JP2020147542A - Multilayer tablet comprising dabigatran etexilate or pharmaceutically acceptable salt thereof - Google Patents
Multilayer tablet comprising dabigatran etexilate or pharmaceutically acceptable salt thereof Download PDFInfo
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- KSGXQBZTULBEEQ-UHFFFAOYSA-N dabigatran etexilate Chemical compound C1=CC(C(N)=NC(=O)OCCCCCC)=CC=C1NCC1=NC2=CC(C(=O)N(CCC(=O)OCC)C=3N=CC=CC=3)=CC=C2N1C KSGXQBZTULBEEQ-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 229960000288 dabigatran etexilate Drugs 0.000 title claims abstract description 28
- 150000003839 salts Chemical class 0.000 title claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 53
- 239000007787 solid Substances 0.000 claims abstract description 52
- 239000002253 acid Substances 0.000 claims abstract description 27
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 25
- 238000004519 manufacturing process Methods 0.000 claims abstract description 20
- -1 carboxypropyl Chemical group 0.000 claims abstract description 9
- 229920002678 cellulose Polymers 0.000 claims abstract description 9
- 239000001913 cellulose Substances 0.000 claims abstract description 9
- 235000010980 cellulose Nutrition 0.000 claims abstract description 9
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 8
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 8
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 5
- 238000013268 sustained release Methods 0.000 claims abstract description 4
- 239000012730 sustained-release form Substances 0.000 claims abstract description 4
- 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 abstract description 3
- 239000001856 Ethyl cellulose Substances 0.000 claims abstract description 3
- 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 abstract description 3
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 claims abstract description 3
- 235000019325 ethyl cellulose Nutrition 0.000 claims abstract description 3
- 229920000609 methyl cellulose Polymers 0.000 claims abstract description 3
- 235000010981 methylcellulose Nutrition 0.000 claims abstract description 3
- 239000001923 methylcellulose Substances 0.000 claims abstract description 3
- 229920003087 methylethyl cellulose Polymers 0.000 claims abstract 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 claims abstract 2
- 239000008187 granular material Substances 0.000 claims description 53
- 239000000203 mixture Substances 0.000 claims description 46
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 41
- 239000007884 disintegrant Substances 0.000 claims description 36
- 239000000314 lubricant Substances 0.000 claims description 26
- 238000002156 mixing Methods 0.000 claims description 26
- 229940079593 drug Drugs 0.000 claims description 24
- 239000003814 drug Substances 0.000 claims description 24
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 24
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 20
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 20
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 20
- 238000001035 drying Methods 0.000 claims description 15
- 239000011230 binding agent Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 235000019359 magnesium stearate Nutrition 0.000 claims description 12
- 150000007524 organic acids Chemical class 0.000 claims description 9
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 8
- 238000009472 formulation Methods 0.000 claims description 8
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 8
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 7
- 239000003086 colorant Substances 0.000 claims description 7
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 7
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 7
- 239000000454 talc Substances 0.000 claims description 7
- 229910052623 talc Inorganic materials 0.000 claims description 7
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 6
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 6
- 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 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 6
- 229930195725 Mannitol Natural products 0.000 claims description 6
- 229920000881 Modified starch Polymers 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 229920002472 Starch Polymers 0.000 claims description 6
- 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 6
- 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 6
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 6
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 6
- 229950008138 carmellose Drugs 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 6
- 229960000913 crospovidone Drugs 0.000 claims description 6
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 6
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 6
- 239000000594 mannitol Substances 0.000 claims description 6
- 235000010355 mannitol Nutrition 0.000 claims description 6
- 239000011812 mixed powder Substances 0.000 claims description 6
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 6
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 6
- 235000012239 silicon dioxide Nutrition 0.000 claims description 6
- 239000008107 starch Substances 0.000 claims description 6
- 235000019698 starch Nutrition 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 238000000748 compression moulding Methods 0.000 claims description 5
- 238000005550 wet granulation Methods 0.000 claims description 5
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 4
- 229920001577 copolymer Polymers 0.000 claims description 4
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 claims description 4
- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-UHFFFAOYSA-N 0.000 claims description 4
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 4
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 claims description 4
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- 229920002261 Corn starch Polymers 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 235000021355 Stearic acid Nutrition 0.000 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 3
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 claims description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 239000001506 calcium phosphate Substances 0.000 claims description 3
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 3
- 235000011010 calcium phosphates 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
- 235000013539 calcium stearate Nutrition 0.000 claims description 3
- 239000008116 calcium stearate Substances 0.000 claims description 3
- 239000008120 corn starch Substances 0.000 claims description 3
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 3
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000000194 fatty acid Substances 0.000 claims description 3
- 229930195729 fatty acid Natural products 0.000 claims description 3
- 239000001530 fumaric acid Substances 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- 235000001727 glucose Nutrition 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
- 229920001592 potato starch Polymers 0.000 claims description 3
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 3
- 239000008117 stearic acid Substances 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 3
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 3
- 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 claims description 3
- 244000215068 Acacia senegal Species 0.000 claims 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 claims description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 2
- 229920000084 Gum arabic Polymers 0.000 claims description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- 239000000205 acacia gum Substances 0.000 claims description 2
- 235000010489 acacia gum Nutrition 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 235000011087 fumaric acid Nutrition 0.000 claims description 2
- 239000004220 glutamic acid Substances 0.000 claims description 2
- 235000013922 glutamic acid Nutrition 0.000 claims description 2
- 235000005985 organic acids Nutrition 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 238000003860 storage Methods 0.000 abstract description 11
- 239000004480 active ingredient Substances 0.000 abstract description 8
- 238000010828 elution Methods 0.000 abstract description 2
- 239000010410 layer Substances 0.000 description 67
- 239000003826 tablet Substances 0.000 description 59
- 239000000654 additive Substances 0.000 description 20
- 239000000243 solution Substances 0.000 description 19
- 238000000034 method Methods 0.000 description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- 230000000996 additive effect Effects 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 239000002775 capsule Substances 0.000 description 7
- 239000011162 core material Substances 0.000 description 7
- 238000007922 dissolution test Methods 0.000 description 7
- 238000013112 stability test Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 239000002274 desiccant Substances 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 4
- 210000004211 gastric acid Anatomy 0.000 description 4
- 238000005469 granulation Methods 0.000 description 4
- 230000003179 granulation Effects 0.000 description 4
- 239000012488 sample solution Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229960003850 dabigatran Drugs 0.000 description 3
- YBSJFWOBGCMAKL-UHFFFAOYSA-N dabigatran Chemical compound N=1C2=CC(C(=O)N(CCC(O)=O)C=3N=CC=CC=3)=CC=C2N(C)C=1CNC1=CC=C(C(N)=N)C=C1 YBSJFWOBGCMAKL-UHFFFAOYSA-N 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 2
- 239000011247 coating layer Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000007888 film coating Substances 0.000 description 2
- 238000009501 film coating Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 229940066336 pradaxa Drugs 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000004704 ultra performance liquid chromatography Methods 0.000 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 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 229940123900 Direct thrombin inhibitor Drugs 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 1
- 229910000387 ammonium dihydrogen phosphate Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
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- 239000007941 film coated tablet Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007942 layered tablet Substances 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 235000019837 monoammonium phosphate Nutrition 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000011253 protective coating Substances 0.000 description 1
- 238000013094 purity test Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000005060 rubber Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は、ダビガトランエテキシラートまたはその薬学的に許容される塩を有効成分として含有する多層錠に関する。 The present invention relates to a multi-layer tablet containing dabigatran etexilate or a pharmaceutically acceptable salt thereof as an active ingredient.
