JP6321131B2 - Dissolution improvement method of amlodipine-containing combination tablets - Google Patents
Dissolution improvement method of amlodipine-containing combination tablets Download PDFInfo
- Publication number
- JP6321131B2 JP6321131B2 JP2016256790A JP2016256790A JP6321131B2 JP 6321131 B2 JP6321131 B2 JP 6321131B2 JP 2016256790 A JP2016256790 A JP 2016256790A JP 2016256790 A JP2016256790 A JP 2016256790A JP 6321131 B2 JP6321131 B2 JP 6321131B2
- Authority
- JP
- Japan
- Prior art keywords
- manufactured
- tablet
- irbesartan
- amlodipine besylate
- carmellose
- 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.)
- Active
Links
- 238000004090 dissolution Methods 0.000 title description 23
- 229960000528 amlodipine Drugs 0.000 title description 8
- 238000000034 method Methods 0.000 title description 8
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 title 1
- 239000003826 tablet Substances 0.000 claims description 141
- ZPBWCRDSRKPIDG-UHFFFAOYSA-N amlodipine benzenesulfonate Chemical group OS(=O)(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl ZPBWCRDSRKPIDG-UHFFFAOYSA-N 0.000 claims description 78
- 229960004005 amlodipine besylate Drugs 0.000 claims description 70
- 239000002947 C09CA04 - Irbesartan Substances 0.000 claims description 59
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 claims description 59
- 229960002198 irbesartan Drugs 0.000 claims description 59
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 47
- 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 47
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 47
- 229950008138 carmellose Drugs 0.000 claims description 47
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 24
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 24
- 239000007884 disintegrant Substances 0.000 claims description 20
- 229940088679 drug related substance Drugs 0.000 claims description 15
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 14
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 13
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 11
- 239000011575 calcium Substances 0.000 claims description 11
- 229910052791 calcium Inorganic materials 0.000 claims description 11
- 229920001577 copolymer Polymers 0.000 claims description 5
- 239000007888 film coating Substances 0.000 claims description 5
- 238000009501 film coating Methods 0.000 claims description 5
- 239000010410 layer Substances 0.000 claims description 5
- 239000008187 granular material Substances 0.000 claims description 4
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 3
- 239000007941 film coated tablet Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 229920002261 Corn starch Polymers 0.000 description 71
- 239000008120 corn starch Substances 0.000 description 71
- 229940099112 cornstarch Drugs 0.000 description 71
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 50
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 44
- 239000000126 substance Substances 0.000 description 33
- 235000019359 magnesium stearate Nutrition 0.000 description 22
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 21
- 229960000913 crospovidone Drugs 0.000 description 20
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 20
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 20
- 230000000052 comparative effect Effects 0.000 description 18
- 238000001035 drying Methods 0.000 description 18
- 235000010355 mannitol Nutrition 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000008213 purified water Substances 0.000 description 17
- 239000000843 powder Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- 238000013019 agitation Methods 0.000 description 13
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 12
- 239000006191 orally-disintegrating tablet Substances 0.000 description 12
- 238000004080 punching Methods 0.000 description 12
- 229920002678 cellulose Polymers 0.000 description 10
- 239000001913 cellulose Substances 0.000 description 10
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 10
- 229920002785 Croscarmellose sodium Polymers 0.000 description 8
- 239000001856 Ethyl cellulose Substances 0.000 description 8
- 239000004376 Sucralose Substances 0.000 description 8
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 8
- 229960001681 croscarmellose sodium Drugs 0.000 description 8
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 229920001249 ethyl cellulose Polymers 0.000 description 8
- 235000019325 ethyl cellulose Nutrition 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 8
- 235000019408 sucralose Nutrition 0.000 description 8
- 239000011230 binding agent Substances 0.000 description 7
- 239000011248 coating agent Substances 0.000 description 7
- 239000006185 dispersion Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 239000000314 lubricant Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 238000005469 granulation Methods 0.000 description 4
- 230000003179 granulation Effects 0.000 description 4
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 4
- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-UHFFFAOYSA-N 0.000 description 4
- 229910001220 stainless steel Inorganic materials 0.000 description 4
- 239000010935 stainless steel Substances 0.000 description 4
- 239000001069 triethyl citrate Substances 0.000 description 4
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 4
- 235000013769 triethyl citrate Nutrition 0.000 description 4
- -1 1H-tetrazol-5-yl Chemical group 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- UBVSIAHUTXHQTD-UHFFFAOYSA-N 2-n-(4-bromophenyl)-1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(NC=2C=CC(Br)=CC=2)=N1 UBVSIAHUTXHQTD-UHFFFAOYSA-N 0.000 description 2
- 239000002051 C09CA08 - Olmesartan medoxomil Substances 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- UQGKUQLKSCSZGY-UHFFFAOYSA-N Olmesartan medoxomil Chemical compound C=1C=C(C=2C(=CC=CC=2)C2=NNN=N2)C=CC=1CN1C(CCC)=NC(C(C)(C)O)=C1C(=O)OCC=1OC(=O)OC=1C UQGKUQLKSCSZGY-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- 235000012732 erythrosine Nutrition 0.000 description 2
- 238000009775 high-speed stirring Methods 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 229960003943 hypromellose Drugs 0.000 description 2
- 229960001199 olmesartan medoxomil Drugs 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 229940032147 starch Drugs 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 238000005550 wet granulation Methods 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- QQUGAJMOSWOMFG-UHFFFAOYSA-N 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid Chemical compound OC(=O)C1=C(COCCN)NC(C)=C(C(O)=O)C1C1=CC=CC=C1Cl QQUGAJMOSWOMFG-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 244000024675 Eruca sativa Species 0.000 description 1
- 235000014755 Eruca sativa Nutrition 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 description 1
- 229960004977 anhydrous lactose Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000007931 coated granule Substances 0.000 description 1
- 239000011247 coating layer Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- OWMBTIRJFMGPAC-UHFFFAOYSA-N dimethylamino 2-methylprop-2-enoate Chemical compound CN(C)OC(=O)C(C)=C OWMBTIRJFMGPAC-UHFFFAOYSA-N 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 238000009837 dry grinding Methods 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 238000012812 general test Methods 0.000 description 1
- 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 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000006068 taste-masking agent Substances 0.000 description 1
- 239000012085 test solution Substances 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
- 229960004699 valsartan Drugs 0.000 description 1
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 1
- 238000001238 wet grinding Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は原薬としてアムロジピン又は其の塩（特にアムロジピンベシル酸塩）を含有する配合錠（特に原薬としてイルベサルタンを共に含有するもの）に関するものであり、アムロジピンの溶出性を改善するための詳細な方法を提示するものである。 The present invention relates to a combination tablet containing amlodipine or a salt thereof (particularly amlodipine besylate) as an active ingredient (especially containing irbesartan as an active ingredient), and details for improving the dissolution of amlodipine Presents a new method.
アムロジピン（一般名）は、化学名が２−（２−アミノエトキシメチル）−４−（２−クロロフェニル）−１，４−ジヒドロ−６−メチルピリジン−３，５−ジカルボン酸３−エチル５−メチルと記される持続性カルシウム拮抗薬であり、一般的にベンゼンスルホン酸との塩、即ちアムロジピンベシル酸塩が特に好ましく治療に用いられている。また、イルベサルタン（一般名）は、化学名が２−ブチル−３−｛４−［２−（１Ｈ−テトラゾール−５−イル）フェニル］ベンジル｝−１，３−ジアザスピロ［４．４］ノン−１−エン−４−オンと記される長期作用性アンギオテンシンＩＩ受容体拮抗剤である。イルベサルタン／アムロジピンベシル酸塩の配合錠は、有用な高血圧治療薬として医療現場で広く提供されている（非特許文献１等参考）。 Amlodipine (generic name) has the chemical name 2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1,4-dihydro-6-methylpyridine-3,5-dicarboxylate 3-ethyl 5- It is a long-lasting calcium antagonist, denoted as methyl, and generally a salt with benzenesulfonic acid, ie amlodipine besylate, is particularly preferably used for treatment. Irbesartan (generic name) has a chemical name of 2-butyl-3- {4- [2- (1H-tetrazol-5-yl) phenyl] benzyl} -1,3-diazaspiro [4.4] non- It is a long acting angiotensin II receptor antagonist labeled 1-en-4-one. Irbesartan / amlodipine besylate combination tablets are widely provided in the medical field as useful antihypertensive drugs (see Non-Patent Document 1, etc.).
イルベサルタン／アムロジピンベシル酸塩の配合錠については、以下の先行特許文献１〜３で製剤処方及び製造方法が紹介されている。
特許文献１では、イルベサルタンを含む顆粒と、其の顆粒外に位置して物理的に分離されたアムロジピンベシル酸塩を含有する錠剤が記載され、其の錠剤は長期保存条件下での原薬の化学的な安定性が高いことが示されている。特許文献２では、イルベサルタンを含む湿式造粒された造粒物と、アムロジピンベシル酸塩、ポリビニルアルコールを含有する錠剤が記載され、其の錠剤は３０分溶出率が良好であることが示されている。特許文献３では、イルベサルタンを含む湿式造粒された造粒物と、アムロジピンベシル酸塩、ヒドロキシプロピルセルロースや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等から選ばれる結合剤を含有する錠剤が記載され、其の錠剤は高湿度保存条件下での原薬の化学的な安定性が高いことが示されている。
尚、関連する特許文献として、特許文献４ではオルメサルタンメドキソミル／アムロジピンベシル酸塩の配合錠が記載され、特許文献５ではアムロジピンベシル酸塩と種種の崩壊剤を含有する錠剤が記載されている。
About the combination tablet of irbesartan / amlodipine besilate, the following prescription patent documents 1-3 introduce the formulation and manufacturing method.
Patent Document 1 describes a granule containing irbesartan and a tablet containing amlodipine besylate physically separated and located outside the granule, and the tablet is a drug substance under long-term storage conditions. High chemical stability has been shown. Patent Document 2 describes a granulated product obtained by wet granulation containing irbesartan, an amlodipine besylate salt, and a tablet containing polyvinyl alcohol, and shows that the tablet has a good dissolution rate for 30 minutes. Yes. Patent Document 3 describes a tablet containing a granulated product obtained by wet granulation containing irbesartan and a binder selected from amlodipine besylate, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, and the like. Has been shown to have high chemical stability of the drug substance under high humidity storage conditions.
As related patent documents, Patent Document 4 describes a combination tablet of olmesartan medoxomil / amlodipine besylate, and Patent Document 5 describes a tablet containing amlodipine besylate and various disintegrants.
本発明者は先行技術を踏まえて、より高品質なイルベサルタン／アムロジピンベシル酸塩の配合錠を製造することを目指して、原薬の溶出性を改善する技術的手段の開発を目指した。 Based on the prior art, the present inventor aimed to produce a higher quality irbesartan / amlodipine besylate combination tablet and aimed to develop technical means for improving the dissolution of the drug substance.
本発明は、アムロジピンベシル酸塩の溶出速度が有意に改善された配合錠を製造するための技術的手段を提供するものである。 The present invention provides a technical means for producing a combination tablet in which the dissolution rate of amlodipine besylate is significantly improved.
本発明者は、上記の課題を解決するべく鋭意検討した結果、イルベサルタン／アムロジピンベシル酸塩の配合錠において崩壊剤であるカルメロースを含有した場合には、アムロジピンベシル酸塩の溶出速度が有意に改善されることを見出した。本発明者はその知見に基づいて更に鋭意検討を重ね、下記の本発明を完成するに至った。 As a result of intensive studies to solve the above-mentioned problems, the present inventor significantly improved the dissolution rate of amlodipine besylate when the disintegrant carmellose was contained in the combination tablet of irbesartan / amlodipine besylate. I found out that The inventor has conducted further intensive studies based on the findings, and has completed the present invention described below.
すなわち本発明は、アムロジピンベシル酸塩である原薬と特定の崩壊剤を含む配合錠に関するものであり、好適な形態は以下（１）〜（６）において記述されるものである。
（１）アムロジピンベシル酸塩である原薬を含み、カルメロース、カルメロースカルシウム、及びカルメロースナトリウムから選択される崩壊剤を含む、配合錠。
（２）崩壊剤がカルメロースである、前記（１）に記載の配合錠。
（３）素錠又は口腔内崩壊錠である、前記（１）又は（２）に記載の配合錠。
（４）前記（１）又は（２）に記載の配合錠である素錠がフィルムコーティング層で覆われた、フィルムコーティング錠。
（５）イルベサルタンである原薬を含む、前記（１）〜（４）のいずれかに記載の配合錠。
（６）アムロジピンベシル酸塩でない原薬を含有する造粒物を含む配合錠であって、其の造粒物中に結晶セルロース又はクロスポピドンが含有されている、前記（１）〜（５）のいずれかに記載の配合錠。
That is, the present invention relates to a combination tablet containing a drug substance that is amlodipine besylate and a specific disintegrant, and preferred forms are described in (1) to (6) below.
(1) A combination tablet comprising a drug substance that is amlodipine besylate and a disintegrant selected from carmellose, carmellose calcium, and carmellose sodium.
(2) The combination tablet according to (1), wherein the disintegrant is carmellose.
(3) The combination tablet according to (1) or (2), which is an uncoated tablet or an orally disintegrating tablet.
(4) A film-coated tablet in which the uncoated tablet that is the combination tablet according to (1) or (2) is covered with a film coating layer.
(5) The combination tablet according to any one of (1) to (4) above, which contains an active pharmaceutical ingredient that is irbesartan.
(6) A combination tablet comprising a granulated product containing a drug substance that is not amlodipine besylate, wherein the granulated product contains crystalline cellulose or crospovidone, (1) to (5) A combination tablet according to any one of the above.
本発明のアムロジピンベシル酸塩を含有する配合錠は、アムロジピンベシル酸塩の溶出速度が有意に改善された効果をもち、医療現場に高品質な錠剤を提供することを可能にする。 The combination tablet containing amlodipine besylate according to the present invention has an effect that the dissolution rate of amlodipine besylate is significantly improved, and makes it possible to provide high-quality tablets in the medical field.
以下で本発明の、アムロジピンベシル酸塩である原薬と特定の崩壊剤を含む配合錠の処方及び製造方法、を詳細に説明する。但し以下の記載は本発明を説明するための例示であり、本発明をこの記載範囲にのみ特別限定する趣旨ではない。 The prescription and manufacturing method of the combination tablet containing the drug substance which is amlodipine besylate and a specific disintegrant according to the present invention will be described in detail below. However, the following description is an example for explaining the present invention, and is not intended to specifically limit the present invention to this description range.
＜錠剤の形態＞
本発明の錠剤は、２以上の原薬を含む配合錠であり、素錠（フィルムコーティング層や糖衣層等で覆われていない、打錠等により成形したままの錠剤を指す。以下同じ。）であることが好ましく、特に好ましくは素錠である口腔内崩壊錠である。本発明の錠剤に係る素錠は、フィルムコーティング層で被覆することでフィルムコーティング錠とすることが可能である。
また、本発明に係る口腔内崩壊錠は口腔内崩壊時間が６０秒未満のものであり、４０秒未満であるものが特に好ましい。
本発明に係る錠剤の形状は特に限定されず、円形錠｛円形平錠（隅角錠等含む）、円形Ｒ錠（隅角錠、２段Ｒ錠等含む）等｝や異形錠等のいずれの形状でもよいが、円形Ｒ錠であることが好ましい。
<Tablet form>
The tablet of the present invention is a combination tablet containing two or more drug substances, and is an uncoated tablet (refers to a tablet that is not covered with a film coating layer, a sugar coating layer, or the like, but is still molded by tableting, etc.). Orally disintegrating tablets that are uncoated tablets are particularly preferable. The uncoated tablet according to the tablet of the present invention can be formed into a film-coated tablet by coating with a film coating layer.
In addition, the orally disintegrating tablet according to the present invention has an oral disintegration time of less than 60 seconds and particularly preferably less than 40 seconds.
The shape of the tablet according to the present invention is not particularly limited, and any of round tablets {circular flat tablets (including corner locks, etc.), round R tablets (including corner locks, 2-stage R locks, etc.)}, deformed tablets, etc. However, a round R tablet is preferable.
＜原薬の物性＞
本発明の錠剤は原薬として、アムロジピンベシル酸塩と、アムロジピンベシル酸塩でない原薬を一以上含む。アムロジピンベシル酸塩でない原薬の例としては、オルメサルタンメドキソミル、イルベサルタン、バルサルタン等が挙げられるが、特に好ましくはイルベサルタンである。
本発明の錠剤の製造に使用されるアムロジピンベシル酸塩のメディアン径（ｄ５０）は０．１〜１００．０μｍが好ましく、より好ましくは１．０〜５０．０μｍである。アムロジピンベシル酸塩は、必要に応じて適宜乾式又は湿式粉砕を行い、任意の粒子径に調整することも可能である。アムロジピンベシル酸塩は錠剤全重量に対して好ましくは１．０〜１５．０重量％の範囲で素錠中に含有され、より好ましくは２．０〜１０．０重量％の範囲で素錠中に含有される。
本発明の錠剤の製造に使用されるイルベサルタンのメディアン径（ｄ５０）は１．０〜１００．０μｍが好ましく、より好ましくは５．０〜５０．０μｍである。イルベサルタンは、必要に応じて適宜乾式又は湿式粉砕を行い、任意の粒子径に調整することも可能である。イルベサルタンは錠剤全重量に対して好ましくは２５．０〜７０．０重量％の範囲で素錠中に含有され、より好ましくは３５．０〜６５．０重量％の範囲で素錠中に含有される。
<Physical properties of API>
The tablet of the present invention contains amlodipine besylate and one or more drug substances that are not amlodipine besylate as drug substances. Examples of drug substances that are not amlodipine besylate include olmesartan medoxomil, irbesartan, valsartan, etc., with irbesartan being particularly preferred.
The median diameter (d 50 ) of amlodipine besylate used for the production of the tablet of the present invention is preferably 0.1 to 100.0 μm, more preferably 1.0 to 50.0 μm. Amlodipine besylate can be adjusted to an arbitrary particle size by appropriately performing dry or wet grinding as required. Amlodipine besylate is preferably contained in the uncoated tablet in the range of 1.0 to 15.0% by weight, more preferably in the range of 2.0 to 10.0% by weight based on the total weight of the tablet. Contained in
The median diameter (d 50 ) of irbesartan used for producing the tablet of the present invention is preferably 1.0 to 100.0 μm, more preferably 5.0 to 50.0 μm. Irbesartan can be adjusted to an arbitrary particle size by appropriately performing dry or wet pulverization as necessary. Irbesartan is preferably contained in the uncoated tablet in the range of 25.0 to 70.0% by weight, more preferably 35.0 to 65.0% by weight, based on the total weight of the tablet. The
＜錠剤の製造に使用可能な医薬添加剤＞
本発明の錠剤の製造に用いられる、医薬的に許容可能な医薬添加剤としては、通常使用されている賦形剤、崩壊剤、結合剤、可塑剤、滑沢剤、矯味剤、界面活性剤、着色剤、コーティング剤等が使用できる。
<Pharmaceutical additives that can be used to produce tablets>
The pharmaceutically acceptable pharmaceutical additives used in the production of the tablet of the present invention include commonly used excipients, disintegrants, binders, plasticizers, lubricants, corrigents, surfactants. , Coloring agents, coating agents and the like can be used.
＜賦形剤＞
本発明に係る賦形剤は、例えば、乳糖水和物、結晶セルロース、無水乳糖、Ｄ−マンニトール、トウモロコシデンプン等から選ばれ、好ましくはＤ−マンニトール、トウモロコシデンプンから選ばれる。賦形剤は素錠の全重量に対して好ましくは２５．０〜６０．０重量％の範囲で素錠中に含有される。
<Excipient>
The excipient according to the present invention is selected from, for example, lactose hydrate, crystalline cellulose, anhydrous lactose, D-mannitol, corn starch and the like, preferably D-mannitol, corn starch. The excipient is preferably contained in the uncoated tablet in the range of 25.0 to 60.0% by weight based on the total weight of the uncoated tablet.
＜崩壊剤＞
本発明に係る崩壊剤は、例えば、低置換度ヒドロキシプロピルセルロース、カルメロース、カルメロースカルシウム、カルメロースナトリウム、カルボキシメチルスターチナトリウム、クロスカルメロースナトリウム、クロスポビドン、結晶セルロース等から選ばれ、好ましくはカルメロース、カルメロースカルシウム、カルメロースナトリウム、クロスポビドン、クロスカルメロースナトリウムから選ばれる。崩壊剤は素錠の全重量に対して好ましくは２．０〜３０．０重量％、より好ましくは８．０〜２５．０重量％、さらに好ましくは１２．０〜２０．０重量％の範囲で素錠中に含有される。
本発明の錠剤に含まれる特定の崩壊剤は、カルメロース、カルメロースカルシウム、カルメロースナトリウムから選ばれるが、好ましくはカルメロース又はカルメロースカルシウムであり、最も好ましくはカルメロースである。特定の崩壊剤は素錠の全重量に対して１．０〜１５．０重量％、好ましくは２．０〜１０．０重量％の範囲で素錠中に含有される。
<Disintegrant>
The disintegrant according to the present invention is selected from, for example, low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, crystalline cellulose and the like, preferably carmellose , Carmellose calcium, carmellose sodium, crospovidone, croscarmellose sodium. The disintegrant is preferably in the range of 2.0 to 30.0% by weight, more preferably 8.0 to 25.0% by weight, still more preferably 12.0 to 20.0% by weight, based on the total weight of the uncoated tablet. It is contained in uncoated tablets.
The specific disintegrant contained in the tablet of the present invention is selected from carmellose, carmellose calcium, and carmellose sodium, preferably carmellose or carmellose calcium, and most preferably carmellose. The specific disintegrant is contained in the uncoated tablet in an amount of 1.0 to 15.0% by weight, preferably 2.0 to 10.0% by weight, based on the total weight of the uncoated tablet.
＜結合剤＞
本発明に係る結合剤は、例えば、ヒプロメロース、ヒドロキシプロピルセルロース、ポビドン、糊化デンプン、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等から選ばれ、好ましくは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である。結合剤は素錠の全重量に対して０．０５〜１０．０重量％の範囲で素錠中に含有されることが好ましい。
<Binder>
The binder according to the present invention is selected from, for example, hypromellose, hydroxypropyl cellulose, povidone, gelatinized starch, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, and preferably polyvinyl alcohol / acrylic acid / It is a methyl methacrylate copolymer. The binder is preferably contained in the uncoated tablet in a range of 0.05 to 10.0% by weight based on the total weight of the uncoated tablet.
＜滑沢剤＞
本発明に係る滑沢剤は、例えば、ステアリン酸マグネシウム、ステアリン酸カルシウム、ステアリルフマル酸ナトリウム等から選ばれ、好ましくはステアリン酸マグネシウムである。滑沢剤は素錠の全重量に対して０．５〜３．０重量％の範囲で素錠中に含有されることが好ましい。
<Lubricant>
The lubricant according to the present invention is selected from, for example, magnesium stearate, calcium stearate, sodium stearyl fumarate, etc., preferably magnesium stearate. The lubricant is preferably contained in the uncoated tablet in the range of 0.5 to 3.0% by weight based on the total weight of the uncoated tablet.
＜矯味剤＞
本発明に係る矯味剤は、例えばスクラロース、ソルビトール、トレハロース、フマル酸、フマル酸一ナトリウム等から選ばれ、好ましくはスクラロースである。矯味剤は素錠の全重量に対して１．０〜１０．０重量％の範囲で素錠中に含有されることが好ましい。
<Flavoring agent>
The taste-masking agent according to the present invention is selected from, for example, sucralose, sorbitol, trehalose, fumaric acid, monosodium fumarate, etc., preferably sucralose. The corrigent is preferably contained in the uncoated tablet in the range of 1.0 to 10.0% by weight based on the total weight of the uncoated tablet.
＜コーティング剤＞
本発明に係るコーティング剤は、ヒプロメロース、エチルセルロース、エチルセルロース分散液、アクリル酸エチル・メタクリル酸メチルコポリマー分散液、ジメチルアミノメタアクリレート・メチルメタアクリレートコポリマー等から選ばれ、好ましくはエチルセルロース又はエチルセルロース水分散液である。コーティング剤は錠剤の全重量に対して０．０５〜１０．０重量％の範囲で錠剤中に含有されることが好ましい。
<Coating agent>
The coating agent according to the present invention is selected from hypromellose, ethyl cellulose, ethyl cellulose dispersion, ethyl acrylate / methyl methacrylate copolymer dispersion, dimethylamino methacrylate / methyl methacrylate copolymer, etc., preferably ethyl cellulose or ethyl cellulose aqueous dispersion is there. The coating agent is preferably contained in the tablet in the range of 0.05 to 10.0% by weight based on the total weight of the tablet.
＜着色剤＞
本発明に係る着色剤は、酸化チタン、三二酸化鉄、黄色三二酸化鉄、赤色３号、黄色４号、黄色５号、赤色３号アルミニウムレーキ、黄色４号アルミニウムレーキ、黄色５号アルミニウムレーキ等から選ばれ、好ましくは酸化チタン、三二酸化鉄、黄色三二酸化鉄又は黄色４号アルミニウムレーキである。着色剤は錠剤の全重量に対して０．０１〜１０．０重量％の範囲で錠剤中に含有されることが好ましい。
<Colorant>
The colorant according to the present invention includes titanium oxide, iron sesquioxide, yellow iron sesquioxide, red No. 3, yellow No. 4, yellow No. 5, red No. 3 aluminum lake, yellow No. 4 aluminum lake, yellow No. 5 aluminum lake and the like. Preferred is titanium oxide, iron sesquioxide, yellow iron sesquioxide or yellow No. 4 aluminum lake. The colorant is preferably contained in the tablet in the range of 0.01 to 10.0% by weight based on the total weight of the tablet.
＜造粒物の構成及び製造方法＞
本発明の錠剤は造粒物を含む場合があり、造粒物は結合剤を含有する溶液を用いて攪拌造粒や流動層造粒、噴霧乾燥造粒等の方法によって製造することが可能である。本発明の錠剤に係る造粒物は、アムロジピンベシル酸塩又はアムロジピンベシル酸塩でない原薬を含む。アムロジピンベシル酸塩を含む造粒物においてはコーティング剤で被覆した被覆造粒物とすることが可能であり、其の具体的な製造方法例として流動層コーティング法（ワースター法を含む）等が挙げられる。造粒物（好適にはアムロジピンベシル酸塩でない原薬を含むもの）には崩壊剤（カルメロースは除く。）を適量（好適には造粒物全重量に対して１０．０〜２０．０重量％）含むことが好ましく、特に結晶セルロース又はクロスポピドンである崩壊剤を含むことが好ましい。カルメロース等の特定の崩壊剤は錠剤中において造粒物中又は造粒物外のどちら側に含有されていても構わない。
<Structure and production method of granulated product>
The tablet of the present invention may contain a granulated product, and the granulated product can be produced by a method such as stirring granulation, fluidized bed granulation, spray drying granulation or the like using a solution containing a binder. is there. The granulated product according to the tablet of the present invention contains amlodipine besylate or a drug substance that is not amlodipine besylate. Granules containing amlodipine besylate can be coated granules coated with a coating agent, and examples of specific production methods include fluidized bed coating methods (including Wurster method). It is done. Appropriate amount of disintegrant (except carmellose) for granulated products (preferably containing drug substance that is not amlodipine besylate) (preferably 10.0 to 20.0 weights based on the total weight of the granulated product) %)), Preferably a disintegrant that is crystalline cellulose or crospovidone. A specific disintegrant such as carmellose may be contained in the tablet either on the side of the granulated product or outside the granulated product.
＜錠剤の製造方法＞
本発明の錠剤である素錠は、一般的な製造方法によって作成することが可能であり、例えば以下の製造方法によって作成することが可能である。
まず、イルベサルタン、賦形剤、崩壊剤、矯味剤を混合した粉末に水に溶解した結合剤を加えて湿式高速撹拌造粒を行って造粒物を製造する。本発明で使用する高速撹拌造粒機は、例えば、バーチカルグラニュレーター（株式会社パウレック）やハイスピードミキサー（アーステクニカ）である。更に、前記造粒物を、アムロジピンベシル酸塩（又は、アムロジピンベシル酸塩を含有する造粒物）、崩壊剤及び滑沢剤等と混合した後に打錠機によって圧縮成形して錠剤とする。さらに、得られた錠剤に通気型パン式コーティング装置等によってフィルムコーティング層の被覆を施してもよい。
<Tablet production method>
The uncoated tablet which is the tablet of the present invention can be produced by a general production method, for example, can be produced by the following production method.
First, a binder dissolved in water is added to a powder obtained by mixing irbesartan, an excipient, a disintegrant, and a corrigent, and wet high speed agitation granulation is performed to produce a granulated product. The high-speed agitation granulator used in the present invention is, for example, a vertical granulator (Paurec Co., Ltd.) or a high-speed mixer (Earth Technica). Further, the granulated product is mixed with amlodipine besylate (or a granulated product containing amlodipine besylate), a disintegrant, a lubricant and the like, and then compressed into a tablet by a tableting machine. Further, the obtained tablet may be coated with a film coating layer by using a vent type pan coating apparatus or the like.
以下に実施例等により本発明を説明するが、本発明はこれらの実施例等に限定されるものではない。 EXAMPLES The present invention will be described below with reference to examples and the like, but the present invention is not limited to these examples and the like.
＜イルベサルタン造粒物の製造＞
イルベサルタン１５０．０ｇ（ＨＵＡＨＡＩ製）、Ｄ−マンニトール５９．７ｇ（マンニットＣ／三菱商事フードテック製）、トウモロコシデンプン３０．０ｇ（局方コーンスターチホワイト／日本コーンスターチ製）及びクロスポビドン１５．０ｇ（ＣＬ−ＳＦ／ＢＡＳＦ製）を高速撹拌造粒機（ＶＧ−０１型／パウレック製）に投入し、ＰＶＡ共重合体０．３ｇ（ＰＯＶＡＣＯＡＴ Ｔｙｐｅ Ｆ／大同化成工業製）を精製水６５ｇに溶解した液を滴下して造粒した。引き続き、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径４ｍｍのスクリーンを用いて湿式整粒した後、流動層乾燥機（ＭＰ−０１型／パウレック製）に投入して給気温度８０℃で排気温度が３５℃になるまで乾燥した。乾燥後、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径１ｍｍのスクリーンを用いて乾式解砕してイルベサルタン造粒物品を得た。
<Manufacture of irbesartan granulated product>
Irbesartan 150.0 g (manufactured by HUAHAI), D-mannitol 59.7 g (mannit k / manufactured by Mitsubishi Corporation Foodtech), corn starch 30.0 g (pharmacopoeia corn starch white / manufactured by Nippon corn starch) and crospovidone 15.0 g (CL -SF / BASF) was charged into a high-speed agitation granulator (VG-01 type / Paurec), and 0.3 g of PVA copolymer (POVACOAT Type F / Daido Kasei Kogyo) was dissolved in 65 g of purified water. Was dropped and granulated. Subsequently, after wet-regulating using a screen with a diameter of 4 mm in a crusher (Comil QC-197S / manufactured by Paulek), it is put into a fluidized bed dryer (MP-01 type / manufactured by Pauleck) and an air supply temperature of 80 ° C. And dried until the exhaust temperature reached 35 ° C. After drying, the powder was crushed dry using a screen having a diameter of 1 mm in a pulverizer (Comil QC-197S / Pauleck) to obtain an irbesartan granulated article.
実施例１で得られたイルベサルタン造粒物品１７０．０ｇ、アムロジピンベシル酸塩１３．８７ｇ（Ｍｏｅｈｓ製）、トウモロコシデンプン４．１３ｇ（局方コーンスターチホワイト／日本コーンスターチ製）、カルメロース１０．０ｇ（ＮＳ−３００／ニチリン化学工業製）及びステアリン酸マグネシウム２．０ｇ（太平化学産業製）と共に混合し、打圧８００ｋｇｆで打錠して１錠質量２００．０ｍｇ、直径８ｍｍの錠剤（円形Ｒ錠）を得た。 170.0 g of irbesartan granulated article obtained in Example 1, 13.87 g of amlodipine besylate (manufactured by Moehs), 4.13 g of corn starch (manufactured by Pharmacopoeia Corn Starch White / Nihon Corn Starch), 10.0 g of Carmellose (NS- 300 / manufactured by Nichirin Chemical Industry Co., Ltd.) and 2.0 g of magnesium stearate (manufactured by Taihei Chemical Industrial Co., Ltd.), and compressed with a punching pressure of 800 kgf to obtain a tablet having a mass of 200.0 mg and a diameter of 8 mm (round R tablet). It was.
イルベサルタン１５０．０ｇ（ＨＵＡＨＡＩ製）、Ｄ−マンニトール５９．７ｇ（マンニットＣ／三菱商事フードテック製）、トウモロコシデンプン３０．０ｇ（局方コーンスターチホワイト／日本コーンスターチ製）及びカルメロース１５．０ｇ（ＮＳ−３００／ニチリン化学製）を高速撹拌造粒機（ＶＧ−０１型／パウレック製）に投入し、ＰＶＡ共重合体０．３ｇ（ＰＯＶＡＣＯＡＴ Ｔｙｐｅ Ｆ／大同化成工業製）を精製水６５ｇに溶解した液を滴下して造粒した。引き続き、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径４ｍｍのスクリーンを用いて湿式整粒した後、流動層乾燥機（ＭＰ−０１型／パウレック製）に投入して給気温度８０℃で排気温度が３５℃になるまで乾燥した。乾燥後、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径１ｍｍのスクリーンを用いて乾式解砕してイルベサルタン造粒物品を得た。得られた造粒物品１７０．０ｇ、アムロジピンベシル酸塩１３．８７ｇ（Ｍｏｅｈｓ製）、トウモロコシデンプン４．１３ｇ（局方コーンスターチホワイト／日本コーンスターチ製）及びステアリン酸マグネシウム２．０ｇ（太平化学産業製）と共に混合し、打圧８００ｋｇｆで打錠して１錠質量１９０．０ｍｇ、直径８ｍｍの錠剤（円形Ｒ錠）を得た。 Irbesartan 150.0 g (manufactured by HUAHAI), D-mannitol 59.7 g (mannit k / manufactured by Mitsubishi Corporation Foodtech), corn starch 30.0 g (pharmacopoeia corn starch white / manufactured by Nippon corn starch) and carmellose 15.0 g (NS- 300 / manufactured by Nichirin Chemical Co., Ltd.) into a high-speed stirring granulator (VG-01 type / manufactured by Paulek), and a solution obtained by dissolving 0.3 g of PVA copolymer (POVACOAT Type F / manufactured by Daido Kasei Kogyo) in 65 g of purified water. Was dropped and granulated. Subsequently, after wet-regulating using a screen with a diameter of 4 mm in a crusher (Comil QC-197S / manufactured by Paulek), it is put into a fluidized bed dryer (MP-01 type / manufactured by Pauleck) and an air supply temperature of 80 ° C. And dried until the exhaust temperature reached 35 ° C. After drying, the powder was crushed dry using a screen having a diameter of 1 mm in a pulverizer (Comil QC-197S / Pauleck) to obtain an irbesartan granulated article. 170.0 g of the obtained granulated article, 13.87 g of amlodipine besylate (manufactured by Moehs), 4.13 g of corn starch (manufactured by Pharmacopoeia Cornstarch White / Nihon Cornstarch) and 2.0 g of magnesium stearate (manufactured by Taihei Chemical Sangyo) The mixture was mixed with each other and tableted with a punching pressure of 800 kgf to obtain a tablet having a mass of 190.0 mg and a diameter of 8 mm (round R tablet).
イルベサルタン１５０．０ｇ（ＨＵＡＨＡＩ製）、Ｄ−マンニトール５９．７ｇ（マンニットＣ／三菱商事フードテック製）、結晶セルロース３０．０ｇ（ＵＦ−７１１／旭化成ケミカルズ製）及びカルメロース１５．０ｇ（ＮＳ−３００／ニチリン化学製）を高速撹拌造粒機（ＶＧ−０１型／パウレック製）に投入し、ＰＶＡ共重合体０．３ｇ（ＰＯＶＡＣＯＡＴ Ｔｙｐｅ Ｆ／大同化成工業製）を精製水６５ｇに溶解した液を滴下して造粒した。引き続き、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径４ｍｍのスクリーンを用いて湿式整粒した後、流動層乾燥機（ＭＰ−０１型／パウレック製）に投入して給気温度８０℃で排気温度が３５℃になるまで乾燥した。乾燥後、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径１ｍｍのスクリーンを用いて乾式解砕してイルベサルタン造粒物品を得た。得られた造粒物品１７０．０ｇ、アムロジピンベシル酸塩１３．８７ｇ（Ｍｏｅｈｓ製）、トウモロコシデンプン４．１３ｇ（局方コーンスターチホワイト／日本コーンスターチ製）及びステアリン酸マグネシウム２．０ｇ（太平化学産業製）と共に混合し、打圧８００ｋｇｆで打錠して１錠質量１９０．０ｍｇ、直径８ｍｍの錠剤（円形Ｒ錠）を得た。 Irbesartan 150.0 g (manufactured by HUAHAI), D-mannitol 59.7 g (mannit k / manufactured by Mitsubishi Corporation Foodtech), crystalline cellulose 30.0 g (UF-71 / Asahi Kasei Chemicals) and carmellose 15.0 g (NS-300) / Manufactured by Nichirin Chemical Co., Ltd.) into a high-speed agitation granulator (VG-01 type / manufactured by POWREC), and a solution obtained by dissolving 0.3 g of PVA copolymer (POVACOAT Type F / manufactured by Daido Kasei Kogyo) in 65 g of purified water. Dropped and granulated. Subsequently, after wet-regulating using a screen with a diameter of 4 mm in a crusher (Comil QC-197S / manufactured by Paulek), it is put into a fluidized bed dryer (MP-01 type / manufactured by Pauleck) and an air supply temperature of 80 ° C. And dried until the exhaust temperature reached 35 ° C. After drying, the powder was crushed dry using a screen having a diameter of 1 mm in a pulverizer (Comil QC-197S / Pauleck) to obtain an irbesartan granulated article. 170.0 g of the obtained granulated article, 13.87 g of amlodipine besylate (manufactured by Moehs), 4.13 g of corn starch (manufactured by Pharmacopoeia Cornstarch White / Nihon Cornstarch) and 2.0 g of magnesium stearate (manufactured by Taihei Chemical Sangyo) The mixture was mixed with each other and tableted with a punching pressure of 800 kgf to obtain a tablet having a mass of 190.0 mg and a diameter of 8 mm (round R tablet).
