JP6125957B2 - Topiramate-containing solid preparation - Google Patents
Topiramate-containing solid preparation Download PDFInfo
- Publication number
- JP6125957B2 JP6125957B2 JP2013188248A JP2013188248A JP6125957B2 JP 6125957 B2 JP6125957 B2 JP 6125957B2 JP 2013188248 A JP2013188248 A JP 2013188248A JP 2013188248 A JP2013188248 A JP 2013188248A JP 6125957 B2 JP6125957 B2 JP 6125957B2
- Authority
- JP
- Japan
- Prior art keywords
- topiramate
- solid preparation
- sodium
- mill
- crystals
- 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
- KJADKKWYZYXHBB-XBWDGYHZSA-N Topiramic acid Chemical compound C1O[C@@]2(COS(N)(=O)=O)OC(C)(C)O[C@H]2[C@@H]2OC(C)(C)O[C@@H]21 KJADKKWYZYXHBB-XBWDGYHZSA-N 0.000 title claims description 102
- 229960004394 topiramate Drugs 0.000 title claims description 101
- 238000002360 preparation method Methods 0.000 title claims description 78
- 239000007787 solid Substances 0.000 title claims description 58
- 239000013078 crystal Substances 0.000 claims description 50
- 238000000034 method Methods 0.000 claims description 29
- 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 19
- 238000004519 manufacturing process Methods 0.000 claims description 17
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 12
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 12
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 12
- 239000008187 granular material Substances 0.000 claims description 12
- 238000010298 pulverizing process Methods 0.000 claims description 9
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000002775 capsule Substances 0.000 claims description 8
- 230000006641 stabilisation Effects 0.000 claims description 7
- 238000011105 stabilization Methods 0.000 claims description 7
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 claims description 7
- 239000006188 syrup Substances 0.000 claims description 6
- 235000020357 syrup Nutrition 0.000 claims description 6
- 239000004503 fine granule Substances 0.000 claims description 5
- 239000003826 tablet Substances 0.000 claims description 5
- 239000000654 additive Substances 0.000 description 28
- 239000002245 particle Substances 0.000 description 21
- 150000007942 carboxylates Chemical class 0.000 description 20
- 230000000996 additive effect Effects 0.000 description 19
- 239000011248 coating agent Substances 0.000 description 18
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 17
- 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 17
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 17
- 229950008138 carmellose Drugs 0.000 description 17
- 239000001913 cellulose Substances 0.000 description 17
- 235000010980 cellulose Nutrition 0.000 description 16
- 229920002678 cellulose Polymers 0.000 description 16
- -1 Organic acid salts Chemical class 0.000 description 15
- 238000000576 coating method Methods 0.000 description 15
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 14
- 229920002472 Starch Polymers 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- 239000008107 starch Substances 0.000 description 12
- 235000019698 starch Nutrition 0.000 description 12
- 238000005469 granulation Methods 0.000 description 11
- 230000003179 granulation Effects 0.000 description 11
- 238000002156 mixing Methods 0.000 description 10
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 9
- 239000000378 calcium silicate Substances 0.000 description 9
- 229910052918 calcium silicate Inorganic materials 0.000 description 9
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 235000012239 silicon dioxide Nutrition 0.000 description 8
- 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 7
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 7
- 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 7
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 229960005069 calcium Drugs 0.000 description 7
- 229910052791 calcium Inorganic materials 0.000 description 7
- 239000011575 calcium Substances 0.000 description 7
- 229910000019 calcium carbonate Inorganic materials 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 239000007888 film coating Substances 0.000 description 7
- 238000009501 film coating Methods 0.000 description 7
- 239000008101 lactose Substances 0.000 description 7
- 239000011591 potassium Substances 0.000 description 7
- 229910052700 potassium Inorganic materials 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- FSBVERYRVPGNGG-UHFFFAOYSA-N dimagnesium dioxido-bis[[oxido(oxo)silyl]oxy]silane hydrate Chemical compound O.[Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O FSBVERYRVPGNGG-UHFFFAOYSA-N 0.000 description 6
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 6
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 6
- 235000019797 dipotassium phosphate Nutrition 0.000 description 6
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 description 6
- 239000000314 lubricant Substances 0.000 description 6
- 239000011777 magnesium Substances 0.000 description 6
- 229910052749 magnesium Inorganic materials 0.000 description 6
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 6
- 239000001095 magnesium carbonate Substances 0.000 description 6
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 6
- 239000000391 magnesium silicate Substances 0.000 description 6
- 229910052919 magnesium silicate Inorganic materials 0.000 description 6
- 235000019792 magnesium silicate Nutrition 0.000 description 6
- 235000013923 monosodium glutamate Nutrition 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 6
- 235000010413 sodium alginate Nutrition 0.000 description 6
- 239000000661 sodium alginate Substances 0.000 description 6
- 229940005550 sodium alginate Drugs 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 229940073490 sodium glutamate Drugs 0.000 description 6
- WTWSHHITWMVLBX-DKWTVANSSA-M sodium;(2s)-2-aminobutanedioate;hydron Chemical compound [Na+].[O-]C(=O)[C@@H](N)CC(O)=O WTWSHHITWMVLBX-DKWTVANSSA-M 0.000 description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 5
- PGZIKUPSQINGKT-UHFFFAOYSA-N dialuminum;dioxido(oxo)silane Chemical compound [Al+3].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O.[O-][Si]([O-])=O PGZIKUPSQINGKT-UHFFFAOYSA-N 0.000 description 5
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 4
- 229920000881 Modified starch Polymers 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 239000007884 disintegrant Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 238000005096 rolling process Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 3
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 238000007922 dissolution test Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000001747 exhibiting effect Effects 0.000 description 3
- 238000001125 extrusion Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 3
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 3
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 3
- 229940117841 methacrylic acid copolymer Drugs 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 230000000087 stabilizing effect Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 244000215068 Acacia senegal Species 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 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 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000004373 Pullulan Substances 0.000 description 2
- 229920001218 Pullulan Polymers 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 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 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229920003144 amino alkyl methacrylate copolymer Polymers 0.000 description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 239000008199 coating composition Substances 0.000 description 2
- 238000000748 compression moulding Methods 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 2
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 238000007908 dry granulation Methods 0.000 description 2
- IKBJGZQVVVXCEQ-UHFFFAOYSA-N efonidipine hydrochloride Chemical compound Cl.CCO.CC=1NC(C)=C(C(=O)OCCN(CC=2C=CC=CC=2)C=2C=CC=CC=2)C(C=2C=C(C=CC=2)[N+]([O-])=O)C=1P1(=O)OCC(C)(C)CO1 IKBJGZQVVVXCEQ-UHFFFAOYSA-N 0.000 description 2
- LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 238000009775 high-speed stirring 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
- 239000004014 plasticizer Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 235000019423 pullulan Nutrition 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- WLDHEUZGFKACJH-ZRUFZDNISA-K Amaranth Chemical compound [Na+].[Na+].[Na+].C12=CC=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(O)=C1\N=N\C1=CC=C(S([O-])(=O)=O)C2=CC=CC=C12 WLDHEUZGFKACJH-ZRUFZDNISA-K 0.000 description 1
- GOJCZVPJCKEBQV-UHFFFAOYSA-N Butyl phthalyl butylglycolate Chemical compound CCCCOC(=O)COC(=O)C1=CC=CC=C1C(=O)OCCCC GOJCZVPJCKEBQV-UHFFFAOYSA-N 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000282341 Mustela putorius furo Species 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 239000004115 Sodium Silicate Substances 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000001744 Sodium fumarate Substances 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 229940081735 acetylcellulose Drugs 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 description 1
- 239000001527 calcium lactate Substances 0.000 description 1
- 235000011086 calcium lactate Nutrition 0.000 description 1
- 229960002401 calcium lactate Drugs 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 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
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000006229 carbon black Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- MSJMDZAOKORVFC-SEPHDYHBSA-L disodium fumarate Chemical compound [Na+].[Na+].[O-]C(=O)\C=C\C([O-])=O MSJMDZAOKORVFC-SEPHDYHBSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- 235000012732 erythrosine Nutrition 0.000 description 1
- 229940116333 ethyl lactate Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940087068 glyceryl caprylate Drugs 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000001341 hydroxy propyl starch Substances 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- WTFXARWRTYJXII-UHFFFAOYSA-N iron(2+);iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[O-2].[Fe+2].[Fe+3].[Fe+3] WTFXARWRTYJXII-UHFFFAOYSA-N 0.000 description 1
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 150000004667 medium chain fatty acids Chemical class 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- HWPKGOGLCKPRLZ-UHFFFAOYSA-M monosodium citrate Chemical compound [Na+].OC(=O)CC(O)(C([O-])=O)CC(O)=O HWPKGOGLCKPRLZ-UHFFFAOYSA-M 0.000 description 1
- 235000018342 monosodium citrate Nutrition 0.000 description 1
- 239000002524 monosodium citrate Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- SOQBVABWOPYFQZ-UHFFFAOYSA-N oxygen(2-);titanium(4+) Chemical class [O-2].[O-2].[Ti+4] SOQBVABWOPYFQZ-UHFFFAOYSA-N 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
- 239000000049 pigment Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 229920003124 powdered cellulose Polymers 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 150000003377 silicon compounds Chemical class 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229960004249 sodium acetate Drugs 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
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 235000019294 sodium fumarate Nutrition 0.000 description 1
- 229940005573 sodium fumarate Drugs 0.000 description 1
- 235000019795 sodium metasilicate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 description 1
- 239000004324 sodium propionate Substances 0.000 description 1
- 235000010334 sodium propionate Nutrition 0.000 description 1
- 229960003212 sodium propionate Drugs 0.000 description 1
- NTHWMYGWWRZVTN-UHFFFAOYSA-N sodium silicate Chemical compound [Na+].[Na+].[O-][Si]([O-])=O NTHWMYGWWRZVTN-UHFFFAOYSA-N 0.000 description 1
- 229910052911 sodium silicate Inorganic materials 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、抗てんかん作用等を有するトピラマートを含有する固形製剤に関する。 The present invention relates to a solid preparation containing topiramate having an antiepileptic effect or the like.