エチル 3-[(2-{[4-(ヘキシルオキシカルボニルアミノ-イミノ-メチル)-フェニルアミノ]-メチル}-1-メチル-1H-ベンズイミダゾール-5-イル-カルボニル)-ピリジン-2-イル-アミノ]-プロピオナートは、一般名ダビガトランエテキシラート（Ｄａｂｉｇａｔｒａｎ Ｅｔｈｅｘｉｌａｔｅ）と命名され、直接トロンビン阻害剤、抗凝固剤として知られている。ダビガトランエテキシラートのメタンスルホン酸塩を含有するカプセル剤は、本邦を含め世界中で広く使用されている。（非特許文献１） Ethyl 3-[(2-{[4- (hexyloxycarbonylamino-imino-methyl) -phenylamino] -methyl} -1-methyl-1H-benzimidazole-5-yl-carbonyl) -pyridine-2-yl -Amino] -Propionate is given the generic name Dabigatran Ethexilate and is known as a direct thrombin inhibitor and anticoagulant. Capsules containing methanesulfonate of dabigatran etexilate are widely used all over the world including Japan. (Non-Patent Document 1)
特許文献１には、ダビガトランエテキシラートの合成法、該化合物がトロンビン時間を延長する効果を有すること、製剤例として、カプセル剤、湿式造粒法で得られた錠剤等が記載されている。
特許文献２には、有機酸含有のコア材料を、ダビガトランエテキシラートを含有する被覆層で被覆した医薬組成物が開示され、該医薬組成物は更にコーティングされていても良く、斯くして得られたペレットはカプセルへ充填されている。
特許文献３には、ダビガトランエテキシラート、フマル酸、賦形剤・充填剤からなる直打法で製造された錠剤が開示されている。
特許文献４には、ダビガトランエテキシラートと無機酸添加剤を含有する経口用医薬組成物が記載されている。
特許文献５には、ダビガトランエテキシラートを含有する粒子と有機酸を含有する粒子を含み、前記の何れかの粒子が保護コーティング層を有する組成物を含有するカプセル剤が記載されている。
ダビガトランエテキシラートを含有する二層錠、三層錠は、特許文献６〜９に記載されている。
特許文献６には、中間層にPVP（ポリビニルピロリドン）やα化デンプンを含有する三層錠が記載されている。
また特許文献７には、HPMC（ヒプロメロース）でコーティングされた有機酸のペレットを含有する層を有する二層錠が記載されている。特許文献６及び７には溶出試験や安定性試験結果等の試験結果に関する記載はない。
また特許文献８には、HPMC等の徐放材を含有する有機酸含有層を有する二又は三層錠が記載されている。
さらにまた、特許文献９には、主薬含有層、有機酸含有層の何れの層にもHPMCを含有する二又は三層錠が記載されている。
Patent Document 1 describes a method for synthesizing dabigatran etexilate, the fact that the compound has an effect of prolonging the thrombin time, capsules, tablets obtained by a wet granulation method, and the like as preparation examples.
Patent Document 2 discloses a pharmaceutical composition in which a core material containing an organic acid is coated with a coating layer containing dabigatran etexilate, and the pharmaceutical composition may be further coated, thus obtaining. The pellets are filled into capsules.
Patent Document 3 discloses a tablet produced by a direct hit method, which comprises dabigatran etexilate, fumaric acid, and an excipient / filler.
Patent Document 4 describes an oral pharmaceutical composition containing dabigatran etexilate and an inorganic acid additive.
Patent Document 5 describes a capsule containing particles containing dabigatran etexilate and particles containing an organic acid, and any of the above particles contains a composition having a protective coating layer.
Two-layer tablets and three-layer tablets containing dabigatran etexilate are described in Patent Documents 6 to 9.
Patent Document 6 describes a three-layer tablet containing PVP (polyvinylpyrrolidone) or pregelatinized starch in the intermediate layer.
Further, Patent Document 7 describes a two-layer tablet having a layer containing pellets of an organic acid coated with HPMC (hypromellose). Patent Documents 6 and 7 do not describe test results such as dissolution test and stability test results.
Further, Patent Document 8 describes a two- or three-layer tablet having an organic acid-containing layer containing a sustained-release material such as HPMC.
Furthermore, Patent Document 9 describes a two- or three-layer tablet containing HPMC in both the main drug-containing layer and the organic acid-containing layer.
ダビガトランエテキシラート・メタンスルホン酸塩の溶解度は、ｐＨ依存性が高く、酸性溶液中では、高い溶解度を示すが、中性・塩基性溶液中では、極めて低い溶解度しか示さない（特許文献４，特許文献５）。また、ＦＤＡ のＣｈｅｍｉｓｔｒｙ Ｒｅｖｉｅｗ（ｓ）では、ダビガトランエテキシラート・メタンスルホン酸塩の溶解度は、ｐＨ１では、４０ｍｇ／ｍＬ、ｐＨ６では、５μｇ／ｍＬであり、そして、ＢＣＳ クラス２（ｌｏｗ ｓｏｌｕｂｉｌｉｔｙ／ｈｉｇｈ ｐｅｒｍｅａｂｉｌｉｔｙ）の薬物として記載されている。 低胃酸患者やＰＰＩの前投与患者に前記製剤を経口投与する場合、通常製剤では、胃内での溶解度が低く、生物学的利用率の低下が予想される。
また、現在、本邦で市販されているダビガトランエテキシラート・メタンスルホン酸塩製剤は、カプセル剤のみで、一包化や服薬コンプライアンスの向上のため、市場への錠剤の提供が望まれている。
The solubility of dabigatran etexilate / methanesulfonate is highly pH-dependent and shows high solubility in acidic solutions, but very low solubility in neutral / basic solutions (Patent Documents 4 and 4). Patent Document 5). Also, in the FDA Chemistry Review (s), the solubility of dabigatlan etexilate methanesulfonate is 40 mg / mL at pH 1, 5 μg / mL at pH 6, and BCS class 2 (sulfur utility / high). It is described as a drug of permeability). When the above-mentioned preparation is orally administered to patients with low gastric acid or pre-administered PPI, it is expected that the usual preparation has low solubility in the stomach and a decrease in bioavailability.
In addition, the dabigatran etexilate / methanesulfonate preparation currently marketed in Japan is only a capsule, and it is desired to provide tablets to the market in order to package and improve medication compliance.
本発明者らは、ダビガトランエテキシラート・メタンスルホン酸塩を含有する製剤に関する研究を進めた結果、ダビガトランエテキシラート・メタンスルホン酸塩を含有する特定の多層錠が製造トラブルもなく、また得られた多層錠は保存安定性に優れ、しかも低胃酸患者に対しても良好な溶出性を期待できることを見いだし、本発明を完成した。
本発明の目的は、中性領域での溶出性が向上し、低胃酸患者等における消化管内での溶出性が向上し、優れた保存安定性を有するダビガトランエテキシラート・メタンスルホン酸塩を有効成分として含有する多層錠を提供することにある。
さらにまた本発明は、簡便な方法で、ダビガトランエテキシラート・メタンスルホン酸塩を有効成分として含有する多層錠の製造方法を提供することにある。
As a result of conducting research on a formulation containing dabigatran etexilate / methanesulfonate, the present inventors have obtained a specific multi-layer tablet containing dabigatran etexilate / methanesulfonate without any manufacturing trouble. The present invention has been completed by finding that the obtained multi-layer tablet has excellent storage stability and can be expected to have good dissolution property even for patients with low gastric acid.
