JP2022140430A - Rivaroxaban-containing tablet - Google Patents
Rivaroxaban-containing tablet Download PDFInfo
- Publication number
- JP2022140430A JP2022140430A JP2022052554A JP2022052554A JP2022140430A JP 2022140430 A JP2022140430 A JP 2022140430A JP 2022052554 A JP2022052554 A JP 2022052554A JP 2022052554 A JP2022052554 A JP 2022052554A JP 2022140430 A JP2022140430 A JP 2022140430A
- Authority
- JP
- Japan
- Prior art keywords
- tablet
- manufactured
- rivaroxaban
- cellulose
- tablet according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- KGFYHTZWPPHNLQ-AWEZNQCLSA-N rivaroxaban Chemical compound S1C(Cl)=CC=C1C(=O)NC[C@@H]1OC(=O)N(C=2C=CC(=CC=2)N2C(COCC2)=O)C1 KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 title claims abstract description 67
- 229960001148 rivaroxaban Drugs 0.000 title claims abstract description 55
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 24
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 24
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 24
- 229920002678 cellulose Polymers 0.000 claims abstract description 21
- 239000001913 cellulose Substances 0.000 claims abstract description 21
- 235000010980 cellulose Nutrition 0.000 claims abstract description 21
- 229960003943 hypromellose Drugs 0.000 claims abstract description 20
- 229920000642 polymer Polymers 0.000 claims abstract description 18
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims abstract description 11
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims abstract description 11
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims abstract description 11
- 239000003826 tablet Substances 0.000 claims description 106
- 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 51
- 235000010355 mannitol Nutrition 0.000 claims description 30
- 238000005469 granulation Methods 0.000 claims description 28
- 230000003179 granulation Effects 0.000 claims description 28
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 24
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 22
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 17
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 17
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 17
- 235000019359 magnesium stearate Nutrition 0.000 claims description 14
- 239000007941 film coated tablet Substances 0.000 claims description 13
- 239000008187 granular material Substances 0.000 claims description 13
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 12
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 12
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 claims description 12
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 12
- 229950008138 carmellose Drugs 0.000 claims description 12
- 229960000913 crospovidone Drugs 0.000 claims description 12
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 12
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 12
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 12
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 12
- 239000007884 disintegrant Substances 0.000 claims description 10
- 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 8
- 239000000314 lubricant Substances 0.000 claims description 8
- 229920000609 methyl cellulose Polymers 0.000 claims description 7
- 239000001923 methylcellulose Substances 0.000 claims description 7
- 235000010981 methylcellulose Nutrition 0.000 claims description 7
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 7
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 7
- 229940068968 polysorbate 80 Drugs 0.000 claims description 7
- 229920000053 polysorbate 80 Polymers 0.000 claims description 7
- -1 sucrose fatty acid ester Chemical class 0.000 claims description 7
- 239000004094 surface-active agent Substances 0.000 claims description 7
- 229920002261 Corn starch Polymers 0.000 claims description 6
- 229930006000 Sucrose Natural products 0.000 claims description 6
- 229920003174 cellulose-based polymer Polymers 0.000 claims description 6
- 239000008120 corn starch Substances 0.000 claims description 6
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 claims description 6
- 235000012239 silicon dioxide Nutrition 0.000 claims description 6
- 239000005720 sucrose Substances 0.000 claims description 6
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 5
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 5
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 5
- 244000215068 Acacia senegal Species 0.000 claims description 4
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 4
- 229920000084 Gum arabic Polymers 0.000 claims description 4
- 235000010489 acacia gum Nutrition 0.000 claims description 4
- 239000000205 acacia gum Substances 0.000 claims description 4
- 239000006191 orally-disintegrating tablet Substances 0.000 claims description 4
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- 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-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
- 239000004375 Dextrin Substances 0.000 claims description 3
- 229920001353 Dextrin Polymers 0.000 claims description 3
- 229920000881 Modified starch Polymers 0.000 claims description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 3
- 239000004373 Pullulan Substances 0.000 claims description 3
- 229920001218 Pullulan Polymers 0.000 claims description 3
- 229920002472 Starch Polymers 0.000 claims description 3
- 235000021355 Stearic acid Nutrition 0.000 claims description 3
- 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 3
- 238000013019 agitation Methods 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 229960005069 calcium Drugs 0.000 claims description 3
- 235000001465 calcium Nutrition 0.000 claims description 3
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 3
- 239000008116 calcium stearate Substances 0.000 claims description 3
- 235000013539 calcium stearate Nutrition 0.000 claims description 3
- 239000004359 castor oil Substances 0.000 claims description 3
- 235000019438 castor oil Nutrition 0.000 claims description 3
- 229940099112 cornstarch Drugs 0.000 claims description 3
- 235000019425 dextrin Nutrition 0.000 claims description 3
- JAUGGEIKQIHSMF-UHFFFAOYSA-N dialuminum;dimagnesium;dioxido(oxo)silane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O.[O-][Si]([O-])=O JAUGGEIKQIHSMF-UHFFFAOYSA-N 0.000 claims description 3
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 3
- 239000000194 fatty acid Substances 0.000 claims description 3
- 229930195729 fatty acid Natural products 0.000 claims description 3
- 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 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 3
- 239000003921 oil Substances 0.000 claims description 3
- 229920001592 potato starch Polymers 0.000 claims description 3
- 229940116317 potato starch Drugs 0.000 claims description 3
- 235000019423 pullulan Nutrition 0.000 claims description 3
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 229960002920 sorbitol Drugs 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- 239000008117 stearic acid Substances 0.000 claims description 3
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229960002900 methylcellulose Drugs 0.000 claims description 2
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 abstract 1
- 239000000843 powder Substances 0.000 description 32
- 239000011230 binding agent Substances 0.000 description 28
- 239000000243 solution Substances 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 239000000126 substance Substances 0.000 description 16
- 239000011248 coating agent Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 238000000034 method Methods 0.000 description 12
- 239000008213 purified water Substances 0.000 description 12
- 238000004090 dissolution Methods 0.000 description 11
- 238000002156 mixing Methods 0.000 description 11
- 229940055725 xarelto Drugs 0.000 description 11
- 229930195725 Mannitol Natural products 0.000 description 10
- 239000000594 mannitol Substances 0.000 description 10
- 238000000576 coating method Methods 0.000 description 9
- 229920003115 HPC-SL Polymers 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 7
- 239000008194 pharmaceutical composition Substances 0.000 description 7
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 7
- STFSJTPVIIDAQX-LTRPLHCISA-M sodium;(e)-4-octadecoxy-4-oxobut-2-enoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOC(=O)\C=C\C([O-])=O STFSJTPVIIDAQX-LTRPLHCISA-M 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000000454 talc Substances 0.000 description 6
- 229910052623 talc Inorganic materials 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- 238000007922 dissolution test Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 5
- 229960003511 macrogol Drugs 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 description 5
- 235000013311 vegetables Nutrition 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 239000004203 carnauba wax Substances 0.000 description 4
- 235000013869 carnauba wax Nutrition 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 235000013305 food Nutrition 0.000 description 4
- 238000005498 polishing Methods 0.000 description 4
- DVQHRBFGRZHMSR-UHFFFAOYSA-N sodium methyl 2,2-dimethyl-4,6-dioxo-5-(N-prop-2-enoxy-C-propylcarbonimidoyl)cyclohexane-1-carboxylate Chemical compound [Na+].C=CCON=C(CCC)[C-]1C(=O)CC(C)(C)C(C(=O)OC)C1=O DVQHRBFGRZHMSR-UHFFFAOYSA-N 0.000 description 4
- 239000001993 wax Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 3
- 235000012054 meals Nutrition 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 206010051055 Deep vein thrombosis Diseases 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- 208000010378 Pulmonary Embolism Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 206010047249 Venous thrombosis Diseases 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000004088 foaming agent Substances 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 2
- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-UHFFFAOYSA-N 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 1
- OALHHIHQOFIMEF-UHFFFAOYSA-N 3',6'-dihydroxy-2',4',5',7'-tetraiodo-3h-spiro[2-benzofuran-1,9'-xanthene]-3-one Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(I)=C(O)C(I)=C1OC1=C(I)C(O)=C(I)C=C21 OALHHIHQOFIMEF-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 229920006310 Asahi-Kasei Polymers 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 239000004378 Glycyrrhizin Substances 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 208000032382 Ischaemic stroke Diseases 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 206010062237 Renal impairment Diseases 0.000 description 1
- 244000228451 Stevia rebaudiana Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- OIQPTROHQCGFEF-UHFFFAOYSA-L chembl1371409 Chemical compound [Na+].[Na+].OC1=CC=C2C=C(S([O-])(=O)=O)C=CC2=C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 OIQPTROHQCGFEF-UHFFFAOYSA-L 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical compound [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960005191 ferric oxide Drugs 0.000 description 1
- 239000004503 fine granule Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000009477 fluid bed granulation Methods 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 1
- 229960004949 glycyrrhizic acid Drugs 0.000 description 1
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 1
- 235000019410 glycyrrhizin Nutrition 0.000 description 1
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- WTFXARWRTYJXII-UHFFFAOYSA-N iron(2+);iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[O-2].[Fe+2].[Fe+3].[Fe+3] WTFXARWRTYJXII-UHFFFAOYSA-N 0.000 description 1
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 235000019223 lemon-lime Nutrition 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000892 thaumatin Substances 0.000 description 1
- 235000010436 thaumatin Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
- SWGJCIMEBVHMTA-UHFFFAOYSA-K trisodium;6-oxido-4-sulfo-5-[(4-sulfonatonaphthalen-1-yl)diazenyl]naphthalene-2-sulfonate Chemical compound [Na+].[Na+].[Na+].C1=CC=C2C(N=NC3=C4C(=CC(=CC4=CC=C3O)S([O-])(=O)=O)S([O-])(=O)=O)=CC=C(S([O-])(=O)=O)C2=C1 SWGJCIMEBVHMTA-UHFFFAOYSA-K 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Images
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は、溶出性及び経口吸収性が改善されてなる、リバーロキサバン含有医薬錠剤に関する。 The present invention relates to pharmaceutical tablets containing rivaroxaban with improved dissolution and oral absorbability.