トピラマートは、てんかん等の疾病や症状の治療に有用な化合物として知られている(特許文献1および2参照)。また、トピラマート含有固形製剤は、湿度および熱により、トピラマートが分解し、物理的外観の変化(錠剤の外観の褐色もしくは黒色化等)が生じることおよび当業者に知られた標準法(例えば、高速液体クロマトグラフィー)により容易に検出することができる硫酸イオンが生成することが知られており、また製剤中の水分をなるべく除去することで安定化する方法が知られている(特許文献3参照)。 Topiramate is known as a compound useful for the treatment of diseases and symptoms such as epilepsy (see Patent Documents 1 and 2). In addition, solid preparations containing topiramate are subject to degradation of topiramate by humidity and heat, resulting in a change in physical appearance (such as brown or blackening of the appearance of the tablet) and standard methods known to those skilled in the art (for example, high speed It is known that sulfate ions that can be easily detected by liquid chromatography are generated, and a method of stabilizing by removing water in the preparation as much as possible is known (see Patent Document 3). .
しかし、トピラマートは治療に要する用量が比較的高く、トピラマート含有固形製剤中のトピラマートの含量が高いので、該固形製剤の物理的外観の変化を抑えることは、これまで困難であった。 However, since topiramate requires a relatively high dose for treatment and the content of topiramate in the topiramate-containing solid preparation is high, it has been difficult to suppress changes in the physical appearance of the solid preparation.
本発明の目的は、トピラマート含有固形製剤の物理的外観の変化を抑えて、安定なトピラマート含有固形製剤を提供すること等である。 An object of the present invention is to provide a stable topiramate-containing solid preparation while suppressing changes in the physical appearance of the topiramate-containing solid preparation.
本発明は以下の(1)〜(20)に関する。
(1) トピラマート結晶を含有し、該結晶の体積平均粒子径が1.0〜100.0μmであることを特徴とするトピラマート含有固形製剤。
(2) トピラマート結晶の体積平均粒子径が、30.0〜80.0μmであることを特徴とする前記(1)のトピラマート含有固形製剤。
(3) さらに、カルボン酸塩である添加剤を含有する前記(1)または(2)のトピラマート含有固形製剤。
(4) カルボン酸塩である添加剤が、クロスカルメロースナトリウム、カルメロースナトリウム、カルメロースカリウム、カルメロースカルシウム、カルボキシメチルスターチナトリウム、グルタミン酸ナトリウム、アスパラギン酸ナトリウムおよびアルギン酸ナトリウムから選ばれる1以上である前記(3)のトピラマート含有固形製剤。
(5) さらに、微結晶セルロース、含水二酸化ケイ素、軽質無水ケイ酸、ケイ酸アルミニウム、ケイ酸カルシウムおよびメタケイ酸アルミン酸マグネシウムから選ばれる1以上を含有する前記(1)〜(4)のいずれかのトピラマート含有固形製剤。
(6) 固形製剤が、錠剤、細粒剤、顆粒剤、カプセル剤およびドライシロップ剤から選ばれる前記(1)〜(5)のいずれかのトピラマート含有固形製剤。
(7) トピラマートを含有する固形製剤の製造方法において、体積平均粒子径が1.0〜100.0μmのトピラマート結晶を選択する工程を含むことを特徴とするトピラマート含有固形製剤の製造方法。
(8) トピラマート結晶を選択する工程が、体積平均粒子径が30.0〜80.0μmのトピラマート結晶を選択する工程であることを特徴とする前記(7)の製造方法。
(9) トピラマート結晶と、カルボン酸塩である添加剤とを混合する工程を含む前記(7)または(8)の製造方法。
(10) カルボン酸塩である添加剤が、クロスカルメロースナトリウム、カルメロースナトリウム、カルメロースカリウム、カルメロースカルシウム、カルボキシメチルスターチナトリウム、グルタミン酸ナトリウム、アスパラギン酸ナトリウムおよびアルギン酸ナトリウムから選ばれる1以上である前記(9)の製造方法。
(11) トピラマート結晶と、微結晶セルロース、含水二酸化ケイ素、軽質無水ケイ酸、ケイ酸アルミニウム、ケイ酸カルシウムおよびメタケイ酸アルミン酸マグネシウムから選ばれる1以上とを混合する工程を含む前記(7)〜(10)のいずれかの製造方法。
(12) 固形製剤が、錠剤、細粒剤、顆粒剤、カプセル剤またはドライシロップ剤である前記(7)〜(11)のいずれかの製造方法。
(13) 体積平均粒子径が1.0〜100.0μmのトピラマート結晶が、粗結晶を、高速回転ミルに分類される粉砕機を用いて粉砕して得られた結晶であることを特徴とする前記(7)〜(12)のいずれかの製造方法。
(14) トピラマートを含有する固形製剤の製造に用いるトピラマートとして、体積平均粒子径が1.0〜100.0μmのトピラマート結晶を用いることを特徴とするトピラマート含有固形製剤の安定化方法。
(15) 用いるトピラマート結晶の体積平均粒子径が30.0〜80.0μmのトピラマート結晶であることを特徴とする前記(14)の安定化方法。
(16) トピラマート結晶と共に、カルボン酸塩である添加剤を、製剤内に共存させることを特徴とする前記(14)または(15)の安定化方法。
(17) カルボン酸塩である添加剤が、クロスカルメロースナトリウム、カルメロースナトリウム、カルメロースカリウム、カルメロースカルシウム、カルボキシメチルスターチナトリウム、グルタミン酸ナトリウム、アスパラギン酸ナトリウムおよびアルギン酸ナトリウムから選ばれる1以上である前記(16)の安定化方法。
(18) 微結晶セルロース、含水二酸化ケイ素、軽質無水ケイ酸、ケイ酸アルミニウム、ケイ酸カルシウムおよびメタケイ酸アルミン酸マグネシウムから選ばれる1以上を、製剤内に共存させることを特徴とする前記(14)〜(17)のいずれかの安定化方法。
(19) 固形製剤が、錠剤、細粒剤、顆粒剤、カプセル剤またはドライシロップ剤である前記(14)〜(18)のいずれかの安定化方法。
(20) トピラマート結晶が、粗結晶を、高速回転ミルに分類される粉砕機を用いて粉砕して得られた結晶であることを特徴とする前記(14)〜(19)のいずれかの安定化方法。
The present invention relates to the following (1) to (20).
(1) A topiramate-containing solid preparation comprising topiramate crystals, wherein the crystals have a volume average particle diameter of 1.0 to 100.0 μm.
(2) The topiramate-containing solid preparation according to the above (1), wherein the volume average particle diameter of the topiramate crystals is 30.0 to 80.0 μm.
(3) The topiramate-containing solid preparation according to (1) or (2), further comprising an additive which is a carboxylate.