An object of the present invention is to use dabigatran etexilate / methanesulfonate, which has improved dissolution in the neutral region, improved dissolution in the gastrointestinal tract in patients with low gastric acid, and excellent storage stability. The purpose is to provide a multi-layer tablet containing as an ingredient.
Furthermore, the present invention is to provide a method for producing a multilayer tablet containing dabigatran etexylate / methanesulfonate as an active ingredient by a simple method.
即ち
（１）
本発明は、ダビガトランエテキシラート又はその薬学的に許容される塩（以下、（ａ）という）及び薬学的に許容される酸（以下、（ｂ）という）を含有する固形製剤であって、前記（ａ）及び（ｂ）が互いに接触しないように別々の層に分離配合されていることを特徴とする多層錠であって、
1錠中、ダビガトランエテキシラートとして、２５〜２５０ｍｇ含有し、
そして、（ｂ）を含有する層はヒドロキシプロピルメチルセルロース、メチルセルロース、エチルセルロース、ヒドロキシエチルセルロース及びカルボキシプロピルセルロースから選択される徐放剤を含有していないことを特徴とする固形製剤に関する。
（２）
また本発明は、ダビガトランエテキシラートとして、１錠中、７５〜１５０ｍｇ含有する上記１記載の固形製剤に関する。
（３）
また本発明は、該多層錠が、フィルムコーティングされている上記１又は２記載の固形製剤に関する。
（４）
また本発明は、多層錠が二層錠であって、第１の層に上記（ａ）、賦形剤、崩壊剤を含有する層を有し、他方の層に上記(ｂ)、賦形剤、崩壊剤を含有する層を有する上記１〜３記載の固形製剤に関する。
（５）
また本発明は、多層錠が三層錠であって、第１の層に上記（ａ）、賦形剤、崩壊剤を含有する層を有し、これと賦形剤を含有し、PVP及びα化デンプンから選択される結合剤を含有しない中間層を挟んで、他方の層に上記(ｂ)、賦形剤、崩壊剤を含有する第２の層を有する上記１〜３記載の固形製剤に関する。
（６）
また本発明は、多層錠が内核と外層からなる有核錠であって、内核は上記(ｂ)、賦形剤、崩壊剤を含有し、外層は上記（ａ）、賦形剤、崩壊剤を含有する上記１〜３記載の固形製剤に関する。
（７）
また本発明は、打錠圧が２〜８ｋＮである上記１〜６記載の固形製剤に関する。
（８）
また本発明は、上記（ｂ）が有機酸である上記１〜７記載の固形製剤に関する。
（９）
また本発明は、上記（ｂ）が２０℃で１ｇ／２５０ｍＬよりも大きい水溶性を有する薬学的に許容される有機酸の１又は２種以上の組み合わせであるである上記８記載の固形製剤に関する。
（１０）
また本発明は、上記（ｂ）が酒石酸、フマル酸、クエン酸、コハク酸、グルタミン酸から選択される１又は２種以上の組み合わせである上記８記載の固形製剤に関する。
（１１）
また本発明は、賦形剤が、乳糖水和物、結晶セルロース、マンニトール、ブドウ糖、トウモロコシデンプン、馬鈴薯デンプン、無水リン酸カルシウムから選択される１又は２種以上の組み合わせである上記４〜１０記載の固形製剤に関する。
（１２）
また本発明は、賦形剤が、マンニトール又は結晶セルロースである上記４〜１０記載の固形製剤に関する。
（１３）
また本発明は、結合剤がヒドロキシプロピルセルロース、アラビアゴム、ポリビニルピロリドン、ポリビニルアルコール、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体から選択される１又は２種以上の組み合わせである上記４〜１２記載の固形製剤に関する。
（１４）
また本発明は、結合剤がヒドロキシプロピルセルロースである上記４〜１２記載の固形製剤に関する。
（１５）
また本発明は、崩壊剤が、低置換度ヒドロキシプロピルセルロース、クロスポビドン、クロスカルメロースナトリウム、カルメロースカルシウム、カルボキシメチルスターチ、カルメロース、カルボキシメチルスターチナトリウム、部分アルファー化でんぷんから選択される１又は２種以上の組み合わせである上記４〜１４記載の固形製剤に関する。
（１６）
また本発明は、崩壊剤が、低置換度ヒドロキシプロピルセルロース、クロスポビドン、クロスカルメロースナトリウムから選択される１又は２種以上の組み合わせである上記４〜１４記載の固形製剤に関する。
（１７）
また本発明は、更に流動化剤及び／又は滑沢剤を含有する上記４〜１６記載の固形製剤に関する。
（１８）
また本発明は、流動化剤が、軽質無水ケイ酸、含水二酸化ケイ素、タルク、メタケイ酸アルミン酸マグネシウムから選択される１又は２種以上の組み合わせである上記１７記載の固形製剤に関する。
（１９）
また本発明は、滑沢剤がステアリン酸マグネシウム、ステアリン酸、ステアリン酸カルシウム、ショ糖脂肪酸エステル、タルク、フマル酸ステアリルナトリウムから選択される１又は２種以上の組み合わせである上記１７記載の固形製剤に関する。
（２０）
また本発明は、さらに着色剤を含有する上記４〜１９記載の固形製剤に関する。
（２１）
また本発明は、着色剤が、酸化チタン、食用黄色５号、食用青色２号、三二酸化鉄、黄色三二酸化鉄
から選択される１又は２種以上の組み合わせである上記２０記載の固形製剤に関する。
（２２）
また本発明は、上記（ａ）を含有する層が湿式造粒により得られた顆粒を圧縮して得られるものである上記１〜２１記載の固形製剤に関する。
（２３）
また本発明は、上記（ｂ）を含有する層が湿式造粒により得られた顆粒を圧縮して得られたものである上記１〜２２記載の固形製剤に関する。
（２４）
また本発明は、上記（ｂ）を含有する層中、上記（ｂ）がコーティングされていない上記２３記載の固形製剤に関する。
（２５）
また本発明は、次の（１）〜（４）の工程を含有することを特徴とする二層錠の製造方法に関する。
（１）上記（ａ）と賦形剤、崩壊剤、流動化剤を混合し、得られた混合物に、造粒液を加え、造粒し、乾燥することで、薬物含有顆粒を得る工程、
（２）別に、上記（ｂ）と賦形剤、崩壊剤、流動化剤を混合し、得られた混合物に、造粒液を加え、造粒し、乾燥し、酸含有顆粒を得る工程、
（３）酸含有顆粒と滑沢剤を混合後、打錠機に投入後、打錠する工程、
（４）次いで、薬物含有顆粒と滑沢剤との混合物をこれに投入後、打錠する工程。
（２６）
また本発明は、次の（１）〜（５）の工程を含有することを特徴とする三層錠の製造方法に関する。
（１）上記（ａ）と賦形剤、崩壊剤、流動化剤を混合し、得られた混合物に、造粒液を加え、造粒し、乾燥することで、薬物含有顆粒を得る工程、
（２）別に、上記（ｂ）と賦形剤、崩壊剤、流動化剤を混合し、得られた混合物に、造粒液を加え、造粒し、乾燥し、酸含有顆粒を得る工程、
（３）酸含有顆粒と滑沢剤を混合後、打錠機に投入後、打錠する工程、
（４）次いで、これに賦形剤と滑沢剤の混合物を投入後、打錠する工程、
（５）さらにこれに薬物含有顆粒と滑沢剤の混合物を投入後、打錠する工程。
（２７）
更にまた本発明は、次の（１）〜（５）の工程を含有することを特徴とする有核錠の製造方法に関する。
（１）上記（ｂ）と賦形剤、崩壊剤、流動化剤を混合し、造粒液を加え、造粒し、乾燥し、造粒物を得る工程、
（２）（１）で得られた造粒物に滑沢剤を加え、混合後、圧縮成形することで内核錠を得る工程、
（３）別に上記（ａ）と賦形剤、崩壊剤、流動化剤を混合し、造粒液を加え、造粒し、乾燥し、造粒物を得る工程、
（４）上記（３）で得られた造粒物に滑沢剤を加え、混合し、混合末を得る工程、
（５）上記（４）の混合末を上記（２）の内核錠に外層として配合し、圧縮成形する工程。
That is, (1)
The present invention is a solid preparation containing dabigatran etexilate or a pharmaceutically acceptable salt thereof (hereinafter referred to as (a)) and a pharmaceutically acceptable acid (hereinafter referred to as (b)). A multi-layer tablet characterized in that (a) and (b) are separately blended in separate layers so as not to come into contact with each other.
One tablet contains 25 to 250 mg of dabigatran etexilate,
The layer containing (b) relates to a solid preparation which does not contain a sustained-release agent selected from hydroxypropylmethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose and carboxypropyl cellulose.
(2)
The present invention also relates to the solid preparation according to 1 above, which contains 75 to 150 mg of dabigatran etexilate in one tablet.
(3)
The present invention also relates to the solid preparation according to 1 or 2 above, wherein the multilayer tablet is film-coated.
(4)
Further, in the present invention, the multi-layer tablet is a two-layer tablet, the first layer has a layer containing the above (a), an excipient and a disintegrant, and the other layer has the above (b), shaping. The present invention relates to the solid preparations described in 1 to 3 above, which have a layer containing an agent and a disintegrant.
(5)
Further, in the present invention, the multi-layer tablet is a three-layer tablet, and the first layer has a layer containing the above (a), an excipient and a disintegrant, and contains this and an excipient, PVP and The solid preparation according to the above 1 to 3 having an intermediate layer containing no binder selected from pregelatinized starch and a second layer containing the above (b), an excipient and a disintegrant in the other layer. Regarding.
(6)
Further, in the present invention, the multilayer tablet is a nucleated tablet composed of an inner core and an outer layer, the inner core contains the above (b), an excipient and a disintegrant, and the outer layer is the above (a), an excipient and a disintegrant. The present invention relates to the solid preparations described in 1 to 3 above.
(7)
The present invention also relates to the solid preparation according to the above 1 to 6, wherein the tableting pressure is 2 to 8 kN.
(8)
The present invention also relates to the solid preparation according to the above 1 to 7, wherein the above (b) is an organic acid.
(9)
The present invention also relates to the solid preparation according to 8 above, wherein (b) is one or a combination of two or more pharmaceutically acceptable organic acids having a water solubility greater than 1 g / 250 mL at 20 ° C. ..
(10)
The present invention also relates to the solid preparation according to 8 above, wherein (b) is one or a combination of two or more selected from tartaric acid, fumaric acid, citric acid, succinic acid, and glutamic acid.
(11)
Further, in the present invention, the solid according to the above 4-10, wherein the excipient is one or a combination of two or more selected from lactose hydrate, crystalline cellulose, mannitol, glucose, corn starch, potato starch, and anhydrous calcium phosphate. Regarding formulations.
(12)
The present invention also relates to the solid preparation according to the above 4 to 10, wherein the excipient is mannitol or crystalline cellulose.
(13)
Further, in the present invention, the binder is one or a combination of two or more selected from hydroxypropyl cellulose, arabic rubber, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymers 4 to 12 above. With respect to the described solid formulations.
(14)
The present invention also relates to the solid preparation according to the above 4 to 12, wherein the binder is hydroxypropyl cellulose.
(15)
Further, in the present invention, the disintegrant is selected from 1 or 2 having a low degree of substitution hydroxypropyl cellulose, crospovidone, croscarmellose sodium, carmellose calcium, carboxymethyl starch, carmellose, carboxymethyl starch sodium, and partially pregelatinized starch. The present invention relates to the solid preparation according to the above 4 to 14, which is a combination of species or more.
(16)
The present invention also relates to the solid preparation according to the above 4 to 14, wherein the disintegrant is one or a combination of two or more selected from low-degree-of-substitution hydroxypropyl cellulose, crospovidone, and croscarmellose sodium.
(17)
The present invention also relates to the solid preparations described in 4 to 16 above, which further contain a fluidizing agent and / or a lubricant.
(18)
The present invention also relates to the solid preparation according to the above 17, wherein the fluidizing agent is one or a combination of two or more selected from light anhydrous silicic acid, hydrous silicon dioxide, talc, and magnesium aluminate metasilicate.
(19)
The present invention also relates to the solid preparation according to the above 17, wherein the lubricant is one or a combination of two or more selected from magnesium stearate, stearic acid, calcium stearate, sucrose fatty acid ester, talc, and sodium stearyl fumarate. ..
(20)
The present invention also relates to the solid preparations described in 4 to 19 above, which further contain a colorant.
(21)
The present invention also relates to the solid preparation according to the above 20, wherein the colorant is one or a combination of two or more selected from titanium oxide, edible yellow No. 5, edible blue No. 2, iron sesquioxide, and yellow sesquioxide. ..
(22)
The present invention also relates to the solid preparation according to the above 1 to 21, wherein the layer containing the above (a) is obtained by compressing the granules obtained by wet granulation.
(23)
The present invention also relates to the solid preparation according to the above 1 to 22, wherein the layer containing the above (b) is obtained by compressing the granules obtained by wet granulation.
(24)
The present invention also relates to the solid preparation according to the above 23, wherein the layer containing the above (b) is not coated with the above (b).
(25)
The present invention also relates to a method for producing a two-layer tablet, which comprises the following steps (1) to (4).
(1) A step of mixing the above (a) with an excipient, a disintegrant, and a fluidizing agent, adding a granulating solution to the obtained mixture, granulating, and drying to obtain drug-containing granules.
(2) Separately, a step of mixing the above (b) with an excipient, a disintegrant, and a fluidizing agent, adding a granulating solution to the obtained mixture, granulating, drying, and obtaining acid-containing granules.
(3) A step of mixing acid-containing granules and a lubricant, putting the granules into a tableting machine, and then tableting.
(4) Next, a step of adding a mixture of the drug-containing granules and the lubricant to the mixture and then tableting.
(26)
The present invention also relates to a method for producing a three-layer tablet, which comprises the following steps (1) to (5).
(1) A step of mixing the above (a) with an excipient, a disintegrant, and a fluidizing agent, adding a granulating solution to the obtained mixture, granulating, and drying to obtain drug-containing granules.
(2) Separately, a step of mixing the above (b) with an excipient, a disintegrant, and a fluidizing agent, adding a granulating solution to the obtained mixture, granulating, drying, and obtaining acid-containing granules.
(3) A step of mixing acid-containing granules and a lubricant, putting the granules into a tableting machine, and then tableting.
(4) Next, a step of adding a mixture of an excipient and a lubricant to the mixture and then tableting.
(5) Further, a step of adding a mixture of drug-containing granules and a lubricant to the mixture and then tableting.
(27)
Furthermore, the present invention relates to a method for producing a nucleated tablet, which comprises the following steps (1) to (5).
(1) A step of mixing the above (b) with an excipient, a disintegrant, and a fluidizing agent, adding a granulating solution, granulating, drying, and obtaining a granulated product.
(2) A step of adding a lubricant to the granules obtained in (1), mixing, and compression molding to obtain an inner core tablet.
(3) Separately, a step of mixing the above (a) with an excipient, a disintegrant, and a fluidizing agent, adding a granulating solution, granulating, drying, and obtaining a granulated product.
(4) A step of adding a lubricant to the granules obtained in (3) above and mixing them to obtain a mixed powder.
(5) A step of blending the mixed powder of (4) above with the inner core tablet of (2) above as an outer layer and compression molding.
本発明は、ダビガトランエテキシラートまたはその薬学的に許容される塩を有効成分として含有する多層錠を簡便な方法で、製造トラブルもなく製造でき、また得られた多層錠は良好な溶出性を示し、優れた保存安定性を有する。 INDUSTRIAL APPLICABILITY According to the present invention, a multi-layer tablet containing dabigatran etexilate or a pharmaceutically acceptable salt thereof as an active ingredient can be produced by a simple method without any manufacturing trouble, and the obtained multi-layer tablet has good dissolution property. Shown and has excellent storage stability.
以下、本発明を詳細に説明する。
本発明において、賦形剤としては、乳糖水和物、結晶セルロース、マンニトール、ブドウ糖、トウモロコシデンプン、馬鈴薯デンプン、無水リン酸カルシウムから選択される１又は２種以上の組み合わせが用いられる。
好ましくは、賦形剤としては、マンニトール又は結晶セルロースである。
本発明において、結合剤としては、ヒドロキシプロピルセルロース、アラビアゴム、ポリビニルピロリドン、ポリビニルアルコール、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体から選択される１又は２種以上の組み合わせが用いられる。
好ましくは、結合剤としては、ヒドロキシプロピルセルロースである。
本発明において、崩壊剤としては、低置換度ヒドロキシプロピルセルロース、クロスポビドン、クロスカルメロースナトリウム、カルメロースカルシウム、カルボキシメチルスターチ、カルメロース、カルボキシメチルスターチナトリウム、部分アルファー化でんぷんから選択される１又は２種以上の組み合わせが用いられる。
好ましくは、崩壊剤としては、低置換度ヒドロキシプロピルセルロース、クロスポビドン、クロスカルメロースナトリウムから選択される１又は２種以上の組み合わせである。
本発明において、流動化剤としては、軽質無水ケイ酸、含水二酸化ケイ素、タルク、メタケイ酸アルミン酸マグネシウムから選択される１又は２種以上の組み合わせが用いられる。
本発明において、滑沢剤としては、ステアリン酸マグネシウム、ステアリン酸、ステアリン酸カルシウム、ショ糖脂肪酸エステル、タルク、フマル酸ステアリルナトリウムから選択される１又は２種以上の組み合わせが用いられる。
本発明において、着色剤としては、酸化チタン、食用黄色５号、食用青色２号、三二酸化鉄、黄色三二酸化鉄から選択される１又は２種以上の組み合わせが用いられる。
Hereinafter, the present invention will be described in detail.
In the present invention, as the excipient, one or a combination of two or more selected from lactose hydrate, crystalline cellulose, mannitol, glucose, corn starch, potato starch, and anhydrous calcium phosphate is used.
Preferably, the excipient is mannitol or crystalline cellulose.
In the present invention, as the binder, one or a combination of two or more selected from hydroxypropyl cellulose, gum arabic, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer is used.
Preferably, the binder is hydroxypropyl cellulose.
In the present invention, the disintegrant is 1 or 2 selected from low-degree-of-substitution hydroxypropyl cellulose, crospovidone, croscarmellose sodium, carmellose calcium, carboxymethyl starch, carmellose, carboxymethyl starch sodium, and partially pregelatinized starch. A combination of more than a species is used.
Preferably, the disintegrant is one or a combination of two or more selected from low degree of substitution hydroxypropyl cellulose, crospovidone, and croscarmellose sodium.
In the present invention, as the fluidizing agent, one or a combination of two or more selected from light anhydrous silicic acid, hydrous silicon dioxide, talc, and magnesium aluminate metasilicate is used.
In the present invention, as the lubricant, one or a combination of two or more selected from magnesium stearate, stearic acid, calcium stearate, sucrose fatty acid ester, talc, and sodium stearyl fumarate is used.
In the present invention, as the colorant, one or a combination of two or more selected from titanium oxide, edible yellow No. 5, edible blue No. 2, iron sesquioxide, and yellow sesquioxide is used.
本発明の二層錠、三層錠、有核錠は、例えば上記の特許文献６〜９、特許第５６６６４７１号、製剤機械技術研究会誌, 2004, 13(2), 6-15「新規有核錠(OSDRC)ロータリー打錠機の開発」や以下の方法等と同様な方法により製造することができる。
（A）二層錠の製造方法
有効成分と賦形剤、崩壊剤、流動化剤等の添加剤を混合し、得られた混合物に、結合剤等の添加剤を水等の溶剤に分散・溶解した液を加え、造粒し、乾燥することで、薬物含有顆粒を得る。
別に、酸と賦形剤、崩壊剤、流動化剤等の添加剤を混合し、得られた混合物に、結合剤等の添加剤を水等の溶剤に分散・溶解した液を加え、造粒し、乾燥することで酸含有顆粒を得る。
薬物含有顆粒と滑沢剤等の添加剤を混合し、打錠機に投入後、打錠し、次いで、酸含有顆粒と滑沢剤等の添加剤との混合物をこれに投入し、打錠することで本発明の二層錠が得られる。
（B）三層錠の製造方法
有効成分と賦形剤、崩壊剤、流動化剤等の添加剤を混合し、得られた混合物に、結合剤等の添加剤を水等の溶剤に分散・溶解した液を加え、造粒し、乾燥することで、薬物含有顆粒を得る。
別に、酸と賦形剤、崩壊剤、流動化剤等の添加剤を混合し、得られた混合物に、結合剤等の添加剤を水等の溶剤に分散・溶解した液を加え、造粒し、乾燥することで酸含有顆粒を得る。
薬物含有顆粒と滑沢剤等の添加剤を混合し、打錠機に投入し、打錠後、これに賦形剤と滑沢剤等の添加剤の混合物を投入し、打錠した後、さらにこれに酸含有顆粒と滑沢剤等の添加剤との混合物をこれに投入し、打錠することで本発明の三層錠を得られる。
（C）有核錠の製造方法
酸と賦形剤、流動化剤等の添加剤を混合し、結合剤等の添加剤を水等の溶剤に分散・溶解した液を加え、造粒し、乾燥することで造粒物を得る。得られた造粒物に崩壊剤、滑沢剤等の添加剤を加え、混合後、圧縮成形することで内核錠を得る。
別に有効成分と賦形剤、流動化剤等の添加剤を混合し、得られた混合物に結合剤等の添加剤を水等の溶剤に分散・溶解した液を加え、造粒、乾燥することで造粒物を得る。得られた造粒物に崩壊剤、滑沢剤などの添加剤を加え、混合末を得る。
この混合末を上記内核錠に外層として配合し、圧縮成形することで本発明の有核錠が得られる。
かくして得られた二層錠、三層錠及び有核錠は、常法のフィルムコーティングを施すことでフィルムコーティング錠を得ることができる。
フィルムコーティングにおいて、コーティング基剤としては、ポリビニルアルコール、ヒドロキシプロピルメチルセルロース、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、マクロゴール６０００、タルク、酸化チタンが用いられ、コーティング層には、着色剤（例えば、黄色三二酸化鉄など）を含有していても良い。
次に実施例を挙げて本発明を更に詳細に説明する。
The two-layer, three-layer, and nucleated tablets of the present invention are, for example, the above-mentioned Patent Documents 6 to 9, Patent No. 5666471, Journal of Pharmaceutical Machinery Technology, 2004, 13 (2), 6-15 "New Nucleated". It can be manufactured by the same method as "Development of lock (OSDRC) rotary tableting machine" and the following methods.