イルベサルタン１５０．０ｇ（ＨＵＡＨＡＩ製）、Ｄ−マンニトール５９．７ｇ（マンニットＣ／三菱商事フードテック製）、クロスポビドン３０．０ｇ（ＣＬ−ＳＦ／ＢＡＳＦ製）及びカルメロース１５．０ｇ（ＮＳ−３００／ニチリン化学製）を高速撹拌造粒機（ＶＧ−０１型／パウレック製）に投入し、ＰＶＡ共重合体０．３ｇ（ＰＯＶＡＣＯＡＴ Ｔｙｐｅ Ｆ／大同化成工業製）を精製水６５ｇに溶解した液を滴下して造粒した。引き続き、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径４ｍｍのスクリーンを用いて湿式整粒した後、流動層乾燥機（ＭＰ−０１型／パウレック製）に投入して給気温度８０℃で排気温度が３５℃になるまで乾燥した。乾燥後、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径１ｍｍのスクリーンを用いて乾式解砕してイルベサルタン造粒物品を得た。得られた造粒物品１７０．０ｇ、アムロジピンベシル酸塩１３．８７ｇ（Ｍｏｅｈｓ製）、トウモロコシデンプン４．１３ｇ（局方コーンスターチホワイト／日本コーンスターチ製）及びステアリン酸マグネシウム２．０ｇ（太平化学産業製）と共に混合し、打圧８００ｋｇｆで打錠して１錠質量１９０．０ｍｇ、直径８ｍｍの錠剤（円形Ｒ錠）を得た。 Irbesartan 150.0 g (manufactured by HUAHAI), D-mannitol 59.7 g (mannit C / manufactured by Mitsubishi Corporation Foodtech), crospovidone 30.0 g (manufactured by CL-SF / BASF) and carmellose 15.0 g (NS-300 / Nichirin Chemical Co., Ltd.) is charged into a high-speed agitation granulator (VG-01 type / Paurec), and a solution obtained by dissolving 0.3 g of PVA copolymer (POVACOAT Type F / manufactured by Daido Kasei Kogyo) in 65 g of purified water is added dropwise. And granulated. Subsequently, after wet-regulating using a screen with a diameter of 4 mm in a crusher (Comil QC-197S / manufactured by Paulek), it is put into a fluidized bed dryer (MP-01 type / manufactured by Pauleck) and an air supply temperature of 80 ° C. And dried until the exhaust temperature reached 35 ° C. After drying, the powder was crushed dry using a screen having a diameter of 1 mm in a pulverizer (Comil QC-197S / Pauleck) to obtain an irbesartan granulated article. 170.0 g of the obtained granulated article, 13.87 g of amlodipine besylate (manufactured by Moehs), 4.13 g of corn starch (manufactured by Pharmacopoeia Cornstarch White / Nihon Cornstarch) and 2.0 g of magnesium stearate (manufactured by Taihei Chemical Sangyo) The mixture was mixed with each other and tableted with a punching pressure of 800 kgf to obtain a tablet having a mass of 190.0 mg and a diameter of 8 mm (round R tablet).
イルベサルタン１５０．０ｇ（ＨＵＡＨＡＩ製）、Ｄ−マンニトール６７．２ｇ（マンニットＣ／三菱商事フードテック製）、結晶セルロース３０．０ｇ（ＵＦ−７１１／旭化成ケミカルズ製）及びカルメロース７．５ｇ（ＮＳ−３００／ニチリン化学製）を高速撹拌造粒機（ＶＧ−０１型／パウレック製）に投入し、ＰＶＡ共重合体０．３ｇ（ＰＯＶＡＣＯＡＴ Ｔｙｐｅ Ｆ／大同化成工業製）を精製水６５ｇに溶解した液を滴下して造粒した。引き続き、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径４ｍｍのスクリーンを用いて湿式整粒した後、流動層乾燥機（ＭＰ−０１型／パウレック製）に投入して給気温度８０℃で排気温度が３５℃になるまで乾燥した。乾燥後、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径１ｍｍのスクリーンを用いて乾式解砕してイルベサルタン造粒物品を得た。得られた造粒物品１７０．０ｇ、アムロジピンベシル酸塩１３．８７ｇ（Ｍｏｅｈｓ製）、トウモロコシデンプン４．１３ｇ（局方コーンスターチホワイト／日本コーンスターチ製）及びステアリン酸マグネシウム２．０ｇ（太平化学産業製）と共に混合し、打圧８００ｋｇｆで打錠して１錠質量１９０．０ｍｇ、直径８ｍｍの錠剤（円形Ｒ錠）を得た。 Irbesartan 150.0 g (manufactured by HUAHAI), D-mannitol 67.2 g (mannit K / manufactured by Mitsubishi Corporation Foodtech), crystalline cellulose 30.0 g (UF-71 / Asahi Kasei Chemicals) and carmellose 7.5 g (NS-300) / Manufactured by Nichirin Chemical Co., Ltd.) into a high-speed agitation granulator (VG-01 type / manufactured by POWREC), and a solution obtained by dissolving 0.3 g of PVA copolymer (POVACOAT Type F / manufactured by Daido Kasei Kogyo) in 65 g of purified water. Dropped and granulated. Subsequently, after wet-regulating using a screen with a diameter of 4 mm in a crusher (Comil QC-197S / manufactured by Paulek), it is put into a fluidized bed dryer (MP-01 type / manufactured by Pauleck) and an air supply temperature of 80 ° C. And dried until the exhaust temperature reached 35 ° C. After drying, the powder was crushed dry using a screen having a diameter of 1 mm in a pulverizer (Comil QC-197S / Pauleck) to obtain an irbesartan granulated article. 170.0 g of the obtained granulated article, 13.87 g of amlodipine besylate (manufactured by Moehs), 4.13 g of corn starch (manufactured by Pharmacopoeia Cornstarch White / Nihon Cornstarch) and 2.0 g of magnesium stearate (manufactured by Taihei Chemical Sangyo) The mixture was mixed with each other and tableted with a punching pressure of 800 kgf to obtain a tablet having a mass of 190.0 mg and a diameter of 8 mm (round R tablet).
イルベサルタン１５０．０ｇ（ＨＵＡＨＡＩ製）、Ｄ−マンニトール７１．７ｇ（マンニットＣ／三菱商事フードテック製）、トウモロコシデンプン３０．０ｇ（局方コーンスターチホワイト／日本コーンスターチ製）、クロスポビドン１５．０ｇ（ＣＬ−ＳＦ／ＢＡＳＦ製）、カルメロース１５．０ｇ（ＮＳ−３００／ニチリン化学工業製）及びスクラロース１５．０ｇ（スクラロース（Ｐ）／三栄原エフ・エフ・アイ製）を高速撹拌造粒機（ＶＧ−０１型／パウレック製）に投入し、ＰＶＡ共重合体０．３ｇ（ＰＯＶＡＣＯＡＴ Ｔｙｐｅ Ｆ／大同化成工業製）を精製水６５．０ｇに溶解した液を滴下して造粒した。引き続き、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径４ｍｍのスクリーンを用いて湿式整粒した後、流動層乾燥機（ＭＰ−０１型／パウレック製）に投入して給気温度８０℃で排気温度が３５℃になるまで乾燥した。乾燥後、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径１ｍｍのスクリーンを用いて乾式解砕してイルベサルタン造粒物品を得た。
アムロジピンベシル酸塩３４６．７５ｇ（Ｍｏｅｈｓ製）及びトウモロコシデンプン７３．２５ｇ（局方コーンスターチホワイト／日本コーンスターチ製)を流動層造粒機（ＭＰ−０１型／パウレック製）に投入し、ＰＶＡ共重合体１２．５ｇ（ＰＯＶＡＣＯＡＴ Ｔｙｐｅ Ｆ／大同化成工業製）を精製水３００ｇに溶解した液を噴霧し、給気温度７５℃で造粒した。引き続きエチルセルロース水分散液１５０．０ｇ（アクアコートＥＣＤ／ＦＭＣ製）、Ｄ−マンニトール１１．２５ｇ（マンニットＣ／三菱商事フードテック製）及びクエン酸トリエチル１１．２５ｇ（シトロフレックス２ ＳＣ−６０／森村産業製）を分散した液を噴霧し、給気温度７５℃でコーティング（被覆）した。引き続き、給気温度８５℃で排気温度が３５℃になるまで乾燥した後、網目３０ｍｅｓｈのステンレス製篩で篩過してアムロジピンベシル酸塩被覆造粒物品を得た。
上記によって得られたイルベサルタン造粒物品１９８．０ｇ、アムロジピンベシル酸塩被覆造粒物品２０．０ｇ、クロスポビドン１０．０ｇ（ＣＬ−ＳＦ／ＢＡＳＦ製）及びステアリン酸マグネシウム２．０ｇ（太平化学産業製）と共に混合し、ロータリー式打錠機（ＶＩＲＧＯ型／菊水製作所製）にて、打圧６００ｋｇｆで打錠して１錠質量２３０．０ｍｇ、直径９．５ｍｍ、硬度３９Ｎ、口腔内崩壊時間３６秒の口腔内崩壊錠（円形２段Ｒ錠）を得た。
Irbesartan 150.0 g (manufactured by HUAHAI), D-mannitol 71.7 g (mannit C / manufactured by Mitsubishi Corporation Foodtech), corn starch 30.0 g (pharmacopoeia cornstarch white / manufactured by Nippon Cornstarch), crospovidone 15.0 g (CL -SF / BASF), Carmellose 15.0 g (NS-300 / Nichirin Chemical Industries) and Sucralose 15.0 g (Sucralose (P) / Saneihara FFI) high speed agitation granulator (VG- 01 type / manufactured by Paul Wrec Co., Ltd.) A solution of 0.3 g of PVA copolymer (POVACOAT Type F / manufactured by Daido Kasei Kogyo Co., Ltd.) in 65.0 g of purified water was dropped and granulated. Subsequently, after wet-regulating using a screen with a diameter of 4 mm in a crusher (Comil QC-197S / manufactured by Paulek), it is put into a fluidized bed dryer (MP-01 type / manufactured by Pauleck) and an air supply temperature of 80 ° C. And dried until the exhaust temperature reached 35 ° C. After drying, the powder was crushed dry using a screen having a diameter of 1 mm in a pulverizer (Comil QC-197S / Pauleck) to obtain an irbesartan granulated article.
346.75 g of amlodipine besylate (manufactured by Moehs) and 73.25 g of corn starch (manufactured by Pharmacopoeia Cornstarch White / manufactured by Nippon Cornstarch) were charged into a fluidized bed granulator (MP-01 type / manufactured by Paulek), and PVA copolymer A solution obtained by dissolving 12.5 g (POVACOAT Type F / manufactured by Daido Kasei Kogyo Co., Ltd.) in 300 g of purified water was sprayed and granulated at an air supply temperature of 75 ° C. Subsequently, 150.0 g of ethyl cellulose aqueous dispersion (manufactured by Aquacoat ECD / FMC), 11.25 g of D-mannitol (manufactured by Mannit C / Mitsubishi Corporation Foodtech) and 11.25 g of triethyl citrate (Citroflex 2 SC-60 / Morimura) A liquid in which (manufactured by Kogyo) was dispersed was sprayed and coated at a supply air temperature of 75 ° C. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature reached 35 ° C., the product was sieved with a stainless steel sieve having a mesh of 30 mesh to obtain an amlodipine besylate-coated granulated article.
198.0 g of irbesartan granulated article obtained as described above, 20.0 g of amlodipine besylate-coated granulated article, 10.0 g of crospovidone (CL-SF / BASF) and 2.0 g of magnesium stearate (manufactured by Taihei Chemical Sangyo) ) And tableting with a rotary tableting machine (VIRGO type / manufactured by Kikusui Seisakusho) with a punching pressure of 600 kgf, each tablet has a mass of 230.0 mg, a diameter of 9.5 mm, a hardness of 39 N, and an oral disintegration time of 36 seconds. Orally disintegrating tablets (circular two-stage R tablets) were obtained.
イルベサルタン１５０．０ｇ（ＨＵＡＨＡＩ製）、Ｄ−マンニトール７１．７ｇ（マンニットＣ／三菱商事フードテック製）、トウモロコシデンプン３０．０ｇ（局方コーンスターチホワイト／日本コーンスターチ製）、クロスポビドン１５．０ｇ（ＣＬ−ＳＦ／ＢＡＳＦ製）及びスクラロース１５．０ｇ（スクラロース（Ｐ）／三栄原エフ・エフ・アイ製）を高速撹拌造粒機（ＶＧ−０１型／パウレック製）に投入し、ＰＶＡ共重合体０．３ｇ（ＰＯＶＡＣＯＡＴ Ｔｙｐｅ Ｆ／大同化成工業製）を精製水６５．０ｇに溶解した液を滴下して造粒した。引き続き、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径４ｍｍのスクリーンを用いて湿式整粒した後、流動層乾燥機（ＭＰ−０１型／パウレック製）に投入して給気温度８０℃で排気温度が３５℃になるまで乾燥した。乾燥後、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径１ｍｍのスクリーンを用いて乾式解砕してイルベサルタン造粒物品を得た。
アムロジピンベシル酸塩３４６．７５ｇ（Ｍｏｅｈｓ製）及びトウモロコシデンプン７３．２５ｇ（局方コーンスターチホワイト／日本コーンスターチ製)を流動層造粒機（ＭＰ−０１型／パウレック製）に投入し、ＰＶＡ共重合体１２．５ｇ（ＰＯＶＡＣＯＡＴ Ｔｙｐｅ Ｆ／大同化成工業製）を精製水３００ｇに溶解した液を噴霧し、給気温度７５℃で造粒した。引き続きエチルセルロース水分散液１５０．０ｇ（アクアコートＥＣＤ／ＦＭＣ製）、Ｄ−マンニトール１１．２５ｇ（マンニットＣ／三菱商事フードテック製）及びクエン酸トリエチル１１．２５ｇ（シトロフレックス２ ＳＣ−６０／森村産業製）を分散した液を噴霧し、給気温度７５℃でコーティング（被覆）した。引き続き、給気温度８５℃で排気温度が３５℃になるまで乾燥した後、網目３０ｍｅｓｈのステンレス製篩で篩過してアムロジピンベシル酸塩被覆造粒物品を得た。
上記によって得られたイルベサルタン造粒物品１８８．０ｇ、アムロジピンベシル酸塩被覆造粒物品２０．０ｇ、カルメロース１０．０ｇ（ＮＳ−３００／ニチリン化学工業製）、クロスポビドン１０．０ｇ（ＣＬ−ＳＦ／ＢＡＳＦ製）及びステアリン酸マグネシウム２．０ｇ（太平化学産業製）と共に混合し、ロータリー式打錠機（ＶＩＲＧＯ型／菊水製作所製）にて、打圧６００ｋｇｆで打錠して１錠質量２３０．０ｍｇ、直径９．５ｍｍ、硬度４３Ｎ、口腔内崩壊時間３２秒の口腔内崩壊錠（円形２段Ｒ錠）を得た。
Irbesartan 150.0 g (manufactured by HUAHAI), D-mannitol 71.7 g (mannit C / manufactured by Mitsubishi Corporation Foodtech), corn starch 30.0 g (pharmacopoeia cornstarch white / manufactured by Nippon Cornstarch), crospovidone 15.0 g (CL -SF / BASF) and 15.0 g of sucralose (Sucralose (P) / manufactured by Saneihara FFI) were charged into a high-speed agitation granulator (VG-01 type / manufactured by Paulek), and PVA copolymer 0 .3 g (POVACOAT Type F / manufactured by Daido Kasei Kogyo Co., Ltd.) in 65.0 g of purified water was added dropwise and granulated. Subsequently, after wet-regulating using a screen with a diameter of 4 mm in a crusher (Comil QC-197S / manufactured by Paulek), it is put into a fluidized bed dryer (MP-01 type / manufactured by Pauleck) and an air supply temperature of 80 ° C. And dried until the exhaust temperature reached 35 ° C. After drying, the powder was crushed dry using a screen having a diameter of 1 mm in a pulverizer (Comil QC-197S / Pauleck) to obtain an irbesartan granulated article.
346.75 g of amlodipine besylate (manufactured by Moehs) and 73.25 g of corn starch (manufactured by Pharmacopoeia Cornstarch White / manufactured by Nippon Cornstarch) were charged into a fluidized bed granulator (MP-01 type / manufactured by Paulek), and PVA copolymer A solution obtained by dissolving 12.5 g (POVACOAT Type F / manufactured by Daido Kasei Kogyo Co., Ltd.) in 300 g of purified water was sprayed and granulated at an air supply temperature of 75 ° C. Subsequently, 150.0 g of ethyl cellulose aqueous dispersion (manufactured by Aquacoat ECD / FMC), 11.25 g of D-mannitol (manufactured by Mannit C / Mitsubishi Corporation Foodtech) and 11.25 g of triethyl citrate (Citroflex 2 SC-60 / Morimura) A liquid in which (manufactured by Kogyo) was dispersed was sprayed and coated at a supply air temperature of 75 ° C. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature reached 35 ° C., the product was sieved with a stainless steel sieve having a mesh of 30 mesh to obtain an amlodipine besylate-coated granulated article.
188.0 g of irbesartan granulated article obtained as described above, 20.0 g of amlodipine besylate-coated granulated article, 10.0 g of carmellose (NS-300 / manufactured by Nichirin Chemical Industries), 10.0 g of crospovidone (CL-SF / BASF) and 2.0 g of magnesium stearate (made by Taihei Chemical Sangyo Co., Ltd.), and tableted with a rotary tableting machine (VIRGO type / manufactured by Kikusui Seisakusho) with a punching pressure of 600 kgf. An orally disintegrating tablet (circular two-stage R tablet) having a diameter of 9.5 mm, a hardness of 43 N, and an oral disintegration time of 32 seconds was obtained.
イルベサルタン１，２００．０ｇ（ＨＵＡＨＡＩ製）、低置換度ヒドロキシプロピルセルロース２２８．８４ｇ（ＬＨ−１１／信越化学工業製）、クロスカルメロースナトリウム４８．０ｇ（ＮＤ−２ＨＳ／ニチリン化学製）及びカルメロースカルシウム１５．０ｇ（ＥＣＧ−５０５／ニチリン化学製）を高速撹拌造粒機（パウレック製／ＶＧ−１０型）に投入し、ＰＶＡ共重合体４８．０ｇ（ＰＯＶＡＣＯＡＴ Ｔｙｐｅ Ｆ／大同化成工業製）を精製水４３２ｇに溶解した液を滴下して造粒した。引き続き、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径４ｍｍのスクリーンを用いて湿式整粒した後、流動層乾燥機（ＭＰ−０１型／パウレック製）に投入して給気温度８５℃で排気温度が４０℃になるまで乾燥した。乾燥後、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径１ｍｍのスクリーンを用いて乾式解砕してイルベサルタン造粒品を得た。
得られたイルベサルタン造粒物品１４５２．７７ｇとアムロジピンベシル酸７６．２３ｇ（Ｍｏｅｈｓ製）、低置換度ヒドロキシプロピルセルロース３３０．０ｇ（ＮＢＤ−０２１／信越化学工業製）、クロスカルメロースナトリウム４４．０ｇ（ＮＤ−２ＨＳ／ニチリン化学製）及びステアリン酸マグネシウム２２．０ｇ（太平化学産業製）と共に混合し、打圧１０００ｋｇｆで打錠して１錠質量１７５．０ｍｇ、直径８ｍｍの錠剤（円形Ｒ錠）を得た。
Irbesartan 1,200.0 g (manufactured by HUAHAI), low substituted hydroxypropylcellulose 228.84 g (LH-11 / manufactured by Shin-Etsu Chemical Co., Ltd.), croscarmellose sodium 48.0 g (ND-2HS / manufactured by Nichirin Chemical) and carmellose 15.0 g of calcium (ECG-505 / manufactured by Nichirin Chemical Co., Ltd.) was charged into a high-speed stirring granulator (manufactured by Paulek / VG-10), and 48.0 g of PVA copolymer (POVACOAT Type F / manufactured by Daido Kasei Kogyo) A solution dissolved in 432 g of purified water was dropped and granulated. Subsequently, after wet-regulating using a screen with a diameter of 4 mm in a crusher (Comil QC-197S / manufactured by Paulek), it is put into a fluidized bed dryer (MP-01 type / manufactured by Pauleck) and an air supply temperature of 85 ° C. And dried until the exhaust temperature reached 40 ° C. After drying, the powder was pulverized dry using a screen having a diameter of 1 mm with a pulverizer (Comil QC-197S / manufactured by Paulek) to obtain an irbesartan granulated product.
1452.77 g of the obtained irbesartan granulated article, 76.23 g of amlodipine besilic acid (manufactured by Moehs), 330.0 g of low-substituted hydroxypropyl cellulose (manufactured by NBD-021 / Shin-Etsu Chemical Co., Ltd.), 44.0 g of croscarmellose sodium (manufactured by Moehs) ND-2HS / manufactured by Nichirin Chemical Co., Ltd.) and 22.0 g of magnesium stearate (manufactured by Taihei Chemical Sangyo Co., Ltd.), compressed into tablets with a pressure of 1000 kgf to give a tablet with a mass of 175.0 mg and a diameter of 8 mm (round R tablet). Obtained.
イルベサルタン１，２００ｇ（ＨＵＡＨＡＩ製）、低置換度ヒドロキシプロピルセルロース１４５．５６ｇ（ＬＨ−１１／信越化学工業製）、クロスカルメロースナトリウム４８．０ｇ（ＮＤ−２ＨＳ／ニチリン化学製）及びカルメロースカルシウム１５．０ｇ（ＥＣＧ−５０５／ニチリン化学製）を高速撹拌造粒機（パウレック製／ＶＧ−１０型）に投入し、ＰＶＡ共重合体４８．０ｇ（ＰＯＶＡＣＯＡＴ Ｔｙｐｅ Ｆ／大同化成工業製）を精製水４３２ｇに溶解した液を滴下して造粒した。引き続き、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径４ｍｍのスクリーンを用いて湿式整粒した後、流動層乾燥機（ＭＰ−０１型／パウレック製）に投入して給気温度８５℃で排気温度が４０℃になるまで乾燥した。乾燥後、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径１ｍｍのスクリーンを用いて乾式解砕してイルベサルタン造粒品を得た。
得られたイルベサルタン造粒物品１３７６．４３ｇとアムロジピンベシル酸１５２．５７ｇ（Ｍｏｅｈｓ製）、低置換度ヒドロキシプロピルセルロース３３０．０ｇ（ＮＢＤ−０２１／信越化学工業製）、クロスカルメロースナトリウム４４．０ｇ（ＮＤ−２ＨＳ／ニチリン化学製）及びステアリン酸マグネシウム２２．０ｇ（太平化学産業製）と共に混合し、打圧１０００ｋｇｆで打錠して１錠質量１７５．０ｍｇ、直径８ｍｍの錠剤（円形Ｒ錠）を得た。
Irbesartan 1,200 g (manufactured by HUAHAI), low-substituted hydroxypropylcellulose 145.56 g (manufactured by LH-11 / Shin-Etsu Chemical Co., Ltd.), croscarmellose sodium 48.0 g (ND-2HS / manufactured by Nichirin Chemical) and carmellose calcium 15 0.0g (ECG-505 / manufactured by Nichirin Chemical Co., Ltd.) was charged into a high-speed agitation granulator (manufactured by Paulek / VG-10), and 48.0 g of PVA copolymer (POVACOAT Type F / manufactured by Daido Kasei Kogyo) was purified. A solution dissolved in 432 g was dropped and granulated. Subsequently, after wet-regulating using a screen with a diameter of 4 mm in a crusher (Comil QC-197S / manufactured by Paulek), it is put into a fluidized bed dryer (MP-01 type / manufactured by Pauleck) and an air supply temperature of 85 ° C. And dried until the exhaust temperature reached 40 ° C. After drying, the powder was pulverized dry using a screen having a diameter of 1 mm with a pulverizer (Comil QC-197S / manufactured by Paulek) to obtain an irbesartan granulated product.
1376.43 g of the obtained irbesartan granulated article, 152.57 g of amlodipine besylic acid (manufactured by Moehs), 330.0 g of low-substituted hydroxypropylcellulose (manufactured by NBD-021 / Shin-Etsu Chemical Co., Ltd.), 44.0 g of croscarmellose sodium (manufactured by Moehs) ND-2HS / manufactured by Nichirin Chemical Co., Ltd.) and 22.0 g of magnesium stearate (manufactured by Taihei Chemical Sangyo Co., Ltd.), compressed into tablets with a pressure of 1000 kgf to give a tablet with a mass of 175.0 mg and a diameter of 8 mm (round R tablet). Obtained.
イルベサルタン１，２００ｇ（ＨＵＡＨＡＩ製）、アムロジピンベシル酸塩８３．１６ｇ（Ｍｏｅｈｓ製）及び低置換度ヒドロキシプロピルセルロース２２８．８４ｇ（ＬＨ−１１／信越化学工業製）を高速撹拌造粒機（ＶＧ−１０型／パウレック製）に投入し、ＰＶＡ共重合体４８．０ｇ（ＰＯＶＡＣＯＡＴ Ｔｙｐｅ Ｆ／大同化成工業製）を精製水４３２ｇに溶解した液を滴下して造粒した。引き続き、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径４ｍｍのスクリーンを用いて湿式整粒した後、流動層乾燥機（ＭＰ−０１型／パウレック製）に投入して給気温度８５℃で排気温度が４０℃になるまで乾燥した。乾燥後、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径１ｍｍのスクリーンを用いて乾式解砕しイルベサルタン造粒品を得た。
得られたイルベサルタン造粒品１４３０．０ｇ、低置換度ヒドロキシプロピルセルロース３３０．０ｇ（ＬＨ−Ｂ１／信越化学工業製）、クロスカルメロースナトリウム８８．０ｇ（ＮＤ−２ＨＳ／ニチリン化学製）、カルメロースカルシウム５５．０ｇ（ＥＣＧ−５０５／ニチリン化学製）及びステアリン酸マグネシウム２２．０ｇ（太平化学産業製）と共に混合し、打圧１０００ｋｇｆで打錠し１錠質量１７５．０ｍｇ、直径８ｍｍの錠剤（円形Ｒ錠）を得た。
Irbesartan 1,200 g (manufactured by HUAHAI), amlodipine besylate 83.16 g (manufactured by Moehs) and low-substituted hydroxypropylcellulose 228.84 g (manufactured by LH-11 / Shin-Etsu Chemical Co., Ltd.) were mixed with a high-speed agitation granulator (VG-10). Type / manufactured by POWREC Co., Ltd., and a solution prepared by dissolving 48.0 g of PVA copolymer (POVACOAT Type F / manufactured by Daido Kasei Kogyo Co., Ltd.) in 432 g of purified water was added dropwise and granulated. Subsequently, after wet-regulating using a screen with a diameter of 4 mm in a crusher (Comil QC-197S / manufactured by Paulek), it is put into a fluidized bed dryer (MP-01 type / manufactured by Pauleck) and an air supply temperature of 85 ° C. And dried until the exhaust temperature reached 40 ° C. After drying, the powder was pulverized dry using a screen having a diameter of 1 mm with a pulverizer (Comil QC-197S / manufactured by Paulek) to obtain an irbesartan granulated product.
1430.0 g of the obtained irbesartan granulated product, 330.0 g of low-substituted hydroxypropylcellulose (LH-B1 / Shin-Etsu Chemical Co., Ltd.), croscarmellose sodium 88.0 g (ND-2HS / manufactured by Nichirin Chemical), carmellose A mixture of 55.0 g of calcium (ECG-505 / manufactured by Nichirin Chemical Co., Ltd.) and 22.0 g of magnesium stearate (manufactured by Taihei Chemical Industrial Co., Ltd.), tableted with a pressure of 1000 kgf, 1 tablet mass 175.0 mg, 8 mm diameter tablet (round) R tablets).
イルベサルタン１，２００ｇ（ＨＵＡＨＡＩ製）、アムロジピンベシル酸塩１６６．４４ｇ（Ｍｏｅｈｓ製）及び低置換度ヒドロキシプロピルセルロース１４５．５６ｇ（ＬＨ−１１／信越化学工業製）を高速撹拌造粒機（パウレック製／ＶＧ−１０型）に投入し、ＰＶＡ共重合体４８．０ｇ（ＰＯＶＡＣＯＡＴ Ｔｙｐｅ Ｆ／大同化成工業製）を精製水４３２ｇに溶解した液を滴下して造粒した。引き続き、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径４ｍｍのスクリーンを用いて湿式整粒した後、流動相乾燥機（ＭＰ−０１型／パウレック製）に投入して給気温度８５℃で排気温度が４０℃になるまで乾燥した。乾燥後、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径１ｍｍのスクリーンを用いて乾式解砕しイルベサルタン造粒品を得た。
得られたイルベサルタン造粒品１４３０．０ｇ、低置換度ヒドロキシプロピルセルロース３３０．０ｇ（ＬＨ−Ｂ１／信越化学工業製）、クロスカルメロースナトリウム８８．０ｇ（ＮＤ−２ＨＳ／ニチリン化学製）、カルメロースカルシウム５５．０ｇ（ＥＣＧ−５０５／ニチリン化学製）及びステアリン酸マグネシウム２２．０ｇ（太平化学産業製）と共に混合し、打圧１０００ｋｇｆで打錠し１錠質量１７５．０ｍｇ、直径８ｍｍの錠剤（円形Ｒ錠）を得た。
Irbesartan 1,200 g (manufactured by HUAHAI), amlodipine besylate 166.44 g (manufactured by Moehs) and low substituted hydroxypropylcellulose 145.56 g (manufactured by LH-11 / Shin-Etsu Chemical Co., Ltd.) VG-10 type), and a solution obtained by dissolving 48.0 g of PVA copolymer (POVACOAT Type F / manufactured by Daido Kasei Kogyo) in 432 g of purified water was dropped and granulated. Subsequently, after wet-regulating using a screen with a diameter of 4 mm in a crusher (Comil QC-197S / manufactured by Paulek), it is put into a fluid phase dryer (MP-01 type / manufactured by Pauleck) and an air supply temperature of 85 ° C. And dried until the exhaust temperature reached 40 ° C. After drying, the powder was pulverized dry using a screen having a diameter of 1 mm with a pulverizer (Comil QC-197S / manufactured by Paulek) to obtain an irbesartan granulated product.
1430.0 g of the obtained irbesartan granulated product, 330.0 g of low-substituted hydroxypropylcellulose (LH-B1 / Shin-Etsu Chemical Co., Ltd.), croscarmellose sodium 88.0 g (ND-2HS / manufactured by Nichirin Chemical), carmellose A mixture of 55.0 g of calcium (ECG-505 / manufactured by Nichirin Chemical Co., Ltd.) and 22.0 g of magnesium stearate (manufactured by Taihei Chemical Industrial Co., Ltd.), tableted with a pressure of 1000 kgf, 1 tablet mass 175.0 mg, 8 mm diameter tablet (round) R tablets).
［比較例１]
Ｄ−マンニトール１７０．０ｇ（グラニュトールＳ／フロイント産業製）、アムロジピンベシル酸塩１３．８７ｇ（Ｍｏｅｈｓ製）、トウモロコシデンプン４．１３ｇ（局方コーンスターチホワイト／日本コーンスターチ製）、クロスポビドン１０．０ｇ（ＣＬ−ＳＦ／ＢＡＳＦ製）及びステアリン酸マグネシウム２．０ｇ（太平化学産業製）と共に混合し、打圧８００ｋｇｆで打錠して１錠質量２００．０ｍｇ、直径８ｍｍの錠剤（円形Ｒ錠）を得た。
[Comparative Example 1]
D-mannitol 170.0 g (manufactured by Granitol S / Freund Sangyo), amlodipine besylate 13.87 g (manufactured by Moehs), 4.13 g corn starch (manufactured by Pharmacopoeia Cornstarch White / manufactured by Nippon Cornstarch), 10.0 g crospovidone ( CL-SF / BASF) and 2.0 g magnesium stearate (produced by Taihei Chemical Sangyo Co., Ltd.) and tableting with a punching pressure of 800 kgf gives a tablet with a mass of 200.0 mg and a diameter of 8 mm (round R tablet). It was.
［比較例２］
実施例１で得られたイルベサルタン造粒物品１７０．０ｇ、アムロジピンベシル酸塩１３．８７ｇ（Ｍｏｅｈｓ製）、トウモロコシデンプン４．１３ｇ（局方コーンスターチホワイト／日本コーンスターチ製）、クロスポビドン１０．０ｇ（ＣＬ−ＳＦ／ＢＡＳＦ製）及びステアリン酸マグネシウム２．０ｇ（太平化学産業製）と共に混合し、打圧８００ｋｇｆで打錠して１錠質量２００．０ｍｇ、直径８ｍｍの錠剤（円形Ｒ錠）を得た。
[Comparative Example 2]
170.0 g of irbesartan granulated article obtained in Example 1, 13.87 g of amlodipine besylate (manufactured by Moehs), 4.13 g of corn starch (manufactured by Pharmacopoeia Cornstarch White / Nihon Cornstarch), 10.0 g of crospovidone (CL -SF / BASF) and 2.0 g of magnesium stearate (manufactured by Taihei Chemical Sangyo Co., Ltd.) and tableted with a punching pressure of 800 kgf to obtain tablets (round R tablets) having a mass of 200.0 mg and a diameter of 8 mm. .
［比較例３］
実施例１で得られたイルベサルタン造粒物品１７０．０ｇ、アムロジピンベシル酸塩１３．８７ｇ（Ｍｏｅｈｓ製）、トウモロコシデンプン４．１３ｇ（局方コーンスターチホワイト／日本コーンスターチ製）、低置換度ヒドロキシプロピルセルロース１０．０ｇ（ＬＨ−Ｂ１／信越化学工業製）及びステアリン酸マグネシウム２．０ｇ（太平化学産業製）と共に混合し、打圧８００ｋｇｆで打錠して１錠質量２００．０ｍｇ、直径８ｍｍの錠剤（円形Ｒ錠）を得た。
[Comparative Example 3]
170.0 g of irbesartan granulated product obtained in Example 1, 13.87 g of amlodipine besylate (manufactured by Moehs), 4.13 g of corn starch (manufactured by Pharmacopoeia Cornstarch White / Nihon Cornstarch), low-substituted hydroxypropylcellulose 10 0.0 g (LH-B1 / Shin-Etsu Chemical Co., Ltd.) and 2.0 g of magnesium stearate (Taihei Chemical Industrial Co., Ltd.), mixed with a tableting pressure of 800 kgf, 1 tablet weight 200.0 mg, 8 mm diameter tablet (round) R tablets).
［比較例４］
実施例１で得られたイルベサルタン造粒物品１７０．０ｇ、アムロジピンベシル酸塩１３．８７ｇ（Ｍｏｅｈｓ製）、トウモロコシデンプン４．１３ｇ（局方コーンスターチホワイト／日本コーンスターチ製）、デンプングリコール酸ナトリウム１０．０ｇ（ＧＬＹＣＯＬＹＳ／Ｒｏｑｕｅｔｔｅ製）及びステアリン酸マグネシウム２．０ｇ（太平化学産業製）と共に混合し、打圧８００ｋｇｆで打錠して１錠質量２００．０ｍｇ、直径８ｍｍの錠剤（円形Ｒ錠）を得た。
[Comparative Example 4]
170.0 g of irbesartan granulated article obtained in Example 1, 13.87 g of amlodipine besylate (manufactured by Moehs), 4.13 g of corn starch (manufactured by Pharmacopoeia Cornstarch White / Nihon Cornstarch), 10.0 g of sodium starch glycolate (GLYCOLYS / Roquette) and 2.0 g of magnesium stearate (manufactured by Taihei Kagaku Sangyo) were mixed and tableted with a punching pressure of 800 kgf to obtain a tablet with a mass of 200.0 mg and a diameter of 8 mm (round R tablet). .
［比較例５］
実施例１で得られたイルベサルタン造粒物品１７０．０ｇ、アムロジピンベシル酸塩１３．８７ｇ（Ｍｏｅｈｓ製）、トウモロコシデンプン４．１３ｇ（局方コーンスターチホワイト／日本コーンスターチ製）、結晶セルロース１０．０ｇ（ＵＦ−７０２／旭化成ケミカルズ製）及びステアリン酸マグネシウム２．０ｇ（太平化学産業製）と共に混合し、打圧８００ｋｇｆで打錠して１錠質量２００．０ｍｇ、直径８ｍｍの錠剤（円形Ｒ錠）を得た。
[Comparative Example 5]
170.0 g of irbesartan granulated product obtained in Example 1, 13.87 g of amlodipine besylate (manufactured by Moehs), 4.13 g of corn starch (manufactured by Pharmacopoeia Cornstarch White / Nihon Cornstarch), 10.0 g of crystalline cellulose (UF -702 / manufactured by Asahi Kasei Chemicals) and 2.0 g of magnesium stearate (manufactured by Taihei Chemical Sangyo Co., Ltd.) and tableted with a punching pressure of 800 kgf to obtain a tablet with a mass of 200.0 mg and a diameter of 8 mm (round R tablet). It was.
［比較例６］
イルベサルタン１５０．０ｇ（ＨＵＡＨＡＩ製）、Ｄ−マンニトール５９．７ｇ（マンニットＣ／三菱商事フードテック製）、トウモロコシデンプン３０．０ｇ（局方コーンスターチホワイト／日本コーンスターチ製）及びクロスポビドン１５．０ｇ（ＣＬ−ＳＦ／ＢＡＳＦ製）を高速撹拌造粒機（ＶＧ−０１型／パウレック製）に投入し、ＰＶＡ共重合体０．３ｇ（ＰＯＶＡＣＯＡＴ Ｔｙｐｅ Ｆ／大同化成工業製）を精製水６５ｇに溶解した液を滴下して造粒した。引き続き、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径４ｍｍのスクリーンを用いて湿式整粒した後、流動層乾燥機（ＭＰ−０１型／パウレック製）に投入して給気温度８０℃で排気温度が３５℃になるまで乾燥した。乾燥後、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径１ｍｍのスクリーンを用いて乾式解砕してイルベサルタン造粒物品を得た。得られた造粒物品１７０．０ｇ、アムロジピンベシル酸塩１３．８７ｇ（Ｍｏｅｈｓ製）、トウモロコシデンプン４．１３ｇ（局方コーンスターチホワイト／日本コーンスターチ製）、及びステアリン酸マグネシウム２．０ｇ（太平化学産業製）と共に混合し、打圧８００ｋｇｆで打錠して１錠質量１９０．０ｍｇ、直径８ｍｍの錠剤（円形Ｒ錠）を得た。
[Comparative Example 6]
Irbesartan 150.0 g (manufactured by HUAHAI), D-mannitol 59.7 g (mannit k / manufactured by Mitsubishi Corporation Foodtech), corn starch 30.0 g (pharmacopoeia corn starch white / manufactured by Nippon corn starch) and crospovidone 15.0 g (CL -SF / BASF) was charged into a high-speed agitation granulator (VG-01 type / Paurec), and 0.3 g of PVA copolymer (POVACOAT Type F / Daido Kasei Kogyo) was dissolved in 65 g of purified water. Was dropped and granulated. Subsequently, after wet-regulating using a screen with a diameter of 4 mm in a crusher (Comil QC-197S / manufactured by Paulek), it is put into a fluidized bed dryer (MP-01 type / manufactured by Pauleck) and an air supply temperature of 80 ° C. And dried until the exhaust temperature reached 35 ° C. After drying, the powder was crushed dry using a screen having a diameter of 1 mm in a pulverizer (Comil QC-197S / Pauleck) to obtain an irbesartan granulated article. 170.0 g of the obtained granulated article, 13.87 g of amlodipine besylate (manufactured by Moehs), 4.13 g of corn starch (manufactured by Pharmacopoeia Cornstarch White / manufactured by Nippon Cornstarch), and 2.0 g of magnesium stearate (manufactured by Taihei Chemical Industry) ), And tableting was performed at a pressure of 800 kgf to obtain a tablet (round R tablet) having a mass of 190.0 mg and a diameter of 8 mm.
［比較例７］
イルベサルタン１５０．０ｇ（ＨＵＡＨＡＩ製）、Ｄ−マンニトール５９．７ｇ（マンニットＣ／三菱商事フードテック製）、トウモロコシデンプン３０．０ｇ（局方コーンスターチホワイト／日本コーンスターチ製）及びクロスポビドン１５．０ｇ（ＣＬ−ＳＦ／ＢＡＳＦ製）を高速撹拌造粒機（ＶＧ−０１型／パウレック製）に投入し、ＰＶＡ共重合体０．３ｇ（ＰＯＶＡＣＯＡＴ Ｔｙｐｅ Ｆ／大同化成工業製）を精製水６５ｇに溶解した液を滴下して造粒した。引き続き、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径４ｍｍのスクリーンを用いて湿式整粒した後、流動層乾燥機（ＭＰ−０１型／パウレック製）に投入して給気温度８０℃で排気温度が３５℃になるまで乾燥した。乾燥後、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径１ｍｍのスクリーンを用いて乾式解砕してイルベサルタン造粒物品を得た。得られた造粒物品１７０．０ｇ、トウモロコシデンプン１８．０ｇ（局方コーンスターチホワイト／日本コーンスターチ製）及びステアリン酸マグネシウム２．０ｇ（太平化学産業製）と共に混合し、打圧８００ｋｇｆで打錠して１錠質量１９０．０ｍｇ、直径８ｍｍの錠剤（円形Ｒ錠）を得た。
[Comparative Example 7]
Irbesartan 150.0 g (manufactured by HUAHAI), D-mannitol 59.7 g (mannit k / manufactured by Mitsubishi Corporation Foodtech), corn starch 30.0 g (pharmacopoeia corn starch white / manufactured by Nippon corn starch) and crospovidone 15.0 g (CL -SF / BASF) was charged into a high-speed agitation granulator (VG-01 type / Paurec), and 0.3 g of PVA copolymer (POVACOAT Type F / Daido Kasei Kogyo) was dissolved in 65 g of purified water. Was dropped and granulated. Subsequently, after wet-regulating using a screen with a diameter of 4 mm in a crusher (Comil QC-197S / manufactured by Paulek), it is put into a fluidized bed dryer (MP-01 type / manufactured by Pauleck) and an air supply temperature of 80 ° C. And dried until the exhaust temperature reached 35 ° C. After drying, the powder was crushed dry using a screen having a diameter of 1 mm in a pulverizer (Comil QC-197S / Pauleck) to obtain an irbesartan granulated article. Mix with 170.0g of the resulting granulated article, 18.0g of corn starch (manufactured by Pharmacopoeia Corn Starch White / Nihon Corn Starch) and 2.0g of Magnesium Stearate (manufactured by Taihei Chemical Sangyo), and tablet at a compression pressure of 800kgf. A tablet having a mass of 190.0 mg and a diameter of 8 mm (round R tablet) was obtained.
［比較例８］
アムロジピンベシル酸塩３４６．７５ｇ（Ｍｏｅｈｓ製）及びトウモロコシデンプン７３．２５ｇ（局方コーンスターチホワイト／日本コーンスターチ製)を流動層造粒機（ＭＰ−０１型／パウレック製）に投入し、ＰＶＡ共重合体１２．５ｇ（ＰＯＶＡＣＯＡＴ Ｔｙｐｅ Ｆ／大同化成工業製）を精製水３００ｇに溶解した液を噴霧し、給気温度７５℃で造粒した。引き続きエチルセルロース水分散液１５０．０ｇ（アクアコートＥＣＤ／ＦＭＣ製）、Ｄ−マンニトール１１．２５ｇ（マンニットＣ／三菱商事フードテック製）及びクエン酸トリエチル１１．２５ｇ（シトロフレックス２ ＳＣ−６０／森村産業製）を分散した液を噴霧し、給気温度７５℃でコーティング（被覆）した。引き続き、給気温度８５℃で排気温度が３５℃になるまで乾燥した後、網目３０ｍｅｓｈのステンレス製篩で篩過してアムロジピンベシル酸塩被覆造粒物品を得た。
上記によって得られたアムロジピンベシル酸塩被覆造粒物品２０．０ｇ、Ｄ−マンニトール１９８．０ｇ（グラニュトールＳ／フロイント産業製）、クロスポビドン１０．０ｇ（ＣＬ−ＳＦ／ＢＡＳＦ製）及びステアリン酸マグネシウム２．０ｇ（太平化学産業製）と共に混合し、ロータリー式打錠機（ＶＩＲＧＯ型／菊水製作所製）にて、打圧６００ｋｇｆで打錠して１錠質量２３０．０ｍｇ、直径９．５ｍｍ、硬度４８Ｎ、口腔内崩壊時間２３秒の口腔内崩壊錠（円形２段Ｒ錠）を得た。
[Comparative Example 8]
346.75 g of amlodipine besylate (manufactured by Moehs) and 73.25 g of corn starch (manufactured by Pharmacopoeia Cornstarch White / manufactured by Nippon Cornstarch) were charged into a fluidized bed granulator (MP-01 type / manufactured by Paulek), and PVA copolymer A solution obtained by dissolving 12.5 g (POVACOAT Type F / manufactured by Daido Kasei Kogyo Co., Ltd.) in 300 g of purified water was sprayed and granulated at an air supply temperature of 75 ° C. Subsequently, 150.0 g of ethyl cellulose aqueous dispersion (manufactured by Aquacoat ECD / FMC), 11.25 g of D-mannitol (manufactured by Mannit C / Mitsubishi Corporation Foodtech) and 11.25 g of triethyl citrate (Citroflex 2 SC-60 / Morimura) A liquid in which (manufactured by Kogyo) was dispersed was sprayed and coated at a supply air temperature of 75 ° C. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature reached 35 ° C., the product was sieved with a stainless steel sieve having a mesh of 30 mesh to obtain an amlodipine besylate-coated granulated article.
Amlodipine besylate-coated granulated article 20.0 g obtained in the above, D-mannitol 198.0 g (Granitol S / Freund Sangyo), Crospovidone 10.0 g (CL-SF / BASF) and magnesium stearate 2.0g (made by Taihei Chemical Industrial Co., Ltd.) and mixed with a rotary tableting machine (VIRGO type / manufactured by Kikusui Seisakusho Co., Ltd.) with tableting pressure of 600kgf, 1 tablet weight 230.0mg, diameter 9.5mm, hardness An orally disintegrating tablet (circular two-stage R tablet) having an oral disintegration time of 48 N was obtained.
［比較例９］
イルベサルタン１５０．０ｇ（ＨＵＡＨＡＩ製）、Ｄ−マンニトール８６．７ｇ（マンニットＣ／三菱商事フードテック製）、トウモロコシデンプン３０．０ｇ（日局コーンスターチホワイト／日本コーンスターチ製）、クロスポビドン１５．０ｇ（ＣＬ−ＳＦ／ＢＡＳＦ製）及びスクラロース１５．０ｇ（スクラロース（Ｐ）／三栄原エフ・エフ・アイ製）を高速撹拌造粒機（ＶＧ−０１型／パウレック製）に投入し、ＰＶＡ共重合体０．３ｇ（ＰＯＶＡＣＯＡＴ Ｔｙｐｅ Ｆ／大同化成工業製）を精製水６５．０ｇに溶解した液を滴下して造粒した。引き続き、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径４ｍｍのスクリーンを用いて湿式整粒した後、流動層乾燥機（ＭＰ−０１型／パウレック製）に投入して給気温度８０℃で排気温度が３５℃になるまで乾燥した。乾燥後、解砕機（コーミルＱＣ−１９７Ｓ／パウレック製）にて直径１ｍｍのスクリーンを用いて乾式解砕してイルベサルタン造粒物品を得た。
アムロジピンベシル酸塩３４６．７５ｇ（Ｍｏｅｈｓ製）及びトウモロコシデンプン７３．２５ｇ（局方コーンスターチホワイト／日本コーンスターチ製)を流動層造粒機（ＭＰ−０１型／パウレック製）に投入し、ＰＶＡ共重合体１２．５ｇ（ＰＯＶＡＣＯＡＴ Ｔｙｐｅ Ｆ／大同化成工業製）を精製水３００ｇに溶解した液を噴霧し、給気温度７５℃で造粒した。引き続きエチルセルロース水分散液１５０．０ｇ（アクアコートＥＣＤ／ＦＭＣ製）、Ｄ−マンニトール１１．２５ｇ（マンニットＣ／三菱商事フードテック製）及びクエン酸トリエチル１１．２５ｇ（シトロフレックス２ ＳＣ−６０／森村産業製）を分散した液を噴霧し、給気温度７５℃でコーティング（被覆）した。引き続き、給気温度８５℃で排気温度が３５℃になるまで乾燥した後、網目３０ｍｅｓｈのステンレス製篩で篩過してアムロジピンベシル酸塩被覆造粒物品を得た。
上記によって得られたイルベサルタン造粒物品１９８．０ｇ、アムロジピンベシル酸塩被覆造粒物品２０．０ｇ、クロスポビドン１０．０ｇ（ＣＬ−ＳＦ／ＢＡＳＦ製）及びステアリン酸マグネシウム２．０ｇ（太平化学産業製）と共に混合し、ロータリー式打錠機（ＶＩＲＧＯ型／菊水製作所製）にて、打圧６００ｋｇｆで打錠して１錠質量２３０．０ｍｇ、直径９．５ｍｍ、硬度３３Ｎ、口腔内崩壊時間３１秒の口腔内崩壊錠（円形２段Ｒ錠）を得た。
[Comparative Example 9]
Irbesartan 150.0 g (manufactured by HUAHAI), D-mannitol 86.7 g (mannit k / manufactured by Mitsubishi Corporation Foodtech), corn starch 30.0 g (manufactured by JP cornstarch white / Japan cornstarch), crospovidone 15.0 g (CL -SF / BASF) and 15.0 g of sucralose (Sucralose (P) / manufactured by Saneihara FFI) were charged into a high-speed agitation granulator (VG-01 type / manufactured by Paulek), and PVA copolymer 0 .3 g (POVACOAT Type F / manufactured by Daido Kasei Kogyo Co., Ltd.) in 65.0 g of purified water was added dropwise and granulated. Subsequently, after wet-regulating using a screen with a diameter of 4 mm in a crusher (Comil QC-197S / manufactured by Paulek), it is put into a fluidized bed dryer (MP-01 type / manufactured by Pauleck) and an air supply temperature of 80 ° C. And dried until the exhaust temperature reached 35 ° C. After drying, the powder was crushed dry using a screen having a diameter of 1 mm in a pulverizer (Comil QC-197S / Pauleck) to obtain an irbesartan granulated article.
346.75 g of amlodipine besylate (manufactured by Moehs) and 73.25 g of corn starch (manufactured by Pharmacopoeia Cornstarch White / manufactured by Nippon Cornstarch) were charged into a fluidized bed granulator (MP-01 type / manufactured by Paulek), and PVA copolymer A solution obtained by dissolving 12.5 g (POVACOAT Type F / manufactured by Daido Kasei Kogyo Co., Ltd.) in 300 g of purified water was sprayed and granulated at an air supply temperature of 75 ° C. Subsequently, 150.0 g of ethyl cellulose aqueous dispersion (manufactured by Aquacoat ECD / FMC), 11.25 g of D-mannitol (manufactured by Mannit C / Mitsubishi Corporation Foodtech) and 11.25 g of triethyl citrate (Citroflex 2 SC-60 / Morimura) A liquid in which (manufactured by Kogyo) was dispersed was sprayed and coated at a supply air temperature of 75 ° C. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature reached 35 ° C., the product was sieved with a stainless steel sieve having a mesh of 30 mesh to obtain an amlodipine besylate-coated granulated article.