(4) The additive which is a carboxylate is at least one selected from croscarmellose sodium, carmellose sodium, carmellose potassium, carmellose calcium, sodium carboxymethyl starch, sodium glutamate, sodium aspartate and sodium alginate (3) Topiramate-containing solid preparation.
(5) Further, any one of (1) to (4), further comprising one or more selected from microcrystalline cellulose, hydrous silicon dioxide, light anhydrous silicic acid, aluminum silicate, calcium silicate and magnesium aluminate metasilicate Topiramate-containing solid preparation.
(6) The topiramate-containing solid preparation according to any one of (1) to (5), wherein the solid preparation is selected from tablets, fine granules, granules, capsules and dry syrups.
(7) A method for producing a topiramate-containing solid preparation, comprising a step of selecting a topiramate crystal having a volume average particle size of 1.0 to 100.0 μm in the method for producing a solid preparation containing topiramate.
(8) The method according to (7), wherein the step of selecting topiramate crystals is a step of selecting topiramate crystals having a volume average particle diameter of 30.0 to 80.0 μm.
(9) The production method of the above (7) or (8), comprising a step of mixing a topiramate crystal and an additive which is a carboxylate.
(10) The additive which is a carboxylate is at least one selected from croscarmellose sodium, carmellose sodium, carmellose potassium, carmellose calcium, sodium carboxymethyl starch, sodium glutamate, sodium aspartate and sodium alginate (9) The production method of (9).
(11) comprising the step of mixing topiramate crystals and one or more selected from microcrystalline cellulose, hydrous silicon dioxide, light anhydrous silicic acid, aluminum silicate, calcium silicate and magnesium aluminate metasilicate (7) to The production method according to any one of (10).
(12) The production method of any one of (7) to (11), wherein the solid preparation is a tablet, fine granule, granule, capsule or dry syrup.
(13) The topiramate crystal having a volume average particle diameter of 1.0 to 100.0 μm is a crystal obtained by pulverizing a crude crystal using a pulverizer classified as a high-speed rotary mill (7 ) To (12).
(14) A method for stabilizing a topiramate-containing solid preparation, wherein topiramate crystals having a volume average particle diameter of 1.0 to 100.0 μm are used as the topiramate used in the production of a solid preparation containing topiramate.
(15) The stabilization method of (14), wherein the topiramate crystal used is a topiramate crystal having a volume average particle diameter of 30.0 to 80.0 μm.
(16) The method according to the above (14) or (15), wherein an additive which is a carboxylate is allowed to coexist in a preparation together with a topiramate crystal.
(17) The additive which is a carboxylate is at least one selected from croscarmellose sodium, carmellose sodium, carmellose potassium, carmellose calcium, carboxymethyl starch sodium, sodium glutamate, sodium aspartate and sodium alginate The stabilization method of (16) above.
(18) One or more selected from microcrystalline cellulose, hydrous silicon dioxide, light anhydrous silicic acid, aluminum silicate, calcium silicate, and magnesium aluminate metasilicate are allowed to coexist in the preparation (14) The stabilization method in any one of (17).
(19) The stabilization method according to any one of (14) to (18), wherein the solid preparation is a tablet, fine granule, granule, capsule or dry syrup.
(20) The stable form according to any one of (14) to (19), wherein the topiramate crystal is a crystal obtained by pulverizing a crude crystal using a pulverizer classified as a high-speed rotary mill. Method.
本発明によれば、トピラマート含有固形製剤の物理的外観の変化を抑えて、安定なトピラマート含有固形製剤等を提供することができる。 According to the present invention, it is possible to provide a stable topiramate-containing solid preparation and the like by suppressing changes in the physical appearance of the topiramate-containing solid preparation.
本発明のトピラマート含有固形製剤は、有効成分としてトピラマートを含有し、その形状は特に限定されないが、錠剤、細粒剤、顆粒剤、カプセル剤またはドライシロップ剤の形状であるのが好ましい。また、本発明のトピラマート含有固形製剤は、トピラマートを含有する素製剤と、該素製剤を覆う皮膜を含む固形製剤であることが好ましく、例えば遮光性を呈する化合物を含有するコーティング組成物をコーティングして形成される皮膜を含む固形製剤であることがより好ましい。 The topiramate-containing solid preparation of the present invention contains topiramate as an active ingredient, and the shape thereof is not particularly limited, but is preferably in the form of a tablet, fine granule, granule, capsule or dry syrup. In addition, the topiramate-containing solid preparation of the present invention is preferably a solid preparation comprising a raw preparation containing topiramate and a film covering the raw preparation. For example, a coating composition containing a compound exhibiting light-shielding properties is coated. It is more preferable that it is a solid preparation containing the film formed in this way.
本発明におけるトピラマートは、式(I) Topiramate in the present invention has the formula (I)
で表される2,3:4,5-ビス-O-(1-メチルエチリデン)-β-D-フルクトピラノーススルファメートである。
本発明のトピラマート含有固形製剤は、好ましくは体積平均粒子径が1.0〜100.0μmのトピラマート結晶を含有し、より好ましくは体積平均粒子径が、30.0〜80.0μmのトピラマート結晶を含有する。
2,3: 4,5-bis-O- (1-methylethylidene) -β-D-fructopyranose sulfamate represented by
The topiramate-containing solid preparation of the present invention preferably contains topiramate crystals having a volume average particle diameter of 1.0 to 100.0 μm, and more preferably contains topiramate crystals having a volume average particle diameter of 30.0 to 80.0 μm.
本発明のトピラマート含有固形製剤は、カルボン酸塩である添加剤を含有することが好ましく、本発明におけるカルボン酸塩である添加剤としては、例えばクロスカルメロースナトリウム、カルメロースナトリウム、カルメロースカリウム、カルメロースカルシウム、カルボキシメチルスターチナトリウム、アルギン酸ナトリウムなどの高分子、クエン酸ナトリウム、クエン酸ニ水素ナトリウム、フマル酸ナトリウム、プロピオン酸ナトリウム、酢酸ナトリウム、乳酸カルシウム、酒石酸ナトリウム、オレイン酸ナトリウム、グルタミン酸ナトリウム、アスパラギン酸ナトリウムなどの有機酸塩等などがあげられ、より好ましくはクロスカルメロースナトリウム、カルメロースナトリウム、カルメロースカリウム、カルメロースカルシウム、カルボキシメチルスターチナトリウム、アルギン酸ナトリウム、グルタミン酸ナトリウムおよびアスパラギン酸ナトリウムから選ばれる1以上があげられ、さらに好ましくはクロスカルメロースナトリウム、カルメロースナトリウム、カルメロースカリウム、カルメロースカルシウムがあげられる。また、炭酸カルシウム、炭酸ナトリウム、炭酸マグネシウム、ケイ酸カルシウム、ケイ酸マグネシウム、ケイ酸アルミン酸マグネシウム、リン酸ニカリウム等を含有してもよい。 The topiramate-containing solid preparation of the present invention preferably contains an additive that is a carboxylate, and examples of the additive that is a carboxylate in the present invention include croscarmellose sodium, carmellose sodium, carmellose potassium, Polymers such as carmellose calcium, sodium carboxymethyl starch, sodium alginate, sodium citrate, sodium dihydrogen citrate, sodium fumarate, sodium propionate, sodium acetate, calcium lactate, sodium tartrate, sodium oleate, sodium glutamate, Organic acid salts such as sodium aspartate and the like, and more preferably croscarmellose sodium, carmellose sodium, carmellose potassium, carmellose calcium, Carboxymethyl starch sodium, sodium alginate, one or more can be mentioned selected from sodium glutamate and sodium aspartate, more preferably croscarmellose sodium, carmellose sodium, carmellose potassium, carmellose calcium and the like. Further, calcium carbonate, sodium carbonate, magnesium carbonate, calcium silicate, magnesium silicate, magnesium aluminate silicate, dipotassium phosphate and the like may be contained.
カルボン酸塩である添加剤の配合量は、特に限定はされないが、好ましく錠剤中の配合割合で、0.01〜50%、より好ましくは0.1〜20%、さらに好ましくは1〜10%である。カルボン酸塩である添加剤には、一般的な固形製剤において、例えば賦形剤、崩壊剤、結合剤、滑沢剤等の用途に用いられるものがあり、本発明のトピラマート含有固形製剤においても、それらの用途に用いて含有していてもよく、例えばクロスカルメロースナトリウム、カルメロースカルシウム、カルボキシメチルスターチナトリウム等は崩壊剤として、カルメロースナトリウム、カルメロースカリウム、アルギン酸ナトリウム等は結合剤として、グルタミン酸ナトリウム、アスパラギン酸ナトリウム等は賦形剤として含有していてもよい。また、炭酸カルシウム、炭酸ナトリウム、炭酸マグネシウム、ケイ酸カルシウム、ケイ酸マグネシウム、ケイ酸アルミン酸マグネシウム、リン酸ニカリウム等は、賦形剤または滑沢剤として含有してもよい。 The blending amount of the additive which is a carboxylate is not particularly limited, but is preferably 0.01 to 50%, more preferably 0.1 to 20%, and further preferably 1 to 10% in a blending ratio in the tablet. The additives that are carboxylates include those used in general solid preparations such as excipients, disintegrants, binders, lubricants, etc., and also in the topiramate-containing solid preparations of the present invention. , For example, croscarmellose sodium, carmellose calcium, sodium carboxymethyl starch as a disintegrating agent, carmellose sodium, carmellose potassium, sodium alginate and the like as a binder, Sodium glutamate, sodium aspartate and the like may be contained as excipients. Further, calcium carbonate, sodium carbonate, magnesium carbonate, calcium silicate, magnesium silicate, magnesium aluminate silicate, dipotassium phosphate and the like may be contained as an excipient or a lubricant.
本発明のトピラマート含有固形製剤は、トピラマート結晶およびカルボン酸塩である添加剤の他に、他の有効成分および/または他の添加剤を含有していてもよい。
他の添加剤としては、一般的な固形製剤において、例えば賦形剤、崩壊剤、結合剤、滑沢剤等の用途に用いられるものがあげられる。
他の添加剤としての賦形剤は、例えば糖(例えば乳糖、白糖、マルトース等)、糖アルコール(例えばマンニトール、マルチトール、エリスリトール等)、デンプン(例えばトウモロコシデンプン、コメデンプン、コムギデンプン等)、セルロース(例えば結晶セルロース、粉末セルロース等)、難水溶性無機塩(例えばタルク、軽質無水ケイ酸、メタケイ酸アルミン酸ナトリウム、リン酸カルシウム等)等があげられ、これらは単独でまたは2種以上を組み合わせて用いられ、好ましくは、糖、デンプン、セルロース等から選ばれる1つ以上の物質があげられ、さらに好ましくは、乳糖、トウモロコシデンプン、結晶セルロースから選ばれる1つ以上の物質があげられる。また、本発明のトピラマート含有固形製剤は、良好な製造性および/または速やかな薬物の溶出性を呈するために、賦形剤として、糖、デンプン、セルロース等から選ばれる1つ以上の物質が含有していることが好ましく、乳糖、トウモロコシデンプン、結晶セルロースから選ばれる1つ以上の物質を含有していることがより好ましい。
The topiramate-containing solid preparation of the present invention may contain other active ingredients and / or other additives in addition to the additive which is topiramate crystals and carboxylate.
Examples of other additives include those used in general solid preparations such as excipients, disintegrants, binders and lubricants.
Excipients as other additives include, for example, sugar (for example, lactose, sucrose, maltose, etc.), sugar alcohol (for example, mannitol, maltitol, erythritol, etc.), starch (for example, corn starch, rice starch, wheat starch, etc.), Cellulose (e.g., crystalline cellulose, powdered cellulose, etc.), sparingly water-soluble inorganic salts (e.g., talc, light anhydrous silicic acid, sodium metasilicate sodium phosphate, calcium phosphate, etc.) and the like are included, and these may be used alone or in combination of two or more. One or more substances selected from sugar, starch, cellulose and the like are preferably used, and one or more substances selected from lactose, corn starch and crystalline cellulose are more preferable. Further, the topiramate-containing solid preparation of the present invention contains one or more substances selected from sugar, starch, cellulose and the like as an excipient in order to exhibit good manufacturability and / or rapid drug dissolution. It is preferable to contain one or more substances selected from lactose, corn starch, and crystalline cellulose.
他の添加剤としての崩壊剤は、例えばセルロース誘導体(例えば低置換ヒドロキシプロピルセルロース、カルメロース等)、デンプン(例えばα化デンプン、部分α化デンプン等)、デンプン誘導体(ヒドロキシプロピルスターチ等)、クロスポビドン、ベントナイト等があげられ、これらを単独でまたは2種以上用いてもよい。
他の添加剤としての結合剤は、例えばセルロース誘導体(例えばメチルセルロース、カルメロース、カルボキシプロピルセルロース、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等)、セルロース(例えば結晶セルロース等)、デンプン(例えばα化デンプン等)、ポリビニルアルコール、ポリビニルピロリドン、プルラン、デキストリン、アラビアゴム、ゼラチン等があげられ、これらを単独でまたは2種以上用いてもよい。
Disintegrants as other additives include, for example, cellulose derivatives (for example, low-substituted hydroxypropyl cellulose, carmellose, etc.), starch (for example, pregelatinized starch, partially pregelatinized starch, etc.), starch derivatives (hydroxypropyl starch, etc.), crospovidone And bentonite. These may be used alone or in combination of two or more.
Examples of binders as other additives include cellulose derivatives (e.g., methylcellulose, carmellose, carboxypropylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose), cellulose (e.g., crystalline cellulose), starch (e.g., pregelatinized starch), Examples thereof include polyvinyl alcohol, polyvinyl pyrrolidone, pullulan, dextrin, gum arabic, and gelatin. These may be used alone or in combination of two or more.
他の添加剤としての滑沢剤としては、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、硬化油、ショ糖脂肪酸エステル、ポリエチレングリコール等があげられ、これらを単独でまたは2種以上用いてもよい。
本発明のトピラマート含有固形製剤が被膜を含む場合の皮膜は、遮光性を呈する化合物を含有する皮膜であることが好ましく、該化合物としては例えば遮光性を呈する金属化合物、ケイ素化合物、有機化合物、錯体物質等があげられ、好ましくは酸化チタン、酸化鉄(具体的には黄色三二酸化鉄、三二酸化鉄、黄酸化鉄、黒酸化鉄等)、酸化亜鉛、酸化ケイ素等があげられ、より好ましくは酸化チタンがあげられる。本発明における酸化チタンは、ルチル型およびアナターゼ型のいずれの結晶形でもよく、その粒子径についても特に限定されない。これらの酸化チタンは、結晶形や粒子径の異なる2種以上を併せて用いてもよい。
Examples of lubricants as other additives include magnesium stearate, calcium stearate, hydrogenated oil, sucrose fatty acid ester, polyethylene glycol and the like, and these may be used alone or in combination of two or more.
When the topiramate-containing solid preparation of the present invention contains a film, the film is preferably a film containing a compound having a light-shielding property. Examples of the compound include a metal compound, a silicon compound, an organic compound, and a complex having a light-shielding property. Examples thereof include titanium oxide, iron oxide (specifically, yellow iron sesquioxide, iron sesquioxide, yellow iron oxide, black iron oxide, etc.), zinc oxide, silicon oxide, etc., more preferably An example is titanium oxide. The titanium oxide in the present invention may be in the rutile type or anatase type crystal form, and the particle diameter is not particularly limited. These titanium oxides may be used in combination of two or more having different crystal forms and particle sizes.
本発明のトピラマート含有固形製剤における皮膜は、前記遮光性を呈する化合物に加えて、別途、色素、遮光剤、滑沢剤または分散剤を含有していてもよく、例えば、ベンガラ、カーボンブラック、薬用炭、硫酸バリウム、食用黄色4号アルミニウムレーキ、食用赤色2号、食用赤色3号、食用赤色102号、銅クロロフィン等があげられる。
本発明のトピラマート含有固形製剤における皮膜は、さらに例えばコーティング基剤、可塑剤、その他のコーティング剤等を含有していてもよく、それぞれ2種以上混合して用いてもよい。
The film in the topiramate-containing solid preparation of the present invention may contain a pigment, a light-shielding agent, a lubricant or a dispersing agent in addition to the compound exhibiting the light-shielding property. For example, Bengala, carbon black, medicinal Examples include charcoal, barium sulfate, edible yellow No. 4 aluminum lake, edible red No. 2, edible red No. 3, edible red No. 102, and copper chlorofin.
The film in the topiramate-containing solid preparation of the present invention may further contain, for example, a coating base, a plasticizer, other coating agents, etc., and may be used in a mixture of two or more.
