- We Claim:
I . An oral pharmaceutical composition comprising Rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts prepared by drug layering technology. - 2. The composition claimed in claim 1, further comprising one or more excipients which are selected from diluents/fillers, binders, disintegrants, glidants, lubricants, surfactants, solubilizers and other excipients.
- 3. The composition as claimed in claims 1 and 2, wherein said diluents is microcrystalline cellulose, powdered cellulose, lactose (anhydrous or monohydrate), compressible sugar, fructose, dextranes, other sugars such as mannitol, sorbitol, lactitol, saccharose or a mixture thereof, siliconised microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, calcium lactate or mixtures thereof.
- 4. The composition as claimed in claims 1 and 2, wherein said binder is polyvinyl pyrollidone, polyvinylpyrrolidone/vinyl acetate copolymer, polyvinyl alcohol, polymers of acrylic acid and its salts, starch, celluloses and celluloses derivatives like methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyl propyl cellulose, ethylhydroxyethylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose etc., maltrin, sucrose solution, dextrose solution, acacia, tragacanth, locust bean gum, gelatine, guar gum, starch, pregelatinised starch, partially hydrolysed starch, alginates, xanthan or polymethacrylate, or mixtures thereof.
- 5. The composition as claimed in claims 1 and 2, wherein said disintegrants is carboxymethylcellulose, carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC-Na), crosslinked sodium carboxymethyl cellulose as e.g. Ac-Di-Sol , Primellose , Pharmacelt XL, Explocel , and Nymcel ZSX having a molecular weight of 90 000-700 000, sodium starch glycolate e.g. Explosol , Explotab , Glycolys , Primojel , Tablo , Vivastar P, in particular having molecular weight is 500000-11000000, crosslinked polyvinylpolypyrrolidone (Plasone-XL , Polyplasdone XL and Kollidon CL) in particular having a molecular weight in excess of 1000000, more particularly having a particle size distribution of less than 400 microns or less than 74 microns, microcrystalline cellulose, L-HPC (low-substituted hydroxypropylcellulose), sodium carboxymethyl starch, sodium glycolate of potato starch, partially hydrolysed starch, wheat starch, maize starch, rice starch or potato starch, cornstarch, pregelatinized starch, crospovidone, for example, POLYPLASDONE XL (International Specialty Products), magnesium aluminium silicate or mixtures thereof.
- 6. The composition as claimed in claims 1 and 2, wherein said glidant is talc, fumed silica, magnesium stearate, stearic acid, kaolin, magnesium trisilicate either alone or in combination thereof.
- 7. The composition as claimed in claims 1 and 2, wherein said lubricant is stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, macrogols, or mixtures thereof.
- 8. An oral pharmaceutical composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, prepared by a process comprising steps of::
a) Dissolving excipients in mixture of ethanol and Purified water, b) Dispersing drug in step 1 solution until smooth dispersion forms, c) Spraying step 2 dispersion on to sugar pellets, and d) Adding extragranular materials to step 3 pellets and blend followed by compression and optional coating. - 9. An oral pharmaceutical composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, prepared by a process comprising steps of::
a) Dissolving Hydroxypropyl cellulose, Croscarmellose sodium and Sodium lauryl sulphate in mixture of ethanol and Purified water, b) Dispersing Rivaroxaban in step 1 solution until smooth dispersion forms, c) Spraying step 2 dispersion on to sugar pellets in Fluid bed dryer, d) Adding extragranular materials to step 3 pellets and blend, e) Compressing the tablets using step 4 blend, f) Dispersing Opadry brown in Purified water, and g) Coating the tablets of step 5 with step 6 dispersion. - 10. An oral pharmaceutical composition comprising rivaroxaban its solvates, hydrates and/or pharmaceutically acceptable salts, prepared by a process comprising steps of:
a) Preparing binder solution, b) Dispersing Drug in step 1 solution until smooth dispersion forms, c) Sifting and blending the excipients, d) Spraying step 2 dispersion on to step 3 blend until proper granules obtains, and e) Adding extragranular materials and compression with optional coating.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN201641023129 | 2016-07-05 | ||
IN201641023129 | 2016-07-05 | ||
PCT/IB2017/054031 WO2018007945A1 (en) | 2016-07-05 | 2017-07-04 | Solid composition containing oral anticoagulant |
Publications (1)
Publication Number | Publication Date |
---|---|
CA3028346A1 true CA3028346A1 (en) | 2018-01-11 |
Family
ID=60912395
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA3028346A Abandoned CA3028346A1 (en) | 2016-07-05 | 2017-07-04 | Solid composition containing oral anticoagulant |
Country Status (4)
Country | Link |
---|---|
BR (1) | BR112019000187A2 (en) |
CA (1) | CA3028346A1 (en) |
WO (1) | WO2018007945A1 (en) |
ZA (1) | ZA201900719B (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GR1009619B (en) * | 2018-05-09 | 2019-10-23 | Φαρμαζακ Α.Φ.Ε.Β.Ε. | Pharmaceutical composition containing rivaroxaban and method for the preparation thereof |
WO2022259118A1 (en) * | 2021-06-10 | 2022-12-15 | Shilpa Medicare Limited | Fast dissolving oral film preparation comprising rivaroxaban |
WO2023067620A1 (en) * | 2021-10-18 | 2023-04-27 | Unison Pharmaceuticals Pvt. Ltd. | Orally disintegrating pharmaceutical compositions of rivaroxaban |
CN116327726B (en) * | 2023-02-24 | 2024-02-02 | 沈阳药科大学 | Platelet membrane coated bionic nano-particle and preparation method and application thereof |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10355461A1 (en) * | 2003-11-27 | 2005-06-23 | Bayer Healthcare Ag | Solid, high bioavailabilty oral formulations of N-substituted 5-chloro-2-thiophene-carboxamide derivative in hydrophilized form, useful for combating thrombo-embolic diseases |
DE102004062475A1 (en) * | 2004-12-24 | 2006-07-06 | Bayer Healthcare Ag | Solid, orally administrable, modified release pharmaceutical dosage forms |
WO2010003641A1 (en) * | 2008-07-08 | 2010-01-14 | Ratiopharm Gmbh | Pharmaceutical compositions comprising 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophencarboxamid |
CA2733611A1 (en) * | 2008-08-11 | 2010-02-18 | Ratiopharm Gmbh | Pharmaceutical compositions with modified release properties comprising 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophencarboxamid |
WO2010146179A2 (en) * | 2009-06-18 | 2010-12-23 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Solid pharmaceutical composition comprising rivaroxaban |
-
2017
- 2017-07-04 BR BR112019000187A patent/BR112019000187A2/en not_active IP Right Cessation
- 2017-07-04 WO PCT/IB2017/054031 patent/WO2018007945A1/en active Application Filing
- 2017-07-04 CA CA3028346A patent/CA3028346A1/en not_active Abandoned
-
2019
- 2019-02-04 ZA ZA2019/00719A patent/ZA201900719B/en unknown
Also Published As
Publication number | Publication date |
---|---|
ZA201900719B (en) | 2022-02-23 |
BR112019000187A2 (en) | 2019-04-24 |
WO2018007945A1 (en) | 2018-01-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6061438B2 (en) | Pharmaceutical composition containing diamine derivative | |
CA3028346A1 (en) | Solid composition containing oral anticoagulant | |
US9937153B2 (en) | Oral pharmaceutical formulation of omarigliptin | |
JP2011098964A5 (en) | ||
US8449896B2 (en) | Pharmaceutical composition having improved solubility | |
WO2011115067A1 (en) | Method for improving dissolvability of anticoagulant | |
US20100136119A1 (en) | Controlled-release preparation containing cilostazol and process for the preparation thereof | |
US20090226511A1 (en) | Novel pharmaceutical formulation in the form of cellulose capsules suitable for benzimidazole derivatives | |
TWI592154B (en) | Allisartan-based solid dispersions and pharmaceutical compositions containing the solid dispersions | |
KR20160026714A (en) | Choline alfoscerate-containing tablet and process for preparing the same | |
EP3292863A1 (en) | Solid pharmaceutical dosage form comprising sofosbuvir | |
JPH1192369A (en) | Pharmaceutical preparation, its production and use of acidic additive for stabilization of cilansetron | |
KR102206104B1 (en) | Granule comprising silodosin, and pharmaceutical composition and formulation comprising the same | |
EP2568970B1 (en) | Stable pharmaceutical formulations containing an antihistaminic | |
WO2014115082A1 (en) | Pharmaceutical formulations of imatinib | |
AU2002214524A1 (en) | Capsule of cellulose derivatives such as HPMC containing benzimidazole derivatives such as omeprazole | |
WO2014053974A1 (en) | Pharmaceutical compositions of sirolimus | |
CA2769616A1 (en) | Solid oral formulations and crystalline forms of an inhibitor of apoptosis protein | |
JP2020045323A (en) | Solifenacin succinate-containing preparation | |
JP6272328B2 (en) | Candesartan cilexetil-containing preparation | |
JP2007297348A (en) | Tablet comprising ebastine | |
JP6423034B2 (en) | Imidafenacin-containing tablets | |
US20070299054A1 (en) | Oral pharmaceutical composition of a poorly water-soluble active agent | |
US20110160213A1 (en) | Pharmaceutical compositions for the treatment of inflammatory and allergic disorders | |
EP3275432A1 (en) | Dosage form with ace inhibitor |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FZDE | Discontinued |
Effective date: 20230105 |
|
FZDE | Discontinued |
Effective date: 20230105 |