リバーロキサバンは選択的直接作用型第Xa因子阻害剤であり、血栓塞栓性疾患の予防及び治療に有用である。 Rivaroxaban is a selective direct-acting factor Xa inhibitor and is useful for the prevention and treatment of thromboembolic diseases.
リバーロキサバンを有効成分とし、「イグザレルト(登録商標)錠」、「イグザレルト(登録商標)OD錠」及び「イグザレルト(登録商標)細粒分包」とする医薬製剤として販売(バイエル薬品株式会社)されており、また、該錠剤に関する医薬添付文書には、同錠剤がヒプロメロースを含有するフィルムコーティング錠であることが記載されている(非特許文献1)。 Sales of pharmaceutical preparations such as "Xarelto® Tablets", "Xarelto® OD Tablets" and "Xarelto® Fine Granule Packages" containing rivaroxaban as an active ingredient (Bayer Yakuhin, Ltd.) In addition, the pharmaceutical package insert for the tablet describes that the tablet is a film-coated tablet containing hypromellose (Non-Patent Document 1).
他方、リバーロキサバンを有効成分とする製剤として「イグザレルト(登録商標)錠」、「イグザレルト(登録商標)OD錠」及び「イグザレルト(登録商標)細粒分包」に関連するであろう特許文献1には、リバーロキサバンは比較的水溶解性に乏しいこと(約7mg/L)、経口バイオアベイラビリティー(Bioavailability;以下、BA)の低さ及び吸収速度の生物学的変動性の増加が生じることから、製剤化工程において、湿式造粒法(流動層造粒)の採用により、BAが改善されてなる、リバーロキサバン含有医薬組成物に関する発明が記載されている。また、特定処方については、流動層造粒、或いは高速撹拌造粒により製造された、医薬組成物について記載されている。 On the other hand, there are patent documents that may be related to "Xarelto (registered trademark) tablets", "Xarelto (registered trademark) OD tablets" and "Xarelto (registered trademark) fine granules" as formulations containing rivaroxaban as an active ingredient. 1, rivaroxaban is relatively poorly soluble in water (approximately 7 mg/L), resulting in low oral bioavailability (BA) and increased biological variability in absorption rate. Therefore, an invention relating to a rivaroxaban-containing pharmaceutical composition is described in which BA is improved by adopting a wet granulation method (fluid bed granulation) in the formulation process. Also, with regard to specific formulations, pharmaceutical compositions manufactured by fluidized bed granulation or high-speed agitation granulation are described.
「イグザレルト(登録商標)錠」の医薬添付文書には、結晶セルロース、クロスカルメロースナトリウム、ヒプロメロース、乳糖水和物、ステアリン酸マグネシウム、ラウリル硫酸ナトリウム、三二酸化鉄、マクロゴール4000、酸化チタンを含有するフィルムコーティング錠剤であることが記載されている(非特許文献1)。「イグザレルト(登録商標)OD錠」の医薬添付文書には、クロスカルメロースナトリウム、ヒプロメロース、軽質無水ケイ酸、D-マンニトール、ラウリル硫酸ナトリウム、クロスポビドン、結晶セルロース、フマル酸ステアリルナトリウムを含有する口腔内崩壊錠であることが記載されている(非特許文献2)。 The pharmaceutical package insert of "Xarelto (registered trademark) tablet" contains crystalline cellulose, croscarmellose sodium, hypromellose, lactose hydrate, magnesium stearate, sodium lauryl sulfate, ferric oxide, macrogol 4000, and titanium oxide. (Non-Patent Document 1). The pharmaceutical package insert of "Xarelto (registered trademark) OD tablet" contains croscarmellose sodium, hypromellose, light anhydrous silicic acid, D-mannitol, sodium lauryl sulfate, crospovidone, crystalline cellulose, sodium stearyl fumarate. It is described that it is an internal disintegrating tablet (Non-Patent Document 2).
特許文献2には、特許文献1とほとんど成分の変わらない特定処方について、高速撹拌造粒や流動層造粒により製造された、リバーロキサバン含有錠剤に関する発明が記載されている。 Patent Document 2 describes an invention relating to a rivaroxaban-containing tablet manufactured by high-speed agitation granulation or fluidized bed granulation with a specific formulation having almost the same ingredients as in
また、特許文献3には、溶出性が改善され、高い経口BAを有している医薬組成物に関する発明が記載されている。実施例に具体的に開示された錠剤において、微結晶セルロースがリバーロキサバンの溶出性を低下させていること(課題)が見出されたこと、課題を解決するための手段について、結晶セルロースの配合量を5%以下とする医薬組成物に関する発明が記載されている。 In addition, Patent Document 3 describes an invention relating to a pharmaceutical composition having improved dissolution properties and a high oral BA. In the tablets specifically disclosed in the Examples, it was found that microcrystalline cellulose reduces the dissolution of rivaroxaban (problem), and regarding the means for solving the problem, crystalline cellulose An invention relating to a pharmaceutical composition containing 5% or less is disclosed.
しかしながら、リバーロキサバンの溶解性が改善され、良好なバイオアベイラビリティーが期待できる新たな技術開発が求められている。 However, there is a demand for the development of a new technology in which the solubility of rivaroxaban is improved and good bioavailability can be expected.
リバーロキサバンは難水溶性薬物に該当するため、経口投与に際して溶出性及び経口吸収性を改善することが必要である。リバーロキサバンを有効成分として含有する医薬組成物であって、改善された溶出性を備えており、優れた経口バイオアベイラビリティーを有する医薬組成物を提供する。 Since rivaroxaban corresponds to a poorly water-soluble drug, it is necessary to improve dissolution and oral absorption upon oral administration. Provided is a pharmaceutical composition containing rivaroxaban as an active ingredient, which has improved dissolution properties and excellent oral bioavailability.
したがって、本発明の目的は、溶出性及び経口吸収性が改善されてなる、リバーロキサバン含有医薬錠剤を提供することである。 Accordingly, an object of the present invention is to provide a rivaroxaban-containing pharmaceutical tablet with improved dissolution and oral absorbability.
本発明の発明者らは、各種ポリマーについて、溶液中におけるリバーロキサバンの溶出性の観点から、特定のセルロース系ポリマーが、本発明の効果を有することを確認して、本発明を完成するに至った。 The inventors of the present invention have confirmed that a specific cellulose-based polymer has the effects of the present invention from the viewpoint of the dissolution of rivaroxaban in a solution with respect to various polymers. Arrived.
すなわち、本発明は、以下の通りである:
(1)リバーロキサバン、並びに、低置換度ヒドロキシプロピルセルロース、ヒプロメロース、ヒドロキシプロピルセルロース、及びメチルセルロースからなる群より選択される1種又は2種以上のセルロース系ポリマーを含有してなる、錠剤、
(2)セルロース系ポリマーとして、少なくとも低置換度ヒドロキシプロピルセルロースを含有してなる、前記(1)記載の錠剤、
(3)セルロース系ポリマーとして、更にその粘度が、1~10mPa・sのセルロース系ポリマーを含有してなる前記(1)~(2)のいずれかに記載の錠剤、
(4)更に、医薬品添加物を含む、前記(1)~(3)のいずれかに記載の錠剤、
(5)医薬品添加物が、賦形剤、崩壊剤、滑沢剤、及び界面活性剤からなる群より選択される1種又は2種以上含む、前記(1)~(4)のいずれかに記載の錠剤、
(6)賦形剤が、D-マンニトール、乳糖水和物、D-ソルビトール、白糖、デンプン、α化デンプン、結晶セルロース、カルメロースナトリウム、アラビアゴム、デキストリン、プルラン、軽質無水ケイ酸、合成ケイ酸アルミニウム、及びメタケイ酸アルミン酸マグネシウムからなる群より選択される1種又は2種以上含む、前記(1)~(5)のいずれかに記載の錠剤、
(7)賦形剤が、D-マンニトールである前記(5)~(6)のいずれかに記載の錠剤、
(8)崩壊剤が、トウモロコシデンプン、バレイショデンプン、カルメロース、カルメロースカルシウム、クロスカルメロースナトリウム、及びクロスポビドンからなる群より選択される1種又は2種以上含む、前記(1)~(7)のいずれかに記載の錠剤、
(9)滑沢剤が、フマル酸ステアリルナトリウム、ステアリン酸、ステアリン酸ナトリウム、ステアリン酸マグネシウム、ステアリン酸カルシウム、硬化油、及びショ糖脂肪酸エステルからなる群より選択される1種又は2種以上含む、前記(1)~(8)のいずれかに記載の錠剤、
(10)界面活性剤が、ポリソルベート80、ラウリル硫酸ナトリウム、及びポリオキシエチレン硬化ヒマシ油からなる群より選択される1種又は2種以上含む、前記(1)~(9)のいずれかに記載の錠剤、
(11)セルロース系ポリマーの配合量が、錠剤全量に対して、0.1~10重量%である、前記(1)~(10)のいずれかに記載の錠剤、
(12)フィルムコーティング錠、口腔内崩壊錠である前記(1)~(11)のいずれかに記載の錠剤、
(13)リバーロキサバン、低置換度ヒドロキシプロピルセルロースを含む混合物に対して、その粘度が、1~10mPa・sのセルロース系ポリマーを含む溶媒を加えて、撹拌造粒により製造されたリバーロキサバンを含む造粒物を含有してなる、錠剤の製造方法、に関する。That is, the present invention is as follows:
(1) a tablet comprising rivaroxaban and one or more cellulosic polymers selected from the group consisting of low-substituted hydroxypropylcellulose, hypromellose, hydroxypropylcellulose, and methylcellulose;
(2) The tablet according to (1) above, which contains at least low-substituted hydroxypropyl cellulose as the cellulosic polymer,
(3) The tablet according to any one of (1) to (2), further comprising a cellulose polymer having a viscosity of 1 to 10 mPa·s as the cellulose polymer,
(4) The tablet according to any one of (1) to (3), further comprising a pharmaceutical additive,
(5) Any of the above (1) to (4), wherein the pharmaceutical excipient contains one or more selected from the group consisting of excipients, disintegrants, lubricants, and surfactants. listed tablets,
(6) excipients include D-mannitol, lactose hydrate, D-sorbitol, sucrose, starch, pregelatinized starch, crystalline cellulose, carmellose sodium, gum arabic, dextrin, pullulan, light anhydrous silicic acid, synthetic silicic acid The tablet according to any one of (1) to (5) above, comprising one or more selected from the group consisting of aluminum acid and magnesium aluminometasilicate,
(7) the tablet according to any one of the above (5) to (6), wherein the excipient is D-mannitol;
(8) The disintegrant contains one or more selected from the group consisting of corn starch, potato starch, carmellose, carmellose calcium, croscarmellose sodium, and crospovidone (1) to (7). A tablet according to any one of
(9) the lubricant contains one or more selected from the group consisting of sodium stearyl fumarate, stearic acid, sodium stearate, magnesium stearate, calcium stearate, hydrogenated oil, and sucrose fatty acid ester; The tablet according to any one of (1) to (8) above,
(10) Any one of (1) to (9) above, wherein the surfactant includes one or more selected from the group consisting of polysorbate 80, sodium lauryl sulfate, and polyoxyethylene hydrogenated castor oil. tablets of
(11) The tablet according to any one of (1) to (10) above, wherein the content of the cellulose polymer is 0.1 to 10% by weight with respect to the total weight of the tablet.