コーティング基剤としては、例えば胃溶性フィルムコーティング剤、腸溶性フィルムコーティング剤、徐放性フィルムコーティング剤等があげられ、胃溶性フィルムコーティング基剤としては、例えば、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、ヒドロキシエチルセルロース、メチルヒドロキシエチルセルロース等のセルロース系高分子、ポリビニルアセタールジエチルアミノアセテート、アミノアルキルメタクリレートコポリマーE、ポリビニルピロリドン等の合成高分子、プルラン等の多糖類等があげられ、腸溶性フィルムコーティング基剤としては、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、カルボキシメチルエチルセルロース、酢酸フタル酸セルロース等のセルロース系高分子、メタクリル酸コポリマーL、メタクリル酸コポリマーLD、メタクリル酸コポリマーS等のアクリル酸系高分子、セラック等の天然物等があげられ、徐放性フィルムコーティング基剤としては、例えば、エチルセルロース等のセルロース系高分子、アミノアルキルメタクリレートコポリマーRS、アクリル酸エチル・メタクリル酸メチルコポリマー等のアクリル酸系高分子等があげられる。 Examples of the coating base include gastric film coating agents, enteric film coating agents, sustained-release film coating agents, and the like. Examples of gastric film coating bases include hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxy Cellulose polymers such as ethyl cellulose and methylhydroxyethyl cellulose, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, synthetic polymers such as polyvinylpyrrolidone, polysaccharides such as pullulan, etc., and enteric film coating bases include: For example, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethyl cell Cellulose polymers such as cellulose acetate, cellulose acetate phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD, acrylic acid polymers such as methacrylic acid copolymer S, natural products such as shellac, etc. Examples of the coating base include cellulose polymers such as ethyl cellulose, and acrylic acid polymers such as aminoalkyl methacrylate copolymer RS and ethyl acrylate / methyl methacrylate copolymer.
可塑剤としては、例えばクエン酸トリエチル、中鎖脂肪酸トリグリセリド、フタル酸ジエチル、フタル酸ジブチル、トリアセチン、ブチルフタリルブチルグリコレート、グリセリルカプリル酸エステル等のエステル;グリセリン、プロピレングリコール、ポリエチレングリコール等のアルコール等があげられる。
その他のコーティング剤としては、例えば乳糖、白糖、タルク、炭酸カルシウム、ゼラチン、アラビアゴム、カルナバロウ等があげられる。
Examples of the plasticizer include triethyl citrate, medium chain fatty acid triglyceride, diethyl phthalate, dibutyl phthalate, triacetin, butyl phthalyl butyl glycolate, glyceryl caprylate ester, etc .; alcohols such as glycerin, propylene glycol, polyethylene glycol, etc. Etc.
Examples of other coating agents include lactose, sucrose, talc, calcium carbonate, gelatin, gum arabic, and carnauba wax.
本発明のトピラマートを含有する固形製剤の製造方法は、既知の固形製剤の製造方法であればよいが、体積平均粒子径が1.0〜100.0μmのトピラマート結晶を選択する工程を含むことを特徴とし、体積平均粒子径が30.0〜80.0μmのトピラマート結晶を選択するのが好ましい。
体積平均粒子径が1.0〜100.0μmのトピラマート結晶は、例えば特開平3-230011号公報に記載の製造方法等に従って製造されたトピラマート結晶(粗結晶)を、篩によって分級して、体積平均粒子径が1.0〜100.0μmのものを得てもよいが、粗結晶を、例えば高速回転ミル、ローラーミル、ジェットミル、ボールミル等に分類される粉砕機、好ましくは高速回転ミルに分類される粉砕機を用いて粉砕して体積平均粒子径が1.0〜100.0μmのものを得ることが好ましい。高速回転ミルに分類される粉砕機としては、例えばハンマーミル、ケージミル、せん断型ミル、インパクトミル、エアロフォールミル等があげられ、好ましくはハンマーミルがあげられる。
The production method of the solid preparation containing the topiramate of the present invention may be any known solid preparation production method, and includes a step of selecting topiramate crystals having a volume average particle size of 1.0 to 100.0 μm, It is preferable to select a topiramate crystal having a volume average particle diameter of 30.0 to 80.0 μm.
A topiramate crystal having a volume average particle diameter of 1.0 to 100.0 μm is obtained by classifying a topiramate crystal (crude crystal) produced according to the production method described in JP-A-3-230011, for example, with a sieve to obtain a volume average particle diameter. May be obtained in a range of 1.0 to 100.0 μm. For example, a pulverizer classified as a high-speed rotary mill, a roller mill, a jet mill, a ball mill or the like, preferably a pulverizer classified as a high-speed rotary mill, may be used. It is preferable to obtain a powder having a volume average particle size of 1.0 to 100.0 μm by pulverization. Examples of the pulverizer classified as a high-speed rotating mill include a hammer mill, a cage mill, a shearing mill, an impact mill, an aerofall mill, and the like, and preferably a hammer mill.
また、本発明のトピラマートを含有する固形製剤の製造方法において、トピラマート結晶と、カルボン酸塩である添加剤(前記と同義)とを混合する工程を含むことが好ましい。また、本発明のトピラマートを含有する固形製剤の製造方法において、トピラマート結晶と、炭酸カルシウム、炭酸ナトリウム、炭酸マグネシウム、ケイ酸カルシウム、ケイ酸マグネシウム、ケイ酸アルミン酸マグネシウム、リン酸ニカリウム等とを混合する工程を含むことが好ましい。 Further, the method for producing a solid preparation containing topiramate of the present invention preferably includes a step of mixing topiramate crystals and an additive (as defined above) that is a carboxylate. Further, in the method for producing a solid preparation containing topiramate of the present invention, topiramate crystals are mixed with calcium carbonate, sodium carbonate, magnesium carbonate, calcium silicate, magnesium silicate, magnesium aluminate silicate, dipotassium phosphate, etc. It is preferable that the process to include is included.
また、本発明のトピラマートを含有する固形製剤の製造方法において、トピラマート結晶およびカルボン酸塩である添加剤の他に、他の有効成分および/または他の添加剤(前記と同義)を、トピラマート結晶と混合する工程を含むことが好ましい。
いずれの混合工程においても、用いる混合機に制限はないが、例えばV型混合機、コーン型混合機、水平円筒型混合機、リボン型混合機、高速攪拌型、気流攪拌型等の混合専用機で混合しても、例えば流動層造粒乾燥機、高速攪拌造粒機等の造粒機で混合してもよい。
In addition, in the method for producing a solid preparation containing topiramate of the present invention, in addition to the additive that is topiramate crystal and carboxylate, other active ingredients and / or other additives (as defined above) are added to topiramate crystals. It is preferable to include the process of mixing with.
In any mixing step, there is no limitation on the mixer to be used. For example, a V-type mixer, a cone-type mixer, a horizontal cylindrical mixer, a ribbon-type mixer, a high-speed stirring type, an airflow stirring type, etc. Or may be mixed with a granulator such as a fluidized bed granulator / dryer or a high-speed stirring granulator.
混合工程で得られた混合物は、そのまま散剤や、カプセルに充填してカプセル剤としてもよいが、造粒を行って、細粒剤または顆粒剤にしてもよい。また、混合工程で得られた混合物は、そのまま直接打錠法で打錠するか、水等を加えて造粒した後に打錠(間接打錠法)して、錠剤にしてもよい。本発明において、トピラマートを含有する固形製剤の製造方法としては、混合工程で得られた混合物を、水等を加えて造粒した後に打錠して、錠剤とすることが最も好ましい。
(1)造粒工程
造粒物の製造は、例えば湿式造粒法、乾式造粒法等により行うことができる。湿式造粒法としては、例えば押し出し造粒法(スクリュー押し出し造粒装置、ロール押し出し式造粒装置等による)、転動造粒法(回転ドラム型造粒装置、遠心転動型造粒装置等による)、流動層造粒法(流動層造粒装置、転動流動層造粒装置等による)、攪拌造粒法(攪拌造粒装置等による)等があげられるが、好ましくは流動層造粒法があげられる。乾式造粒法としては、例えば市販の乾式造粒機を用いフレークを製造するか、打錠機によってスラッグ錠を製造し、得られたフレークまたはスラッグ錠を市販の解砕機または整粒機で破砕することで造粒物を得る破砕造粒法等があげられる。また、好ましくはそれぞれの造粒物は、適宜粉砕および/または篩い分けすることにより所望の粒子径を有するようにされる。
(2)打錠工程
前記(1)で得られた造粒物を乾燥後、滑沢剤を加えて混合し圧縮成形する。このとき、カルボン酸塩である添加剤(前記と同義)、他の有効成分および/または他の添加剤(前記と同義)を加えることもできる。
The mixture obtained in the mixing step may be used as it is in powders or capsules filled into capsules, or may be granulated to form fine granules or granules. Further, the mixture obtained in the mixing step may be directly compressed by a tableting method, or may be granulated by adding water or the like and then tableted (indirect tableting method) to form tablets. In the present invention, as a method for producing a solid preparation containing topiramate, it is most preferable that the mixture obtained in the mixing step is granulated by adding water or the like and then compressed into tablets.
(1) Granulation step The granulated product can be produced, for example, by a wet granulation method, a dry granulation method or the like. Examples of wet granulation methods include extrusion granulation (by screw extrusion granulation apparatus, roll extrusion granulation apparatus, etc.), rolling granulation method (rotary drum type granulation apparatus, centrifugal rolling granulation apparatus, etc.) ), Fluidized bed granulation method (by fluidized bed granulator, rolling fluidized bed granulator, etc.), stirring granulation method (by stirring granulator, etc.), etc., preferably fluidized bed granulation The law is raised. As the dry granulation method, for example, flakes are produced using a commercially available dry granulator, or slug tablets are produced using a tableting machine, and the obtained flakes or slug tablets are crushed with a commercially available crusher or granulator. The crushing granulation method etc. which obtain a granulated material by doing are mention | raise | lifted. Preferably, each granulated product has a desired particle size by appropriate pulverization and / or sieving.
(2) Tableting process After the granulated product obtained in the above (1) is dried, a lubricant is added and mixed and compression molded. At this time, an additive which is a carboxylate (as defined above), another active ingredient and / or another additive (as defined above) may be added.
圧縮成形に用いる打錠機は、特に限定されないが、ロータリー打錠機を用いるのが好ましく、圧縮成形圧力は、300kgf〜2000kgfであることが好ましい。
また、本発明のトピラマート含有固形製剤が被膜を含む場合の皮膜は、遮光性を呈する化合物(前記と同義)を含むコーティング剤を適当な溶媒、例えば水、メタノール、エタノール、2-プロパノール、酢酸エチル、乳酸エチル、アセトン、塩化メチレン、1,1,1-トリクロロエタン等またはこれらの混合溶媒等で溶解または分散させたコーティング剤液を素製剤にスプレーしてコーティングすることで得られる。この時のコーティング装置は、特に限定されるものではないが、細粒または顆粒にコーティングを行う際のコーティング装置は、好ましくは流動層コーティング乾燥装置、遠心流動造粒装置、転動流動コーティング乾燥装置等が用いられる。錠剤にコーティングを行う際のコーティング装置は、特に限定されるものではないが、好ましくはドラム式フィルムコーティング乾燥装置または流動層コーティング装置が用いられる。
The tableting machine used for compression molding is not particularly limited, but a rotary tableting machine is preferably used, and the compression molding pressure is preferably 300 kgf to 2000 kgf.
Further, when the topiramate-containing solid preparation of the present invention contains a film, the film contains a coating agent containing a light-shielding compound (as defined above) in a suitable solvent such as water, methanol, ethanol, 2-propanol, ethyl acetate. , Ethyl lactate, acetone, methylene chloride, 1,1,1-trichloroethane, etc. or a mixed solvent thereof or the like can be obtained by spraying and coating the raw material with a coating solution. The coating apparatus at this time is not particularly limited, but the coating apparatus for coating fine granules or granules is preferably a fluidized bed coating drying apparatus, a centrifugal fluidized granulator, a rolling fluidized coating drying apparatus. Etc. are used. The coating apparatus for coating tablets is not particularly limited, but a drum type film coating drying apparatus or a fluidized bed coating apparatus is preferably used.
本発明のトピラマート含有固形製剤の製造方法は、高含量の薬物を含有することができ、例えば錠剤の場合、実用十分な錠剤硬度を有し、速やかな溶出速度を示す製剤を得ることもできる。本発明のトピラマート含有固形製剤におけるトピラマートの使用量としては、例えば錠剤の場合、1錠中30〜200mgが好ましく、錠剤中5〜80質量%が好ましく、さらに好ましくは10〜60質量%である。 The method for producing a topiramate-containing solid preparation of the present invention can contain a high content of drug. For example, in the case of a tablet, a preparation having a practically sufficient tablet hardness and a rapid dissolution rate can be obtained. The amount of topiramate used in the topiramate-containing solid preparation of the present invention is, for example, preferably 30 to 200 mg in one tablet, preferably 5 to 80% by mass, more preferably 10 to 60% by mass in the tablet.
本発明のトピラマートを含有する固形製剤の安定化方法は、前記トピラマートを含有する固形製剤の製造方法に用いるトピラマートとして、体積平均粒子径が1.0〜100.0μmのトピラマート結晶を用いることを特徴とする安定化方法であり、体積平均粒子径が30.0〜80.0μmのトピラマート結晶を用いることがより好ましい。
一般的には、結晶の粒子径を小さくすれば、比表面積が大きくなり、加水分解等は進行しやすいことが知られているが、本願発明者らは、鋭意検討した結果、むしろ逆に粒子径を小さくすることでトピラマートを含有する固形製剤を安定化することができることを見い出した。
The method for stabilizing a solid preparation containing topiramate according to the present invention comprises using a topiramate crystal having a volume average particle size of 1.0 to 100.0 μm as the topiramate used in the method for producing a solid preparation containing topiramate. More preferably, topiramate crystals having a volume average particle diameter of 30.0 to 80.0 μm are used.
In general, it is known that if the particle diameter of the crystal is reduced, the specific surface area is increased, and hydrolysis and the like are likely to proceed. It has been found that a solid preparation containing topiramate can be stabilized by reducing the diameter.
また、本発明者らは、カルボン酸塩である添加剤(前記と同義)、炭酸カルシウム、炭酸ナトリウム、炭酸マグネシウム、ケイ酸カルシウム、ケイ酸マグネシウム、ケイ酸アルミン酸マグネシウム、リン酸ニカリウム等を配合することで、トピラマート含有固形製剤の安定性をより改善することができることも見いだした。本願発明者らは、トピラマートの分解機構に着目し、その分解反応の促進を抑制することを試みた。すなわち、トピラマートは加温加湿下に保存するとスルファミンの加水分解により、酸が発生する。その酸の存在はさらに加水分解を促進し、結果的に自己触媒的に加速度的に分解が進行する。そこで本発明では、さまざまな添加剤を配合し、トピラマートの分解を抑制することを試みたところ、カルボン酸塩である添加剤(前記と同義)、炭酸カルシウム、炭酸ナトリウム、炭酸マグネシウム、ケイ酸カルシウム、ケイ酸マグネシウム、ケイ酸アルミン酸マグネシウム、リン酸ニカリウム等、好ましくはカルボン酸塩である添加剤を製剤内に共存させると、トピラマートの分解に由来して生じる黒色化をより抑制できることを見出した。 In addition, the present inventors blended an additive (as defined above) which is a carboxylate, calcium carbonate, sodium carbonate, magnesium carbonate, calcium silicate, magnesium silicate, magnesium aluminate silicate, dipotassium phosphate, etc. It has also been found that the stability of the topiramate-containing solid preparation can be further improved. The inventors of the present application paid attention to the decomposition mechanism of topiramate and tried to suppress the promotion of the decomposition reaction. That is, when topiramate is stored under warm and humid conditions, acid is generated by hydrolysis of sulfamine. The presence of the acid further promotes hydrolysis, resulting in autocatalytic and accelerated degradation. Therefore, in the present invention, when various additives were blended and an attempt was made to suppress the decomposition of topiramate, the additive as a carboxylate (as defined above), calcium carbonate, sodium carbonate, magnesium carbonate, calcium silicate , Magnesium silicate, magnesium aluminate, dipotassium phosphate, etc., preferably a carboxylate additive coexisting in the formulation, it was found that the blackening caused by the decomposition of topiramate can be further suppressed .
また、本発明者らは、本発明のトピラマート含有固形製剤が、トピラマートを含有する素製剤と、該素製剤を覆う皮膜を含む固形製剤であり、遮光性を呈する化合物を含有するコーティング組成物をコーティングして形成される皮膜を含む固形製剤であることで、トピラマート製剤の安定性をより改善することができることも見いだした。この場合、トピラマートを含有する素製剤に、カルボン酸塩である添加剤(前記と同義)、炭酸カルシウム、炭酸ナトリウム、炭酸マグネシウム、ケイ酸カルシウム、ケイ酸マグネシウム、ケイ酸アルミン酸マグネシウム、リン酸ニカリウム等(好ましくは、カルボン酸塩である添加剤(前記と同義))を配合することがより好ましい。 The inventors of the present invention also provide a coating composition containing a compound exhibiting light-shielding properties, wherein the topiramate-containing solid preparation of the present invention is a solid preparation containing a topiramate-containing raw preparation and a film covering the raw preparation. It has also been found that the stability of a topiramate formulation can be further improved by being a solid formulation containing a film formed by coating. In this case, the additive containing the carboxylate (as defined above), calcium carbonate, sodium carbonate, magnesium carbonate, calcium silicate, magnesium silicate, magnesium aluminate silicate, dipotassium phosphate Etc. (preferably, an additive which is a carboxylate (as defined above)) is more preferably blended.
以下に、実施例および試験例に基づいて本発明をより詳細に説明するが、本発明はこれら実施例および試験例に限定されるものではない。
参考例1
従来の方法により得られた粉砕前のトピラマートをハンマーミル(サンプルミル/不二パウダル)を用い、スクリーン穴が直径1 mm、スクリュー回転速度18 rpmで粉砕した。画像解析装置(TMN-1528-01;オリンパス光学工業)を用い、粉砕前後のトピラマートの粒子径(体積平均径、フェレ径)を測定した。結果を第1表に示す。
Hereinafter, the present invention will be described in more detail based on examples and test examples, but the present invention is not limited to these examples and test examples.
Reference example 1
The topiramate before pulverization obtained by the conventional method was pulverized using a hammer mill (sample mill / Fuji powder) at a screen hole diameter of 1 mm and a screw rotation speed of 18 rpm. Using an image analyzer (TMN-1528-01; Olympus Optical Co., Ltd.), the particle diameter (volume average diameter, ferret diameter) of topiramate before and after pulverization was measured. The results are shown in Table 1.
参考例1で得られた粉砕後のトピラマート結晶のそれぞれを用いて、以下の手順で製剤を製造した。第2表に示した組成に従った量のトピラマート、乳糖、結晶セルロースおよびクロスカルメロースナトリウムを流動層造粒機(FLO-5EX;フロイント産業)に入れて混合し、ヒドロキシプロピルセルロース水溶液をスプレーして造粒した。得られた造粒物を整粒(ランデルミル;徳寿製作所)し、ついでステアリン酸マグネシウムと混合(V型混合機;徳寿製作所)した。この混合物を打錠(コレクト12;菊水製作所)し、製剤を得た。 Using each of the pulverized topiramate crystals obtained in Reference Example 1, a preparation was produced by the following procedure. The amount of topiramate, lactose, crystalline cellulose and croscarmellose sodium according to the composition shown in Table 2 is mixed in a fluid bed granulator (FLO-5EX; Freund Sangyo) and sprayed with an aqueous hydroxypropylcellulose solution. And granulated. The resulting granulated product was sized (Landel mill; Tokuju Seisakusho) and then mixed with magnesium stearate (V-type mixer; Tokusu Seisakusho). This mixture was tableted (Collect 12; Kikusui Seisakusho) to obtain a preparation.
比較例1
比較例として、参考例1で得られた粉砕前のトピラマート結晶のそれぞれを用いて、実施例1と同様に製剤を得た。
試験例1
実施例1および比較例1でロットBおよびCの原薬を用いて製造された製剤をガラス容器に入れ、開放状態で40℃/75%RH下で経時的に目視観察を行うとともに、色差計(SQ-2000/日本電色工業)により色差を測定した。結果を第3表に示す。実施例1(粉砕した結晶を使用)は、比較例1(粉砕前の結晶を使用)と比べ明らかに着色しにくかった。
Comparative Example 1
As a comparative example, a preparation was obtained in the same manner as in Example 1 using each of the topiramate crystals before pulverization obtained in Reference Example 1.
Test example 1
In Example 1 and Comparative Example 1, the preparations produced using the APIs of lots B and C were placed in a glass container, and visually observed over time at 40 ° C./75% RH in an open state. The color difference was measured by (SQ-2000 / Nippon Denshoku Industries Co., Ltd.). The results are shown in Table 3. Example 1 (using crushed crystals) was clearly less colored than Comparative Example 1 (using crystals before pulverization).
試験例2
実施例1および比較例1でロットDおよびEの原薬を用いて製造された製剤をガラス容器に入れ、開放状態で60℃/75%RH下で経時的に色差計(SQ-2000/日本電色工業)により色差を測定した。結果を第4表に示すように、実施例1(粉砕した結晶を使用)は、比較例1(粉砕前の結晶を使用)と比べ明らかに着色しにくかった。
Test example 2
The preparations produced in Example 1 and Comparative Example 1 using the APIs of lots D and E were placed in a glass container and color difference meter (SQ-2000 / Japan) over time at 60 ° C / 75% RH in an open state. The color difference was measured by Denshi Kogyo). As shown in Table 4, Example 1 (using crushed crystals) was clearly less colored than Comparative Example 1 (using crushed crystals).
試験例3
実施例1で製造された製剤を、硬度計(PTB-311/ジャパンマシナリー)を用いて、錠剤硬度を測定した。結果を第5表に示す。
Test example 3
The tablet hardness of the preparation produced in Example 1 was measured using a hardness meter (PTB-311 / Japan Machinery). The results are shown in Table 5.
試験例4
実施例1でロットCおよびEを用いて製造された製剤について、溶出試験を実施した。試験液は水900 mL用い、パドル毎分50回転で、経時的にサンプリングを行い、HPLCにより定量を行った。結果を図1および2に結果を示す。
Test example 4
A dissolution test was performed on the formulations produced in Example 1 using lots C and E. The test solution was 900 mL of water, sampled with time at 50 paddles per minute, and quantified by HPLC. The results are shown in FIGS.
参考例1と同様にして得られた粉砕後のトピラマート結晶を、以下の手順で製剤を製造した。第6表に示した組成に従って、トピラマート結晶100 g、乳糖52 g、結晶セルロース18 g、ステアリン酸マグネシウム1 gおよび崩壊剤としてのクロス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、低置換度ヒドロキシプロピルセルロースまたはカルメロース9 gをビニール袋で混合し、180 mg分秤量後、油圧プレスで50 kg/cm2で圧縮成形し、錠剤を得た。 A pulverized topiramate crystal obtained in the same manner as in Reference Example 1 was produced by the following procedure. According to the composition shown in Table 6, topiramate crystals 100 g, lactose 52 g, crystalline cellulose 18 g, magnesium stearate 1 g and croscarmellose sodium as disintegrant, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose or Carmellose 9 g was mixed in a plastic bag, weighed 180 mg, and compressed with a hydraulic press at 50 kg / cm 2 to obtain tablets.
試験例5
実施例2で得られた錠剤をガラス容器に入れ、開放状態で40℃/75%RH下で4ヶ月保存後、色差計(SQ-2000/日本電色工業)を用いて色差を測定した。結果を第7表に示す。
Test Example 5
The tablet obtained in Example 2 was placed in a glass container, stored in an open state at 40 ° C./75% RH for 4 months, and then the color difference was measured using a color difference meter (SQ-2000 / Nippon Denshoku Industries). The results are shown in Table 7.
参考例1と同様にして得られた粉砕後のトピラマート結晶を、以下の手順で製剤を製造した。第8表に示した組成に従って、トピラマート、乳糖、結晶セルロースおよびクロスカルメロースナトリウムまたは低置換度ヒドロキシプロピルセルロースを流動層造粒機(FLO-5EX;フロイント産業)に入れて混合し、ヒドロキシプロピルセルロース水溶液をスプレーして造粒した。得られた造粒物を整粒(ランデルミル;徳寿製作所)し、ついでステアリン酸マグネシウムと混合(V型混合機;徳寿製作所)した。この混合物を打錠(コレクト12;菊水製作所)し、製剤を得た。 A pulverized topiramate crystal obtained in the same manner as in Reference Example 1 was produced by the following procedure. According to the composition shown in Table 8, topiramate, lactose, crystalline cellulose and croscarmellose sodium or low-substituted hydroxypropylcellulose are mixed in a fluid bed granulator (FLO-5EX; Freund Sangyo) The aqueous solution was sprayed and granulated. The resulting granulated product was sized (Landel mill; Tokuju Seisakusho) and then mixed with magnesium stearate (V-type mixer; Tokusu Seisakusho). This mixture was tableted (Collect 12; Kikusui Seisakusho) to obtain a preparation.
実施例3で得られた錠剤を、コーティング機(ハイコータ;フロイント産業)を用い、ヒドロキシプロピルメチルセルロース、酸化チタン、軽質無水ケイ酸を含有するフィルムコーティング剤をスプレーしてコーティングを施して、それぞれフィルムコーティング錠を得た(以下、第8表における実施例3-1、3-2、3-3および3-4をそれぞれコーティングした製剤を実施例4-1、4-2、4-3および4-4と表す)。
試験例6
実施例3および4で得られた製剤をガラス容器に入れ、開放状態で40℃/75%RH下で経時的に目視観察を行うとともに、色差計(SQ-2000/日本電色工業)により色差を測定した。
結果を第9表に示す。
The tablets obtained in Example 3 were coated by spraying a film coating agent containing hydroxypropylmethylcellulose, titanium oxide, and light silicic acid anhydride using a coating machine (Hicoater; Freund Industries). Tablets were obtained (hereinafter, preparations coated with Examples 3-1, 3-2, 3-3 and 3-4 in Table 8 were prepared in Examples 4-1, 4-2, 4-3 and 4-, respectively. 4).
Test Example 6
The preparations obtained in Examples 3 and 4 were placed in a glass container and visually observed over time at 40 ° C./75% RH in an open state, and color difference was measured with a color difference meter (SQ-2000 / Nippon Denshoku Industries Co., Ltd.). Was measured.
The results are shown in Table 9.
Claims (5)
5. The topiramate crystal is a crystal obtained by pulverizing a crude crystal using a pulverizer selected from a hammer mill, a cage mill, a shear mill, an impact mill, and an aerofall mill. The stabilization method described.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2013188248A JP6125957B2 (en) | 2007-04-12 | 2013-09-11 | Topiramate-containing solid preparation |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2007104853 | 2007-04-12 | ||
JP2007104853 | 2007-04-12 | ||
JP2013188248A JP6125957B2 (en) | 2007-04-12 | 2013-09-11 | Topiramate-containing solid preparation |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2008103209A Division JP5424571B2 (en) | 2007-04-12 | 2008-04-11 | Topiramate-containing solid preparation |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016207609A Division JP2017014289A (en) | 2007-04-12 | 2016-10-24 | Topiramate-containing solid preparation |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2013241476A JP2013241476A (en) | 2013-12-05 |
JP2013241476A5 JP2013241476A5 (en) | 2014-02-13 |
JP6125957B2 true JP6125957B2 (en) | 2017-05-10 |
Family
ID=40141447
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2008103209A Active JP5424571B2 (en) | 2007-04-12 | 2008-04-11 | Topiramate-containing solid preparation |
JP2013188248A Active JP6125957B2 (en) | 2007-04-12 | 2013-09-11 | Topiramate-containing solid preparation |
JP2016207609A Pending JP2017014289A (en) | 2007-04-12 | 2016-10-24 | Topiramate-containing solid preparation |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2008103209A Active JP5424571B2 (en) | 2007-04-12 | 2008-04-11 | Topiramate-containing solid preparation |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016207609A Pending JP2017014289A (en) | 2007-04-12 | 2016-10-24 | Topiramate-containing solid preparation |
Country Status (1)
Country | Link |
---|---|
JP (3) | JP5424571B2 (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110009347A1 (en) | 2009-07-08 | 2011-01-13 | Yin Liang | Combination therapy for the treatment of diabetes |
KR101931209B1 (en) | 2010-05-11 | 2018-12-20 | 얀센 파마슈티카 엔.브이. | Pharmaceutical formulations comprising 1-(beta-d-glucopyranosyl)-2-thienyl-methylbenzene derivatives as inhibitors of sglt |
AU2012241897C1 (en) | 2011-04-13 | 2017-05-11 | Janssen Pharmaceutica Nv | Process for the preparation of compounds useful as inhibitors of SGLT2 |
IN2013MU02470A (en) * | 2013-07-25 | 2015-06-26 | Cadila Healthcare Ltd | |
CN108379588A (en) * | 2018-03-05 | 2018-08-10 | 合肥合源药业有限公司 | Topiramate composition |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL103172A (en) * | 1991-09-19 | 1997-01-10 | Mcneilab Inc | Preparation of chlorosulfate and sulfamate derivatives of 2, 3:4, 5-bis-o-(1-methylethylidene)-beta-d-fructopyranose and (1-methylcyclohexyl) methanol |
UA65607C2 (en) * | 1998-03-04 | 2004-04-15 | Орто-Макнейл Фармацевтикал, Інк. | Pharmaceutical composition (variants) and process for its preparation |
EP1157682A1 (en) * | 2000-05-25 | 2001-11-28 | Cilag AG | Blister package for topiramate tablets |
DE10153078A1 (en) * | 2001-10-30 | 2003-05-22 | Degussa | Use of granules based on pyrogenic silicon dioxide in pharmaceutical compositions |
EP1587499A1 (en) * | 2003-01-31 | 2005-10-26 | Elan Pharma International Limited | Nanoparticulate topiramate formulations |
EP1701708A2 (en) * | 2003-12-29 | 2006-09-20 | Alza Corporation | Novel drug compositions and dosage forms of topiramate |
EP1973528B1 (en) * | 2006-11-17 | 2012-11-07 | Supernus Pharmaceuticals, Inc. | Sustained-release formulations of topiramate |
WO2008070670A2 (en) * | 2006-12-04 | 2008-06-12 | Supernus Pharmaceuticals, Inc. | Enhanced immediate release formulations of topiramate |
-
2008
- 2008-04-11 JP JP2008103209A patent/JP5424571B2/en active Active
-
2013
- 2013-09-11 JP JP2013188248A patent/JP6125957B2/en active Active
-
2016
- 2016-10-24 JP JP2016207609A patent/JP2017014289A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
JP2008280345A (en) | 2008-11-20 |
JP5424571B2 (en) | 2014-02-26 |
JP2013241476A (en) | 2013-12-05 |
JP2017014289A (en) | 2017-01-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP2017014289A (en) | Topiramate-containing solid preparation | |
EP2229938B9 (en) | Ezetimibe compositions | |
EP2614816A1 (en) | Granules containing bitter drug and orally disintegrating tablet | |
JP5750847B2 (en) | Particulate pharmaceutical composition for oral administration of atorvastatin | |
EA013161B1 (en) | An oral dosage form | |
JP6133009B2 (en) | Topiramate granules | |
JPWO2005097070A1 (en) | Solid formulation with improved stability and method for producing the same | |
CN101103965A (en) | Stable solid preparation containing amorphous cefditoren pivoxil and preparation method thereof | |
JP2015063521A (en) | Tablet with high drug content and production method thereof | |
AU2014225449B2 (en) | Stabilization of moisture-sensitive drugs | |
WO2007073389A1 (en) | Compressed solid dosage forms with drugs of low solubility and process for making the same | |
JP2012041293A (en) | Intraoral collapsible tablet containing lactobacillus or extracted ingredient thereof | |
JP4754211B2 (en) | Granular pharmaceutical composition and method for producing the same | |
US20070148245A1 (en) | Compressed solid dosage forms with drugs of low solubility and process for making the same | |
JP5198001B2 (en) | Stabilized solid formulation | |
Kestur et al. | Excipients for conventional oral solid dosage forms | |
US20090048336A1 (en) | Escitalopram oxalate powders | |
WO2013130584A2 (en) | Formulation containing ws727713 | |
JP4993274B2 (en) | Method for producing fenofibrate-containing pharmaceutical composition | |
JP2024076228A (en) | Nintedanib Ethanesulfonate Tablets | |
JP2021070658A (en) | Abiraterone acetate-containing preparation | |
JP2023038181A (en) | zinc acetate tablets | |
JP2023180494A (en) | Zonisamide-containing orally disintegrating tablet | |
JP2016098187A (en) | Orally disintegrating tablet | |
JP2022047194A (en) | Pharmaceutical tablet containing axitinib as active ingredient and method for producing the same |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20131008 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20131128 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20131218 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20140930 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20141120 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20150519 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20150812 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20150827 |
|
A912 | Re-examination (zenchi) completed and case transferred to appeal board |
Free format text: JAPANESE INTERMEDIATE CODE: A912 Effective date: 20151023 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20161024 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170203 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20170406 |
|
R151 | Written notification of patent or utility model registration |
Ref document number: 6125957 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R151 |
|
S531 | Written request for registration of change of domicile |
Free format text: JAPANESE INTERMEDIATE CODE: R313531 |
|
S533 | Written request for registration of change of name |
Free format text: JAPANESE INTERMEDIATE CODE: R313533 |
|
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 |