(A) Method for producing double-layered tablets The active ingredient is mixed with additives such as excipients, disintegrants and fluidizers, and additives such as binders are dispersed in a solvent such as water in the obtained mixture. Drug-containing granules are obtained by adding the dissolved solution, granulating, and drying.
Separately, an acid and an additive such as an excipient, a disintegrant, and a fluidizing agent are mixed, and a liquid in which an additive such as a binder is dispersed and dissolved in a solvent such as water is added to the obtained mixture to granulate. And dry to obtain acid-containing granules.
The drug-containing granules and additives such as a lubricant are mixed, put into a tableting machine and then tableted, and then a mixture of acid-containing granules and an additive such as a lubricant is added to the tablet and tableted. By doing so, the bilayer tablet of the present invention can be obtained.
(B) Method for producing three-layer tablets The active ingredient and additives such as excipients, disintegrants and fluidizers are mixed, and the additives such as binders are dispersed in a solvent such as water in the obtained mixture. Drug-containing granules are obtained by adding the dissolved solution, granulating, and drying.
Separately, an acid and an additive such as an excipient, a disintegrant, and a fluidizing agent are mixed, and a liquid in which an additive such as a binder is dispersed and dissolved in a solvent such as water is added to the obtained mixture to granulate. And dry to obtain acid-containing granules.
The drug-containing granules and additives such as a lubricant are mixed and put into a tableting machine. After tableting, a mixture of excipients and additives such as a lubricant is added to the mixture, and after tableting, Further, a mixture of acid-containing granules and an additive such as a lubricant is added thereto and the mixture is beaten to obtain the three-layer tablet of the present invention.
(C) Method for producing nucleated tablets Mix acid with additives such as excipients and fluidizing agents, add a solution in which additives such as binders are dispersed and dissolved in a solvent such as water, and granulate. Granules are obtained by drying. Additives such as a disintegrant and a lubricant are added to the obtained granules, mixed, and compression-molded to obtain an inner core tablet.
Separately, the active ingredient and additives such as excipients and fluidizing agents are mixed, and a solution obtained by dispersing and dissolving the additive such as a binder in a solvent such as water is added to the obtained mixture, and the mixture is granulated and dried. To obtain the granulated product. Additives such as a disintegrant and a lubricant are added to the obtained granules to obtain a mixed powder.
The nucleated tablet of the present invention can be obtained by blending this mixed powder with the inner core tablet as an outer layer and compression molding.
The two-layer tablet, the three-layer tablet and the nucleated tablet thus obtained can be obtained as a film-coated tablet by applying a conventional film coating.
In film coating, polyvinyl alcohol, hydroxypropylmethyl cellulose, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, macrogol 6000, talc, and titanium oxide are used as the coating base, and the coating layer is a colorant (colorant (). For example, yellow iron sesquioxide, etc.) may be contained.
Next, the present invention will be described in more detail with reference to examples.
（実施例１）
三層錠
（薬物含有顆粒の製造）
表１の薬物層で、ヒドロキシプロピルセルロース及びステアリン酸マグネシウムを除く成分を混合し、これに別に調整した造粒液（ヒドロキシプロピルセルロースを水に溶解）を加え、造粒し、乾燥後、分級することで薬物含有顆粒を得た。
（酸含有顆粒の製造）
表１の酸層で、ヒドロキシプロピルセルロース及びステアリン酸マグネシウムを除く成分を混合し、これに別に調整した造粒液（ヒドロキシプロピルセルロースを水に溶解）を加え、造粒し、乾燥後、分級することで酸含有顆粒を得た。
（三層錠の製造）
酸含有顆粒とステアリン酸マグネシウムを混合後、単発打錠機に投入、１ｋNで打錠し、次いで乳糖とステアリン酸マグネシウムの混合物を加え、１ｋNで打錠後、更に薬物含有顆粒とステアリン酸マグネシウムとの混合物をこれに投入し、５ｋNで打錠することで本発明の三層錠を得た。
(Example 1)
Three-layer lock
(Manufacturing of drug-containing granules)
In the drug layer shown in Table 1, components other than hydroxypropyl cellulose and magnesium stearate are mixed, and a separately prepared granulation solution (hydroxypropyl cellulose is dissolved in water) is added thereto, granulated, dried, and then classified. As a result, drug-containing granules were obtained.
(Manufacturing of acid-containing granules)
In the acid layer shown in Table 1, components other than hydroxypropyl cellulose and magnesium stearate are mixed, and a separately prepared granulation solution (hydroxypropyl cellulose is dissolved in water) is added thereto, granulated, dried, and then classified. As a result, acid-containing granules were obtained.
(Manufacturing of three-layer tablets)
After mixing the acid-containing granules and magnesium stearate, put them in a single-shot tableting machine, tablet them at 1 kN, then add a mixture of lactose and magnesium stearate, tablet them at 1 kN, and then add the drug-containing granules and magnesium stearate. The mixture of the above was added thereto and tableted at 5 kN to obtain a three-layer tablet of the present invention.
（実施例２）
二層錠
（薬物含有顆粒の製造）
表２の薬物層で、ヒドロキシプロピルセルロース及びステアリン酸マグネシウムを除く成分を混合し、これに別に調整した造粒液（ヒドロキシプロピルセルロースを水に溶解）を加え、造粒し、乾燥後、分級することで薬物含有顆粒を得た。
（酸含有顆粒の製造）
表２の酸層で、ヒドロキシプロピルセルロース及びステアリン酸マグネシウムを除く成分を混合し、これに別に調整した造粒液（ヒドロキシプロピルセルロースを水に溶解）を加え、造粒し、乾燥後、分級することで酸含有顆粒を得た。
（二層錠の製造）
酸含有顆粒とステアリン酸マグネシウムを混合後、単発打錠機に投入後、１ｋNで打錠後、薬物含有顆粒とステアリン酸マグネシウムとの混合物をこれに投入し、５ｋNで打錠することで本発明の二層錠を得た。
(Example 2)
Double layer lock
(Manufacturing of drug-containing granules)
In the drug layer shown in Table 2, components other than hydroxypropyl cellulose and magnesium stearate are mixed, and a separately prepared granulation solution (hydroxypropyl cellulose is dissolved in water) is added thereto, granulated, dried, and then classified. As a result, drug-containing granules were obtained.
(Manufacturing of acid-containing granules)
In the acid layer of Table 2, components other than hydroxypropyl cellulose and magnesium stearate are mixed, and a separately prepared granulation solution (hydroxypropyl cellulose is dissolved in water) is added to the mixture, granulated, dried, and then classified. As a result, acid-containing granules were obtained.
(Manufacturing of double-layer tablets)
The present invention is obtained by mixing acid-containing granules and magnesium stearate, putting them into a single-shot tableting machine, tableting at 1 kN, then putting a mixture of drug-containing granules and magnesium stearate into this, and tableting at 5 kN. I got a double layer tablet of.
（実施例３）
安定性試験結果
実施例１及び２で得られた製剤及ぶ通常錠（単層錠）について、６０℃閉鎖系（乾燥剤入り）２週間及び４０℃７５％閉鎖系（乾燥剤入り）１か月の保存安定性試験を行った。
通常錠は実施例２の二層錠の酸層と薬物層を混合して単発打錠機にて５ｋＮで打錠したものである。
結果を表４，５に示す。
表４，５記載の数値は、UPLCで測定した類縁物質の総量（％）である。
純度試験条件（別途、言及がなければ他の実施例も同様）
UPLC条件
移動相A：50mM酢酸アンモニウム溶液に薄めた酢酸（1→100）を加えてpH5.55〜5.60に調整する。この液を10倍希釈する。
移動相B：アセトニトリル
溶解溶媒：移動相Aと移動相Bを2:3の割合で混合する。
試料溶液：ダビガトランエテキシラートメタンスルホン酸塩として12.5mg相当量の試料を秤取し、溶解溶媒50mLで溶解した溶液をフィルターろ過したものを試料溶液とする。
流量：ダビガトランエテキシラートの保持時間が約15分になるように調整する。
グラジエント：下記表のとおりとする。
(Example 3)
Stability test results
Storage stability of the formulations obtained in Examples 1 and 2 and the conventional tablets (single layer tablets) at 60 ° C. closed system (with desiccant) for 2 weeks and at 40 ° C. 75% closed system (with desiccant) for 1 month. The test was conducted.
The ordinary tablet is obtained by mixing the acid layer and the drug layer of the two-layer tablet of Example 2 and tableting at 5 kN with a single-shot tableting machine.
The results are shown in Tables 4 and 5.
The numerical values shown in Tables 4 and 5 are the total amount (%) of related substances measured by UPLC.
Purity test conditions (same for other examples unless otherwise mentioned)
UPLC conditions Mobile phase A: Add diluted acetic acid (1 → 100) to a 50 mM ammonium acetate solution to adjust the pH to 5.55 to 5.60. Dilute this solution 10-fold.
Mobile phase B: Acetonitrile dissolving solvent: Mobile phase A and mobile phase B are mixed at a ratio of 2: 3.
Sample solution: A sample equivalent to 12.5 mg of dabigatran etexilate methanesulfonate is weighed, and the solution dissolved in 50 mL of the dissolving solvent is filtered and used as the sample solution.
Flow rate: Adjust the retention time of dabigatran etexilate to about 15 minutes.
Gradient: As shown in the table below.
（試験結果）
６０℃閉鎖系（乾燥剤入り）で２週間の保存安定性試験
(Test results)
Storage stability test for 2 weeks in a 60 ° C closed system (with desiccant)
４０℃７５％閉鎖系（乾燥剤入り）１か月の保存安定性試験40 ° C 75% closed system (with desiccant) 1 month storage stability test
表４及び５記載のように、実施例１及び２記載の製剤は良好な保存安定性を有することが明らかになった。
As shown in Tables 4 and 5, the formulations described in Examples 1 and 2 were found to have good storage stability.
（実施例４）
溶出試験
実施例１（三層錠）及び実施例２（二層錠）及び通常錠について、溶出試験を行った。
その結果を表６に記載する。表中の値は３回試験を行った平均溶出率を示す。
溶出試験条件
溶出試験液：水
溶出試験条件：パドル法（回転数：50 rpm、37°C、900 mL）
ダビガトランの定量；
HPLC条件
移動相：10mM リン酸二水素アンモニウム溶液に薄めたアンモニア水（28）
（1→100）を加えてpH5.5に調整する。この液450mLにアセトニトリル550mLを加える。
試料溶液：溶出液をフィルターろ過し、同量の移動相を加えたものを試料溶液とする。
試験結果
(Example 4)
Dissolution test
An dissolution test was conducted on Example 1 (three-layer tablet), Example 2 (two-layer tablet), and ordinary tablet.
The results are shown in Table 6. The values in the table indicate the average elution rate of the three tests.
Dissolution test conditions <br /> Dissolution test solution: Water Dissolution test conditions: Paddle method (rotation speed: 50 rpm, 37 ° C, 900 mL)
Quantification of dabigatran;
HPLC Condition Mobile Phase: Ammonia water diluted in 10 mM ammonium dihydrogen phosphate solution (28)
Add (1 → 100) to adjust to pH 5.5. Add 550 mL of acetonitrile to 450 mL of this solution.
Sample solution: The eluate is filtered and the same amount of mobile phase is added to obtain the sample solution.
Test results
表６から明らかなように実施例1及び２記載の多層錠は、水を用いた溶出試験において、６０分後には８５％以上、溶出することが明らかになった。
As is clear from Table 6, the multi-layer tablets described in Examples 1 and 2 were found to elute by 85% or more after 60 minutes in the dissolution test using water.
（実施例５）
打錠圧の影響
実施例２記載の製剤処方で、表７記載の打錠圧を用い、類縁物質の変化を測定した。
６０℃閉鎖系（乾燥剤入り）で２週間の保存安定性試験を行い、その結果を表８に示す。
なお、保存安定性試験では、指標として、類縁物質のＤＡＢ−９−ａｍｉｄｅの量（％）を測定することで行った。
ＤＡＢ−９−ａｍｉｄｅは、相対保持時間が０．９７である非特許文献１の８頁記載のＢＩＢＲ１１５４（ダビガトランエテキシラートの加水分解物）である。
(試験製剤)
(Example 5)
Effect of tableting pressure
In the formulation according to Example 2, changes in related substances were measured using the tableting pressure shown in Table 7.
A storage stability test was conducted for 2 weeks in a closed system at 60 ° C. (containing a desiccant), and the results are shown in Table 8.
In the storage stability test, the amount (%) of the related substance DAB-9-amide was measured as an index.
DAB-9-amide is BIBR1154 (hydrolyzate of dabigatran etexilate) described on page 8 of Non-Patent Document 1 having a relative retention time of 0.97.
(Test formulation)
（安定性試験結果）
(Stability test result)
表８の結果から打錠圧を５ｋNと低めにすることで、安定性が向上することが明らかになった。
From the results in Table 8, it was clarified that the stability was improved by lowering the tableting pressure to 5 kN.
本発明においては、ダビガトランエテキシラートまたはその薬学的に許容される塩を有効成分として含有する多層錠を簡便な方法で、製造トラブルもなく製造でき、また得られた多層錠は保存安定性に優れ、しかも低胃酸患者に対しても使用できる。 In the present invention, a multi-layer tablet containing dabigatran etexilate or a pharmaceutically acceptable salt thereof as an active ingredient can be produced by a simple method without any manufacturing trouble, and the obtained multi-layer tablet has storage stability. It is excellent and can be used for patients with low gastric acid.
Claims (27)
1錠中、ダビガトランエテキシラートとして、２５〜２５０ｍｇ含有し、
そして、（ｂ）を含有する層はヒドロキシプロピルメチルセルロース、メチルセルロース、エチルセルロース、ヒドロキシエチルセルロース及びカルボキシプロピルセルロースから選択される徐放剤を含有していないことを特徴とする固形製剤。 A solid preparation containing dabigatran etexilate or a pharmaceutically acceptable salt thereof (hereinafter referred to as (a)) and a pharmaceutically acceptable acid (hereinafter referred to as (b)), wherein the above (a) is used. And (b) are multi-layer tablets characterized in that they are separately blended in separate layers so as not to come into contact with each other.
One tablet contains 25 to 250 mg of dabigatran etexilate,
A solid preparation characterized in that the layer containing (b) does not contain a sustained-release agent selected from hydroxypropylmethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose and carboxypropyl cellulose.
から選択される１又は２種以上の組み合わせである請求項２０記載の固形製剤。 The solid preparation according to claim 20, wherein the colorant is one or a combination of two or more selected from titanium oxide, edible yellow No. 5, edible blue No. 2, iron sesquioxide, and yellow sesquioxide.
（１）上記（ａ）と賦形剤、崩壊剤、流動化剤を混合し、得られた混合物に、造粒液を加え、造粒し、乾燥することで、薬物含有顆粒を得る工程、
（２）別に、上記（ｂ）と賦形剤、崩壊剤、流動化剤を混合し、得られた混合物に、造粒液を加え、造粒し、乾燥し、酸含有顆粒を得る工程、
（３）酸含有顆粒と滑沢剤を混合後、打錠機に投入後、打錠する工程、
（４）次いで、薬物含有顆粒と滑沢剤との混合物をこれに投入後、打錠する工程。 A method for producing a two-layer tablet, which comprises the following steps (1) to (4).
(1) A step of mixing the above (a) with an excipient, a disintegrant, and a fluidizing agent, adding a granulating solution to the obtained mixture, granulating, and drying to obtain drug-containing granules.
(2) Separately, a step of mixing the above (b) with an excipient, a disintegrant, and a fluidizing agent, adding a granulating solution to the obtained mixture, granulating, drying, and obtaining acid-containing granules.
(3) A step of mixing acid-containing granules and a lubricant, putting the granules into a tableting machine, and then tableting.
(4) Next, a step of adding a mixture of the drug-containing granules and the lubricant to the mixture and then tableting.
（１）上記（ａ）と賦形剤、崩壊剤、流動化剤を混合し、得られた混合物に、造粒液を加え、造粒し、乾燥することで、薬物含有顆粒を得る工程、
（２）別に、上記（ｂ）と賦形剤、崩壊剤、流動化剤を混合し、得られた混合物に、造粒液を加え、造粒し、乾燥し、酸含有顆粒を得る工程、
（３）酸含有顆粒と滑沢剤を混合後、打錠機に投入後、打錠する工程、
（４）次いで、これに賦形剤と滑沢剤の混合物を投入後、打錠する工程、
（５）さらにこれに薬物含有顆粒と滑沢剤の混合物を投入後、打錠する工程。 A method for producing a three-layer tablet, which comprises the following steps (1) to (5).
(1) A step of mixing the above (a) with an excipient, a disintegrant, and a fluidizing agent, adding a granulating solution to the obtained mixture, granulating, and drying to obtain drug-containing granules.
(2) Separately, a step of mixing the above (b) with an excipient, a disintegrant, and a fluidizing agent, adding a granulating solution to the obtained mixture, granulating, drying, and obtaining acid-containing granules.
(3) A step of mixing acid-containing granules and a lubricant, putting the granules into a tableting machine, and then tableting.
(4) Next, a step of adding a mixture of an excipient and a lubricant to the mixture and then tableting.
(5) Further, a step of adding a mixture of drug-containing granules and a lubricant to the mixture and then tableting.
（１）上記（ｂ）と賦形剤、崩壊剤、流動化剤を混合し、造粒液を加え、造粒し、乾燥し、造粒物を得る工程、
（２）（１）で得られた造粒物に滑沢剤を加え、混合後、圧縮成形することで内核錠を得る工程、
（３）別に上記（ａ）と賦形剤、崩壊剤、流動化剤を混合し、造粒液を加え、造粒し、乾燥し、造粒物を得る工程、
（４）上記（３）で得られた造粒物に滑沢剤を加え、混合し、混合末を得る工程、
（５）上記（４）の混合末を上記（２）の内核錠に外層として配合し、圧縮成形する工程。 A method for producing a nucleated tablet, which comprises the following steps (1) to (5).
(1) A step of mixing the above (b) with an excipient, a disintegrant, and a fluidizing agent, adding a granulating solution, granulating, drying, and obtaining a granulated product.
(2) A step of adding a lubricant to the granulated product obtained in (1), mixing, and compression molding to obtain an inner core tablet.
(3) Separately, the step of mixing the above (a) with an excipient, a disintegrant, and a fluidizing agent, adding a granulating solution, granulating, drying, and obtaining a granulated product.
(4) A step of adding a lubricant to the granules obtained in (3) above and mixing them to obtain a mixed powder.
(5) A step of blending the mixed powder of (4) above with the inner core tablet of (2) above as an outer layer and compression molding.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2020180099A (en) * | 2019-04-26 | 2020-11-05 | 沢井製薬株式会社 | Dabigatran etexylate methanesulfonate formulation |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102793699A (en) * | 2012-08-06 | 2012-11-28 | 严轶东 | Medicinal composition containing dabigatran etexilate |
| JP2014517843A (en) * | 2011-05-24 | 2014-07-24 | テバ ファーマシューティカル インダストリーズ リミティド | Compressed core for pharmaceutical composition |
| CN104042588A (en) * | 2014-06-17 | 2014-09-17 | 浙江京新药业股份有限公司 | Multi-layer tablets containing dabigatran etexilate mesylate |
| CN105919962A (en) * | 2015-12-18 | 2016-09-07 | 重庆两江药物研发中心有限公司 | Dabigatran tablet, and preparation method and application thereof |
| WO2018104387A1 (en) * | 2016-12-07 | 2018-06-14 | Sanovel Ilac Sanayi Ve Ticaret A.S. | Multilayered tablet compositions of dabigatran |
| WO2018122262A1 (en) * | 2016-12-28 | 2018-07-05 | Sanovel Ilac Sanayi Ve Ticaret A.S. | Bilayer tablet formulations of dabigatran etexilate |
| JP2020029441A (en) * | 2018-08-24 | 2020-02-27 | 東和薬品株式会社 | Preparation containing dabigatran etexilate |
| JP2020147529A (en) * | 2019-03-13 | 2020-09-17 | 東和薬品株式会社 | Preparation containing dabigatran etexilate and stabilization method |
-
2019
- 2019-03-14 JP JP2019047600A patent/JP2020147542A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014517843A (en) * | 2011-05-24 | 2014-07-24 | テバ ファーマシューティカル インダストリーズ リミティド | Compressed core for pharmaceutical composition |
| CN102793699A (en) * | 2012-08-06 | 2012-11-28 | 严轶东 | Medicinal composition containing dabigatran etexilate |
| CN104042588A (en) * | 2014-06-17 | 2014-09-17 | 浙江京新药业股份有限公司 | Multi-layer tablets containing dabigatran etexilate mesylate |
| CN105919962A (en) * | 2015-12-18 | 2016-09-07 | 重庆两江药物研发中心有限公司 | Dabigatran tablet, and preparation method and application thereof |
| WO2018104387A1 (en) * | 2016-12-07 | 2018-06-14 | Sanovel Ilac Sanayi Ve Ticaret A.S. | Multilayered tablet compositions of dabigatran |
| WO2018122262A1 (en) * | 2016-12-28 | 2018-07-05 | Sanovel Ilac Sanayi Ve Ticaret A.S. | Bilayer tablet formulations of dabigatran etexilate |
| JP2020029441A (en) * | 2018-08-24 | 2020-02-27 | 東和薬品株式会社 | Preparation containing dabigatran etexilate |
| JP2020147529A (en) * | 2019-03-13 | 2020-09-17 | 東和薬品株式会社 | Preparation containing dabigatran etexilate and stabilization method |
Non-Patent Citations (3)
| Title |
|---|
| 新・薬剤学総論, JPN6023009133, pages 373 - 403, ISSN: 0005011451 * |
| 新・薬剤学総論, JPN6023009135, pages 133 - 162, ISSN: 0005011450 * |
| 第十三改正日本薬局方解説書（通則その他）, JPN6023009136, 1996, pages 97 - 104, ISSN: 0005011449 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2020180099A (en) * | 2019-04-26 | 2020-11-05 | 沢井製薬株式会社 | Dabigatran etexylate methanesulfonate formulation |
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