(12) The tablet according to any one of (1) to (11), which is a film-coated tablet or an orally disintegrating tablet,
(13) Rivaroxaban produced by adding a solvent containing a cellulose-based polymer having a viscosity of 1 to 10 mPa·s to a mixture containing rivaroxaban and low-substituted hydroxypropyl cellulose, and subjecting the mixture to agitating granulation. A method for producing a tablet comprising granules containing
本発明の構成を採用することにより、溶液中においてリバーロキサバンが過飽和状態にあってはその過飽和状態を維持することができる(後記試験例1参照)等、リバーロキサバンの溶解性を改善して、リバーロキサバンの溶出性を高め、その結果、リバーロキサバンの経口バイオアベイラビリティーを改善する効果が期待できる。 By adopting the configuration of the present invention, the solubility of rivaroxaban is improved, such as the ability to maintain the supersaturated state when rivaroxaban is in a supersaturated state in a solution (see Test Example 1 below). As a result, the effect of improving the oral bioavailability of rivaroxaban can be expected.
以下に本発明のリバーロキサバン含有医薬組成物に関して説明する。 The rivaroxaban-containing pharmaceutical composition of the present invention is described below.
本発明に用いられるリバーロキサバンは、一般名5-クロロ-N-([{5S}-2-オキソ-3-[4-(3-オキソモルホリン-4-イル)-フェニル]-1、3-オキサゾリジン-5-イル]メチル)チオフェン-2-カルボキサミドと称し、当該有効成分を含有する医薬は既に臨床に使用されており、リバーロキサバンは容易に入手することができる。リバーロキサバンの形態は、結晶状態、非晶質状態のいずれでも使用することができる。 Rivaroxaban used in the present invention has the generic name 5-chloro-N-([{5S}-2-oxo-3-[4-(3-oxomorpholin-4-yl)-phenyl]-1,3 -Oxazolidin-5-yl]methyl)thiophene-2-carboxamide and containing this active ingredient are already in clinical use, and rivaroxaban is readily available. The form of rivaroxaban can be used in either a crystalline state or an amorphous state.
効能及び効果は、非弁膜症性心房細動患者における虚血性脳卒中及び全身性塞栓症の発症抑制、深部静脈血栓症及び肺血栓塞栓症の治療及び再発抑制とする。用法及び用量は、前者の場合、通常、成人にはリバーロキサバンとして15mgを1日1回食後に経口投与する。なお、腎障害のある患者に対しては、腎機能の程度に応じて10mg1日1回に減量する。次に後者の場合、通常、成人には深部静脈血栓症又は肺血栓塞栓症発症後の初期3週間はリバーロキサバンとして15mgを1日2回食後に経口投与し、その後は15mgを1日1回食後に経口投与する。 Indications are to suppress the onset of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation, and to treat and suppress recurrence of deep vein thrombosis and pulmonary thromboembolism. In the former case, 15 mg of rivaroxaban is orally administered to adults once a day after meals. For patients with renal impairment, the dose should be reduced to 10 mg once daily according to the degree of renal function. In the latter case, the usual adult dosage is 15 mg of rivaroxaban orally administered twice daily after meals for the first 3 weeks after the onset of deep vein thrombosis or pulmonary thromboembolism, and then 15 mg once daily. Administer orally after meals.
配合量は、医薬品製剤としての用量を構成する製剤中のリバーロキサバン量であれば、特に制限されない。例えば、ある態様として1~20重量%、また、ある態様として5~15重量%である。 The amount of rivaroxaban in the formulation is not particularly limited as long as it constitutes the dose of the pharmaceutical formulation. For example, one embodiment is 1 to 20% by weight, and another embodiment is 5 to 15% by weight.
本発明に用いられるセルロース系ポリマーとしては、溶液中におけるリバーロキサバンの過飽和状態を維持し得るもの等、リバーロキサバンの溶解性を改善するものであれば、特に制限されない。また、セルロース系ポリマーとしては、製薬学的に許容され得るものであり、粘度として1~10mPa・sを示すものであれば、特に制限されない。具体的には、例えば、ヒプロメロース、ヒドロキシプロピルセルロース、メチルセルロース等が含まれる。ある態様として、ヒプロメロースでは、粘度が1~10mPa・s(約4.5mPa・s)のグレード、例えば、TC-5M(商品名、信越化学工業製);ヒドロキシプロピルセルロースでは、粘度が1~10mPa・s(約3~5.9mPa・s)のグレード、例えば、HPC-SL(商品名、日本曹達製);メチルセルロースでは、粘度が1~10mPa・s(約4mPa・s)のグレード、例えば、SM-4(商品名、信越化学工業製)等が含まれる。なお、粘度数値は、20℃における2%水溶液濃度を意味する(日本薬局方)。粘度測定については、第17改正日本薬局方 粘度測定法に従って行うこととする。具体的には、例えば、ウベローデ型による毛細管粘度計法が挙げられる。また、セルロース系ポリマーとしては、低置換度ヒドロキシプロピルセルロースが挙げられる。具体的には、例えば、品番LH-11、LH-21、LH-22、LH-B1、LH-31、LH-32、NBD-022、NBD-021、NBD-020等が含まれる。本発明に用いられるセルロース系ポリマーとしては、ある態様としては、少なくとも、低置換度ヒドロキシプロピルセルロースを含有し、適宜1種または2種以上のセルロース系ポリマーが更に含まれる。なお、低置換度ヒドロキシプロピルセルロースは、崩壊剤としての機能を有する。低置換度ヒドロキシプロピルセルロースの含有量は、溶出性を改善するものであれば、特に制限されないが、1錠剤あたり、ある態様として9重量%以上である。 The cellulosic polymer used in the present invention is not particularly limited as long as it improves the solubility of rivaroxaban, such as those capable of maintaining the supersaturated state of rivaroxaban in the solution. The cellulose-based polymer is not particularly limited as long as it is pharmaceutically acceptable and exhibits a viscosity of 1 to 10 mPa·s. Specific examples include hypromellose, hydroxypropylcellulose, methylcellulose and the like. As one aspect, hypromellose is a grade with a viscosity of 1 to 10 mPa s (about 4.5 mPa s), such as TC-5M (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.); hydroxypropyl cellulose has a viscosity of 1 to 10 mPa.・S (about 3 to 5.9 mPa s) grade, such as HPC-SL (trade name, manufactured by Nippon Soda); Methyl cellulose,
セルロース系ポリマーの配合量は、溶液中におけるリバーロキサバンの過飽和状態を維持し得る等、リバーロキサバンの溶解性を改善する量であれば、特に制限されない。具体的には、例えば、0.1重量%以上、ある態様としては0.5重量%以上であり、20重量%以下、ある態様としては10重量%以下、5重量%以下である(参考例:3重量%相当)。下限値及び/又は上限値の数値は、適宜とり得る数値と組合せることができる。具体的には、例えば、0.1~20重量%、0.1~10重量%、0.5~5重量%、0.5~10重量%、0.5~20重量%、0.1~5重量%等が挙げられる。セルロース系ポリマーの一部分はコーティング剤としてコーティングされていてもよく、錠剤中に含まれる量として解釈される。 The amount of the cellulose-based polymer to be blended is not particularly limited as long as it is an amount that improves the solubility of rivaroxaban, such as maintaining the supersaturated state of rivaroxaban in the solution. Specifically, for example, it is 0.1% by weight or more, in one embodiment 0.5% by weight or more, and 20% by weight or less, in one
セルロース系ポリマーの配合については、本発明の錠剤に含まれる態様であれば、特に制限されない。具体的には、例えば、賦形剤、結合剤、コーティング剤等として含まれる態様を含む。 There are no particular restrictions on the content of the cellulose-based polymer as long as it is included in the tablet of the present invention. Specifically, it includes, for example, an embodiment in which it is included as an excipient, binder, coating agent, or the like.
なお、本明細書において錠剤とは、素錠、口腔内崩壊錠、フィルムコーティング錠が含まれる錠剤を意味する。 In this specification, the tablet means a tablet including uncoated tablet, orally disintegrating tablet, and film-coated tablet.
本発明のリバーロキサバンを含有する錠剤には、賦形剤、崩壊剤、滑沢剤、及び界面活性剤からなる群より選択される1種又は2種以上の医薬品添加物を含む。 The rivaroxaban-containing tablet of the present invention contains one or more pharmaceutical excipients selected from the group consisting of excipients, disintegrants, lubricants and surfactants.