198.0 g of irbesartan granulated article obtained as described above, 20.0 g of amlodipine besylate-coated granulated article, 10.0 g of crospovidone (CL-SF / BASF) and 2.0 g of magnesium stearate (manufactured by Taihei Chemical Sangyo) ) And tableting with a rotary tableting machine (VIRGO type / manufactured by Kikusui Seisakusho) with a punching pressure of 600 kgf, one tablet weight is 230.0 mg, diameter is 9.5 mm, hardness is 33 N, and oral disintegration time is 31 seconds. Orally disintegrating tablets (circular two-stage R tablets) were obtained.
実施例２〜１２及び比較例１〜９で得られた各々の錠剤の処方を下記の表１〜５に一覧して示す（各添加剤の含量及び錠剤の重量の単位はｍｇである。）。 The prescriptions of the tablets obtained in Examples 2 to 12 and Comparative Examples 1 to 9 are listed in Tables 1 to 5 below (the content of each additive and the unit of the tablet weight is mg). .
（試験例１）
実施例２〜１２及び比較例１〜９で得られた各々の錠剤について、第１６改正日本薬局方・一般試験法の溶出試験法により試験開始５分後、１０分後、１５分後、３０分後及び４５分後のアムロジピンベシル酸塩の溶出率を求め、結果（ｎ＝３）を下記の表６〜１０に示した。
使用した装置：溶出試験機／ＮＴＲ‐６１００型（富山産業製）
紫外線吸光光度計／ＵＶ‐１６００型（島津製作所製）
測定条件：試験液：日局第２液
試験液量：９００ｍＬ
パドル回転数：５０ｒｐｍ
液温：３７℃
測定波長（アムロジピンベシル酸塩）：３６０ｎｍ
測定波長（イルベサルタン）：２７２ｎｍ
(Test Example 1)
For each of the tablets obtained in Examples 2 to 12 and Comparative Examples 1 to 9, the dissolution test method of the 16th revised Japanese Pharmacopoeia / General Test Method started 5 minutes, 10 minutes, 15 minutes later, 30 The elution rate of amlodipine besylate after minutes and 45 minutes was determined, and the results (n = 3) are shown in Tables 6 to 10 below.
Equipment used: Dissolution tester / NTR-6100 (Toyama Sangyo)
Ultraviolet absorptiometer / UV-1600 type (manufactured by Shimadzu Corporation)
Measurement conditions: Test liquid: JP 2nd liquid
Test solution volume: 900 mL
Paddle rotation speed: 50 rpm
Liquid temperature: 37 ° C
Measurement wavelength (amlodipine besylate): 360 nm
Measurement wavelength (irbesartan): 272 nm
表６において、カルメロースを含有する実施例２の配合錠は、カルメロースを含有しない比較例２〜５の配合錠と比べて試験開始１５分後の溶出率が約３０〜４３％程高く、アムロジピンベシル酸塩の溶出速度が有意に早いことがみられた。よって、カルメロースが配合錠中のアムロジピンベシル酸塩の溶出速度を顕著に早めることが示された。
尚、カルメロースを含有する比較例１の錠剤及びカルメロースを含有しない比較例８の錠剤では、アムロジピンベシル酸塩の溶出速度がどちらも同程度に早いことがみられた。比較例１及び比較例８の錠剤はどちらも原薬としてアムロジピンベシル酸塩のみを含む単剤であるため、上記のカルメロースによる溶出性の改善効果は配合錠の場合にのみ見られる効果であると考えられる。
In Table 6, the combination tablet of Example 2 containing carmellose has a dissolution rate of about 30 to 43% higher 15 minutes after the start of the test than the combination tablets of Comparative Examples 2 to 5 not containing carmellose, and amlodipine besil It was found that the elution rate of the acid salt was significantly faster. Therefore, it was shown that carmellose markedly accelerates the dissolution rate of amlodipine besylate in the combination tablet.
In addition, in the tablet of Comparative Example 1 containing carmellose and the tablet of Comparative Example 8 not containing carmellose, it was found that the dissolution rate of amlodipine besylate was both about the same. Since both the tablets of Comparative Example 1 and Comparative Example 8 are single agents containing only amlodipine besylate as the drug substance, the above-mentioned improvement effect of dissolution by carmellose is an effect that can be seen only in the case of a combination tablet. Conceivable.
表７において、カルメロースを造粒物中に含有する実施例３〜６は、カルメロースを造粒物中に含有しない比較例６と比べて試験開始１５分後の溶出率が約１６〜３０％程高く、アムロジピンベシル酸塩の溶出速度が優れて早いことがみられた。よって、カルメロースによる溶出性の改善効果は造粒物中に含有された場合にも発揮される効果であることが考えられる。
また、結晶セルロース又はクロスポピドンを造粒物中に含有しない実施例３は結晶セルロース又はクロスポピドンを造粒物中に含有する実施例４〜６と比較して、溶出速度が若干遅いことがみられたため、造粒物中の結晶セルロースやクロスポピドン等の崩壊剤がアムロジピンベシル酸塩の溶出速度を高めることが考えられる。尚、カルメロースの錠剤中の含有量が異なる実施例４、５と実施例６で溶出速度が同程度の早さであったことから、カルメロースは少ない含有量でアムロジピンベシル酸塩の溶出速度を十分に改善する効果をもつことが示唆された。
In Table 7, Examples 3 to 6 containing carmellose in the granulated product have an elution rate of about 16 to 30% 15 minutes after the start of the test compared to Comparative Example 6 not containing carmellose in the granulated product. The dissolution rate of amlodipine besylate was excellent and high. Therefore, it is thought that the improvement effect of the dissolution property by carmellose is an effect exhibited even when contained in the granulated product.
In addition, Example 3 which does not contain crystalline cellulose or crospovidone in the granulated product has a slightly lower elution rate than Examples 4 to 6 which contain crystalline cellulose or crospovidone in the granulated product. Therefore, disintegrants such as crystalline cellulose and crospovidone in the granulated product are considered to increase the dissolution rate of amlodipine besylate. It should be noted that the dissolution rate of carmellose in Examples 4, 5 and Example 6 differed from those of Examples 6 and 6, so the dissolution rate of amlodipine besylate was sufficient with a small content of carmellose. It was suggested that it has an improving effect.
表８において、カルメロースを造粒物中に含有する実施例７の配合口腔内崩壊錠とカルメロースを造粒物中に含有しない実施例８の配合口腔内崩壊錠はアムロジピンベシル酸塩の溶出速度はどちらも同程度に高いことがみられた。よって上記の結果と同様に、カルメロースによるアムロジピンベシル酸塩の溶出性の改善効果は造粒物中外を問わずに発揮される効果であることが考えられる。また、カルメロースを含有しない比較例９の配合口腔内崩壊錠と比べると、実施例７、８の錠剤は試験開始１５分後の溶出率が約９５〜１００％程高く、驚くべきほど有意に改善されることが明らかになり、カルメロースによるアムロジピンベシル酸塩の溶出性改善方法は配合口腔内崩壊錠において適用されることが特に望まれる技術であることが考えられる。 In Table 8, the dissolution rate of amlodipine besylate in the combination orally disintegrating tablet of Example 7 containing carmellose in the granulated product and the compounding orally disintegrating tablet of Example 8 not containing carmellose in the granulated product are as follows: Both were found to be equally high. Therefore, similarly to the above results, it is considered that the effect of improving the dissolution property of amlodipine besylate by carmellose is exhibited regardless of whether it is inside or outside the granulated product. Moreover, compared with the combination orally disintegrating tablet of Comparative Example 9 containing no carmellose, the tablets of Examples 7 and 8 had a dissolution rate of about 95-100% 15 minutes after the start of the test, which was surprisingly significantly improved. Thus, it is considered that the method for improving the dissolution property of amlodipine besylate with carmellose is a technique that is particularly desired to be applied to a compounded orally disintegrating tablet.
以上より、本発明により得られるカルメロース等の特定の崩壊剤とアムロジピンベシル酸塩を含有する配合錠は、アムロジピンベシル酸塩の溶出速度が有意に改善された錠剤であることが示された。 From the above, it was shown that the combination tablet containing a specific disintegrant such as carmellose and amlodipine besylate obtained by the present invention is a tablet in which the dissolution rate of amlodipine besylate is significantly improved.
本発明によれば、アムロジピンベシル酸塩の溶出速度が有意に改善された効果を有する、アムロジピンベシル酸塩を含有する高品質な配合錠（特に配合口腔内崩壊錠）を医療現場に提供することを可能にする。
According to the present invention, a high quality combination tablet containing amlodipine besylate (especially a combination orally disintegrating tablet) having the effect of significantly improving the dissolution rate of amlodipine besylate is provided to the medical field. Enable.
Claims (4)
A film-coated tablet, wherein the uncoated tablet as the combination tablet according to claim 1 or 2 is covered with a film coating layer.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2016025015 | 2016-02-12 | ||
| JP2016025015 | 2016-02-12 | ||
| JP2016128121 | 2016-06-28 | ||
| JP2016128121 | 2016-06-28 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2018002699A JP2018002699A (en) | 2018-01-11 |
| JP2018002699A5 JP2018002699A5 (en) | 2018-02-22 |
| JP6321131B2 true JP6321131B2 (en) | 2018-05-09 |
Family
ID=60945772
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2016256790A Active JP6321131B2 (en) | 2016-02-12 | 2016-12-28 | Dissolution improvement method of amlodipine-containing combination tablets |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP6321131B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP7425560B2 (en) * | 2018-08-10 | 2024-01-31 | アリナミン製薬株式会社 | Method for manufacturing solid preparations |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5421945B2 (en) * | 2010-03-10 | 2014-02-19 | 大日本住友製薬株式会社 | Pharmaceutical composition containing irbesartan and amlodipine or a salt thereof |
| JP6041591B2 (en) * | 2011-09-13 | 2016-12-14 | 大日本住友製薬株式会社 | Stabilized pharmaceutical composition comprising irbesartan and amlodipine or a salt thereof |
| JP6245677B2 (en) * | 2012-01-20 | 2017-12-13 | ニプロ株式会社 | Orally disintegrating tablets |
| JP6199922B2 (en) * | 2015-03-20 | 2017-09-20 | 大原薬品工業株式会社 | Irbesartan-containing tablets with improved chemical stability |
-
2016
- 2016-12-28 JP JP2016256790A patent/JP6321131B2/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| JP2018002699A (en) | 2018-01-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6041919B2 (en) | Salt of 8-[{1- (3,5-bis- (trifluoromethyl) phenyl) -ethoxy} -methyl] -8-phenyl-1,7-diaza-spiro [4.5] decan-2-one Tablet formulations containing and tablets made therefrom | |
| JP6730978B2 (en) | Solid formulation | |
| US20210069207A1 (en) | Pharmaceutical solid preparation comprising benzazepines and production method thereof | |
| JP2010031019A (en) | High drug load tablet | |
| JP2014055173A (en) | Pharmaceutical composition containing irbesartan and amlodipine or salt thereof | |
| TW201827049A (en) | Orally disintegrating tablet containing diamine derivative | |
| TWI418370B (en) | Dissolution-stable pharmaceutical agent | |
| TW201717937A (en) | Pharmaceutical composition containing aryl alkyl amine compound | |
| TW202019430A (en) | Pharmaceutical composition containing hardly soluble basic drug | |
| EP3437645B1 (en) | Film-coated tablet having high chemical stability of active ingredient | |
| JP6321131B2 (en) | Dissolution improvement method of amlodipine-containing combination tablets | |
| TW200826975A (en) | Pharmaceutical tablet formulation | |
| JP7511596B2 (en) | Rivaroxaban-containing tablets | |
| JP2002012540A (en) | Readily water-soluble medicament-containing tablet | |
| JP2017132724A (en) | Orally disintegrating tablet formulation comprising amlodipine-containing coated granulated material | |
| JP6199922B2 (en) | Irbesartan-containing tablets with improved chemical stability | |
| JP7407364B2 (en) | Ramelteon-containing solid preparation | |
| JP6858873B2 (en) | Tablets containing celecoxib | |
| JP6233911B2 (en) | Irbesartan-containing tablets with improved chemical stability | |
| JP6298435B2 (en) | Orally disintegrating tablet containing an angiotensin II receptor antagonist | |
| JP2017137255A (en) | Amlodipine-containing combination tablet of colored uncoated tablet | |
| JP2007290975A (en) | Pranlukast tablet | |
| CA2709624A1 (en) | Immediate release dosage form of bosentan and process of manufacturing such | |
| TW202224681A (en) | Single dosage form of a pharmaceutical composition for the treatment or prevention of hypertension and hypercholesterolemia | |
| JP2018090617A (en) | Orally disintegrating tablet containing angiotensin II receptor antagonist |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20171226 |
|
| A871 | Explanation of circumstances concerning accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A871 Effective date: 20171226 |
|
| A975 | Report on accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A971005 Effective date: 20180117 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20180126 |
|
| RD02 | Notification of acceptance of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7422 Effective date: 20180201 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180309 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20180402 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20180404 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 6321131 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |