JP2018168113A - Coating granule of imidafenacin-containing granulated material - Google Patents
Coating granule of imidafenacin-containing granulated material Download PDFInfo
- Publication number
- JP2018168113A JP2018168113A JP2017067525A JP2017067525A JP2018168113A JP 2018168113 A JP2018168113 A JP 2018168113A JP 2017067525 A JP2017067525 A JP 2017067525A JP 2017067525 A JP2017067525 A JP 2017067525A JP 2018168113 A JP2018168113 A JP 2018168113A
- Authority
- JP
- Japan
- Prior art keywords
- imidafenacin
- coated
- coating agent
- granules
- tablet
- 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.)
- Granted
Links
- SQKXYSGRELMAAU-UHFFFAOYSA-N imidafenacin Chemical compound CC1=NC=CN1CCC(C(N)=O)(C=1C=CC=CC=1)C1=CC=CC=C1 SQKXYSGRELMAAU-UHFFFAOYSA-N 0.000 title claims abstract description 93
- 229950005396 imidafenacin Drugs 0.000 title claims abstract description 92
- 239000011248 coating agent Substances 0.000 title claims abstract description 63
- 239000008187 granular material Substances 0.000 title claims abstract description 55
- 238000000576 coating method Methods 0.000 title claims abstract description 18
- 229920002678 cellulose Polymers 0.000 claims abstract description 34
- 239000001913 cellulose Substances 0.000 claims abstract description 32
- 238000013268 sustained release Methods 0.000 claims abstract description 17
- 239000012730 sustained-release form Substances 0.000 claims abstract description 17
- 238000004519 manufacturing process Methods 0.000 claims abstract description 14
- 239000007931 coated granule Substances 0.000 claims description 37
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 22
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 20
- 239000011732 tocopherol Substances 0.000 claims description 17
- 229960001295 tocopherol Drugs 0.000 claims description 17
- 229930003799 tocopherol Natural products 0.000 claims description 16
- 235000010384 tocopherol Nutrition 0.000 claims description 16
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 12
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 12
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 12
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical group OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 12
- 150000003611 tocopherol derivatives Chemical class 0.000 claims description 7
- 238000000748 compression moulding Methods 0.000 claims description 4
- 238000000465 moulding Methods 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 28
- 238000000354 decomposition reaction Methods 0.000 abstract description 9
- 239000003826 tablet Substances 0.000 description 75
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 72
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 58
- 239000000047 product Substances 0.000 description 54
- 238000005507 spraying Methods 0.000 description 48
- 238000000034 method Methods 0.000 description 35
- 235000010980 cellulose Nutrition 0.000 description 31
- 239000000126 substance Substances 0.000 description 31
- 239000007788 liquid Substances 0.000 description 30
- 235000019359 magnesium stearate Nutrition 0.000 description 29
- 241000196324 Embryophyta Species 0.000 description 25
- 239000000243 solution Substances 0.000 description 25
- 239000007921 spray Substances 0.000 description 25
- 235000019441 ethanol Nutrition 0.000 description 24
- 239000011259 mixed solution Substances 0.000 description 24
- 239000008213 purified water Substances 0.000 description 24
- 238000005096 rolling process Methods 0.000 description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
- 229920002472 Starch Polymers 0.000 description 17
- 235000019698 starch Nutrition 0.000 description 17
- 238000002156 mixing Methods 0.000 description 16
- 239000008107 starch Substances 0.000 description 15
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 13
- 238000005469 granulation Methods 0.000 description 11
- 230000003179 granulation Effects 0.000 description 11
- 239000000546 pharmaceutical excipient Substances 0.000 description 11
- 229920003082 Povidone K 90 Polymers 0.000 description 9
- -1 carboxymethyl ethyl Chemical group 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 8
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 6
- 239000007857 degradation product Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 239000011627 DL-alpha-tocopherol Substances 0.000 description 5
- 235000001815 DL-alpha-tocopherol Nutrition 0.000 description 5
- 229920003149 Eudragit® E 100 Polymers 0.000 description 5
- 229920000881 Modified starch Polymers 0.000 description 5
- NEDGUIRITORSKL-UHFFFAOYSA-N butyl 2-methylprop-2-enoate;2-(dimethylamino)ethyl 2-methylprop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound COC(=O)C(C)=C.CCCCOC(=O)C(C)=C.CN(C)CCOC(=O)C(C)=C NEDGUIRITORSKL-UHFFFAOYSA-N 0.000 description 5
- 229960000984 tocofersolan Drugs 0.000 description 5
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 4
- 239000001856 Ethyl cellulose Substances 0.000 description 4
- 229920003116 HPC-SSL Polymers 0.000 description 4
- 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 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 229920003144 amino alkyl methacrylate copolymer Polymers 0.000 description 4
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229920001249 ethyl cellulose Polymers 0.000 description 4
- 235000019325 ethyl cellulose Nutrition 0.000 description 4
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 235000012239 silicon dioxide Nutrition 0.000 description 4
- DVQHRBFGRZHMSR-UHFFFAOYSA-N sodium methyl 2,2-dimethyl-4,6-dioxo-5-(N-prop-2-enoxy-C-propylcarbonimidoyl)cyclohexane-1-carboxylate Chemical compound [Na+].C=CCON=C(CCC)[C-]1C(=O)CC(C)(C)C(C(=O)OC)C1=O DVQHRBFGRZHMSR-UHFFFAOYSA-N 0.000 description 4
- 150000005846 sugar alcohols Chemical class 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 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 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
- 229950008138 carmellose Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229960000913 crospovidone Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 235000010981 methylcellulose Nutrition 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000001782 photodegradation Methods 0.000 description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 3
- 229940069328 povidone Drugs 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 230000006641 stabilisation Effects 0.000 description 3
- 238000011105 stabilization Methods 0.000 description 3
- 229920002554 vinyl polymer Polymers 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- 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 2
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 2
- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-UHFFFAOYSA-N 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 2
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 2
- 239000006191 orally-disintegrating tablet Substances 0.000 description 2
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 2
- 229920000058 polyacrylate Polymers 0.000 description 2
- 239000002861 polymer material Substances 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- OHVLMTFVQDZYHP-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CN1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O OHVLMTFVQDZYHP-UHFFFAOYSA-N 0.000 description 1
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 1
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
- IHCCLXNEEPMSIO-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 IHCCLXNEEPMSIO-UHFFFAOYSA-N 0.000 description 1
- RLYOPPJABLAKCZ-UHFFFAOYSA-N 2-butoxycarbonylbenzenecarboperoxoic acid Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OO RLYOPPJABLAKCZ-UHFFFAOYSA-N 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 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
- 108010011485 Aspartame Proteins 0.000 description 1
- 102000017925 CHRM3 Human genes 0.000 description 1
- 101150060249 CHRM3 gene Proteins 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
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-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
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 1
- 206010020853 Hypertonic bladder Diseases 0.000 description 1
- 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 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
- VTAJIXDZFCRWBR-UHFFFAOYSA-N Licoricesaponin B2 Natural products C1C(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2)C(O)=O)C)(C)CC2)(C)C2C(C)(C)CC1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O VTAJIXDZFCRWBR-UHFFFAOYSA-N 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 102000007207 Muscarinic M1 Receptor Human genes 0.000 description 1
- 108010008406 Muscarinic M1 Receptor Proteins 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
- 229920001218 Pullulan Polymers 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 244000228451 Stevia rebaudiana Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 208000000921 Urge Urinary Incontinence Diseases 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010358 acesulfame potassium Nutrition 0.000 description 1
- 229960004998 acesulfame potassium Drugs 0.000 description 1
- 239000000619 acesulfame-K Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229960005168 croscarmellose Drugs 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000000796 flavoring agent 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
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 1
- 229960004949 glycyrrhizic acid Drugs 0.000 description 1
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 1
- 239000001685 glycyrrhizic acid Substances 0.000 description 1
- 235000019410 glycyrrhizin Nutrition 0.000 description 1
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 229910052751 metal Chemical class 0.000 description 1
- 239000002184 metal Chemical class 0.000 description 1
- 230000027939 micturition Effects 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical class CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 208000020629 overactive bladder Diseases 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 238000006303 photolysis reaction Methods 0.000 description 1
- 230000015843 photosynthesis, light reaction Effects 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- HRQDCDQDOPSGBR-UHFFFAOYSA-M sodium;octane-1-sulfonate Chemical compound [Na+].CCCCCCCCS([O-])(=O)=O HRQDCDQDOPSGBR-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 229940042585 tocopherol acetate Drugs 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
- 238000012546 transfer Methods 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は、イミダフェナシンを含有造粒物のコーティング顆粒に関する。 The present invention relates to a coated granule of a granulated product containing imidafenacin.
イミダフェナシンはムスカリンＭ１受容体及びＭ３受容体を選択的に阻害する抗コリン薬であり、過活動膀胱における尿意切迫感、頻尿及び切迫性尿失禁の治療薬として広く使用されている。現在、イミダフェナシンを有効成分とする医薬品としては、フィルムコーティング錠（ＦＣ錠）と口腔内崩壊錠（ＯＤ錠）が市販されている（非特許文献１）。 Imidafenacin is an anticholinergic agent that selectively inhibits muscarinic M1 and M3 receptors and is widely used as a therapeutic agent for urgency, frequent urination and urge urinary incontinence in overactive bladder. Currently, film-coated tablets (FC tablets) and orally disintegrating tablets (OD tablets) are commercially available as pharmaceuticals containing imidafenacin as an active ingredient (Non-patent Document 1).