賦形剤としては、例えば、D-マンニトール、D-ソルビトール、乳糖水和物、白糖、デンプン、α化デンプン、結晶セルロース、カルメロースナトリウム、アラビアゴム、デキストリン、プルラン、軽質無水ケイ酸、合成ケイ酸アルミニウム、メタケイ酸アルミン酸マグネシウム、D-マンニトール・低置換度ヒドロキシプロピルセルロース・ポリビニルアルコール(完全けん化物)造粒物等が挙げられる。 Excipients include, for example, D-mannitol, D-sorbitol, lactose hydrate, sucrose, starch, pregelatinized starch, crystalline cellulose, carmellose sodium, gum arabic, dextrin, pullulan, light anhydrous silicic acid, synthetic silicic acid. aluminum acid, magnesium aluminometasilicate, D-mannitol/low-substituted hydroxypropyl cellulose/polyvinyl alcohol (completely saponified product) granules, and the like.
崩壊剤としては、例えば、トウモロコシデンプン、バレイショデンプン、カルメロース、カルメロースカルシウム、クロスカルメロースナトリウム、クロスポビドン等が挙げられる。 Examples of disintegrants include corn starch, potato starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone and the like.
滑沢剤としては、例えば、フマル酸ステアリルナトリウム、ステアリン酸、ステアリン酸ナトリウム、ステアリン酸マグネシウム、ステアリン酸カルシウム、硬化油、ショ糖脂肪酸エステル等が挙げられる。 Lubricants include, for example, sodium stearyl fumarate, stearic acid, sodium stearate, magnesium stearate, calcium stearate, hydrogenated oil, sucrose fatty acid ester and the like.
界面活性剤としては、例えば、ポリソルベート80、ラウリル硫酸ナトリウム、ポリオキシエチレン硬化ヒマシ油等が挙げられる。 Examples of surfactants include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil and the like.
本発明のリバーロキサバンを含有する錠剤には、本発明の所望の効果が達成される範囲で更なる各種医薬品添加物が適宜使用され、製剤化される。かかる医薬品添加物としては、製薬学的に許容され、かつ薬理学的に許容されるものであれば特に制限されない。例えば、結合剤、コーティング剤、酸味料、発泡剤、甘味剤、香料、着色剤、緩衝剤、抗酸化剤等が使用される。 The rivaroxaban-containing tablet of the present invention is formulated by appropriately using various additional pharmaceutical excipients as long as the desired effects of the present invention are achieved. Such pharmaceutical additives are not particularly limited as long as they are pharmaceutically acceptable and pharmacologically acceptable. For example, binders, coating agents, acidulants, foaming agents, sweetening agents, flavoring agents, coloring agents, buffering agents, antioxidants and the like are used.
結合剤としては、例えば、アラビアゴム、ヒドロキシエチルセルロース、ポリビニルピロリドン等が挙げられる。 Binders include, for example, gum arabic, hydroxyethylcellulose, polyvinylpyrrolidone, and the like.
コーティング剤としては、例えば、酸化チタン、タルク等が挙げられる。 Examples of coating agents include titanium oxide and talc.
酸味料としては、例えば、クエン酸、酒石酸、リンゴ酸等が挙げられる。 Acidulants include, for example, citric acid, tartaric acid, and malic acid.
発泡剤としては、例えば、重曹等が挙げられる。 Examples of foaming agents include sodium bicarbonate.
甘味剤としては、例えば、サッカリンナトリウム、グリチルリチン二カリウム、アスパルテーム、ステビア、ソーマチン等が挙げられる。 Sweetening agents include, for example, sodium saccharin, dipotassium glycyrrhizin, aspartame, stevia, thaumatin and the like.
香料としては、例えば、レモン、レモンライム、オレンジ、メントール等を挙げることができる。 Examples of fragrances include lemon, lemon-lime, orange, menthol and the like.
着色剤としては、例えば、三二酸化鉄、黄色三二酸化鉄、黒酸化鉄、食用黄色4号、食用黄色5号、食用赤色3号、食用赤色102号、食用青色3号等が挙げられる。 Examples of coloring agents include iron sesquioxide, yellow iron sesquioxide, black iron oxide, food yellow No. 4, food yellow No. 5, food red No. 3, food red No. 102, and food blue No. 3.
緩衝剤としては、クエン酸、コハク酸、フマル酸、酒石酸、アスコルビン酸又はその塩類、グルタミン酸、グルタミン、グリシン、アスパラギン酸、アラニン、アルギニン又はその塩類、酸化マグネシウム、酸化亜鉛、水酸化マグネシウム、リン酸、ホウ酸又はその塩類等が挙げられる。 Buffers include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or salts thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid , boric acid or salts thereof, and the like.
抗酸化剤としては、例えば、アスコルビン酸、ジブチルヒドロキシトルエン、没食子酸プロピル等が挙げられる。 Examples of antioxidants include ascorbic acid, dibutylhydroxytoluene, propyl gallate and the like.
本発明の錠剤は、粉砕、混合、造粒、乾燥、成形(打錠)、コーティング等の工程を含む、自体公知の方法により、製造することができる。詳細には、本発明の錠剤は、(予め粉砕されてもよい)リバーロキサバン、低置換度ヒドロキシプロピルセルロース、賦形剤(例えば、D-マンニトール、結晶セルロース等)を混合後、低置換度ヒドロキシプロピルセルロース以外のセルロース系ポリマー(例えば、ヒプロメロース、ヒドロキシプロピルセルロース、メチルセルロース等)及び界面活性剤(例えば、ラウリル硫酸ナトリウム等)を溶媒(例えば、水等)に溶解及び/又は懸濁した溶液を結合液として撹拌造粒し、当該造粒物を乾燥・整粒後に、当該造粒物に、崩壊剤(例えば、クロスポビドン等)、滑沢剤(例えば、フマル酸ステアリルナトリウム等)を混合して、当該混合物を圧縮成形(例えば、打錠)し、素錠(本発明の錠剤)が製造される。更に、該素錠に対して、コーティング剤(例えば、ヒプロメロース、マクロゴール6000、酸化チタン、タルク等)が被覆されることにより、フィルムコーティング錠(本発明の錠剤)が製造される。なお、リバーロキサバンを配合する工程については、造粒工程では混合工程、結合剤溶液の調製工程、造粒物に崩壊剤、滑沢剤を添加・混合工程等、いずれでの工程であってよい。 The tablet of the present invention can be produced by a method known per se, including steps such as pulverization, mixing, granulation, drying, molding (tabletting) and coating. Specifically, the tablet of the present invention is prepared by mixing rivaroxaban (which may be pre-pulverized), low-substituted hydroxypropylcellulose, and excipients (eg, D-mannitol, crystalline cellulose, etc.), followed by low-substituted Cellulosic polymers other than hydroxypropyl cellulose (e.g., hypromellose, hydroxypropyl cellulose, methyl cellulose, etc.) and surfactants (e.g., sodium lauryl sulfate, etc.) dissolved and / or suspended in a solvent (e.g., water, etc.) After stirring and granulating as a binding liquid, drying and sizing the granules, the granules are mixed with a disintegrant (e.g., crospovidone, etc.) and a lubricant (e.g., sodium stearyl fumarate, etc.). Then, the mixture is compression-molded (for example, tableted) to produce an uncoated tablet (the tablet of the present invention). Further, the uncoated tablet is coated with a coating agent (eg, hypromellose, macrogol 6000, titanium oxide, talc, etc.) to produce a film-coated tablet (the tablet of the present invention). Regarding the process of blending rivaroxaban, in the granulation process, any process such as the mixing process, the process of preparing a binder solution, the process of adding a disintegrant or a lubricant to the granules and mixing, etc. good.
以下に、実施例により本発明をさらに具体的に説明するが、本発明は下記の実施例に何ら限定されるものではない。 EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited to the following examples.
《試験例1:過飽和維持検討》
リバーロキサバンに対して高い過飽和維持特性を示す結合剤を探索した。本検討で用いた結合剤は下記表1に示す。<<Test Example 1: Examination of supersaturation maintenance>>
We searched for binders with high supersaturation retention properties for rivaroxaban. The binders used in this study are shown in Table 1 below.
結合剤3mgを精製水900ml中に溶解させ得た試験液に対し、リバーロキサバン2gをジメチルスルホキシド30ml中に溶解させ得た原薬溶液を1.5ml滴下し、パドル法200rpmにて溶出試験を行った。試験開始から30分後まで経時的にサンプルを10mL抜き取り、孔径0.45μmのメンブランフィルターでろ過し、ろ液1mLにアセトニトリル4mLを加えた液について、UV測定法により波長248.0nmにおける吸光度から溶出率を算出した。測定結果を図1に示す。 1.5 ml of a drug substance solution of 2 g of rivaroxaban dissolved in 30 ml of dimethyl sulfoxide was added dropwise to a test solution in which 3 mg of a binding agent was dissolved in 900 ml of purified water, and a dissolution test was performed by the paddle method at 200 rpm. gone. 10 mL of the sample was withdrawn over time from the start of the test until 30 minutes later, filtered through a membrane filter with a pore size of 0.45 μm, and 4 mL of acetonitrile was added to 1 mL of the filtrate. rate was calculated. The measurement results are shown in FIG.
図1の結果から、TC-5M及びSM-4、HPC-SLでは、他の結合剤より優れた過飽和維持特性を有することが明らかとなった。 The results in FIG. 1 reveal that TC-5M, SM-4, and HPC-SL have superior supersaturation retention characteristics to those of other binders.
《参考例1》(結合剤:TC-5M)
リバーロキサバン20g、D-マンニトール(三菱商事フードテック製:マンニットP)135g、カルメロース(五徳薬品製:NS300)20g及び結晶セルロース(旭化成製:PH-101)12gを撹拌造粒機(パウレック製:VG-01)に投入して撹拌後、ヒドロキシプロピルメチルセルロース(ヒプロメロース;信越化学工業製:TC-5M)6g及びラウリル硫酸ナトリウム(日光ケミカルズ製:SLS-P)1gを精製水43gに溶解させた結合剤溶液を噴霧し、造粒する。造粒終了後、目開き1.7mmの篩にて篩過した後、流動層造粒乾燥機(パウレック製:MP-01)を用いて乾燥させ、再度目開き1.0mmの篩にて篩過し、整粒末を得る。得られた整粒末にクロスポビドン(BASFジャパン製:Kollidon CL-F)3gを添加して混合後、フマル酸ステアリルナトリウム(JRS Pharma製:PRUV)3gを添加して混合し打錠末を得る。ロータリー式打錠機(菊水製作所製:VEL5)を用いて、錠剤質量100mg、φ6.5mmの円形錠とし、本圧11kgで打錠を行い、参考例1の錠剤を得る。<<Reference Example 1>> (Binder: TC-5M)
20 g of rivaroxaban, 135 g of D-mannitol (manufactured by Mitsubishi Corporation Food Tech: Mannitol P), 20 g of carmellose (manufactured by Gotoku Yakuhin: NS300) and 12 g of crystalline cellulose (manufactured by Asahi Kasei: PH-101) were mixed in a stirring granulator (manufactured by Powrex). : VG-01) and stirred, 6 g of hydroxypropyl methylcellulose (hypromellose; manufactured by Shin-Etsu Chemical Co., Ltd.: TC-5M) and 1 g of sodium lauryl sulfate (manufactured by Nikko Chemicals: SLS-P) were dissolved in 43 g of purified water. The binder solution is sprayed and granulated. After the granulation is finished, the mixture is sieved through a 1.7 mm sieve, dried using a fluidized bed granulator dryer (manufactured by Powrex: MP-01), and sieved again through a 1.0 mm sieve. Strain to obtain a sieved powder. After adding 3 g of crospovidone (Kollidon CL-F, manufactured by BASF Japan) to the obtained sieved powder and mixing, 3 g of sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) is added and mixed to obtain tableting powder. . Using a rotary tableting machine (manufactured by Kikusui Seisakusho: VEL5), round tablets with a tablet weight of 100 mg and a diameter of 6.5 mm are formed and tableted at a main pressure of 11 kg to obtain tablets of Reference Example 1.
《参考例2》(結合剤:HPC-SL)
リバーロキサバン20g、D-マンニトール(三菱商事フードテック製:マンニットP)135g、カルメロース(五徳薬品製:NS300)20g及び結晶セルロース(旭化成製:PH-101)12gを撹拌造粒機(パウレック製:VG-01)に投入して撹拌後、ヒドロキシプロピルセルロース(日本曹達製:HPC-SL)6g及びラウリル硫酸ナトリウム(日光ケミカルズ製:SLS-P)1gを精製水43gに溶解させた結合剤溶液を噴霧し、造粒する。造粒終了後、目開き1.7mmの篩にて篩過した後、流動層造粒乾燥機(パウレック製:MP-01)を用いて乾燥させ、再度目開き1.0mmの篩にて篩過し、整粒末を得る。得られた整粒末にクロスポビドン(BASFジャパン製:Kollidon CL-F)3gを添加して混合後、フマル酸ステアリルナトリウム(JRS Pharma製:PRUV)3gを添加して混合し打錠末を得る。ロータリー式打錠機(菊水製作所製:VEL5)を用いて、錠剤質量100mg、φ6.5mmの円形錠とし、本圧10kgで打錠を行い、参考例2の錠剤を得る。<<Reference Example 2>> (Binder: HPC-SL)
20 g of rivaroxaban, 135 g of D-mannitol (manufactured by Mitsubishi Corporation Food Tech: Mannitol P), 20 g of carmellose (manufactured by Gotoku Yakuhin: NS300) and 12 g of crystalline cellulose (manufactured by Asahi Kasei: PH-101) were mixed in a stirring granulator (manufactured by Powrex). : VG-01) and after stirring, 6 g of hydroxypropyl cellulose (manufactured by Nippon Soda: HPC-SL) and 1 g of sodium lauryl sulfate (manufactured by Nikko Chemicals: SLS-P) were dissolved in 43 g of purified water. is sprayed and granulated. After the granulation is finished, the mixture is sieved through a 1.7 mm sieve, dried using a fluidized bed granulator dryer (manufactured by Powrex: MP-01), and sieved again through a 1.0 mm sieve. Strain to obtain a sieved powder. After adding 3 g of crospovidone (Kollidon CL-F, manufactured by BASF Japan) to the obtained sieved powder and mixing, 3 g of sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) is added and mixed to obtain tableting powder. . Using a rotary tableting machine (manufactured by Kikusui Seisakusho: VEL5), round tablets with a tablet weight of 100 mg and a diameter of 6.5 mm are formed and tableted at a main pressure of 10 kg to obtain tablets of Reference Example 2.
《参考例3》(結合剤:SM-4)
リバーロキサバン20g、D-マンニトール(三菱商事フードテック製:マンニットP)135g、カルメロース(五徳薬品製:NS300)20g及び結晶セルロース(旭化成製:PH-101)12gを撹拌造粒機(パウレック製:VG-01)に投入して撹拌後、メチルセルロース(信越化学工業製:SM-4)6g及びラウリル硫酸ナトリウム(日光ケミカルズ製:SLS-P)1gを精製水43gに溶解させた結合剤溶液を噴霧し、造粒する。造粒終了後、目開き1.7mmの篩にて篩過した後、流動層造粒乾燥機(パウレック製:MP-01)を用いて乾燥させ、再度目開き1.0mmの篩にて篩過し、整粒末を得る。得られた整粒末にクロスポビドン(BASFジャパン製:Kollidon CL-F)3gを添加して混合後、フマル酸ステアリルナトリウム(JRS Pharma製:PRUV)3gを添加して混合し打錠末を得る。ロータリー式打錠機(菊水製作所製:VEL5)を用いて、錠剤質量100mg、φ6.5mmの円形錠とし、本圧11kgで打錠を行い、参考例3の錠剤を得る。<<Reference Example 3>> (Binder: SM-4)
20 g of rivaroxaban, 135 g of D-mannitol (manufactured by Mitsubishi Corporation Food Tech: Mannitol P), 20 g of carmellose (manufactured by Gotoku Yakuhin: NS300) and 12 g of crystalline cellulose (manufactured by Asahi Kasei: PH-101) were mixed in a stirring granulator (manufactured by Powrex). : VG-01) and stirred, then a binder solution prepared by dissolving 6 g of methyl cellulose (manufactured by Shin-Etsu Chemical: SM-4) and 1 g of sodium lauryl sulfate (manufactured by Nikko Chemicals: SLS-P) in 43 g of purified water. Spray and granulate. After the granulation is finished, the mixture is sieved through a 1.7 mm sieve, dried using a fluidized bed granulator dryer (manufactured by Powrex: MP-01), and sieved again through a 1.0 mm sieve. Strain to obtain a sieved powder. After adding 3 g of crospovidone (Kollidon CL-F, manufactured by BASF Japan) to the obtained sieved powder and mixing, 3 g of sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) is added and mixed to obtain tableting powder. . Using a rotary tableting machine (manufactured by Kikusui Seisakusho: VEL5), round tablets with a tablet weight of 100 mg and a diameter of 6.5 mm are formed and tableted at a main pressure of 11 kg to obtain tablets of Reference Example 3.
《参考例4》(結合剤:TC-5M)
D-マンニトール(三菱商事フードテック製:マンニットP)135g、カルメロース(五徳薬品製:NS300)20g及び結晶セルロース(旭化成製:PH-101)12gを撹拌造粒機(パウレック製:VG-01)に投入して撹拌し造粒用混合物とする。ヒドロキシプロピルメチルセルロース(ヒプロメロース;信越化学工業製:TC-5M)6g及びラウリル硫酸ナトリウム(日光ケミカルズ製:SLS-P)1gを精製水43gに溶解させ、さらにリバーロキサバン20gをこの溶液に懸濁して結合剤溶液を得る。造粒用混合物を撹拌しつつ結合剤溶液を滴下し造粒する。造粒終了後、目開き1.7mmの篩にて篩過した後、流動層造粒乾燥機(パウレック製:MP-01)を用いて乾燥させ、再度目開き1.0mmの篩にて篩過し、整粒末を得る。得られた整粒末にクロスポビドン(BASFジャパン製:Kollidon CL-F)3gを添加して混合後、フマル酸ステアリルナトリウム(JRS Pharma製:PRUV)3gを添加して混合し打錠末を得る。ロータリー式打錠機(菊水製作所製:VEL5)を用いて、錠剤質量100mg、φ6.5mmの円形錠とし、打錠を行い、参考例4の錠剤を得る。<<Reference Example 4>> (Binder: TC-5M)
135 g of D-mannitol (manufactured by Mitsubishi Shoji Foodtech: Mannitol P), 20 g of carmellose (manufactured by Gotoku Yakuhin: NS300) and 12 g of crystalline cellulose (manufactured by Asahi Kasei: PH-101) are stirred and granulated (Powrex: VG-01). and stirred to obtain a mixture for granulation. 6 g of hydroxypropyl methylcellulose (hypromellose; Shin-Etsu Chemical Co., Ltd.: TC-5M) and 1 g of sodium lauryl sulfate (Nikko Chemicals Co., Ltd.: SLS-P) were dissolved in 43 g of purified water, and 20 g of rivaroxaban was suspended in this solution. A binder solution is obtained. While stirring the mixture for granulation, the binder solution is added dropwise for granulation. After the granulation is finished, the mixture is sieved through a 1.7 mm sieve, dried using a fluidized bed granulator dryer (manufactured by Powrex: MP-01), and sieved again through a 1.0 mm sieve. Strain to obtain a sieved powder. After adding 3 g of crospovidone (Kollidon CL-F, manufactured by BASF Japan) to the obtained sieved powder and mixing, 3 g of sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) is added and mixed to obtain tableting powder. . Using a rotary tableting machine (manufactured by Kikusui Seisakusho: VEL5), a round tablet having a tablet weight of 100 mg and a diameter of 6.5 mm is formed and tableted to obtain a tablet of Reference Example 4.
《参考例5》(結合剤:HPC-SL)
D-マンニトール(三菱商事フードテック製:マンニットP)135g、カルメロース(五徳薬品製:NS300)20g及び結晶セルロース(旭化成製:PH-101)12gを撹拌造粒機(パウレック製:VG-01)に投入して撹拌し造粒用混合物とする。ヒドロキシプロピルセルロース(日本曹達製:HPC-SL)6g及びラウリル硫酸ナトリウム(日光ケミカルズ製:SLS-P)1gを精製水43gに溶解させ、さらにリバーロキサバン20gをこの溶液に懸濁して結合剤溶液を得る。造粒用混合物を撹拌しつつ結合剤溶液を滴下し造粒する。造粒終了後、目開き1.7mmの篩にて篩過した後、流動層造粒乾燥機(パウレック製:MP-01)を用いて乾燥させ、再度目開き1.0mmの篩にて篩過し、整粒末を得る。得られた整粒末にクロスポビドン(BASFジャパン製:Kollidon CL-F)3gを添加して混合後、フマル酸ステアリルナトリウム(JRS Pharma製:PRUV)3gを添加して混合し打錠末を得る。ロータリー式打錠機(菊水製作所製:VEL5)を用いて、錠剤質量100mg、φ6.5mmの円形錠とし、打錠を行い、参考例5の錠剤を得る。<<Reference Example 5>> (Binder: HPC-SL)
135 g of D-mannitol (manufactured by Mitsubishi Shoji Foodtech: Mannitol P), 20 g of carmellose (manufactured by Gotoku Yakuhin: NS300) and 12 g of crystalline cellulose (manufactured by Asahi Kasei: PH-101) are stirred and granulated (Powrex: VG-01). and stirred to obtain a mixture for granulation. 6 g of hydroxypropyl cellulose (Nippon Soda: HPC-SL) and 1 g of sodium lauryl sulfate (Nikko Chemicals: SLS-P) were dissolved in 43 g of purified water, and 20 g of rivaroxaban was suspended in this solution to prepare a binder solution. get While stirring the mixture for granulation, the binder solution is added dropwise for granulation. After the granulation is finished, the mixture is sieved through a 1.7 mm sieve, dried using a fluidized bed granulator dryer (manufactured by Powrex: MP-01), and sieved again through a 1.0 mm sieve. Strain to obtain a sieved powder. After adding 3 g of crospovidone (Kollidon CL-F, manufactured by BASF Japan) to the obtained sieved powder and mixing, 3 g of sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) is added and mixed to obtain tableting powder. . Using a rotary tableting machine (manufactured by Kikusui Seisakusho: VEL5), round tablets having a tablet weight of 100 mg and a diameter of 6.5 mm are formed and tableted to obtain tablets of Reference Example 5.
《参考例6》(結合剤:SM-4)
D-マンニトール(三菱商事フードテック製:マンニットP)135g、カルメロース(五徳薬品製:NS300)20g及び結晶セルロース(旭化成製:PH-101)12gを撹拌造粒機(パウレック製:VG-01)に投入して撹拌し造粒用混合物とする。メチルセルロース(信越化学工業製:SM-4)6g及びラウリル硫酸ナトリウム(日光ケミカルズ製:SLS-P)1gを精製水43gに溶解させ、さらにリバーロキサバン20gをこの溶液に懸濁して結合剤溶液を得る。造粒用混合物を撹拌しつつ結合剤溶液を滴下し造粒する。造粒終了後、目開き1.7mmの篩にて篩過した後、流動層造粒乾燥機(パウレック製:MP-01)を用いて乾燥させ、再度目開き1.0mmの篩にて篩過し、整粒末を得る。得られた整粒末にクロスポビドン(BASFジャパン製:Kollidon CL-F)3gを添加して混合後、フマル酸ステアリルナトリウム(JRS Pharma製:PRUV)3gを添加して混合し打錠末を得る。ロータリー式打錠機(菊水製作所製:VEL5)を用いて、錠剤質量100mg、φ6.5mmの円形錠とし、打錠を行い、参考例6の錠剤を得る。<<Reference Example 6>> (binder: SM-4)
135 g of D-mannitol (manufactured by Mitsubishi Shoji Foodtech: Mannitol P), 20 g of carmellose (manufactured by Gotoku Yakuhin: NS300) and 12 g of crystalline cellulose (manufactured by Asahi Kasei: PH-101) are stirred and granulated (Powrex: VG-01). and stirred to obtain a mixture for granulation. 6 g of methyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.: SM-4) and 1 g of sodium lauryl sulfate (manufactured by Nikko Chemicals: SLS-P) were dissolved in 43 g of purified water, and 20 g of rivaroxaban was further suspended in this solution to form a binder solution. obtain. While stirring the mixture for granulation, the binder solution is added dropwise for granulation. After the granulation is finished, the mixture is sieved through a 1.7 mm sieve, dried using a fluidized bed granulator dryer (manufactured by Powrex: MP-01), and sieved again through a 1.0 mm sieve. Strain to obtain a sieved powder. After adding 3 g of crospovidone (Kollidon CL-F, manufactured by BASF Japan) to the obtained sieved powder and mixing, 3 g of sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) is added and mixed to obtain tableting powder. . Using a rotary tableting machine (manufactured by Kikusui Seisakusho: VEL5), round tablets having a tablet weight of 100 mg and a diameter of 6.5 mm are formed and tableted to obtain tablets of Reference Example 6.
(低置換度ヒドロキシプロピルセルロース10%)
リバーロキサバン45g、D-マンニトール(三菱商事フードテック製:マンニットP)172.8g及び低置換度ヒドロキシプロピルセルロース(信越化学工業製:LH-21)24gを撹拌造粒機(パウレック製:VG-01)に投入して撹拌後、ヒドロキシプロピルメチルセルロース(ヒプロメロース;信越化学工業製:TC-5M)9g及びラウリル硫酸ナトリウム(日光ケミカルズ製:SLS-P)1.5gを精製水69gに溶解させた結合剤溶液を滴下し、造粒する。造粒終了後、コーミル(QC-U5丸穴、2.972mm)を用いて篩過した後、流動層造粒乾燥機(パウレック製:MP-01)を用いて乾燥させ、再度目開き1.0mmの篩にて篩過し、整粒末を得る。得られた整粒末にステアリン酸マグネシウム(太平化学産業製:ステアリン酸マグネシウム 植物性)2.7gを添加して混合し打錠末を得る。ロータリー式打錠機(菊水製作所製:VEL5)を用いて、錠剤質量85mg、φ6.0mmの円形錠とし、本圧7kgで打錠を行い素錠を得る。得られた素錠に、ヒプロメロース60g、マクロゴール12g、酸化チタン6g、タルク22g、三二酸化鉄2gを水760gに溶解、分散させたコーティング液を用いて、コーティング機(パウレック製:PRC-GTXmini)にて1錠当たり2.5mgコーティングし、フィルムコーティング錠を得る。得られたフィルムコーティング錠をカルナウバロウ(日本ワックス製:ポリシングワックス-105)0.001mgと混合し、錠剤1(87.5mg)を得る。(Low-substituted
45 g of rivaroxaban, 172.8 g of D-mannitol (manufactured by Mitsubishi Shoji Foodtech Co., Ltd.: Mannitol P) and 24 g of low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.: LH-21) were mixed in a stirring granulator (manufactured by Powrex: VG). -01) and stirred, 9 g of hydroxypropyl methylcellulose (hypromellose; manufactured by Shin-Etsu Chemical Co., Ltd.: TC-5M) and 1.5 g of sodium lauryl sulfate (manufactured by Nikko Chemicals: SLS-P) were dissolved in 69 g of purified water. Drop in the binder solution and granulate. After granulation, sieved using Comil (QC-U5 round hole, 2.972 mm), dried using a fluid bed granulator dryer (manufactured by Powrex: MP-01), and opened again. Sieve with a 0 mm sieve to obtain a sized powder. 2.7 g of magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.: magnesium stearate vegetable) is added to the obtained sieved powder and mixed to obtain tableting powder. Using a rotary tableting machine (manufactured by Kikusui Seisakusho: VEL5), round tablets having a tablet mass of 85 mg and a diameter of 6.0 mm are formed and tableted at a main pressure of 7 kg to obtain uncoated tablets. The resulting uncoated tablet was coated with a coating machine (PRC-GTXmini manufactured by Powrex) using a coating liquid prepared by dissolving and dispersing 60 g of hypromellose, 12 g of macrogol, 6 g of titanium oxide, 22 g of talc, and 2 g of ferric oxide in 760 g of water. 2.5 mg per tablet to obtain film-coated tablets. The resulting film-coated tablets are mixed with 0.001 mg of carnauba wax (manufactured by Nippon Wax: Polishing Wax-105) to obtain tablet 1 (87.5 mg).
(低置換度ヒドロキシプロピルセルロース5%)
リバーロキサバン45g、D-マンニトール(三菱商事フードテック製:マンニットP)184.8g及び低置換度ヒドロキシプロピルセルロース(信越化学工業製:LH-21)12gを撹拌造粒機(パウレック製:VG-01)に投入して撹拌後、ヒプロメロース(信越化学工業製:TC-5M)9g及びラウリル硫酸ナトリウム(日光ケミカルズ製:SLS-P)1.5gを精製水58gに溶解させた結合剤溶液を滴下し、造粒する。造粒終了後、コーミル(QC-U5丸穴、2.972mm)を用いて篩過した後、流動層造粒乾燥機(パウレック製:MP-01)を用いて乾燥させ、再度目開き1.0mmの篩にて篩過し、整粒末を得る。得られた整粒末にステアリン酸マグネシウム(太平化学産業製:ステアリン酸マグネシウム 植物性)2.7gを添加して混合し打錠末を得る。ロータリー式打錠機(菊水製作所製:VEL5)を用いて、錠剤質量85mg、φ6.0mmの円形錠とし、本圧7kgで打錠を行い素錠を得る。得られた素錠に、ヒプロメロース60g、マクロゴール12g、酸化チタン6g、タルク22g、三二酸化鉄2gを水760gに溶解、分散させたコーティング液を用いて、コーティング機(パウレック製:PRC-GTXmini)にて1錠当たり2.5mgコーティングし、フィルムコーティング錠を得る。得られたフィルムコーティング錠をカルナウバロウ(日本ワックス製:ポリシングワックス-105)0.001gと混合し、錠剤2を得る。(Low-substituted
45 g of rivaroxaban, 184.8 g of D-mannitol (manufactured by Mitsubishi Shoji Foodtech Co., Ltd.: Mannitol P) and 12 g of low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.: LH-21) were mixed in a stirring granulator (manufactured by Powrex: VG). -01) and stirred, a binder solution prepared by dissolving 9 g of hypromellose (manufactured by Shin-Etsu Chemical Co., Ltd.: TC-5M) and 1.5 g of sodium lauryl sulfate (manufactured by Nikko Chemicals: SLS-P) in 58 g of purified water. Drop and granulate. After granulation, sieved using Comil (QC-U5 round hole, 2.972 mm), dried using a fluid bed granulator dryer (manufactured by Powrex: MP-01), and opened again. Sieve with a 0 mm sieve to obtain a sized powder. 2.7 g of magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.: magnesium stearate vegetable) is added to the obtained sieved powder and mixed to obtain tableting powder. Using a rotary tableting machine (manufactured by Kikusui Seisakusho: VEL5), round tablets having a tablet mass of 85 mg and a diameter of 6.0 mm are formed and tableted at a main pressure of 7 kg to obtain uncoated tablets. The resulting uncoated tablet was coated with a coating machine (PRC-GTXmini manufactured by Powrex) using a coating liquid prepared by dissolving and dispersing 60 g of hypromellose, 12 g of macrogol, 6 g of titanium oxide, 22 g of talc, and 2 g of ferric oxide in 760 g of water. 2.5 mg per tablet to obtain film-coated tablets. The resulting film-coated tablets are mixed with 0.001 g of carnauba wax (manufactured by Nippon Wax: Polishing Wax-105) to obtain tablet 2.
(低置換度ヒドロキシプロピルセルロース15%)
リバーロキサバン45g、D-マンニトール(三菱商事フードテック製:マンニットP)157.8g及び低置換度ヒドロキシプロピルセルロース(信越化学工業製:LH-21)39gを撹拌造粒機(パウレック製:VG-01)に投入して撹拌後、ヒプロメロース(信越化学工業製:TC-5M)9g及びラウリル硫酸ナトリウム(日光ケミカルズ製:SLS-P)1.5gを精製水78gに溶解させた結合剤溶液を滴下し、造粒する。造粒終了後、コーミル(QC-U5 丸穴、2.972mm)を用いて篩過した後、流動層造粒乾燥機(パウレック製:MP-01)を用いて乾燥させ、再度目開き1.0mmの篩にて篩過し、整粒末を得る。得られた整粒末にステアリン酸マグネシウム(太平化学産業製:ステアリン酸マグネシウム 植物性)2.7gを添加して混合し打錠末を得る。ロータリー式打錠機(菊水製作所製:VEL5)を用いて、錠剤質量85mg、φ6.0mmの円形錠とし、本圧7kgで打錠を行い素錠を得る。得られた素錠に、ヒプロメロース60g、マクロゴール12g、酸化チタン6g、タルク22g、三二酸化鉄2gを水760gに溶解、分散させたコーティング液を用いて、コーティング機(パウレック製:PRC-GTXmini)にて1錠当たり2.5mgコーティングし、フィルムコーティング錠を得る。得られたフィルムコーティング錠をカルナウバロウ(日本ワックス製:ポリシングワックス-105)0.001gと混合し、錠剤3を得る。(Low-substituted
45 g of rivaroxaban, 157.8 g of D-mannitol (Mitsubishi Shoji Foodtech: Mannitol P) and 39 g of low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical: LH-21) were mixed in a stirring granulator (Powrex: VG). -01) and stirred, a binder solution prepared by dissolving 9 g of hypromellose (manufactured by Shin-Etsu Chemical Co., Ltd.: TC-5M) and 1.5 g of sodium lauryl sulfate (manufactured by Nikko Chemicals: SLS-P) in 78 g of purified water. Drop and granulate. After granulation, the mixture was sieved using Comil (QC-U5 round hole, 2.972 mm), dried using a fluidized bed granulator dryer (manufactured by Powrex: MP-01), and opened again. Sieve with a 0 mm sieve to obtain a sized powder. 2.7 g of magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.: magnesium stearate vegetable) is added to the obtained sieved powder and mixed to obtain tableting powder. Using a rotary tableting machine (manufactured by Kikusui Seisakusho: VEL5), round tablets having a tablet mass of 85 mg and a diameter of 6.0 mm are formed and tableted at a main pressure of 7 kg to obtain uncoated tablets. The resulting uncoated tablet was coated with a coating machine (PRC-GTXmini manufactured by Powrex) using a coating liquid prepared by dissolving and dispersing 60 g of hypromellose, 12 g of macrogol, 6 g of titanium oxide, 22 g of talc, and 2 g of ferric oxide in 760 g of water. 2.5 mg per tablet to obtain film-coated tablets. The resulting film-coated tablets are mixed with 0.001 g of carnauba wax (manufactured by Nippon Wax: Polishing Wax-105) to obtain tablets 3.
(低置換度ヒドロキシプロピルセルロース10%、HPC-SL)
リバーロキサバン45g、D-マンニトール(三菱商事フードテック製:マンニットP)172.8g及び低置換度ヒドロキシプロピルセルロース(信越化学工業製:LH-21)24gを撹拌造粒機(パウレック製:VG-01)に投入して撹拌後、ヒドロキシプロピルセルロース(日本曹達製:HPC-SL)9g及びラウリル硫酸ナトリウム(日光ケミカルズ製:SLS-P)1.5gを精製水66gに溶解させた結合剤溶液を滴下し、造粒する。造粒終了後、コーミル(QC-U5 丸穴、2.972mm)を用いて篩過した後、流動層造粒乾燥機(パウレック製:MP-01)を用いて乾燥させ、再度目開き1.0mmの篩にて篩過し、整粒末を得る。得られた整粒末にステアリン酸マグネシウム(太平化学産業製:ステアリン酸マグネシウム 植物性)2.7gを添加して混合し打錠末を得る。ロータリー式打錠機(菊水製作所製:VEL5)を用いて、錠剤質量85mg、φ6.0mmの円形錠とし、本圧7kgで打錠を行い素錠を得る。得られた素錠に、ヒプロメロース60g、マクロゴール12g、酸化チタン6g、タルク22g、三二酸化鉄2gを水760gに溶解、分散させたコーティング液を用いて、コーティング機(パウレック製:PRC-GTXmini)にて1錠当たり2.5mgコーティングし、フィルムコーティング錠を得る。得られたフィルムコーティング錠をカルナウバロウ(日本ワックス製:ポリシングワックス-105)0.001gと混合し、錠剤4を得る。(10% low-substituted hydroxypropyl cellulose, HPC-SL)
45 g of rivaroxaban, 172.8 g of D-mannitol (manufactured by Mitsubishi Shoji Foodtech Co., Ltd.: Mannitol P) and 24 g of low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.: LH-21) were mixed in a stirring granulator (manufactured by Powrex: VG). -01) and after stirring, a binder solution in which 9 g of hydroxypropyl cellulose (manufactured by Nippon Soda: HPC-SL) and 1.5 g of sodium lauryl sulfate (manufactured by Nikko Chemicals: SLS-P) are dissolved in 66 g of purified water. is dropped and granulated. After granulation, the mixture was sieved using Comil (QC-U5 round hole, 2.972 mm), dried using a fluidized bed granulator dryer (manufactured by Powrex: MP-01), and opened again. Sieve with a 0 mm sieve to obtain a sized powder. 2.7 g of magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.: magnesium stearate vegetable) is added to the obtained sieved powder and mixed to obtain tableting powder. Using a rotary tableting machine (manufactured by Kikusui Seisakusho: VEL5), round tablets having a tablet mass of 85 mg and a diameter of 6.0 mm are formed and tableted at a main pressure of 7 kg to obtain uncoated tablets. The resulting uncoated tablet was coated with a coating machine (PRC-GTXmini manufactured by Powrex) using a coating liquid prepared by dissolving and dispersing 60 g of hypromellose, 12 g of macrogol, 6 g of titanium oxide, 22 g of talc, and 2 g of ferric oxide in 760 g of water. 2.5 mg per tablet to obtain film-coated tablets. The resulting film-coated tablets are mixed with 0.001 g of carnauba wax (manufactured by Nippon Wax: Polishing Wax-105) to obtain
(口腔内崩壊錠)
リバーロキサバン375g、D-マンニトール(ロケットジャパン製:PEARLITOL 25C)1372.5g、及び低置換度ヒドロキシプロピルセルロース(信越化学工業製:LH-21)225gを撹拌造粒機(パウレック製:VG-10)に投入して撹拌後、ヒプロメロース(信越化学工業製:TC-5E)75g及びラウリル硫酸ナトリウム(日光ケミカルズ製:SLS-P)9.75gを精製水525gに溶解させた結合剤溶液を投入し、造粒する。造粒終了後、コーミル(QC-U5 丸穴、2.972mm)にて篩過した後、流動層造粒乾燥機(パウレック製:MP-01)を用いて乾燥させ、パワーミル(P-04Sメッシュ、0.5mm)にて篩過し、整粒末を得る。得られた整粒末82.29gにD-マンニトール・低置換度ヒドロキシプロピルセルロース・ポリビニルアルコール(完全けん化物)造粒物(信越化学工業製:SmartEx QD-100)55.41g、結晶セルロース(旭化成製:セオラスUF-702)18g、トウモロコシデンプン(日本コーンスターチ製:局方コーンスターチホワイト)18g、クロスポビドン(BASFジャパン製:Kollidon CL-F)4.5g、及びフマル酸ステアリルナトリウム(JRS Pharma製:PRUV)1.8gを加えてポリ袋にて混合し打錠末を得る。ロータリー式打錠機(菊水製作所製:VEL5)を用いて、錠剤質量180mg、φ8mmの円形錠とし、本圧5kgでステアリン酸マグネシウム(太平化学産業製:ステアリン酸マグネシウム 植物性)を外部滑沢装置(菊水製作所製:ELS-P1 Type3)にて噴霧しながら打錠を行い、本発明の錠剤(錠剤5)を得る。(orally disintegrating tablet)
375 g of rivaroxaban, 1372.5 g of D-mannitol (PEARLITOL 25C manufactured by Rocket Japan), and 225 g of low-substituted hydroxypropyl cellulose (LH-21 manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed in a stirring granulator (VG-10 manufactured by Powrex). ) and stirred, then a binder solution prepared by dissolving 75 g of hypromellose (manufactured by Shin-Etsu Chemical Co., Ltd.: TC-5E) and 9.75 g of sodium lauryl sulfate (manufactured by Nikko Chemicals: SLS-P) in 525 g of purified water was added. , to granulate. After granulation, after sieving with Comil (QC-U5 round hole, 2.972 mm), dried using a fluid bed granulator dryer (manufactured by Powrex: MP-01), power mill (P-04S mesh , 0.5 mm) to obtain sieved powder. 55.41 g of D-mannitol/low-substituted hydroxypropyl cellulose/polyvinyl alcohol (fully saponified product) granules (manufactured by Shin-Etsu Chemical Co., Ltd.: SmartEx QD-100), crystalline cellulose (Asahi Kasei Made by: Ceorus UF-702) 18 g, corn starch (manufactured by Nippon Corn Starch: Pharmacopoeia Corn Starch White) 18 g, crospovidone (manufactured by BASF Japan: Kollidon CL-F) 4.5 g, and sodium stearyl fumarate (manufactured by JRS Pharma: PRUV ) is added and mixed in a plastic bag to obtain tableting powder. Using a rotary tableting machine (manufactured by Kikusui Seisakusho: VEL5), round tablets with a tablet weight of 180 mg and a diameter of 8 mm were formed, and magnesium stearate (manufactured by Taihei Kagaku Sangyo: magnesium stearate, vegetable) was applied at a main pressure of 5 kg with an external lubricator. (manufactured by Kikusui Seisakusho: ELS-P1 Type 3), tableting is performed while spraying to obtain the tablet of the present invention (tablet 5).
《試験例2:溶出試験》
実施例1~5及び比較例1(バイエル薬品:イグザレルト(登録商標)錠15mg)で得られた錠剤を用いて溶出試験を行った。錠剤の溶解は溶出試験器(富山産業製)においてパドル法にて50rpmで、0.5%ポリソルベート80(純正化学工業製)を含有する溶出試験第1液または0.5%ポリソルベート80(純正化学工業製)を含有する溶出試験第2液900ml中で行った。試験開始から120分後まで経時的にサンプルを10ml抜き取り、孔径0.45μmのメンブランフィルターでろ過し、ろ液についてUV測定法により波長248.0nmにおける吸光度から溶出率を算出した。0.5%ポリソルベート80(純正化学工業製)を含有する溶出試験第1液での測定結果を表2に、0.5%ポリソルベート80(純正化学工業製)を含有する溶出試験第2液での測定結果を表3に示す。<<Test Example 2: Elution test>>
A dissolution test was performed using the tablets obtained in Examples 1 to 5 and Comparative Example 1 (Bayer Yakuhin: Xarelto (registered trademark)
Claims (13)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2021074453 | 2021-03-10 | ||
JP2021074453 | 2021-03-10 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2022140430A true JP2022140430A (en) | 2022-09-26 |
JP2022140430A5 JP2022140430A5 (en) | 2023-11-10 |
Family
ID=83399839
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2022052554A Pending JP2022140430A (en) | 2021-03-10 | 2022-03-09 | Rivaroxaban-containing tablet |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP2022140430A (en) |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009510138A (en) * | 2005-10-04 | 2009-03-12 | バイエル・ヘルスケア・アクチェンゲゼルシャフト | Solid pharmaceutical dosage form that can be administered orally and has a rapid release of the active ingredient |
JP2010132709A (en) * | 1998-07-28 | 2010-06-17 | Takeda Chem Ind Ltd | Rapidly disintegrable solid preparation |
CN105457036A (en) * | 2014-08-08 | 2016-04-06 | 天津汉瑞药业有限公司 | Rivaroxaban pharmaceutical composition and preparation method thereof |
WO2017146709A1 (en) * | 2016-02-25 | 2017-08-31 | Mylan Inc. | A unique high-shear granulation process for improved bioavailability of rivaroxaban |
CN109620961A (en) * | 2019-01-20 | 2019-04-16 | 黄泳华 | The composition being made of morpholone derivative and cellulose derivative |
JP2019108324A (en) * | 2017-12-15 | 2019-07-04 | エルメッド株式会社 | Rivaroxaban-containing pharmaceutical composition |
WO2020066392A1 (en) * | 2018-09-25 | 2020-04-02 | 日新製薬株式会社 | Orally administered solid preparation and production method therefor |
JP2020103025A (en) * | 2018-12-24 | 2020-07-02 | 日本電産株式会社 | Flux motor and electric product |
-
2022
- 2022-03-09 JP JP2022052554A patent/JP2022140430A/en active Pending
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010132709A (en) * | 1998-07-28 | 2010-06-17 | Takeda Chem Ind Ltd | Rapidly disintegrable solid preparation |
JP2009510138A (en) * | 2005-10-04 | 2009-03-12 | バイエル・ヘルスケア・アクチェンゲゼルシャフト | Solid pharmaceutical dosage form that can be administered orally and has a rapid release of the active ingredient |
CN105457036A (en) * | 2014-08-08 | 2016-04-06 | 天津汉瑞药业有限公司 | Rivaroxaban pharmaceutical composition and preparation method thereof |
WO2017146709A1 (en) * | 2016-02-25 | 2017-08-31 | Mylan Inc. | A unique high-shear granulation process for improved bioavailability of rivaroxaban |
JP2019108324A (en) * | 2017-12-15 | 2019-07-04 | エルメッド株式会社 | Rivaroxaban-containing pharmaceutical composition |
WO2020066392A1 (en) * | 2018-09-25 | 2020-04-02 | 日新製薬株式会社 | Orally administered solid preparation and production method therefor |
JP2020103025A (en) * | 2018-12-24 | 2020-07-02 | 日本電産株式会社 | Flux motor and electric product |
CN109620961A (en) * | 2019-01-20 | 2019-04-16 | 黄泳华 | The composition being made of morpholone derivative and cellulose derivative |
Non-Patent Citations (2)
Title |
---|
医薬品添加物事典2016, JPN6023047308, 18 February 2016 (2016-02-18), pages 340, ISSN: 0005199649 * |
添加剤の特性・選び方・使い方ノウハウ集, JPN6023047307, 31 January 2012 (2012-01-31), pages 30 - 38, ISSN: 0005199648 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4868695B2 (en) | Oral preparation with good disintegration | |
JP2022016638A (en) | Pharmaceutical composition containing irbesartan and amlodipine or salt thereof | |
JP6730978B2 (en) | Solid formulation | |
TWI405574B (en) | Pharmaceutical solid preparation and production method thereof | |
JP6404886B2 (en) | Method for stabilizing pharmaceutical compositions containing irbesartan and amlodipine or a salt thereof | |
JP2011126915A (en) | Pharmaceutical composition | |
TW201729812A (en) | A pharmaceutical composition comprising JAK kinase inhibitor or its medicinal salt thereof | |
JP6574041B2 (en) | Rivaroxaban-containing pharmaceutical composition | |
JP2012149056A (en) | New stabilized solid formulation | |
JP2021038218A (en) | Rivaroxaban-containing tablet | |
JP6813822B2 (en) | Manufacturing method of atomoxetine tablets and atomoxetine tablets | |
TW201827049A (en) | Orally disintegrating tablet containing diamine derivative | |
JP2022140430A (en) | Rivaroxaban-containing tablet | |
JP2020196713A (en) | Edoxaban-containing orally disintegrating tablet | |
JP2020520892A (en) | Tablet containing dabigatran etexilate or a pharmaceutically acceptable salt thereof and method for producing the same | |
JP2016503782A (en) | Of N- [5- [2- (3,5-dimethoxyphenyl) ethyl] -2H-pyrazol-3-yl] -4-[(3R, 5S) -3,5-dimethylpiperazin-1-yl] benzamide Pharmaceutical formulation | |
EP3335703A1 (en) | Pharmaceutical composition comprising omarigliptin | |
JP6423034B2 (en) | Imidafenacin-containing tablets | |
JP2017132724A (en) | Orally disintegrating tablet formulation comprising amlodipine-containing coated granulated material | |
KR20160141045A (en) | Pharmaceutical composition containing of Bosentan | |
JP6707471B2 (en) | Solid composition of pyrrole carboxamide | |
JP2022074102A (en) | Rivaroxaban-containing solid preparation | |
JP6160813B2 (en) | High content levofloxacin tablets | |
JP6344678B2 (en) | Telmisartan-containing preparation and method for producing the same | |
JP2021063077A (en) | Edoxaban-containing granule and orally disintegrable tablet |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20231006 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20231006 |
|
A871 | Explanation of circumstances concerning accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A871 Effective date: 20231006 |
|
RD02 | Notification of acceptance of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7422 Effective date: 20231005 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20231120 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20240119 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20240311 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20240516 |