特許文献１には、イミダフェナシンを有効成分とするＦＣ錠やその製造方法が開示されている。また、特許文献２〜８には、イミダフェナシンを有効成分とするＯＤ錠やその製造方法が開示されている。そして特許文献２〜３及び６には、イミダフェナシン造粒物を特定の非セルロース系賦形剤で被覆することにより、光安定性が向上することが記載されている。また、特許文献６には、トコフェロール等をイミダフェナシンとともに造粒することにより、製造工程分解物が抑制できることが記載されている。 Patent Document 1 discloses an FC tablet containing imidafenacin as an active ingredient and a method for producing the same. Patent Documents 2 to 8 disclose an OD tablet containing imidafenacin as an active ingredient and a method for producing the same. Patent Documents 2 to 3 and 6 describe that light stability is improved by coating an imidafenacin granulated product with a specific non-cellulosic excipient. Patent Document 6 describes that the degradation product of the production process can be suppressed by granulating tocopherol and the like together with imidafenacin.
しかしながら、特許文献１〜８には、イミダフェナシン造粒物をセルロース系コーティング剤で被覆したイミダフェナシン顆粒については開示されていない。 However, Patent Documents 1 to 8 do not disclose imidafenacin granules obtained by coating imidafenacin granules with a cellulose-based coating agent.
イミダフェナシンを含有する造粒物のコーティング顆粒は、核となるイミダフェナシン含有造粒物を製造する工程（以下、造粒工程とも記載する）と、得られた造粒物に対しコーティング剤で被覆する工程（以下、被覆工程とも記載する）を経由して製造される。被覆工程での製造工程分解物の少ないイミダフェナシン含有顆粒を提供することが、本発明が解決しようとする課題である。 The granulated coated granule containing imidafenacin is a process for producing an imidafenacin-containing granulated product as a core (hereinafter also referred to as a granulating step) and a step of coating the obtained granulated product with a coating agent. (Hereinafter also referred to as a coating step). It is a problem to be solved by the present invention to provide an imidafenacin-containing granule that is low in degradation during the coating process.
本発明者らは鋭意検討した結果、イミダフェナシンを含有する造粒物を、水溶性又は徐放性のセルロース系コーティング剤で被覆することで、被覆工程中に生じる分解物量の少ないイミダフェナシン含有顆粒が得られることを見出した。すなわち、本発明は以下の発明を包含する。
［１］イミダフェナシンを含有する造粒物が、水溶性又は徐放性のセルロース系コーティング剤で被覆された顆粒。
［２］前記造粒物が、トコフェロール又はトコフェロール誘導体を含有する、［１］に記載の顆粒。
［３］セルロース系コーティング剤がヒドロキシプロピルメチルセルロースである、［１］又は［２］に記載の顆粒。
［４］イミダフェナシン、及びトコフェロール又はトコフェロール誘導体を含有する造粒物が、水溶性又は徐放性のセルロース系コーティング剤で被覆された顆粒、を含有する錠剤。
［５］前記セルロース系コーティング剤がヒドロキシプロピルメチルセルロースである、［４］に記載の錠剤。
［６］（Ａ）イミダフェナシンを含有する造粒物を、水溶性又は徐放性のセルロース系コーティング剤で被覆し、イミダフェナシン含有顆粒を得る工程、及び
（Ｂ）工程（Ａ）で得られた被覆顆粒を圧縮成型すること、
を特徴とする、錠剤の製造方法。
［７］（Ａ）イミダフェナシン、及びトコフェロール又はトコフェロール誘導体を含有する造粒物を、水溶性又は徐放性のセルロース系コーティング剤で被覆し、イミダフェナシン含有顆粒を得る工程、及び
（Ｂ）工程（Ａ）で得られた被覆顆粒を圧縮成型すること、
を特徴とする、錠剤の製造方法。
As a result of intensive studies, the present inventors obtained imidafenacin-containing granules with a small amount of degradation products generated during the coating process by coating a granulated product containing imidafenacin with a water-soluble or sustained-release cellulose-based coating agent. I found out that That is, the present invention includes the following inventions.
[1] A granule in which a granulated product containing imidafenacin is coated with a water-soluble or sustained-release cellulose coating agent.
[2] The granule according to [1], wherein the granulated product contains tocopherol or a tocopherol derivative.
[3] The granule according to [1] or [2], wherein the cellulose-based coating agent is hydroxypropylmethylcellulose.
[4] A tablet containing imidafenacin and granules containing tocopherol or a tocopherol derivative coated with a water-soluble or sustained-release cellulose coating agent.
[5] The tablet according to [4], wherein the cellulose-based coating agent is hydroxypropylmethylcellulose.
[6] (A) The step of coating the granulated product containing imidafenacin with a water-soluble or sustained-release cellulose-based coating agent to obtain imidafenacin-containing granules, and (B) the coating obtained in step (A) Compression molding the granules,
A method for producing a tablet, comprising:
[7] (A) Imidafenacin and a granulated product containing tocopherol or a tocopherol derivative are coated with a water-soluble or sustained-release cellulosic coating agent to obtain imidafenacin-containing granules, and (B) step (A) Compression-molding the coated granules obtained in
A method for producing a tablet, comprising:
本発明によれば、分解物の少ないイミダフェナシン含有顆粒の提供が可能となった。 According to the present invention, it is possible to provide imidafenacin-containing granules with less degradation products.
本発明において、イミダフェナシンとは４−（２−メチル−１Ｈ−イミダゾール−１−イル）−２，２−ジフェニルブタンアミドを表す。
本発明において、錠剤中のイミダフェナシンの含量は０．０２５〜２ｍｇが好ましく、０．０５〜０．２５ｍｇが更に好ましく、０．１ｍｇが特に好ましい。
In the present invention, imidafenacin represents 4- (2-methyl-1H-imidazol-1-yl) -2,2-diphenylbutanamide.
In the present invention, the content of imidafenacin in the tablet is preferably 0.025 to 2 mg, more preferably 0.05 to 0.25 mg, and particularly preferably 0.1 mg.
本発明において、セルロース系コーティング剤とは、ヒドロキシプロピルメチルセルロースなど、分子内にセルロース構造を有するコーティング剤を意味する。
本発明において、セルロース系コーティング剤は、水溶性のセルロース系コーティング剤、徐放性のセルロース系コーティング剤、及び腸溶性のセルロース系コーティング剤を包含する。
In the present invention, the cellulosic coating agent means a coating agent having a cellulose structure in the molecule, such as hydroxypropylmethylcellulose.
In the present invention, the cellulosic coating agent includes a water-soluble cellulosic coating agent, a sustained-release cellulosic coating agent, and an enteric cellulosic coating agent.
イミダフェナシンを含有する造粒物を被覆するためのコーティング剤としては、被覆工程中にイミダフェナシンが分解することが抑制できるという点で、水溶性又は徐放性のセルロース系コーティング剤を使用することが好ましい。造粒物を被覆するコーティング剤の量は、特に制限はないが、好ましくは造粒物１質量部に対して０．００１〜１０質量部、さらに好ましくは０．０１〜１質量部、特に好ましくは０．０５〜０．５質量部である。
コーティング剤を使用した被覆法は、医薬品製剤の製造に使用可能な方法であれば、特に制限はない。例えば、スプレー法や、ディップ法、熱溶融法が挙げられる。
As the coating agent for coating the granulated product containing imidafenacin, it is preferable to use a water-soluble or sustained-release cellulosic coating agent in that imidafenacin can be prevented from being decomposed during the coating process. . The amount of the coating agent for coating the granulated product is not particularly limited, but is preferably 0.001 to 10 parts by mass, more preferably 0.01 to 1 part by mass, particularly preferably 1 part by mass of the granulated product. Is 0.05 to 0.5 parts by mass.
The coating method using a coating agent is not particularly limited as long as it is a method that can be used for production of a pharmaceutical preparation. For example, a spray method, a dip method, and a heat melting method can be used.
水溶性のセルロース系コーティング剤とは、水に溶解する又は水を加えると粘ちょう性のある液となる、セルロース系コーティング剤を意味する。例えば、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、メチルセルロースなどが挙げられる。
徐放性のセルロース系コーティング剤とは、水難溶性のセルロース系コーティング剤を意味する。例えば、エチルセルロース、カルメロースカルシウム、カルメロースナトリウム、カルボキシメチルエチルセルロース、結晶セルロースなどが挙げられる。
The water-soluble cellulose-based coating agent means a cellulose-based coating agent that dissolves in water or becomes a viscous liquid when water is added. For example, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose and the like can be mentioned.
The sustained release cellulose-based coating agent means a poorly water-soluble cellulose-based coating agent. For example, ethyl cellulose, carmellose calcium, carmellose sodium, carboxymethyl ethyl cellulose, crystalline cellulose and the like can be mentioned.
腸溶性のセルロース系コーティング剤とは、分子内にカルボキシル基などの酸性基を有しており、水酸化ナトリウム試液などのアルカリ溶液に溶解するセルロース系コーティング剤を意味する。例えば、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシプロピルメチルセルロースアセテートサクシネートなどが挙げられる。 The enteric cellulose-based coating agent means a cellulose-based coating agent that has an acidic group such as a carboxyl group in the molecule and dissolves in an alkaline solution such as a sodium hydroxide test solution. Examples thereof include hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate.
本発明において、トコフェロール又はトコフェロール誘導体としては、ｄｌ−α―トコフェロール（ビタミンＥ）、ｄ−σ―トコフェロール、トコフェロール酢酸エステル、トコフェロールリン酸エステル、トコフェロール硫酸エステル、トコフェロールグリコシルエステルやそれらの塩が挙げられる。トコフェロールの含有量は、イミダフェナシン含有顆粒中、０．０５質量％以上が好ましく、より好ましくは０．０５質量％以上１０質量％以下、さらに好ましくは０．０８質量％以上５質量％以下、より好ましくは１質量％以上３質量％以下、特に好ましくは１．５質量％以上２．５質量％以下である。 In the present invention, examples of the tocopherol or tocopherol derivative include dl-α-tocopherol (vitamin E), d-σ-tocopherol, tocopherol acetate, tocopherol phosphate, tocopherol sulfate, tocopherol glycosyl ester and salts thereof. . The content of tocopherol is preferably 0.05% by mass or more, more preferably 0.05% by mass or more and 10% by mass or less, further preferably 0.08% by mass or more and 5% by mass or less, more preferably in the imidafenacin-containing granule. Is 1% by mass or more and 3% by mass or less, and particularly preferably 1.5% by mass or more and 2.5% by mass or less.
本発明の顆粒又は、当該顆粒を含有する錠剤は、任意の薬学的に許容される添加剤を含むことができる。添加剤は有効成分（イミダフェナシン）以外の成分を表し、医薬品添加物事典［日本医薬品添加剤協会、薬事日報社（２０１６年）］に記載されているものを適宜使用できる。例えば、賦形剤、崩壊剤、結合剤、滑沢剤、コーティング剤、着色剤、光沢剤、甘味剤、矯味剤、香料などが挙げられる。 The granule of the present invention or the tablet containing the granule can contain any pharmaceutically acceptable additive. The additive represents an ingredient other than the active ingredient (imidafenacin), and those described in the Pharmaceutical Additives Dictionary [Japan Pharmaceutical Additives Association, Yakuji Nipposha (2016)] can be used as appropriate. For example, excipients, disintegrants, binders, lubricants, coating agents, colorants, brighteners, sweeteners, corrigents, fragrances and the like can be mentioned.
本発明において、薬学的に許容される賦形剤としては、乳糖及び白糖などの糖類、Ｄ−ソルビトール及びマンニトールなどの糖アルコール類、結晶セルロース、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、クロスカルメロースナトリウム、カルボキシメチルセルロースカルシウム、低置換度ヒドロキシプロピルセルロースなどのセルロース類、部分アルファー化デンプン及びトウモロコシデンプンなどのデンプン類などが挙げられる。本発明においては、結晶セルロース、デンプン類、又は糖アルコール類が好ましい。 In the present invention, pharmaceutically acceptable excipients include sugars such as lactose and sucrose, sugar alcohols such as D-sorbitol and mannitol, crystalline cellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose Examples thereof include celluloses such as sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, starches such as partially pregelatinized starch and corn starch. In the present invention, crystalline cellulose, starches, or sugar alcohols are preferred.
また、顆粒中に使用する賦形剤と、顆粒外に使用する賦形剤は、同一又は異なる賦形剤を使用してもよい。顆粒中に使用する賦形剤として、好ましくは、結晶セルロース又は部分アルファー化デンプン、さらに好ましくは部分アルファー化デンプンが挙げられる。顆粒外に使用する賦形剤として、好ましくは糖アルコール類、さらに好ましくはマンニトールが挙げられる。 Moreover, the excipient | filler used in a granule and the excipient | filler used outside a granule may use the same or different excipient | filler. The excipient used in the granule is preferably crystalline cellulose or partially pregelatinized starch, more preferably partially pregelatinized starch. The excipient used outside the granules is preferably sugar alcohols, more preferably mannitol.
本発明において、薬学的に許容される崩壊剤としては、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、低置換度ヒドロキシプロピルセルロース、クロスカルメロースナトリウム及びメチルセルロースなどのセルロース類、部分アルファー化デンプン及びトウモロコシデンプンなどのデンプン類、クロスポビドンなどが挙げられる。より好ましくはクロスポビドンが挙げられる。 In the present invention, pharmaceutically acceptable disintegrants include carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, cellulose such as croscarmellose sodium and methylcellulose, starch such as partially pregelatinized starch and corn starch. And crospovidone. More preferred is crospovidone.
本発明において、薬学的に許容される結合剤としては、結晶セルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシエチルメチルセルロース、エチルセルロースおよびメチルセルロースなどのセルロース類、ポビドン、ポリビニルアセタールジエチルアミノアセテート、ポリビニルアルコール完全けん化物、ポリビニルアルコール部分けん化物、カルボキシビニルポリマー、ポリ塩化ビニルなどのビニル系高分子物質、アミノアルキルメタクリレートコポリマー（Ｅ、ＲＳ）、メタクリル酸コポリマー（Ｌ、Ｓ、ＬＤ）、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などのアクリル系高分子物質、ステアリルアルコール、ゼラチン、デキストリン、アラビアゴム、プルラン、マクロゴール、デンプン、などが挙げられる。より好ましくはポリビニルピロリドンが挙げられる。 In the present invention, pharmaceutically acceptable binders include crystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, celluloses such as ethylcellulose and methylcellulose, povidone, polyvinyl acetal diethylaminoacetate, and a completely saponified polyvinyl alcohol. , Polyvinyl alcohol partial saponification products, carboxyvinyl polymers, vinyl polymer materials such as polyvinyl chloride, aminoalkyl methacrylate copolymers (E, RS), methacrylic acid copolymers (L, S, LD), ethyl acrylate / methyl methacrylate Acrylic polymer materials such as copolymer dispersions, stearyl alcohol, gelatin, dextrin, gum arabic, pullulan, macrogow , Starch, and the like. More preferably, polyvinylpyrrolidone is mentioned.
本発明において、薬学的に許容される滑沢剤としては、ステアリン酸及びその金属塩類、タルク、硬化油、軽質無水ケイ酸、含水二酸化ケイ素、ショ糖脂肪酸エステルなどが挙げられる。より好ましくは、含水二酸化ケイ素又はステアリン酸マグネシウム、さらに好ましくはステアリン酸マグネシウムが挙げられる。 In the present invention, pharmaceutically acceptable lubricants include stearic acid and its metal salts, talc, hydrogenated oil, light anhydrous silicic acid, hydrous silicon dioxide, sucrose fatty acid ester and the like. More preferably, hydrous silicon dioxide or magnesium stearate is used, and magnesium stearate is more preferable.
本発明においては、イミダフェナシン造粒物を被覆するためのコーティング剤とは別に、コーティング剤を使用できる。例えば、錠剤の周囲を被覆するためのコーティング剤が挙げられる。薬学的に許容されるコーティング剤としては、上述のセルロース系コーティング剤に加え、アミノアルキルメタクリレートコポリマー（Ｅ、ＲＳ）、メタクリル酸コポリマー（Ｌ、Ｓ、ＬＤ）、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などのアクリル系高分子物質、ポビドン、ステアリルアルコール、ポリビニルアセタールジエチルアミノアセテートなどの非セルロース系コーティング剤が挙げられる。 In the present invention, a coating agent can be used separately from the coating agent for coating the imidafenacin granulated product. For example, the coating agent for coat | covering the circumference | surroundings of a tablet is mentioned. As pharmaceutically acceptable coating agents, in addition to the above-mentioned cellulose-based coating agents, aminoalkyl methacrylate copolymers (E, RS), methacrylic acid copolymers (L, S, LD), ethyl acrylate / methyl methacrylate copolymer dispersion Non-cellulosic coating agents such as acrylic polymer substances such as liquid, povidone, stearyl alcohol, polyvinyl acetal diethylaminoacetate, and the like can be mentioned.
本発明において、薬学的に許容される着色剤としては、酸化チタン、三二酸化鉄、黄色三二酸化鉄などが挙げられる。 In the present invention, examples of the pharmaceutically acceptable colorant include titanium oxide, iron sesquioxide, and yellow iron sesquioxide.
本発明において、薬学的に許容される光沢剤としては、カルナウバロウなどが挙げられる。 In the present invention, examples of the pharmaceutically acceptable brightener include carnauba wax.
本発明において、薬学的に許容される甘味剤としては、糖類、糖アルコール類、アスパルテーム、サッカリン及びその塩類、グリチルリチン酸及びその塩類、ステビア、並びにアセスルファムカリウムなどが挙げられる。 In the present invention, pharmaceutically acceptable sweeteners include sugars, sugar alcohols, aspartame, saccharin and salts thereof, glycyrrhizic acid and salts thereof, stevia, and acesulfame potassium.
本発明において、薬学的に許容される嬌味剤としては、クエン酸、クエン酸ナトリウム、コハク酸、酒石酸、フマル酸などが挙げられる。 In the present invention, pharmaceutically acceptable flavoring agents include citric acid, sodium citrate, succinic acid, tartaric acid, fumaric acid and the like.
本発明において、薬学的に許容される香料としてメントール、オレンジ油などが挙げられる。 In the present invention, menthol, orange oil and the like are listed as pharmaceutically acceptable fragrances.
本発明の顆粒を含有する錠剤は、当該技術分野において慣用されている方法により製造することができる。例えば、上記の方法で製造した顆粒を任意の打錠機を用いて圧縮成型することで製造することができる。 The tablet containing the granule of the present invention can be produced by a method commonly used in the art. For example, the granules produced by the above method can be produced by compression molding using an arbitrary tableting machine.
本発明において、錠剤とは、日本薬局方１６製剤総則に記載の錠剤を意味する。すなわち、経口投与する一定の形状の固形の製剤を意味する。錠剤には、例えば、ＦＣ錠など、経口投与の際に市販時の形状を保つ錠剤（以下、通常錠とも記載する）に加え、ＯＤ錠、チュアブル錠、発泡錠、分散錠、溶解錠など、特殊な製剤が含有されるが、好ましくはＯＤ錠が挙げられる。 In the present invention, a tablet means a tablet described in the Japanese Pharmacopoeia 16 General Rules for Preparations. That is, it means a solid preparation of a certain shape for oral administration. Tablets include, for example, FC tablets and the like that maintain the shape at the time of oral administration (hereinafter also referred to as normal tablets), OD tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc. Although a special preparation is contained, OD tablets are preferable.
本発明の錠剤をフィルムコーティング錠とする場合は、例えば、国際公開ＷＯ２００１／０３４１４７に記載の方法により行うことができる。 When making the tablet of this invention into a film coating tablet, it can carry out by the method as described in international publication WO2001 / 034147, for example.
以下、実施例により本発明を説明するが、本発明はこれらの実施例によって限定されるものではない。
口腔内速崩壊錠の評価方法は以下の通りである。
［硬度試験］錠剤硬度計(岡田精工社製)を用いて測定した。試験は１０錠で行い、その平均値を示す。
［崩壊試験］崩壊試験機(富山産業社製)を用いて測定した。試験は６錠で行い、その平均値を示す。試験液は水を用い、錠剤が完全に崩壊し溶解するまでの時間を測定した。
なお、以下の実施例及び比較例に用いた商品名で示される化合物は、以下のとおりである（例えば、医薬品添加物事典２０１６（薬事日報社発行）などを参照）。
１．商品名スターチ1500G（日本カラコン）：部分α化デンプン
２．商品名コリドン90F（BASF）：ポビドン
３．商品名dl-α-トコフェロール（BASF）：トコフェロール
４．商品名オイドラギットE100（エボニック）：アミノアルキルメタクリレートコポリマーＥ
５．商品名ステアリン酸マグネシウム植物性（太平化学産業）:ステアリン酸マグネシウム
６．商品名TC-5E（信越化学工業）：ヒドロキシプロピルメチルセルロース
７．商品名エトセル4（ダウケミカル）：エチルセルロース
８．商品名HPC-SSL（日本曹達）：ヒドロキシプロピルセルロース
９．商品名HPMCP55（信越化学工業）：ヒドロキシプロピルメチルフタル酸エステル
１０．商品名ペアリトール（ロケットジャパン）：Ｄ−マンニトール
１１．商品名コリドンCL-F（BASF）：クロスポビドン
１２．商品名カープレックス#67（DSLジャパン）：含水二酸化ケイ素
EXAMPLES Hereinafter, although an Example demonstrates this invention, this invention is not limited by these Examples.
The evaluation method of the intraoral quick disintegrating tablet is as follows.
[Hardness test] The hardness was measured using a tablet hardness tester (Okada Seiko Co., Ltd.). The test is performed with 10 tablets, and the average value is shown.
[Disintegration test] Measured using a disintegration tester (manufactured by Toyama Sangyo Co., Ltd.). The test is performed with 6 tablets, and the average value is shown. The test solution was water, and the time until the tablet completely disintegrated and dissolved was measured.
In addition, the compound shown by the brand name used for the following Examples and Comparative Examples is as follows (for example, refer to Pharmaceutical Additives Dictionary 2016 (published by Yakuji Nippo)).
1. Product name Starch 1500G (Japan Colorcon): Partially pregelatinized starch Product name Kollidon 90F (BASF): Povidone 3. Product name dl-α-tocopherol (BASF): Tocopherol4. Product name Eudragit E100 (Evonik): Aminoalkyl methacrylate copolymer E
5. Product name Magnesium stearate vegetable (Taihei Chemical Industry): Magnesium stearate Product name TC-5E (Shin-Etsu Chemical Co., Ltd.): Hydroxypropyl methylcellulose Trade name Etcel 4 (Dow Chemical): Ethylcellulose Product name HPC-SSL (Nippon Soda): Hydroxypropylcellulose Product name HPMCP55 (Shin-Etsu Chemical Co., Ltd.): Hydroxypropyl methyl phthalate Product name Pairitol (Rocket Japan): D-mannitol11. Product name Kollidon CL-F (BASF): Crospovidone Product name Carplex # 67 (DSL Japan): Hydrous silicon dioxide
本発明の被覆顆粒（主薬顆粒）及び口腔内崩壊錠を表１に、比較例を表２に示す。 Table 1 shows the coated granules (main drug granules) and orally disintegrating tablets of the present invention, and Table 2 shows comparative examples.
（実施例１−１）
イミダフェナシン４ｇ、コリドン９０F（BASF）２ｇを精製水１５７．６ｇ、エタノール２３６．４ｇの混液に溶解した。スターチ１５００G（日本カラコン）７９４ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量２０g／min、噴霧空気圧０．１３MPa、給気温度７０℃）、イミダフェナシン造粒物を得た。別に、TC-5E（信越化学工業）４８ｇ、ステアリン酸マグネシウム植物性（太平化学産業）２４ｇを精製水７２．８ｇ、エタノール６５５．２ｇの混液に溶解した。イミダフェナシン造粒物２４０ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量１５ｇ／ｍｉｎ、噴霧空気圧０．１３MPa、給気温度６０℃）、コーティング顆粒を得た。
さらに、このコーティング顆粒７８．０ｇ、ペアリトール（ロケットジャパン）４３９．２ｇ、コリドンCL-F（BASF）１６．２ｇ及びカープレックス#67（DSLジャパン）１．２ｇを混合後、ステアリン酸マグネシウム植物性（太平化学産業）５．４ｇを加え混合後、ロータリー打錠機を用いて打錠圧８ｋNにて１錠あたりイミダフェナシン０．１ｍｇを含む１８０ｍｇの錠剤を製した。得られた錠剤は硬度５．３ｋｇ(n=１０) 、崩壊時間１２秒(n=６)を示した。
（実施例１−２）
イミダフェナシン４ｇ、オイドラギットE100（エボニック）２０ｇ及びステアリン酸マグネシウム植物性（太平化学産業）１０ｇを精製水１４６．４ｇ、エタノール２１９．６ｇの混液に分散した。スターチ１５００G（日本カラコン）７６６ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量２０g／min、噴霧空気圧０．１３MPa、給気温度７０℃）、イミダフェナシン造粒物を得た。別に、TC-5E（信越化学工業）４８ｇ、ステアリン酸マグネシウム植物性（太平化学産業）２４ｇを精製水７２．８ｇ、エタノール６５５．２ｇの混液に溶解した。イミダフェナシン造粒物２４０ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量１５ｇ／ｍｉｎ、噴霧空気圧０．１５MPa、給気温度６０℃）、コーティング顆粒を得た。
さらに、このコーティング顆粒７８．０ｇ、ペアリトール（ロケットジャパン）４３９．２ｇ、コリドンCL-F（BASF）１６．２ｇ及びカープレックス#67（DSLジャパン）１．２ｇを混合後、ステアリン酸マグネシウム植物性（太平化学産業）５．４ｇを加え混合後、ロータリー打錠機を用いて打錠圧８ｋNにて１錠あたりイミダフェナシン０．１ｍｇを含む１８０ｍｇの錠剤を製した。得られた錠剤は硬度５．１ｋｇ(n=１０) 、崩壊時間１３秒(n=６)を示した。
（実施例１−３）
イミダフェナシン４ｇ、コリドン９０F（BASF）２ｇ及びdl-α-トコフェロール（BASF）２０ｇを精製水３７．４ｇ、エタノール３３６．６ｇの混液に分散した。スターチ１５００G（日本カラコン）７７４ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量２０g／min、噴霧空気圧０．１３MPa、給気温度６０℃）、イミダフェナシン造粒物を得た。別に、TC-5E（信越化学工業）４８ｇ、ステアリン酸マグネシウム植物性（太平化学産業）２４ｇを精製水７２．８ｇ、エタノール６５５．２ｇの混液に溶解した。イミダフェナシン造粒物２４０ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量１５ｇ／ｍｉｎ、噴霧空気圧０．１５MPa、給気温度６０℃）、コーティング顆粒を得た。
さらに、このコーティング顆粒７８．０ｇ、ペアリトール（ロケットジャパン）４３９．２ｇ、コリドンCL-F（BASF）１６．２ｇ及びカープレックス#67（DSLジャパン）１．２ｇを混合後、ステアリン酸マグネシウム植物性（太平化学産業）５．４ｇを加え混合後、ロータリー打錠機を用いて打錠圧８ｋNにて１錠あたりイミダフェナシン０．１ｍｇを含む１８０ｍｇの錠剤を製した。得られた錠剤は硬度４．８ｋｇ(n=１０) 、崩壊時間１３秒(n=６)を示した。
（実施例２−１）
イミダフェナシン４ｇ、コリドン９０F（BASF）２ｇを精製水１５７．６ｇ、エタノール２３６．４ｇの混液に溶解した。スターチ１５００G（日本カラコン）７９４ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量２０g／min、噴霧空気圧０．１３MPa、給気温度７０℃）、イミダフェナシン造粒物を得た。別に、エトセル4（ダウケミカル）４８ｇ、ステアリン酸マグネシウム植物性（太平化学産業）２４ｇを精製水７２．８ｇ、エタノール６５５．２ｇの混液に溶解した。イミダフェナシン造粒物２４０ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量１５ｇ／ｍｉｎ、噴霧空気圧０．１３MPa、給気温度６０℃）、コーティング顆粒を得た。
さらに、このコーティング顆粒７８．０ｇ、ペアリトール（ロケットジャパン）４３９．２ｇ、コリドンCL-F（BASF）１６．２ｇ及びカープレックス#67（DSLジャパン）１．２ｇを混合後、ステアリン酸マグネシウム植物性（太平化学産業）５．４ｇを加え混合後、ロータリー打錠機を用いて打錠圧８ｋNにて１錠あたりイミダフェナシン０．１ｍｇを含む１８０ｍｇの錠剤を製した。得られた錠剤は硬度５．７ｋｇ(n=１０) 、崩壊時間１０秒(n=６)を示した。
（実施例２−２）
イミダフェナシン４ｇ、オイドラギットE100（エボニック）２０ｇ及びステアリン酸マグネシウム植物性（太平化学産業）１０ｇを精製水１４６．４ｇ、エタノール２１９．６ｇの混液に分散した。スターチ１５００G（日本カラコン）７６６ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量２０g／min、噴霧空気圧０．１３MPa、給気温度７０℃）、イミダフェナシン造粒物を得た。別に、エトセル4（ダウケミカル）４８ｇ、ステアリン酸マグネシウム植物性（太平化学産業）２４ｇを精製水７２．８ｇ、エタノール６５５．２ｇの混液に溶解した。イミダフェナシン造粒物２４０ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量１５ｇ／ｍｉｎ、噴霧空気圧０．１３MPa、給気温度６０℃）、コーティング顆粒を得た。
さらに、このコーティング顆粒７８．０ｇ、ペアリトール（ロケットジャパン）４３９．２ｇ、コリドンCL-F（BASF）１６．２ｇ及びカープレックス#67（DSLジャパン）１．２ｇを混合後、ステアリン酸マグネシウム植物性（太平化学産業）５．４ｇを加え混合後、ロータリー打錠機を用いて打錠圧８ｋNにて１錠あたりイミダフェナシン０．１ｍｇを含む１８０ｍｇの錠剤を製した。得られた錠剤は硬度５．３ｋｇ(n=１０) 、崩壊時間１１秒(n=６)を示した。
（実施例２−３）
イミダフェナシン４ｇ、コリドン９０F（BASF）２ｇ及びdl-α-トコフェロール（BASF）２０ｇを精製水３７．４ｇ、エタノール３３６．６ｇの混液に分散した。スターチ１５００G（日本カラコン）７７４ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量２０g／min、噴霧空気圧０．１３MPa、給気温度６０℃）、イミダフェナシン造粒物を得た。別に、エトセル4（ダウケミカル）４８ｇ、ステアリン酸マグネシウム植物性（太平化学産業）２４ｇを精製水７２．８ｇ、エタノール６５５．２ｇの混液に溶解した。イミダフェナシン造粒物２４０ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量１５ｇ／ｍｉｎ、噴霧空気圧０．１３MPa、給気温度６０℃）、コーティング顆粒を得た。
さらに、このコーティング顆粒７８．０ｇ、ペアリトール（ロケットジャパン）４３９．２ｇ、コリドンCL-F（BASF）１６．２ｇ及びカープレックス#67（DSLジャパン）１．２ｇを混合後、ステアリン酸マグネシウム植物性（太平化学産業）５．４ｇを加え混合後、ロータリー打錠機を用いて打錠圧８ｋNにて１錠あたりイミダフェナシン０．１ｍｇを含む１８０ｍｇの錠剤を製した。得られた錠剤は硬度５．２ｋｇ(n=１０) 、崩壊時間１１秒(n=６)を示した。
（実施例３−１）
イミダフェナシン４ｇ、コリドン９０F（BASF）２ｇを精製水１５７．６ｇ、エタノール２３６．４ｇの混液に溶解した。スターチ１５００G（日本カラコン）７９４ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量２０g／min、噴霧空気圧０．１３MPa、給気温度７０℃）、イミダフェナシン造粒物を得た。別に、HPC-SSL（日本曹達）４８ｇ、ステアリン酸マグネシウム植物性（太平化学産業）２４ｇを精製水７２．８ｇ、エタノール６５５．２ｇの混液に溶解した。イミダフェナシン造粒物２４０ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量１５ｇ／ｍｉｎ、噴霧空気圧０．１３MPa、給気温度６０℃）、コーティング顆粒を得た。
さらに、このコーティング顆粒７８．０ｇ、ペアリトール（ロケットジャパン）４３９．２ｇ、コリドンCL-F（BASF）１６．２ｇ及びカープレックス#67（DSLジャパン）１．２ｇを混合後、ステアリン酸マグネシウム植物性（太平化学産業）５．４ｇを加え混合後、ロータリー打錠機を用いて打錠圧８ｋNにて１錠あたりイミダフェナシン０．１ｍｇを含む１８０ｍｇの錠剤を製した。得られた錠剤は硬度５．８ｋｇ(n=１０) 、崩壊時間１２秒(n=６)を示した。
（実施例３−２）
イミダフェナシン４ｇ、オイドラギットE100（エボニック）２０ｇ及びステアリン酸マグネシウム植物性（太平化学産業）１０ｇを精製水１４６．４ｇ、エタノール２１９．６ｇの混液に分散した。スターチ１５００G（日本カラコン）７６６ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量２０g／min、噴霧空気圧０．１３MPa、給気温度７０℃）、イミダフェナシン造粒物を得た。別に、HPC-SSL（日本曹達）４８ｇ、ステアリン酸マグネシウム植物性（太平化学産業）２４ｇを精製水７２．８ｇ、エタノール６５５．２ｇの混液に溶解した。イミダフェナシン造粒物２４０ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量１５ｇ／ｍｉｎ、噴霧空気圧０．１５MPa、給気温度６０℃）、コーティング顆粒を得た。
さらに、このコーティング顆粒７８．０ｇ、ペアリトール（ロケットジャパン）４３９．２ｇ、コリドンCL-F（BASF）１６．２ｇ及びカープレックス#67（DSLジャパン）１．２ｇを混合後、ステアリン酸マグネシウム植物性（太平化学産業）５．４ｇを加え混合後、ロータリー打錠機を用いて打錠圧８ｋNにて１錠あたりイミダフェナシン０．１ｍｇを含む１８０ｍｇの錠剤を製した。得られた錠剤は硬度５．９ｋｇ(n=１０) 、崩壊時間１２秒(n=６)を示した。
（実施例３−３）
イミダフェナシン４ｇ、コリドン９０F（BASF）２ｇ及びdl-α-トコフェロール（BASF）２０ｇを精製水３７．４ｇ、エタノール３３６．６ｇの混液に分散した。スターチ１５００G（日本カラコン）７７４ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量２０g／min、噴霧空気圧０．１３MPa、給気温度６０℃）、イミダフェナシン造粒物を得た。別に、HPC-SSL（日本曹達）４８ｇ、ステアリン酸マグネシウム植物性（太平化学産業）２４ｇを精製水７２．８ｇ、エタノール６５５．２ｇの混液に溶解した。イミダフェナシン造粒物２４０ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量１５ｇ／ｍｉｎ、噴霧空気圧０．１５MPa、給気温度６０℃）、コーティング顆粒を得た。
さらに、このコーティング顆粒７８．０ｇ、ペアリトール（ロケットジャパン）４３９．２ｇ、コリドンCL-F（BASF）１６．２ｇ及びカープレックス#67（DSLジャパン）１．２ｇを混合後、ステアリン酸マグネシウム植物性（太平化学産業）５．４ｇを加え混合後、ロータリー打錠機を用いて打錠圧８ｋNにて１錠あたりイミダフェナシン０．１ｍｇを含む１８０ｍｇの錠剤を製した。得られた錠剤は硬度５．７ｋｇ(n=１０) 、崩壊時間１５秒(n=６)を示した。
（比較例４−１）
イミダフェナシン４ｇ、コリドン９０F（BASF）２ｇを精製水１５７．６ｇ、エタノール２３６．４ｇの混液に溶解した。スターチ１５００G（日本カラコン）７９４ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量２０g／min、噴霧空気圧０．１３MPa、給気温度７０℃）、イミダフェナシン造粒物を得た。別に、HPMCP55（信越化学工業）６０ｇを精製水９１ｇ、エタノール８１９ｇの混液に溶解した。イミダフェナシン造粒物３００ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量１５ｇ／ｍｉｎ、噴霧空気圧０．１５MPa、給気温度６０℃）、コーティング顆粒を得た。
さらに、このコーティング顆粒７２．０ｇ、ペアリトール（ロケットジャパン）４３９．２ｇ、コリドンCL-F（BASF）１６．２ｇ及びカープレックス#67（DSLジャパン）１．２ｇを混合後、ステアリン酸マグネシウム植物性（太平化学産業）１１．４ｇを加え混合後、ロータリー打錠機を用いて打錠圧８ｋNにて１錠あたりイミダフェナシン０．１ｍｇを含む１８０ｍｇの錠剤を製した。得られた錠剤は硬度３．９ｋｇ(n=１０) 、崩壊時間３０秒(n=６)を示した。
（比較例４−２）
イミダフェナシン４ｇ、オイドラギットE100（エボニック）２０ｇ及びステアリン酸マグネシウム植物性（太平化学産業）１０ｇを精製水１４６．４ｇ、エタノール２１９．６ｇの混液に分散した。スターチ１５００G（日本カラコン）７６６ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量２０g／min、噴霧空気圧０．１３MPa、給気温度７０℃）、イミダフェナシン造粒物を得た。別に、HPMCP55（信越化学工業）４８ｇを精製水７２．８ｇ、エタノール６５５．２ｇの混液に溶解した。イミダフェナシン造粒物２４０ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量１５ｇ／ｍｉｎ、噴霧空気圧０．１７MPa、給気温度６０℃）、コーティング顆粒を得た。
さらに、このコーティング顆粒７２．０ｇ、ペアリトール（ロケットジャパン）４３９．２ｇ、コリドンCL-F（BASF）１６．２ｇ及びカープレックス#67（DSLジャパン）１．２ｇを混合後、ステアリン酸マグネシウム植物性（太平化学産業）１１．４ｇを加え混合後、ロータリー打錠機を用いて打錠圧８ｋNにて１錠あたりイミダフェナシン０．１ｍｇを含む１８０ｍｇの錠剤を製した。得られた錠剤は硬度４．２ｋｇ(n=１０) 、崩壊時間３２秒(n=６)を示した。
（比較例４−３）
イミダフェナシン４ｇ、コリドン９０F（BASF）２ｇ及びdl-α-トコフェロール（BASF）２０ｇを精製水３７．４ｇ、エタノール３３６．６ｇの混液に分散した。スターチ１５００G（日本カラコン）７７４ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量２０g／min、噴霧空気圧０．１３MPa、給気温度６０℃）、イミダフェナシン造粒物を得た。別に、HPMCP55（信越化学工業）４８ｇを精製水７２．８ｇ、エタノール６５５．２ｇの混液に溶解した。イミダフェナシン造粒物２４０ｇを転動流動層造粒機(ダルトン製、NQ−１６０)に仕込み、トップスプレー法にてこの溶液をコーティングし（噴霧液量１５ｇ／ｍｉｎ、噴霧空気圧０．１７MPa、給気温度６０℃）、コーティング顆粒を得た。
さらに、このコーティング顆粒７２．０ｇ、ペアリトール（ロケットジャパン）４３９．２ｇ、コリドンCL-F（BASF）１６．２ｇ及びカープレックス#67（DSLジャパン）１．２ｇを混合後、ステアリン酸マグネシウム植物性（太平化学産業）１１．４ｇを加え混合後、ロータリー打錠機を用いて打錠圧８ｋNにて１錠あたりイミダフェナシン０．１ｍｇを含む１８０ｍｇの錠剤を製した。得られた錠剤は硬度４．２ｋｇ(n=１０) 、崩壊時間２５秒(n=６)を示した。
（試験例１）
実施例１−１〜３−３及び比較例４−１〜４−３のコーティング顆粒及び錠剤について光安定性試験を実施した。Ｄ６５ランプ４０００ルクス×約１４日間における分解物の生成量の結果を表３及び４に示す。なお、分解物の定量は液体クロマトグラフ法（ＨＰＬＣ法）により評価した。
HPLC法
カラム：オクタデシルシリル化シリカゲル（平均粒径5 μm，内径4.6 mm×長さ150mm） (ジーエルサイエンス株式会社 商品名Inertsil ODS-3)
A液：1-オクタンスルホン酸ナトリウム1.08 gを薄めたリン酸(1→1000) 1000 mLに溶かす。
B液：液体クロマトグラフィー用アセトニトリル
送液：A液及びB液の混合比を変えて濃度勾配制御する。
検出器：UV
測定波長：220 nm
(Example 1-1)
4 g of imidafenacin and 2 g of Kollidon 90F (BASF) were dissolved in a mixed solution of purified water 157.6 g and ethanol 236.4 g. 794 g of starch 1500G (Nihon Colorcon) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 20 g / min, spraying air pressure 0.13 MPa, Supply air temperature 70 degreeC) and the imidafenacin granulated material were obtained. Separately, 48 g of TC-5E (Shin-Etsu Chemical Co., Ltd.) and 24 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixed solution of 72.8 g of purified water and 655.2 g of ethanol. 240 g of imidafenacin granulation product was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 15 g / min, spraying air pressure 0.13 MPa, air supply At a temperature of 60 ° C.) to obtain coated granules.
Further, after mixing 78.0 g of this coated granule, 439.2 g of Pealitol (Rocket Japan), 16.2 g of Kollidon CL-F (BASF) and 1.2 g of Carplex # 67 (DSL Japan), the magnesium stearate plant ( Taihei Chemical Industry) 5.4 g was added and mixed, and 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 8 kN using a rotary tableting machine. The tablets obtained had a hardness of 5.3 kg (n = 10) and a disintegration time of 12 seconds (n = 6).
(Example 1-2)
4 g of imidafenacin, 20 g of Eudragit E100 (Evonik) and 10 g of magnesium stearate plant (Taihei Chemical Industry) were dispersed in a mixed solution of purified water 146.4 g and ethanol 219.6 g. 766 g of starch 1500G (Nihon Colorcon) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 20 g / min, spraying air pressure 0.13 MPa, Supply air temperature 70 degreeC) and the imidafenacin granulated material were obtained. Separately, 48 g of TC-5E (Shin-Etsu Chemical Co., Ltd.) and 24 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixed solution of 72.8 g of purified water and 655.2 g of ethanol. 240 g of imidafenacin granulation product was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 15 g / min, spraying air pressure 0.15 MPa, air supply At a temperature of 60 ° C.) to obtain coated granules.
Further, after mixing 78.0 g of this coated granule, 439.2 g of Pealitol (Rocket Japan), 16.2 g of Kollidon CL-F (BASF) and 1.2 g of Carplex # 67 (DSL Japan), the magnesium stearate plant ( Taihei Chemical Industry) 5.4 g was added and mixed, and 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 8 kN using a rotary tableting machine. The tablets obtained had a hardness of 5.1 kg (n = 10) and a disintegration time of 13 seconds (n = 6).
(Example 1-3)
4 g of imidafenacin, 2 g of Kollidon 90F (BASF) and 20 g of dl-α-tocopherol (BASF) were dispersed in a mixed solution of 37.4 g of purified water and 336.6 g of ethanol. 774 g of starch 1500G (Nihon Colorcon) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 20 g / min, spraying air pressure 0.13 MPa, A supply temperature of 60 ° C.) and an imidafenacin granulated product were obtained. Separately, 48 g of TC-5E (Shin-Etsu Chemical Co., Ltd.) and 24 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixed solution of 72.8 g of purified water and 655.2 g of ethanol. 240 g of imidafenacin granulation product was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 15 g / min, spraying air pressure 0.15 MPa, air supply At a temperature of 60 ° C.) to obtain coated granules.
Further, after mixing 78.0 g of this coated granule, 439.2 g of Pealitol (Rocket Japan), 16.2 g of Kollidon CL-F (BASF) and 1.2 g of Carplex # 67 (DSL Japan), the magnesium stearate plant ( Taihei Chemical Industry) 5.4 g was added and mixed, and 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 8 kN using a rotary tableting machine. The tablets obtained had a hardness of 4.8 kg (n = 10) and a disintegration time of 13 seconds (n = 6).
(Example 2-1)
4 g of imidafenacin and 2 g of Kollidon 90F (BASF) were dissolved in a mixed solution of purified water 157.6 g and ethanol 236.4 g. 794 g of starch 1500G (Nihon Colorcon) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 20 g / min, spraying air pressure 0.13 MPa, Supply air temperature 70 degreeC) and the imidafenacin granulated material were obtained. Separately, 48 g of etosel 4 (Dow Chemical) and 24 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixed solution of 72.8 g of purified water and 655.2 g of ethanol. 240 g of imidafenacin granulation product was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 15 g / min, spraying air pressure 0.13 MPa, air supply At a temperature of 60 ° C.) to obtain coated granules.
Further, after mixing 78.0 g of this coated granule, 439.2 g of Pealitol (Rocket Japan), 16.2 g of Kollidon CL-F (BASF) and 1.2 g of Carplex # 67 (DSL Japan), the magnesium stearate plant ( Taihei Chemical Industry) 5.4 g was added and mixed, and 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 8 kN using a rotary tableting machine. The obtained tablet had a hardness of 5.7 kg (n = 10) and a disintegration time of 10 seconds (n = 6).
(Example 2-2)
4 g of imidafenacin, 20 g of Eudragit E100 (Evonik) and 10 g of magnesium stearate plant (Taihei Chemical Industry) were dispersed in a mixed solution of purified water 146.4 g and ethanol 219.6 g. 766 g of starch 1500G (Nihon Colorcon) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 20 g / min, spraying air pressure 0.13 MPa, Supply air temperature 70 degreeC) and the imidafenacin granulated material were obtained. Separately, 48 g of etosel 4 (Dow Chemical) and 24 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixed solution of 72.8 g of purified water and 655.2 g of ethanol. 240 g of imidafenacin granulation product was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 15 g / min, spraying air pressure 0.13 MPa, air supply At a temperature of 60 ° C.) to obtain coated granules.
Further, after mixing 78.0 g of this coated granule, 439.2 g of Pealitol (Rocket Japan), 16.2 g of Kollidon CL-F (BASF) and 1.2 g of Carplex # 67 (DSL Japan), the magnesium stearate plant ( Taihei Chemical Industry) 5.4 g was added and mixed, and 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 8 kN using a rotary tableting machine. The obtained tablet had a hardness of 5.3 kg (n = 10) and a disintegration time of 11 seconds (n = 6).
(Example 2-3)
4 g of imidafenacin, 2 g of Kollidon 90F (BASF) and 20 g of dl-α-tocopherol (BASF) were dispersed in a mixed solution of 37.4 g of purified water and 336.6 g of ethanol. 774 g of starch 1500G (Nihon Colorcon) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 20 g / min, spraying air pressure 0.13 MPa, A supply temperature of 60 ° C.) and an imidafenacin granulated product were obtained. Separately, 48 g of etosel 4 (Dow Chemical) and 24 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixed solution of 72.8 g of purified water and 655.2 g of ethanol. 240 g of imidafenacin granulation product was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 15 g / min, spraying air pressure 0.13 MPa, air supply At a temperature of 60 ° C.) to obtain coated granules.
Further, after mixing 78.0 g of this coated granule, 439.2 g of Pealitol (Rocket Japan), 16.2 g of Kollidon CL-F (BASF) and 1.2 g of Carplex # 67 (DSL Japan), the magnesium stearate plant ( Taihei Chemical Industry) 5.4 g was added and mixed, and 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 8 kN using a rotary tableting machine. The obtained tablet had a hardness of 5.2 kg (n = 10) and a disintegration time of 11 seconds (n = 6).
(Example 3-1)
4 g of imidafenacin and 2 g of Kollidon 90F (BASF) were dissolved in a mixed solution of purified water 157.6 g and ethanol 236.4 g. 794 g of starch 1500G (Nihon Colorcon) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 20 g / min, spraying air pressure 0.13 MPa, Supply air temperature 70 degreeC) and the imidafenacin granulated material were obtained. Separately, 48 g of HPC-SSL (Nippon Soda) and 24 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixed solution of 72.8 g of purified water and 655.2 g of ethanol. 240 g of imidafenacin granulation product was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 15 g / min, spraying air pressure 0.13 MPa, air supply At a temperature of 60 ° C.) to obtain coated granules.
Further, after mixing 78.0 g of this coated granule, 439.2 g of Pealitol (Rocket Japan), 16.2 g of Kollidon CL-F (BASF) and 1.2 g of Carplex # 67 (DSL Japan), the magnesium stearate plant ( Taihei Chemical Industry) 5.4 g was added and mixed, and 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 8 kN using a rotary tableting machine. The tablets obtained had a hardness of 5.8 kg (n = 10) and a disintegration time of 12 seconds (n = 6).
(Example 3-2)
4 g of imidafenacin, 20 g of Eudragit E100 (Evonik) and 10 g of magnesium stearate plant (Taihei Chemical Industry) were dispersed in a mixed solution of purified water 146.4 g and ethanol 219.6 g. 766 g of starch 1500G (Nihon Colorcon) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 20 g / min, spraying air pressure 0.13 MPa, Supply air temperature 70 degreeC) and the imidafenacin granulated material were obtained. Separately, 48 g of HPC-SSL (Nippon Soda) and 24 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixed solution of 72.8 g of purified water and 655.2 g of ethanol. 240 g of imidafenacin granulation product was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 15 g / min, spraying air pressure 0.15 MPa, air supply At a temperature of 60 ° C.) to obtain coated granules.
Further, after mixing 78.0 g of this coated granule, 439.2 g of Pealitol (Rocket Japan), 16.2 g of Kollidon CL-F (BASF) and 1.2 g of Carplex # 67 (DSL Japan), the magnesium stearate plant ( Taihei Chemical Industry) 5.4 g was added and mixed, and 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 8 kN using a rotary tableting machine. The tablets obtained had a hardness of 5.9 kg (n = 10) and a disintegration time of 12 seconds (n = 6).
(Example 3-3)
4 g of imidafenacin, 2 g of Kollidon 90F (BASF) and 20 g of dl-α-tocopherol (BASF) were dispersed in a mixed solution of 37.4 g of purified water and 336.6 g of ethanol. 774 g of starch 1500G (Nihon Colorcon) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 20 g / min, spraying air pressure 0.13 MPa, A supply temperature of 60 ° C.) and an imidafenacin granulated product were obtained. Separately, 48 g of HPC-SSL (Nippon Soda) and 24 g of magnesium stearate plant (Taihei Chemical Industry) were dissolved in a mixed solution of 72.8 g of purified water and 655.2 g of ethanol. 240 g of imidafenacin granulation product was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 15 g / min, spraying air pressure 0.15 MPa, air supply At a temperature of 60 ° C.) to obtain coated granules.
Further, after mixing 78.0 g of this coated granule, 439.2 g of Pealitol (Rocket Japan), 16.2 g of Kollidon CL-F (BASF) and 1.2 g of Carplex # 67 (DSL Japan), the magnesium stearate plant ( Taihei Chemical Industry) 5.4 g was added and mixed, and 180 mg tablets containing 0.1 mg imidafenacin per tablet were produced at a tableting pressure of 8 kN using a rotary tableting machine. The tablets obtained had a hardness of 5.7 kg (n = 10) and a disintegration time of 15 seconds (n = 6).
(Comparative Example 4-1)
4 g of imidafenacin and 2 g of Kollidon 90F (BASF) were dissolved in a mixed solution of purified water 157.6 g and ethanol 236.4 g. 794 g of starch 1500G (Nihon Colorcon) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 20 g / min, spraying air pressure 0.13 MPa, Supply air temperature 70 degreeC) and the imidafenacin granulated material were obtained. Separately, 60 g of HPMCP55 (Shin-Etsu Chemical Co., Ltd.) was dissolved in a mixed solution of 91 g of purified water and 819 g of ethanol. 300 g of imidafenacin granulated material was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 15 g / min, spraying air pressure 0.15 MPa, air supply At a temperature of 60 ° C.) to obtain coated granules.
Further, after mixing 72.0 g of this coated granule, 439.2 g of Peeritol (Rocket Japan), 16.2 g of Kollidon CL-F (BASF) and 1.2 g of Carplex # 67 (DSL Japan), magnesium stearate plant ( Taihei Chemical Industry) After adding 11.4 g and mixing, 180 mg tablets containing 0.1 mg imidafenacin per tablet at a tableting pressure of 8 kN were produced using a rotary tableting machine. The obtained tablet had a hardness of 3.9 kg (n = 10) and a disintegration time of 30 seconds (n = 6).
(Comparative Example 4-2)
4 g of imidafenacin, 20 g of Eudragit E100 (Evonik) and 10 g of magnesium stearate plant (Taihei Chemical Industry) were dispersed in a mixed solution of purified water 146.4 g and ethanol 219.6 g. 766 g of starch 1500G (Nihon Colorcon) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 20 g / min, spraying air pressure 0.13 MPa, Supply air temperature 70 degreeC) and the imidafenacin granulated material were obtained. Separately, 48 g of HPMCP55 (Shin-Etsu Chemical Co., Ltd.) was dissolved in a mixed solution of 72.8 g of purified water and 655.2 g of ethanol. 240 g of imidafenacin granulation product was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 15 g / min, spraying air pressure 0.17 MPa, supply air At a temperature of 60 ° C.) to obtain coated granules.
Further, after mixing 72.0 g of this coated granule, 439.2 g of Peeritol (Rocket Japan), 16.2 g of Kollidon CL-F (BASF) and 1.2 g of Carplex # 67 (DSL Japan), magnesium stearate plant ( Taihei Chemical Industry) After adding 11.4 g and mixing, 180 mg tablets containing 0.1 mg imidafenacin per tablet at a tableting pressure of 8 kN were produced using a rotary tableting machine. The obtained tablet had a hardness of 4.2 kg (n = 10) and a disintegration time of 32 seconds (n = 6).
(Comparative Example 4-3)
4 g of imidafenacin, 2 g of Kollidon 90F (BASF) and 20 g of dl-α-tocopherol (BASF) were dispersed in a mixed solution of 37.4 g of purified water and 336.6 g of ethanol. 774 g of starch 1500G (Nihon Colorcon) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 20 g / min, spraying air pressure 0.13 MPa, A supply temperature of 60 ° C.) and an imidafenacin granulated product were obtained. Separately, 48 g of HPMCP55 (Shin-Etsu Chemical Co., Ltd.) was dissolved in a mixed solution of 72.8 g of purified water and 655.2 g of ethanol. 240 g of imidafenacin granulation product was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and this solution was coated by the top spray method (spraying liquid amount 15 g / min, spraying air pressure 0.17 MPa, supply air At a temperature of 60 ° C.) to obtain coated granules.
Further, after mixing 72.0 g of this coated granule, 439.2 g of Peeritol (Rocket Japan), 16.2 g of Kollidon CL-F (BASF) and 1.2 g of Carplex # 67 (DSL Japan), magnesium stearate plant ( Taihei Chemical Industry) After adding 11.4 g and mixing, 180 mg tablets containing 0.1 mg imidafenacin per tablet at a tableting pressure of 8 kN were produced using a rotary tableting machine. The obtained tablet had a hardness of 4.2 kg (n = 10) and a disintegration time of 25 seconds (n = 6).
(Test Example 1)
The photostability test was carried out on the coated granules and tablets of Examples 1-1 to 3-3 and Comparative Examples 4-1 to 4-3. Tables 3 and 4 show the results of the amount of decomposed product produced by D65 lamp 4000 lux × about 14 days. In addition, the quantification of the decomposition product was evaluated by a liquid chromatographic method (HPLC method).
HPLC method column: Octadecylsilylated silica gel (average particle size 5 μm, inner diameter 4.6 mm × length 150 mm) (GL Sciences Inc. trade name Inertsil ODS-3)
Solution A: Dissolve 1.08 g of sodium 1-octanesulfonate in 1000 mL of diluted phosphoric acid (1 → 1000).
Liquid B: Acetonitrile for liquid chromatography Liquid transfer: The concentration gradient is controlled by changing the mixing ratio of liquid A and liquid B.
Detector: UV
Measurement wavelength: 220 nm
表３は、コーティング顆粒について、光線照射前と光線照射後の分解物の生成量（個々の最大量、合計分解物量）の値が記載されている。
光線照射前の値を見れば分かる通り、腸溶性のセルロース系コーティング剤で被覆している顆粒（比較例４−１〜４−３）は、製造工程中の分解物の生成量が大きく、個々の最大量は６％を越える。一方、水溶性又は徐放性のセルロース系コーティング剤で被覆している顆粒（実施例１−１〜３−３）は、製造工程中の分解物の生成量が小さく、個々の最大量は０．２％未満である。腸溶性のセルロース系コーティング剤と比較し、水溶性又は徐放性のセルロース系コーティング剤を用いることで、製造工程中に生じる分解物の少ないイミダフェナシン含有顆粒を提供することができる。
Table 3 describes the values of the amount of decomposition products (the maximum amount of each and the total amount of decomposition products) of the coated granules before and after the light irradiation.
As can be seen from the values before the light irradiation, the granules (Comparative Examples 4-1 to 4-3) coated with the enteric cellulose-based coating agent have a large amount of decomposition products during the production process. The maximum amount exceeds 6%. On the other hand, the granules (Examples 1-1 to 3-3) coated with a water-soluble or sustained-release cellulosic coating agent have a small amount of decomposition products produced during the production process, and the maximum amount of each is 0. Less than 2%. Compared with an enteric cellulose-based coating agent, by using a water-soluble or sustained-release cellulose-based coating agent, it is possible to provide imidafenacin-containing granules with less degradation products generated during the production process.
また、光線照射後の値を見れば分かる通り、セルロース系コーティング剤で被覆したコーティング顆粒は、光分解物の生成量が多い傾向にあり、分解物の合計生成量は１４％以上にもなる（実施例１−１、２−１、３−１）。そして、セルロース系コーティング剤で被覆した顆粒については、従来イミダフェナシンの光分解に対し安定化効果があると知られていたアミノアルキルメタクリレートコポリマーＥを添加しても、その光安定化効果は弱い（実施例１−２、２−２、３−２）。一方で、トコフェロールを配合すると、高い光安定化効果を発揮し、光分解物の生成量を約１／４〜１／２にまで抑制することができる（実施例１−３、２−３、３−３）。イミダフェナシンを含有する造粒物を、水溶性又は徐放性のセルロース系コーティング剤で被覆する場合、その造粒物にはトコフェロールを含有することが好ましい。 In addition, as can be seen from the value after the light irradiation, the coated granules coated with the cellulose-based coating agent tend to generate a large amount of photodegradation product, and the total production amount of the decomposition product is 14% or more ( Examples 1-1, 2-1, 3-1). For granules coated with a cellulose-based coating agent, even if aminoalkyl methacrylate copolymer E, which has been conventionally known to have a stabilizing effect on the photodegradation of imidafenacin, is added, its light stabilizing effect is weak (implementation) Examples 1-2, 2-2, 3-2). On the other hand, when tocopherol is blended, a high light stabilization effect can be exhibited, and the amount of photodegradation products generated can be suppressed to about 1/4 to 1/2 (Examples 1-3, 2-3, 3-3). When the granulated product containing imidafenacin is coated with a water-soluble or sustained-release cellulose coating agent, the granulated product preferably contains tocopherol.
また、特に、ヒドロキシプロピルメチルセルロースで被覆された顆粒は、ヒドロキシプロピルメチルセルロース以外で被覆された顆粒と比べて、工程中の分解物及び光分解物の生成量が少なく好ましい（実施例１−１〜１−３）。 In particular, the granules coated with hydroxypropylmethylcellulose are preferable in comparison with the granules coated with other than hydroxypropylmethylcellulose because the amount of degradation products and photolysis products generated in the process is small (Examples 1-1 to 1-1). -3).
表４は、コーティング顆粒含有錠剤について、光線照射前と光線照射後の分解物の生成量（個々の最大量、合計分解物量）の値が記載されている。トコフェロールによる光安定化効果、ヒドロキシプロピルメチルセルロースについての光安定化効果については、表２に記載のコーティング顆粒と同様の効果が認められる。また、セルロース系コーティング剤で被覆されたコーティング顆粒の場合、錠剤化した方が光に対し安定であることが分かる（表３と表４の比較）。 Table 4 describes the values of the amount of decomposition products (the maximum amount of each and the total amount of decomposition products) of the coated granule-containing tablets before and after the light irradiation. Regarding the light stabilization effect by tocopherol and the light stabilization effect by hydroxypropylmethylcellulose, the same effects as those of the coated granules shown in Table 2 are observed. Moreover, in the case of the coated granule coat | covered with the cellulose type coating agent, it turns out that the direction of tableting is more stable with respect to light (Comparison of Table 3 and Table 4).
表４の実施例１−３の処方は、イミダフェナシンを含有する造粒物中にトコフェロールを配合し、当該造粒物をヒドロキシプロピルメチルセルロースで被覆し、得られた被覆顆粒を錠剤化しているが、分解物の合計生成量が２％と、高度に光安定化された錠剤が得られている（実施例１−３）。
また、腸溶性のセルロース系コーティング剤で被覆された顆粒を用いた錠剤（比較例４−１〜４−３）は、錠剤硬度が低く（３．９〜４．２ｋｇ）、崩壊時間が長い（２５秒〜３０秒）傾向がある。それに比べ、水溶性又は徐放性コーティング剤で被覆された顆粒を用いた錠剤（実施例１−１〜３−３）は、錠剤硬度が高く（４．８〜５．９ｋｇ）、崩壊時間が短い（１１秒〜１５秒）。
包装、輸送、保管中に錠剤が壊れにくいという点で、錠剤硬度は４ｋｇ以上、より好ましくは４．５ｋｇ以上が好ましい。また、口腔内で速やかに崩壊する錠剤が得られるという点で、崩壊時間は３０秒以内、より好ましくは２０秒以内が挙げられる。
Although the formulation of Example 1-3 of Table 4 mix | blends tocopherol in the granulated material containing imidafenacin, the said granulated material is coat | covered with hydroxypropyl methylcellulose, and the obtained coated granule is tableted, Highly light-stabilized tablets with a total degradation product yield of 2% have been obtained (Example 1-3).
In addition, tablets using granules coated with an enteric cellulose-based coating agent (Comparative Examples 4-1 to 4-3) have low tablet hardness (3.9 to 4.2 kg) and a long disintegration time ( 25 seconds to 30 seconds). In comparison, tablets (Examples 1-1 to 3-3) using granules coated with a water-soluble or sustained-release coating agent have high tablet hardness (4.8 to 5.9 kg) and disintegration time. Short (11-15 seconds).
The tablet hardness is preferably 4 kg or more, more preferably 4.5 kg or more, in that the tablet is difficult to break during packaging, transportation and storage. Moreover, the disintegration time is within 30 seconds, more preferably within 20 seconds, in that a tablet that disintegrates rapidly in the oral cavity is obtained.
本発明によれば、製造工程分解物の少ないイミダフェナシン含有顆粒の提供が可能となり、産業上有用である。 INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide imidafenacin-containing granules with little degradation in the production process, which is industrially useful.
Claims (7)
（Ｂ）工程（Ａ）で得られた被覆顆粒を圧縮成型すること、
を特徴とする、錠剤の製造方法。 (A) A granulated product containing imidafenacin is coated with a water-soluble or sustained-release cellulosic coating agent to obtain an imidafenacin-containing granule, and (B) the coated granule obtained in step (A) is compressed. Molding,
A method for producing a tablet, comprising:
（Ｂ）工程（Ａ）で得られた被覆顆粒を圧縮成型すること、
を特徴とする、錠剤の製造方法。 (A) Imidafenacin and a granulated product containing tocopherol or a tocopherol derivative are coated with a water-soluble or sustained-release cellulose coating agent to obtain imidafenacin-containing granules, and (B) obtained in step (A). Compression molding the coated granules,
A method for producing a tablet, comprising:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2017067525A JP6423035B2 (en) | 2017-03-30 | 2017-03-30 | Coated granules of imidafenacin-containing granules |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2017067525A JP6423035B2 (en) | 2017-03-30 | 2017-03-30 | Coated granules of imidafenacin-containing granules |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2018168113A true JP2018168113A (en) | 2018-11-01 |
| JP6423035B2 JP6423035B2 (en) | 2018-11-14 |
Family
ID=64019802
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2017067525A Active JP6423035B2 (en) | 2017-03-30 | 2017-03-30 | Coated granules of imidafenacin-containing granules |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP6423035B2 (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001034147A1 (en) * | 1999-11-11 | 2001-05-17 | Kyorin Pharmaceutical Co., Ltd. | Oral solid preparation |
| WO2006080481A1 (en) * | 2005-01-31 | 2006-08-03 | Kyorin Pharmaceutical Co., Ltd. | Multiple unit oral sustained release preparation and process for production of the same |
| WO2009096559A1 (en) * | 2008-01-31 | 2009-08-06 | Kyorin Pharmaceutical Co., Ltd. | Method for production of orally rapidly disintegrating tablet comprising imidafenacin as active ingredient |
| WO2009096560A1 (en) * | 2008-01-31 | 2009-08-06 | Kyorin Pharmaceutical Co., Ltd. | Orally rapidly disintegrating tablet comprising imidafenacin |
| JP2014172855A (en) * | 2013-03-08 | 2014-09-22 | Kyorin Pharmaceutical Co Ltd | Rapidly disintegrating tablet in oral cavity |
-
2017
- 2017-03-30 JP JP2017067525A patent/JP6423035B2/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001034147A1 (en) * | 1999-11-11 | 2001-05-17 | Kyorin Pharmaceutical Co., Ltd. | Oral solid preparation |
| WO2006080481A1 (en) * | 2005-01-31 | 2006-08-03 | Kyorin Pharmaceutical Co., Ltd. | Multiple unit oral sustained release preparation and process for production of the same |
| WO2009096559A1 (en) * | 2008-01-31 | 2009-08-06 | Kyorin Pharmaceutical Co., Ltd. | Method for production of orally rapidly disintegrating tablet comprising imidafenacin as active ingredient |
| WO2009096560A1 (en) * | 2008-01-31 | 2009-08-06 | Kyorin Pharmaceutical Co., Ltd. | Orally rapidly disintegrating tablet comprising imidafenacin |
| JP2014172855A (en) * | 2013-03-08 | 2014-09-22 | Kyorin Pharmaceutical Co Ltd | Rapidly disintegrating tablet in oral cavity |
Also Published As
| Publication number | Publication date |
|---|---|
| JP6423035B2 (en) | 2018-11-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4524502B2 (en) | Imadafenacin-containing intraoral rapidly disintegrating tablets | |
| JP4656672B2 (en) | Method for producing intraoral rapidly disintegrating tablet containing imidafenacin as active ingredient | |
| US20130064888A1 (en) | Pharmaceutical formulations | |
| WO2008070072A2 (en) | Carvedilol forms, compositions, and methods of preparation thereof | |
| US20100151018A1 (en) | Sustained-release levetiracetam composition and preparation process | |
| JP5973347B2 (en) | Orally disintegrating tablets | |
| JP5881700B2 (en) | Blonanserin oral release controlled pharmaceutical composition | |
| US11576917B2 (en) | Pharmaceutical compositions comprising Ibrutinib | |
| CA3029543C (en) | Immediate release pharmaceutical composition of iron chelating agents | |
| US20200078463A1 (en) | Composition having improved water solubility and bioavailability | |
| JP6423035B2 (en) | Coated granules of imidafenacin-containing granules | |
| JP6423034B2 (en) | Imidafenacin-containing tablets | |
| JP6303037B2 (en) | Imidafenacin-containing intraoral rapidly disintegrating tablets | |
| JP5713544B2 (en) | Imidafenacin-containing intraoral rapidly disintegrating tablets | |
| JP6435363B2 (en) | Method for producing granulated product containing imidafenacin by wet granulation method | |
| JP6435362B2 (en) | Formulation containing imidafenacin with excellent storage stability | |
| JP2019156844A (en) | Memantine hydrochloride-containing tablet | |
| JP2020070260A (en) | Teneligliptin-containing pharmaceutical compositions, methods for making the same, teneligliptin-containing tablets and production methods thereof | |
| JP6303045B1 (en) | Method for producing imidafenacin-containing preparation using stirring granulation method | |
| JP6303038B2 (en) | Imidafenacin-containing intraoral rapidly disintegrating tablets | |
| JP6303044B1 (en) | Method for producing imidafenacin-containing preparation using extrusion granulation method | |
| JP6212588B2 (en) | Imidafenacin-containing intraoral rapidly disintegrating tablets | |
| JP6127295B2 (en) | Imidafenacin-containing intraoral rapidly disintegrating tablets | |
| JP2017132724A (en) | Orally disintegrating tablet formulation comprising amlodipine-containing coated granulated material | |
| JP2019019148A (en) | Method for producing formulation containing imidafenacin with excellent storage stability |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180906 |
|
| 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: 20181002 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20181017 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 6423035 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313111 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |