JP2023170811A - Method for producing tablet - Google Patents
Method for producing tablet Download PDFInfo
- Publication number
- JP2023170811A JP2023170811A JP2022082851A JP2022082851A JP2023170811A JP 2023170811 A JP2023170811 A JP 2023170811A JP 2022082851 A JP2022082851 A JP 2022082851A JP 2022082851 A JP2022082851 A JP 2022082851A JP 2023170811 A JP2023170811 A JP 2023170811A
- Authority
- JP
- Japan
- Prior art keywords
- tablet
- powder composition
- mixing
- granules
- component
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 49
- 238000002156 mixing Methods 0.000 claims abstract description 152
- 239000000843 powder Substances 0.000 claims abstract description 134
- 239000000203 mixture Substances 0.000 claims abstract description 121
- 238000000034 method Methods 0.000 claims abstract description 106
- 239000008187 granular material Substances 0.000 claims abstract description 89
- 239000003814 drug Substances 0.000 claims abstract description 80
- 238000007906 compression Methods 0.000 claims description 115
- 230000006835 compression Effects 0.000 claims description 112
- 238000005469 granulation Methods 0.000 claims description 101
- 230000003179 granulation Effects 0.000 claims description 101
- 229940079593 drug Drugs 0.000 claims description 77
- 229960001680 ibuprofen Drugs 0.000 claims description 45
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 44
- 230000002378 acidificating effect Effects 0.000 claims description 36
- 239000007884 disintegrant Substances 0.000 claims description 29
- 229920003169 water-soluble polymer Polymers 0.000 claims description 28
- 239000002245 particle Substances 0.000 claims description 25
- 238000003756 stirring Methods 0.000 claims description 16
- 238000007873 sieving Methods 0.000 claims description 8
- 239000004484 Briquette Substances 0.000 claims description 6
- 239000002253 acid Substances 0.000 abstract 3
- 239000003826 tablet Substances 0.000 description 170
- 239000010410 layer Substances 0.000 description 88
- 239000004570 mortar (masonry) Substances 0.000 description 25
- 239000011812 mixed powder Substances 0.000 description 20
- 239000004615 ingredient Substances 0.000 description 16
- 239000000314 lubricant Substances 0.000 description 16
- 229940024546 aluminum hydroxide gel Drugs 0.000 description 15
- SMYKVLBUSSNXMV-UHFFFAOYSA-K aluminum;trihydroxide;hydrate Chemical compound O.[OH-].[OH-].[OH-].[Al+3] SMYKVLBUSSNXMV-UHFFFAOYSA-K 0.000 description 15
- 239000011248 coating agent Substances 0.000 description 15
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 14
- 238000010298 pulverizing process Methods 0.000 description 13
- 238000011049 filling Methods 0.000 description 11
- 238000000576 coating method Methods 0.000 description 10
- 238000004090 dissolution Methods 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 238000009775 high-speed stirring Methods 0.000 description 9
- 238000012545 processing Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 229920002472 Starch Polymers 0.000 description 8
- 230000036316 preload Effects 0.000 description 8
- 239000002356 single layer Substances 0.000 description 8
- 239000008107 starch Substances 0.000 description 8
- 229940032147 starch Drugs 0.000 description 8
- 235000019698 starch Nutrition 0.000 description 8
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 7
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 7
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 7
- 238000005461 lubrication Methods 0.000 description 7
- 235000019359 magnesium stearate Nutrition 0.000 description 7
- 241001489705 Aquarius Species 0.000 description 6
- 102100026816 DNA-dependent metalloprotease SPRTN Human genes 0.000 description 6
- 101710175461 DNA-dependent metalloprotease SPRTN Proteins 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- -1 sucrose fatty acid ester Chemical class 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 5
- 239000000654 additive Substances 0.000 description 5
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 5
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 5
- 229950008138 carmellose Drugs 0.000 description 5
- 229920000609 methyl cellulose Polymers 0.000 description 5
- 235000010981 methylcellulose Nutrition 0.000 description 5
- 239000001923 methylcellulose Substances 0.000 description 5
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 5
- 238000009700 powder processing Methods 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- 239000004605 External Lubricant Substances 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- 239000004372 Polyvinyl alcohol Substances 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
- 230000001754 anti-pyretic effect Effects 0.000 description 4
- 229960001948 caffeine Drugs 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 238000000227 grinding Methods 0.000 description 4
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 229920002451 polyvinyl alcohol Polymers 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 238000003825 pressing Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 235000012239 silicon dioxide Nutrition 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 3
- 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 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 229960001138 acetylsalicylic acid Drugs 0.000 description 3
- 229940035676 analgesics Drugs 0.000 description 3
- 239000000730 antalgic agent Substances 0.000 description 3
- 239000002221 antipyretic Substances 0.000 description 3
- 239000001913 cellulose Substances 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
- 239000003086 colorant Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 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
- 235000010355 mannitol Nutrition 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000004014 plasticizer Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 244000215068 Acacia senegal Species 0.000 description 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
- 239000004386 Erythritol Substances 0.000 description 2
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-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
- 229920000084 Gum arabic Polymers 0.000 description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 2
- 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 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 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 2
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 239000000498 cooling water Substances 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 235000019414 erythritol Nutrition 0.000 description 2
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 2
- 229940009714 erythritol Drugs 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 238000005227 gel permeation chromatography Methods 0.000 description 2
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 2
- 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 2
- 239000003326 hypnotic agent Substances 0.000 description 2
- 230000000147 hypnotic effect Effects 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 2
- 229960000991 ketoprofen Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 229960001855 mannitol Drugs 0.000 description 2
- 238000000691 measurement method Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229960005489 paracetamol Drugs 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 229920002432 poly(vinyl methyl ether) polymer Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000932 sedative agent Substances 0.000 description 2
- 229940125723 sedative agent Drugs 0.000 description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229940083542 sodium Drugs 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 238000001931 thermography Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 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
- 235000013311 vegetables Nutrition 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- 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
- AKNNEGZIBPJZJG-MSOLQXFVSA-N (-)-noscapine Chemical compound CN1CCC2=CC=3OCOC=3C(OC)=C2[C@@H]1[C@@H]1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-MSOLQXFVSA-N 0.000 description 1
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 1
- BGRJTUBHPOOWDU-NSHDSACASA-N (S)-(-)-sulpiride Chemical compound CCN1CCC[C@H]1CNC(=O)C1=CC(S(N)(=O)=O)=CC=C1OC BGRJTUBHPOOWDU-NSHDSACASA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- PMGQWSIVQFOFOQ-BDUVBVHRSA-N (e)-but-2-enedioic acid;(2r)-2-[2-[1-(4-chlorophenyl)-1-phenylethoxy]ethyl]-1-methylpyrrolidine Chemical compound OC(=O)\C=C\C(O)=O.CN1CCC[C@@H]1CCOC(C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 PMGQWSIVQFOFOQ-BDUVBVHRSA-N 0.000 description 1
- SERLAGPUMNYUCK-DCUALPFSSA-N 1-O-alpha-D-glucopyranosyl-D-mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O SERLAGPUMNYUCK-DCUALPFSSA-N 0.000 description 1
- 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 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
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 description 1
- CMCCHHWTTBEZNM-UHFFFAOYSA-N 2-bromo-N-carbamoyl-3-methylbutanamide Chemical compound CC(C)C(Br)C(=O)NC(N)=O CMCCHHWTTBEZNM-UHFFFAOYSA-N 0.000 description 1
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 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
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 244000144725 Amygdalus communis Species 0.000 description 1
- 235000011437 Amygdalus communis Nutrition 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- 229920001342 Bakelite® Polymers 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- QMBJSIBWORFWQT-DFXBJWIESA-N Chlormadinone acetate Chemical compound C1=C(Cl)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 QMBJSIBWORFWQT-DFXBJWIESA-N 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 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
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 description 1
- IIUZTXTZRGLYTI-UHFFFAOYSA-N Dihydrogriseofulvin Natural products COC1CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 IIUZTXTZRGLYTI-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- 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 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- BIVBRWYINDPWKA-VLQRKCJKSA-L Glycyrrhizinate dipotassium Chemical compound [K+].[K+].O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C([O-])=O)[C@@H]1O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@H]1O BIVBRWYINDPWKA-VLQRKCJKSA-L 0.000 description 1
- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 description 1
- 229920003116 HPC-SSL Polymers 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 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
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 235000019501 Lemon oil Nutrition 0.000 description 1
- 229920000161 Locust bean gum 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
- OCJYIGYOJCODJL-UHFFFAOYSA-N Meclizine Chemical compound CC1=CC=CC(CN2CCN(CC2)C(C=2C=CC=CC=2)C=2C=CC(Cl)=CC=2)=C1 OCJYIGYOJCODJL-UHFFFAOYSA-N 0.000 description 1
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 description 1
- 235000014435 Mentha Nutrition 0.000 description 1
- 241001072983 Mentha Species 0.000 description 1
- 235000006679 Mentha X verticillata Nutrition 0.000 description 1
- 235000002899 Mentha suaveolens Nutrition 0.000 description 1
- 235000001636 Mentha x rotundifolia Nutrition 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- DDUHZTYCFQRHIY-UHFFFAOYSA-N Negwer: 6874 Natural products COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 description 1
- 244000183278 Nephelium litchi Species 0.000 description 1
- 235000015742 Nephelium litchi Nutrition 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 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
- 239000004376 Sucralose Substances 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
- 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
- 229920001615 Tragacanth Polymers 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- YPTFHLJNWSJXKG-UHFFFAOYSA-N Trepibutone Chemical compound CCOC1=CC(OCC)=C(C(=O)CCC(O)=O)C=C1OCC YPTFHLJNWSJXKG-UHFFFAOYSA-N 0.000 description 1
- FNYLWPVRPXGIIP-UHFFFAOYSA-N Triamterene Chemical compound NC1=NC2=NC(N)=NC(N)=C2N=C1C1=CC=CC=C1 FNYLWPVRPXGIIP-UHFFFAOYSA-N 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
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- QYKIQEUNHZKYBP-UHFFFAOYSA-N Vinyl ether Chemical compound C=COC=C QYKIQEUNHZKYBP-UHFFFAOYSA-N 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- YWXYYJSYQOXTPL-JGWLITMVSA-N [(3r,3ar,6s,6as)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] nitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O)CO[C@@H]21 YWXYYJSYQOXTPL-JGWLITMVSA-N 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
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 229960005142 alclofenac Drugs 0.000 description 1
- ARHWPKZXBHOEEE-UHFFFAOYSA-N alclofenac Chemical compound OC(=O)CC1=CC=C(OCC=C)C(Cl)=C1 ARHWPKZXBHOEEE-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 235000020224 almond Nutrition 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- AKNNEGZIBPJZJG-UHFFFAOYSA-N alpha-noscapine Natural products CN1CCC2=CC=3OCOC=3C(OC)=C2C1C1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-UHFFFAOYSA-N 0.000 description 1
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 229940069428 antacid Drugs 0.000 description 1
- 239000003159 antacid agent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940125716 antipyretic agent Drugs 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- KSUUMAWCGDNLFK-UHFFFAOYSA-N apronal Chemical compound C=CCC(C(C)C)C(=O)NC(N)=O KSUUMAWCGDNLFK-UHFFFAOYSA-N 0.000 description 1
- 229960004459 apronal Drugs 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 1
- 229960000396 atropine Drugs 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-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
- 229960002537 betamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 229960002335 bromhexine hydrochloride Drugs 0.000 description 1
- 229960004064 bumetanide Drugs 0.000 description 1
- MAEIEVLCKWDQJH-UHFFFAOYSA-N bumetanide Chemical compound CCCCNC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1OC1=CC=CC=C1 MAEIEVLCKWDQJH-UHFFFAOYSA-N 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
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 229960001616 chlormadinone acetate Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229960002689 clemastine fumarate Drugs 0.000 description 1
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 1
- 229960001214 clofibrate Drugs 0.000 description 1
- DGBIGWXXNGSACT-UHFFFAOYSA-N clonazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1Cl DGBIGWXXNGSACT-UHFFFAOYSA-N 0.000 description 1
- 229960003120 clonazepam Drugs 0.000 description 1
- 239000011247 coating layer Substances 0.000 description 1
- 229940124579 cold medicine Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000000748 compression moulding Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000003218 coronary vasodilator agent Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- POZRVZJJTULAOH-LHZXLZLDSA-N danazol Chemical compound C1[C@]2(C)[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=CC2=C1C=NO2 POZRVZJJTULAOH-LHZXLZLDSA-N 0.000 description 1
- 229960000766 danazol Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000000280 densification Methods 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 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 1
- GDVKFRBCXAPAQJ-UHFFFAOYSA-A dialuminum;hexamagnesium;carbonate;hexadecahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-]C([O-])=O GDVKFRBCXAPAQJ-UHFFFAOYSA-A 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 description 1
- 229960005156 digoxin Drugs 0.000 description 1
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 description 1
- ADYPXRFPBQGGAH-UMYZUSPBSA-N dihydroergotamine mesylate Chemical compound CS(O)(=O)=O.C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2[C@@H](C=3C=CC=C4NC=C(C=34)C2)C1)C)C1=CC=CC=C1 ADYPXRFPBQGGAH-UMYZUSPBSA-N 0.000 description 1
- 229960000807 dihydroergotamine mesylate Drugs 0.000 description 1
- 229960004993 dimenhydrinate Drugs 0.000 description 1
- MZDOIJOUFRQXHC-UHFFFAOYSA-N dimenhydrinate Chemical compound O=C1N(C)C(=O)N(C)C2=NC(Cl)=N[C]21.C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 MZDOIJOUFRQXHC-UHFFFAOYSA-N 0.000 description 1
- 229940101029 dipotassium glycyrrhizinate Drugs 0.000 description 1
- 229960002768 dipyridamole Drugs 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- UVTNFZQICZKOEM-UHFFFAOYSA-N disopyramide Chemical compound C=1C=CC=NC=1C(C(N)=O)(CCN(C(C)C)C(C)C)C1=CC=CC=C1 UVTNFZQICZKOEM-UHFFFAOYSA-N 0.000 description 1
- 229960001066 disopyramide Drugs 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- YRSGDLIATOURQO-UHFFFAOYSA-N ethyl 4-acetyl-5-oxohexanoate Chemical compound CCOC(=O)CCC(C(C)=O)C(C)=O YRSGDLIATOURQO-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 229960005293 etodolac Drugs 0.000 description 1
- XFBVBWWRPKNWHW-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=N[C]3C(CC)=CC=CC3=C21 XFBVBWWRPKNWHW-UHFFFAOYSA-N 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 230000003419 expectorant effect Effects 0.000 description 1
- 229940066493 expectorants Drugs 0.000 description 1
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 description 1
- 229960001596 famotidine Drugs 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 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
- 150000004676 glycans Chemical class 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 239000011361 granulated particle Substances 0.000 description 1
- 235000021552 granulated sugar Nutrition 0.000 description 1
- DDUHZTYCFQRHIY-RBHXEPJQSA-N griseofulvin Chemical compound COC1=CC(=O)C[C@@H](C)[C@@]11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-RBHXEPJQSA-N 0.000 description 1
- 229960002867 griseofulvin Drugs 0.000 description 1
- 229960003878 haloperidol Drugs 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 229960001545 hydrotalcite Drugs 0.000 description 1
- 229910001701 hydrotalcite Inorganic materials 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 229920013821 hydroxy alkyl cellulose Polymers 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-UHFFFAOYSA-N 0.000 description 1
- XJSFLOJWULLJQS-NGVXBBESSA-N josamycin Chemical compound CO[C@H]1[C@H](OC(C)=O)CC(=O)O[C@H](C)C\C=C\C=C\[C@H](O)[C@H](C)C[C@H](CC=O)[C@@H]1O[C@H]1[C@H](O)[C@@H](N(C)C)[C@H](O[C@@H]2O[C@@H](C)[C@H](OC(=O)CC(C)C)[C@](C)(O)C2)[C@@H](C)O1 XJSFLOJWULLJQS-NGVXBBESSA-N 0.000 description 1
- 229960004144 josamycin Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol 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-JVCRWLNRSA-N 0.000 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- 239000007942 layered tablet Substances 0.000 description 1
- 239000010501 lemon oil Substances 0.000 description 1
- 229940087305 limonene Drugs 0.000 description 1
- 235000001510 limonene Nutrition 0.000 description 1
- 235000010420 locust bean gum Nutrition 0.000 description 1
- 239000000711 locust bean gum Substances 0.000 description 1
- 229960002373 loxoprofen Drugs 0.000 description 1
- WORCCYVLMMTGFR-UHFFFAOYSA-M loxoprofen sodium Chemical compound [Na+].C1=CC(C(C([O-])=O)C)=CC=C1CC1C(=O)CCC1 WORCCYVLMMTGFR-UHFFFAOYSA-M 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 229960001708 magnesium carbonate Drugs 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- 239000000845 maltitol Substances 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
- 229940018415 meclizine hydrochloride Drugs 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- 229960001929 meloxicam Drugs 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 229960004503 metoclopramide Drugs 0.000 description 1
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- PLPRGLOFPNJOTN-UHFFFAOYSA-N narcotine Natural products COc1ccc2C(OC(=O)c2c1OC)C3Cc4c(CN3C)cc5OCOc5c4OC PLPRGLOFPNJOTN-UHFFFAOYSA-N 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- 229960001454 nitrazepam Drugs 0.000 description 1
- KJONHKAYOJNZEC-UHFFFAOYSA-N nitrazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1 KJONHKAYOJNZEC-UHFFFAOYSA-N 0.000 description 1
- 229960004708 noscapine Drugs 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 229960002695 phenobarbital Drugs 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 229960002036 phenytoin Drugs 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
- PHUTUTUABXHXLW-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=NC=C[C]12 PHUTUTUABXHXLW-UHFFFAOYSA-N 0.000 description 1
- 229960002508 pindolol Drugs 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 229920001495 poly(sodium acrylate) polymer Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 229960002386 prazosin hydrochloride Drugs 0.000 description 1
- WFXFYZULCQKPIP-UHFFFAOYSA-N prazosin hydrochloride Chemical compound [H+].[Cl-].N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 WFXFYZULCQKPIP-UHFFFAOYSA-N 0.000 description 1
- 229940088417 precipitated calcium carbonate Drugs 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 229960002393 primidone Drugs 0.000 description 1
- DQMZLTXERSFNPB-UHFFFAOYSA-N primidone Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NCNC1=O DQMZLTXERSFNPB-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 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
- 229930002330 retinoic acid Natural products 0.000 description 1
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 description 1
- 229960001225 rifampicin Drugs 0.000 description 1
- 229940085605 saccharin sodium Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 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 1
- NNMHYFLPFNGQFZ-UHFFFAOYSA-M sodium polyacrylate Chemical compound [Na+].[O-]C(=O)C=C NNMHYFLPFNGQFZ-UHFFFAOYSA-M 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- MNQYNQBOVCBZIQ-JQOFMKNESA-A sucralfate Chemical compound O[Al](O)OS(=O)(=O)O[C@@H]1[C@@H](OS(=O)(=O)O[Al](O)O)[C@H](OS(=O)(=O)O[Al](O)O)[C@@H](COS(=O)(=O)O[Al](O)O)O[C@H]1O[C@@]1(COS(=O)(=O)O[Al](O)O)[C@@H](OS(=O)(=O)O[Al](O)O)[C@H](OS(=O)(=O)O[Al](O)O)[C@@H](OS(=O)(=O)O[Al](O)O)O1 MNQYNQBOVCBZIQ-JQOFMKNESA-A 0.000 description 1
- 229960004291 sucralfate Drugs 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 229960004940 sulpiride Drugs 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000000892 thaumatin Substances 0.000 description 1
- 235000010436 thaumatin Nutrition 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- NZHGWWWHIYHZNX-CSKARUKUSA-N tranilast Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C(=O)NC1=CC=CC=C1C(O)=O NZHGWWWHIYHZNX-CSKARUKUSA-N 0.000 description 1
- 229960005342 tranilast Drugs 0.000 description 1
- 229960004974 trepibutone Drugs 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 229960001288 triamterene Drugs 0.000 description 1
- 229960003386 triazolam Drugs 0.000 description 1
- JOFWLTCLBGQGBO-UHFFFAOYSA-N triazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl JOFWLTCLBGQGBO-UHFFFAOYSA-N 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
- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019159 vitamin B9 Nutrition 0.000 description 1
- 239000011727 vitamin B9 Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Glanulating (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
本発明は、錠剤の製造方法に関する。 The present invention relates to a method for manufacturing tablets.
イブプロフェン等のプロピオン酸系非ステロイド抗炎症剤（ＮＳＡＩＤｓ）は、優れた消炎、鎮痛及び解熱作用を有し、副作用が比較的少ないことから鎮痛・解熱剤及び感冒薬の成分として広く使用されている。ＮＳＡＩＤｓ等の薬物を含有する錠剤が速やかに薬効を発揮するためには、胃内で錠剤が速やかに崩壊し、その後、有効成分が速やかに溶出（溶解）することが求められる。
しかし、イブプロフェンのような酸性の水難溶性薬物は、疎水性が高く錠剤内部への水の浸透を妨げやすいため、錠剤の崩壊性に課題があり、その結果、有効成分の溶出（溶解）が進行しにくく、速効性を十分に発揮しにくいという問題がある。
BACKGROUND OF THE INVENTION Propionic acid non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen have excellent anti-inflammatory, analgesic and antipyretic effects and have relatively few side effects, and are therefore widely used as ingredients in analgesics and antipyretics and cold medicines. In order for tablets containing drugs such as NSAIDs to quickly exert their medicinal effects, the tablets are required to disintegrate quickly in the stomach, and then the active ingredients must be rapidly eluted (dissolved).
However, acidic and poorly water-soluble drugs such as ibuprofen are highly hydrophobic and tend to prevent water from penetrating inside the tablet, which poses a problem with tablet disintegration, resulting in the elution (dissolution) of the active ingredient. There are problems in that it is difficult to use, and it is difficult to fully demonstrate fast-acting properties.
そこで、酸性の水難溶性薬物を含有する錠剤の崩壊性、溶出性に関する課題を解決する方法が検討されている。
例えば特許文献１には、難溶性医薬品に、ポリビニルピロリドン、ヒドロキシプロピルセルロース等を配合して得られた難溶性医薬品配合物を流動層造粒法により造粒した圧縮成型物が開示されている。特許文献１によれば、スプレードライ法やその他湿式造粒法により造粒した圧縮成型物に比べて、優れた崩壊性、吸収性を発現できるとしている。
Therefore, methods for solving problems related to the disintegration and dissolution properties of tablets containing acidic, poorly water-soluble drugs are being investigated.
For example, Patent Document 1 discloses a compression molded product obtained by granulating a poorly soluble pharmaceutical formulation obtained by blending a poorly soluble pharmaceutical with polyvinylpyrrolidone, hydroxypropyl cellulose, etc. by a fluidized bed granulation method. According to Patent Document 1, it is possible to exhibit superior disintegration and absorbency compared to compression molded products granulated by spray drying or other wet granulation methods.
しかし、イブプロフェンの場合、ヒドロキシプロピルセルロース等の汎用の結合剤を含む溶液を用いて流動層造粒や他の湿式造粒を行うと、造粒粒子の溶出性は向上するものの、その前段階である錠剤の崩壊性が著しく低下し、速効性が発揮しにくくなる場合がある。また、流動層造粒法は加水工程及び乾燥工程が必要であり、製造工程数が多く複雑になるため、生産効率の点で課題がある。 However, in the case of ibuprofen, when fluidized bed granulation or other wet granulation is performed using a solution containing a general-purpose binder such as hydroxypropylcellulose, the dissolution of the granulated particles is improved, but the In some cases, the disintegration properties of certain tablets are significantly reduced, making it difficult for them to exhibit immediate efficacy. In addition, the fluidized bed granulation method requires a water addition process and a drying process, and the number of manufacturing steps is large and complicated, which poses a problem in terms of production efficiency.
ローラーコンパクター型、ブリケット型に代表される圧縮造粒装置を用いた圧縮造粒法は、加水工程及び乾燥工程を省略できるため生産性が高い造粒方法であり、有効成分の含量均一性確保、打錠障害を改善するため、錠剤の製造においても汎用されている。
例えば特許文献２には、イブプロフェンと、ショ糖脂肪酸エステルと、軽質無水ケイ酸等の滑沢剤と、結晶セルロース等の賦形剤と、崩壊剤とを含む混合物を圧縮造粒した後に打錠して錠剤を製造する方法が開示されている。
The compression granulation method using a compression granulation device such as a roller compactor type or briquette type is a highly productive granulation method because it can omit the water addition process and drying process, ensuring uniform content of active ingredients, It is also widely used in the manufacture of tablets to improve tableting problems.
For example, Patent Document 2 discloses that a mixture containing ibuprofen, sucrose fatty acid ester, a lubricant such as light silicic anhydride, an excipient such as crystalline cellulose, and a disintegrant is compressed and granulated, and then tableted. A method of manufacturing tablets is disclosed.
しかしながら、イブプロフェンを圧縮造粒した場合、経時による崩壊時間のばらつきが大きくなりやすく、また、経時に伴う崩壊性の低下（崩壊遅延）が生じることもある。
このように、崩壊時間のばらつきが小さく、崩壊遅延が抑制された、酸性の水難溶性薬物を含有する錠剤を生産性よく製造することは困難である。
However, when ibuprofen is compressed and granulated, the disintegration time tends to vary widely over time, and a decrease in disintegration properties (delayed disintegration) may occur over time.
As described above, it is difficult to efficiently produce tablets containing acidic, poorly water-soluble drugs with small disintegration time variations and suppressed disintegration delay.
本発明は、経時に伴う崩壊時間のばらつきが小さく、崩壊遅延が抑制された、酸性の水難溶性薬物を含有する錠剤を生産性よく製造する方法を提供することを目的とする。 An object of the present invention is to provide a method for manufacturing with high productivity tablets containing an acidic, poorly water-soluble drug, with small variations in disintegration time over time and suppressed delay in disintegration.
本発明者らは鋭意検討した結果、圧縮造粒装置に備わるロール圧縮部（１対のロールの間）を通過する造粒前の粉体の密度が不均一であることが、経時による崩壊時間のばらつきや崩壊遅延の原因となることを突き止めた。そこで、圧縮造粒工程の前に、酸性の水難溶性薬物を含有する粉体組成物を２回以上混合することで、ロール圧縮部を通過する粉体の密度が均一となり、経時による崩壊時間のばらつきと崩壊遅延を改善できることを見出し、本発明を完成させるに至った。 As a result of intensive studies, the present inventors found that the density of the powder before granulation passing through the roll compression part (between a pair of rolls) provided in the compression granulation device is non-uniform, and the disintegration time due to time. It was found that this was the cause of the dispersion and delay in disintegration. Therefore, by mixing the powder composition containing the acidic poorly water-soluble drug two or more times before the compression granulation process, the density of the powder passing through the roll compression section becomes uniform, and the disintegration time over time is reduced. It was discovered that variations and disintegration delay could be improved, and the present invention was completed.
すなわち、本発明は以下の態様を有する。
［１］ 酸性の水難溶性薬物（Ａ）を含有する錠剤の製造方法であって、
前記酸性の水難溶性薬物（Ａ）を含有する粉体組成物を混合する混合工程と、
圧縮造粒装置（Ｙ）を用いて、前記混合工程において混合された前記粉体組成物を圧縮造粒し、造粒顆粒を得る圧縮造粒工程と、
を有し、
前記圧縮造粒装置（Ｙ）が、ローラーコンパクター型圧縮造粒装置又はブリケット型圧縮造粒装置であり、
前記圧縮造粒工程の前に前記混合工程を２回以上行い、１回目の混合工程で前記粉体組成物の一部又は全部を混合し、少なくとも前記圧縮造粒工程の直前の混合工程で前記粉体組成物の全部を混合する、錠剤の製造方法。
［２］ １回目の混合工程において混合された前記粉体組成物を２回目以降の混合工程でさらに混合する、前記［１］の錠剤の製造方法。
［３］ 前記混合工程は、撹拌混合機又は容器回転型混合機を用いて前記粉体組成物を混合する工程である、前記［１］又は［２］の錠剤の製造方法。
［４］ 前記酸性の水難溶性薬物（Ａ）が、イブプロフェンである、前記［１］～［３］のいずれかの錠剤の製造方法。
［５］ 前記造粒顆粒中に、崩壊剤（Ｂ）及び水溶性高分子（Ｃ）の少なくとも一方を含有する、前記［１］～［４］のいずれかの錠剤の製造方法。
［６］ 前記圧縮造粒工程の後に、前記造粒顆粒中の粒子径が２５０μｍ以下である粒子の含有割合が３０質量％未満となるように、前記造粒顆粒を篩過する篩過工程をさらに有する、前記［１］～［５］のいずれかの錠剤の製造方法。
That is, the present invention has the following aspects.
[1] A method for producing a tablet containing an acidic poorly water-soluble drug (A), comprising:
a mixing step of mixing a powder composition containing the acidic poorly water-soluble drug (A);
A compression granulation step in which the powder composition mixed in the mixing step is compressed and granulated using a compression granulation device (Y) to obtain granules;
has
The compression granulation device (Y) is a roller compactor type compression granulation device or a briquette type compression granulation device,
The mixing step is performed twice or more before the compression granulation step, and part or all of the powder composition is mixed in the first mixing step, and at least the mixing step immediately before the compression granulation step is performed. A method for manufacturing tablets, which involves mixing all of the powder composition.
[2] The method for producing a tablet according to [1] above, wherein the powder composition mixed in the first mixing step is further mixed in a second or subsequent mixing step.
[3] The method for manufacturing tablets according to [1] or [2], wherein the mixing step is a step of mixing the powder composition using a stirring mixer or a container rotating mixer.
[4] The method for producing a tablet according to any one of [1] to [3] above, wherein the acidic poorly water-soluble drug (A) is ibuprofen.
[5] The method for producing a tablet according to any one of [1] to [4] above, wherein the granules contain at least one of a disintegrant (B) and a water-soluble polymer (C).
[6] After the compression granulation step, a sieving step of sieving the granules such that the content of particles having a particle size of 250 μm or less in the granules is less than 30% by mass. The method for producing a tablet according to any one of [1] to [5] above, further comprising:
本発明によれば、経時に伴う崩壊時間のばらつきが小さく、崩壊遅延が抑制された、酸性の水難溶性薬物を含有する錠剤を生産性よく製造する方法を提供できる。 According to the present invention, it is possible to provide a method for producing with high productivity a tablet containing an acidic, poorly water-soluble drug, which has small variations in disintegration time over time and suppresses delay in disintegration.
本発明の錠剤の製造方法は、酸性の水難溶性薬物（Ａ）を含有する錠剤を製造する方法であり、詳しくは後述するが、混合工程と圧縮造粒工程とを有する。
錠剤は、例えば後述の混合工程と圧縮造粒工程とを経て得られる、酸性の水難溶性薬物（Ａ）を含む造粒顆粒（以下、「造粒顆粒（Ｇ）」ともいう。）を打錠して得られる。
造粒顆粒（Ｇ）は、少なくとも酸性の水難溶性薬物（Ａ）を含むが、酸性の水難溶性薬物（Ａ）以外の成分（任意成分）を含んでいてもよい。例えば、造粒顆粒（Ｇ）は、酸性の水難溶性薬物（Ａ）に加えて、崩壊剤（Ｂ）及び水溶性高分子（Ｃ）の少なくとも一方を含有することが好ましい。また、造粒顆粒（Ｇ）は、本発明の効果等を損なわない範囲内であれば、必要に応じて、崩壊剤（Ｂ）及び水溶性高分子（Ｃ）以外の任意成分（以下、「任意成分（Ｍ）」ともいう。）をさらに含有していてもよい。すなわち、錠剤は、酸性の水難溶性薬物（Ａ）に加えて任意成分を含んでいてもよく、例えば、崩壊剤（Ｂ）及び水溶性高分子（Ｃ）の少なくとも一方を含有することが好ましい。また、錠剤は、任意成分（Ｍ）をさらに含有していてもよい。
なお、以下の明細書において、造粒顆粒（Ｇ）に含まれる酸性の水難溶性薬物（Ａ）を特に「（Ａ）成分」ともいう。造粒顆粒（Ｇ）が崩壊剤（Ｂ）をさらに含有する場合、造粒顆粒（Ｇ）に含まれる崩壊剤（Ｂ）を特に「（Ｂ）成分」ともいう。造粒顆粒（Ｇ）が水溶性高分子（Ｃ）をさらに含有する場合、造粒顆粒（Ｇ）に含まれる水溶性高分子（Ｃ）を特に「（Ｃ）成分」ともいう。崩壊剤（Ｂ）、水溶性高分子（Ｃ）及び任意成分（Ｍ）のそれぞれは、造粒顆粒（Ｇ）として錠剤中に含有されていてもよいし、造粒顆粒（Ｇ）以外として錠剤中に含有されていてもよい。
The method for manufacturing a tablet of the present invention is a method for manufacturing a tablet containing an acidic poorly water-soluble drug (A), and includes a mixing step and a compression granulation step, which will be described in detail later.
Tablets are made by compressing granulated granules (hereinafter also referred to as "granulated granules (G)") containing an acidic poorly water-soluble drug (A), which are obtained, for example, through the mixing step and compression granulation step described below. It can be obtained by
The granulated granules (G) contain at least the acidic, poorly water-soluble drug (A), but may also contain components (optional components) other than the acidic, poorly water-soluble drug (A). For example, the granulated granules (G) preferably contain at least one of a disintegrant (B) and a water-soluble polymer (C) in addition to the acidic poorly water-soluble drug (A). In addition, the granulated granules (G) may contain optional components other than the disintegrant (B) and the water-soluble polymer (C) (hereinafter referred to as " It may further contain an optional component (M). That is, the tablet may contain optional ingredients in addition to the acidic poorly water-soluble drug (A), and preferably contains at least one of a disintegrant (B) and a water-soluble polymer (C), for example. Moreover, the tablet may further contain an optional ingredient (M).
In addition, in the following specification, the acidic poorly water-soluble drug (A) contained in the granules (G) is also particularly referred to as "component (A)." When the granules (G) further contain a disintegrant (B), the disintegrant (B) contained in the granules (G) is also particularly referred to as "component (B)." When the granules (G) further contain a water-soluble polymer (C), the water-soluble polymer (C) contained in the granules (G) is also particularly referred to as "component (C)." Each of the disintegrant (B), the water-soluble polymer (C), and the optional component (M) may be contained in the tablet as granules (G), or may be contained in the tablet as other than the granules (G). It may be contained inside.
＜酸性の水難溶性薬物（Ａ）＞
本発明において「酸性」とは、２５℃におけるｐＫａが７以下をいう。また、水素イオンを複数放出し、複数のｐＫａ値を有するものについては、最も低い値のｐＫａが７以下をいう。
また、本発明において「水難溶性薬物」とは、２０℃の水に対する溶解度が０～１０ｍｇ／ｍＬであり、好ましくは０～８ｍｇ／ｍＬであり、より好ましくは０～６ｍｇ／ｍＬであり、さらに好ましくは０～４ｍｇ／ｍＬである薬物をいう。溶解度の測定は、第十八改正日本薬局方に準じた試験により行われる。
<Acidic poorly water-soluble drug (A)>
In the present invention, "acidic" refers to a pKa at 25° C. of 7 or less. Furthermore, for those that emit multiple hydrogen ions and have multiple pKa values, the lowest pKa value is 7 or less.
Furthermore, in the present invention, a "poorly water-soluble drug" has a solubility in water at 20°C of 0 to 10 mg/mL, preferably 0 to 8 mg/mL, more preferably 0 to 6 mg/mL, and It refers to a drug that is preferably 0 to 4 mg/mL. The solubility is measured by a test according to the 18th edition of the Japanese Pharmacopoeia.
酸性の水難溶性薬物（Ａ）としては、例えばイブプロフェン（溶解度０．１９ｍｇ／ｍＬ）、ナプロキセン（溶解度０．０４ｍｇ／ｍＬ）、ケトプロフェン（溶解度０．２４ｍｇ／ｍＬ）、インドメタシン（溶解度０．０１ｍｇ／ｍＬ）、アセチルサリチル酸（溶解度３．３ｍｇ／ｍＬ）、エトドラック（溶解度０．１１ｍｇ／ｍＬ）、メロキシカム（溶解度０．０１ｍｇ／ｍＬ）、フルルビプロフェン（溶解度０．０１ｍｇ／ｍＬ）、メフェナム酸（溶解度０．００２ｍｇ／ｍＬ）、ピロキシカム（溶解度０．０４ｍｇ／ｍＬ）等の非ステロイド抗炎症剤等の解熱鎮痛剤；ニトラゼパム（溶解度０．０４ｍｇ／ｍＬ）、トリアゾラム（溶解度０．０４ｍｇ／ｍＬ）等の催眠・鎮静剤；ジアゼパム（溶解度０．０５ｍｇ／ｍＬ）等の精神神経用剤等が挙げられる。これらの中でも、本発明の効果が特に顕著に得られることから、解熱鎮痛剤から選ばれる少なくとも１種が好ましく、イブプロフェン、ケトプロフェン、アセチルサリチル酸がより好ましく、イブプロフェン、アセチルサリチル酸がさらに好ましく、イブプロフェンが特に好ましい。
酸性の水難溶性薬物（Ａ）は、１種を単独で用いてもよく、２種以上を組み合わせて用いてもよい。
Examples of acidic poorly water-soluble drugs (A) include ibuprofen (solubility 0.19 mg/mL), naproxen (solubility 0.04 mg/mL), ketoprofen (solubility 0.24 mg/mL), and indomethacin (solubility 0.01 mg/mL). ), acetylsalicylic acid (solubility 3.3 mg/mL), etodolac (solubility 0.11 mg/mL), meloxicam (solubility 0.01 mg/mL), flurbiprofen (solubility 0.01 mg/mL), mefenamic acid (solubility Antipyretic analgesics such as nonsteroidal anti-inflammatory agents such as 0.002 mg/mL) and piroxicam (solubility 0.04 mg/mL); nitrazepam (solubility 0.04 mg/mL), triazolam (solubility 0.04 mg/mL) Hypnotic/sedative agents; psychoneurotic agents such as diazepam (solubility 0.05 mg/mL) and the like. Among these, at least one selected from antipyretic and analgesics is preferred, as the effects of the present invention are particularly noticeable, ibuprofen, ketoprofen, and acetylsalicylic acid are more preferred, ibuprofen and acetylsalicylic acid are even more preferred, and ibuprofen is particularly preferred. preferable.
The acidic poorly water-soluble drug (A) may be used alone or in combination of two or more.
酸性の水難溶性薬物（Ａ）の含有割合は、錠剤の総質量に対して２～９０質量％が好ましく、８～６０質量％がより好ましい。酸性の水難溶性薬物（Ａ）の含有割合が上記下限値以上であれば、錠剤を小型化でき、服用性が良好となる。酸性の水難溶性薬物（Ａ）の含有割合が上記上限値以下であれば、経時に伴う崩壊遅延をより抑制できる。 The content of the acidic poorly water-soluble drug (A) is preferably 2 to 90% by weight, more preferably 8 to 60% by weight, based on the total weight of the tablet. If the content ratio of the acidic poorly water-soluble drug (A) is equal to or higher than the above lower limit, the tablet can be made smaller and easier to take. When the content of the acidic poorly water-soluble drug (A) is below the above upper limit, the delay in disintegration over time can be further suppressed.
＜任意成分＞
任意成分は、錠剤に含まれる、酸性の水難溶性薬物（Ａ）以外の成分である。
任意成分としては、崩壊剤（Ｂ）、水溶性高分子（Ｃ）、酸性の水難溶性薬物（Ａ）以外の生理活性成分（以下、「他の生理活性成分」ともいう。）、崩壊剤（Ｂ）及び水溶性高分子（Ｃ）以外の添加剤（以下、「他の添加剤」ともいう。）等が挙げられる。
なお、本明細書において、崩壊剤（Ｂ）及び水溶性高分子（Ｃ）以外の任意成分を特に「任意成分（Ｍ）」ともいう。
<Optional ingredients>
The optional ingredients are ingredients other than the acidic, poorly water-soluble drug (A) contained in the tablet.
Optional ingredients include a disintegrant (B), a water-soluble polymer (C), a bioactive ingredient other than the acidic poorly water-soluble drug (A) (hereinafter also referred to as "other bioactive ingredient"), a disintegrant ( B) and additives other than the water-soluble polymer (C) (hereinafter also referred to as "other additives").
In this specification, optional components other than the disintegrant (B) and the water-soluble polymer (C) are also referred to as "optional components (M)."
（崩壊剤（Ｂ））
錠剤が崩壊剤（Ｂ）を含有することで、崩壊性が向上し、特に、経時に伴う崩壊遅延をより抑制できる。
崩壊剤（Ｂ）としては、例えば低置換度ヒドロキシプロピルセルロース、カルメロース、カルメロースナトリウム、クロスカルメロースナトリウム、クロスポビドン、カルボキシメチルスターチナトリウム、カルメロースカルシウム等が挙げられる。これらの中でも、低置換度ヒドロキシプロピルセルロース、カルメロースが好ましく、低置換度ヒドロキシプロピルセルロースがより好ましい。
崩壊剤（Ｂ）は、１種を単独で用いてもよく、２種以上を組み合わせて用いてもよい。
(Disintegrant (B))
When the tablet contains the disintegrant (B), the disintegration properties are improved, and in particular, the delay in disintegration over time can be further suppressed.
Examples of the disintegrant (B) include low-substituted hydroxypropylcellulose, carmellose, carmellose sodium, croscarmellose sodium, crospovidone, sodium carboxymethyl starch, and carmellose calcium. Among these, low-substituted hydroxypropylcellulose and carmellose are preferred, and low-substituted hydroxypropylcellulose is more preferred.
The disintegrants (B) may be used alone or in combination of two or more.
崩壊剤（Ｂ）の含有割合は、錠剤の総質量に対して１～２７質量％が好ましく、３～２２質量％がより好ましい。崩壊剤（Ｂ）の含有割合が上記下限値以上であれば、崩壊性がより向上し、特に、経時に伴う崩壊遅延をより抑制できる。崩壊剤（Ｂ）の含有割合が上記上限値以下であれば、錠剤を小型化でき、服用性が良好となる。
なお、錠剤中の崩壊剤（Ｂ）の含有割合は、造粒顆粒（Ｇ）に含まれる（Ｂ）成分と、造粒顆粒（Ｇ）外の崩壊剤（Ｂ）とを合算した量である。
The content of the disintegrant (B) is preferably 1 to 27% by weight, more preferably 3 to 22% by weight based on the total weight of the tablet. When the content of the disintegrant (B) is at least the above lower limit, the disintegration properties will be further improved, and in particular, the delay in disintegration over time can be further suppressed. If the content rate of the disintegrant (B) is below the above upper limit, the tablet can be made smaller and easier to take.
The content ratio of the disintegrant (B) in the tablet is the total amount of the component (B) contained in the granules (G) and the disintegrant (B) outside the granules (G). .
（水溶性高分子（Ｃ））
錠剤が水溶性高分子（Ｃ）を含有することで、酸性の水難溶性薬物（Ａ）の溶出性が向上する。また、水溶性高分子（Ｃ）は結合剤としても作用するため、錠剤の硬度を高め維持することができる。
本発明において「水溶性」とは、２０℃の水に対する溶解度が１．０ｇ／１００ｍＬ以上をいう。２０℃の水に対する溶解度は１．３ｇ／１００ｍＬ以上が好ましく、１０ｇ／１００ｍＬ以上がより好ましく、２０ｇ／１００ｍＬ以上がさらに好ましい。溶解度が高い水溶性高分子（Ｃ）を用いるほど、酸性の水難溶性薬物（Ａ）の溶出性が向上する。
また、本発明において「高分子」とは、重量平均分子量が１，０００以上のものをいう。水溶性高分子（Ｃ）の重量平均分子量は５，０００～２００，０００が好ましく、１０，０００～１５０，０００がより好ましく、１５，０００～１００，０００がさらに好ましい。
なお、重量平均分子量は、ＧＰＣ（ゲルパーミネーションクロマトグラフィー）により測定できる。
(Water-soluble polymer (C))
When the tablet contains the water-soluble polymer (C), the dissolution of the acidic, poorly water-soluble drug (A) is improved. Moreover, since the water-soluble polymer (C) also acts as a binder, it is possible to increase and maintain the hardness of the tablet.
In the present invention, "water-soluble" refers to a solubility in water at 20° C. of 1.0 g/100 mL or more. The solubility in water at 20° C. is preferably 1.3 g/100 mL or more, more preferably 10 g/100 mL or more, and even more preferably 20 g/100 mL or more. The higher the solubility of the water-soluble polymer (C) used, the better the dissolution of the acidic poorly water-soluble drug (A).
Furthermore, in the present invention, the term "polymer" refers to a polymer having a weight average molecular weight of 1,000 or more. The weight average molecular weight of the water-soluble polymer (C) is preferably 5,000 to 200,000, more preferably 10,000 to 150,000, even more preferably 15,000 to 100,000.
Note that the weight average molecular weight can be measured by GPC (gel permeation chromatography).
水溶性高分子（Ｃ）としては、例えばデンプン、可溶性デンプン、デキストリン、α化デンプン、アルギン酸ナトリウム、アラビヤガム、ゼラチン、トラガントガム、ローカストビーンガム、カゼイン等の天然高分子；メチルセルロース；ヒドロキシエチルセルロース（ＨＥＣ）、ヒドロキシプロピルセルロース（ＨＰＣ）、ヒドロキシプロピルメチルセルロース（ヒプロメロース）等のヒドロキシアルキルセルロース；カルボキシメチル化デンプンナトリウム、ヒドロキシエチル化デンプン、デンプンリン酸エステルナトリウム、ポリビニルアルコール（ＰＶＡ）、ポリビニルメチルエーテル（ＰＶＭ）、ポリアクリルアミド、ポリアクリル酸ナトリウム、部分けん化酢酸ビニルとビニルエーテルの共重合体、アクリル酸、メタクリル酸、マレイン酸及びそのエステル又は塩の重合体若しくは共重合体、ポリエチレングリコール（ＰＥＧ）、ポリエチレンオキシド、ポリビニルピロリドン（ＰＶＰ）等の合成高分子等が挙げられる。これらの中でも、ヒドロキシプロピルセルロース、メチルセルロースが好ましく、メチルセルロースがより好ましい。
水溶性高分子（Ｃ）は、１種を単独で用いてもよく、２種以上を組み合わせて用いてもよい。
Examples of the water-soluble polymer (C) include natural polymers such as starch, soluble starch, dextrin, pregelatinized starch, sodium alginate, gum arabic, gelatin, gum tragacanth, locust bean gum, and casein; methyl cellulose; hydroxyethyl cellulose (HEC); Hydroxyalkyl celluloses such as hydroxypropyl cellulose (HPC) and hydroxypropyl methyl cellulose (hypromellose); sodium carboxymethylated starch, hydroxyethylated starch, sodium starch phosphate, polyvinyl alcohol (PVA), polyvinyl methyl ether (PVM), and Acrylamide, sodium polyacrylate, copolymer of partially saponified vinyl acetate and vinyl ether, polymer or copolymer of acrylic acid, methacrylic acid, maleic acid and its esters or salts, polyethylene glycol (PEG), polyethylene oxide, polyvinylpyrrolidone Examples include synthetic polymers such as (PVP). Among these, hydroxypropylcellulose and methylcellulose are preferred, and methylcellulose is more preferred.
The water-soluble polymer (C) may be used alone or in combination of two or more.
水溶性高分子（Ｃ）の含有割合は、錠剤の総質量に対して０．１～５質量％が好ましく、０．４～２．８質量％がより好ましい。水溶性高分子（Ｃ）の含有割合が上記下限値以上であれば、酸性の水難溶性薬物（Ａ）の溶出性が向上すると共に、十分な錠剤硬度が得られる。水溶性高分子（Ｃ）の含有割合が上記上限値以下であれば、崩壊性がより向上し、特に、経時に伴う崩壊遅延をより抑制できる。
なお、錠剤中の水溶性高分子（Ｃ）の含有割合は、造粒顆粒（Ｇ）に含まれる（Ｃ）成分と、造粒顆粒（Ｇ）外の水溶性高分子（Ｃ）とを合算した量である。
The content of the water-soluble polymer (C) is preferably 0.1 to 5% by mass, more preferably 0.4 to 2.8% by mass, based on the total mass of the tablet. If the content ratio of the water-soluble polymer (C) is equal to or higher than the above lower limit, the dissolution of the acidic poorly water-soluble drug (A) will improve, and sufficient tablet hardness will be obtained. If the content ratio of the water-soluble polymer (C) is below the above upper limit, the disintegration properties will be further improved, and in particular, the delay in disintegration over time can be further suppressed.
The content ratio of the water-soluble polymer (C) in the tablet is the sum of the component (C) contained in the granules (G) and the water-soluble polymer (C) outside the granules (G). This is the amount.
（任意成分（Ｍ））
任意成分（Ｍ）としては、他の生理活性成分、他の添加剤等が挙げられる。
(Optional component (M))
Examples of the optional component (M) include other physiologically active ingredients and other additives.
他の生理活性成分としては、例えばロキソプロフェンナトリウム、アセトアミノフェン、ジクロフェナック、アルクロフェナック等の非ステロイド抗炎症剤；フェノバルビタ－ル、アリルイソプロピルアセチル尿素、ブロムワレリル尿素等の催眠・鎮静剤；フェニトイン、プリミドン、クロナゼパム、カルバマゼピン等の抗てんかん剤；塩酸メクリジン、ジメンヒドリナート等の鎮うん剤；ハロペリドール、スルピリド等の精神神経用剤；アトロピン等の鎮けい剤；ジゴキシン等の強心剤；ピンドロール、ジソピラミド等の不整脈剤；ヒドロクロロチアジド、スピロノラクトン、トリアムテレン、フロセミド、ブメタニド等の利尿剤；塩酸プラゾシン等の抗高血圧剤；硝酸イソソルビド、ニフェジピン、ジピリダモール等の冠血管拡張剤；ノスカピン、ツロプテロール、トラニラスト等の鎮咳剤；塩酸ブロムヘキシン等の去痰剤；エリスロマイシン、ジョサマイシン、クロラムフェニコール、リファンピシン、グリセオフルビン等の抗生物質；フマル酸クレマスチン等の抗ヒスタミン剤；安息香酸ナトリウムカフェイン、カフェイン、無水カフェイン等の中枢興奮成分；デキサメタゾン、ベタメタゾン、プレドニソロン、ダナゾール、酢酸クロルマジノン等のステロイド剤；ビタミンＡ類、葉酸（ビタミンＭ類）等のビタミン剤；ファモチジン、メトクロプラミド、オメプラゾール、トレピブトン、スクラルファート等の消化器系疾患治療剤；乾燥水酸化アルミニウムゲル、水酸化アルミニウム、水酸化マグネシウム、ケイ酸アルミン酸マグネシウム、メタケイ酸アルミン酸マグネシウム、酸化マグネシウム、水酸化アルミナマグネシウム、炭酸水素ナトリウム、合成ヒドロタルサイト、炭酸マグネシウム、炭酸カルシウム、沈降炭酸カルシウム、水酸化カルシウム等の制酸剤；クロフィブラート、メルカプトプリン、メトトレキサート、メシル酸ジヒドロエルゴタミン等が挙げられる。
他の生理活性成分は、１種を単独で用いてもよく、２種以上を組み合わせて用いてもよい。
Other physiologically active ingredients include, for example, nonsteroidal anti-inflammatory agents such as loxoprofen sodium, acetaminophen, diclofenac, and alclofenac; hypnotic and sedative agents such as phenobarbital, allylisopropylacetylurea, and bromvaleryl urea; phenytoin and primidone; Antiepileptic drugs such as , clonazepam, and carbamazepine; Antidepressants such as meclizine hydrochloride and dimenhydrinate; Neuropsychiatric drugs such as haloperidol and sulpiride; Anticonvulsants such as atropine; Cardiac drugs such as digoxin; Arrhythmia such as pindolol and disopyramide diuretics such as hydrochlorothiazide, spironolactone, triamterene, furosemide, and bumetanide; antihypertensive agents such as prazosin hydrochloride; coronary vasodilators such as isosorbide nitrate, nifedipine, and dipyridamole; antitussives such as noscapine, tulopterol, and tranilast; and bromhexine hydrochloride, etc. Expectorants; antibiotics such as erythromycin, josamycin, chloramphenicol, rifampicin, griseofulvin; antihistamines such as clemastine fumarate; central stimulants such as sodium benzoate, caffeine, caffeine, anhydrous caffeine; dexamethasone, betamethasone, prednisolone , steroids such as danazol and chlormadinone acetate; vitamins such as vitamin A and folic acid (vitamin M); agents for treating digestive system diseases such as famotidine, metoclopramide, omeprazole, trepibutone, and sucralfate; dried aluminum hydroxide gel, water Aluminum oxide, magnesium hydroxide, magnesium aluminate silicate, magnesium aluminate metasilicate, magnesium oxide, magnesium alumina hydroxide, sodium hydrogen carbonate, synthetic hydrotalcite, magnesium carbonate, calcium carbonate, precipitated calcium carbonate, calcium hydroxide, etc. antacids; clofibrate, mercaptopurine, methotrexate, dihydroergotamine mesylate, etc.
One type of other physiologically active ingredients may be used alone, or two or more types may be used in combination.
他の添加剤としては、例えば賦形剤、香料、滑沢剤、甘味剤、酸味剤等が挙げられる。
賦形剤としては、例えば糖類、コーンスターチ、タルク、結晶セルロース、含水二酸化ケイ素、軽質無水ケイ酸、炭酸カルシウム、無水リン酸水素カルシウム、塩化ナトリウム、塩化カリウム、Ｌ－システイン等が挙げられる。糖類として具体的には、単糖類（キシロース等）、二糖類以上の多糖類（砂糖（グラニュー糖等）、乳糖、マルトース、スクロース、トレハロース、異性化乳糖、その他各種オリゴ糖等）、糖アルコール（パラチニット、ソルビトール、ラクチトール、エリスリトール、キシリトール、マルチトール、マンニトール等）、水飴、異性化糖類、還元澱粉糖化物（還元澱粉分解物）等が挙げられる。
香料としては、例えばメントール、リモネン、植物精油（ハッカ油、ミント油、ライチ油、オレンジ油、レモン油等）等が挙げられる。
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、ポリエチレングリコール、フマル酸ステアリルナトリウム、ショ糖脂肪酸エステル、軽質無水ケイ酸、含水二酸化ケイ素、タルク等が挙げられる。
甘味剤としては、例えばサッカリンナトリウム、アスパルテーム、ステビア、グリチルリチン酸二カリウム、アセスルファムカリウム、ソーマチン、スクラロース、マンニトール、エリスリトール等が挙げられる。
酸味剤としては、例えばクエン酸、酒石酸、リンゴ酸、コハク酸、フマル酸、乳酸及びこれらの塩等が挙げられる。
他の添加剤は、１種を単独で用いてもよく、２種以上を組み合わせて用いてもよい。
Examples of other additives include excipients, fragrances, lubricants, sweeteners, and acidulants.
Examples of excipients include sugars, corn starch, talc, crystalline cellulose, hydrated silicon dioxide, light anhydrous silicic acid, calcium carbonate, anhydrous calcium hydrogen phosphate, sodium chloride, potassium chloride, L-cysteine, and the like. Specifically, sugars include monosaccharides (such as xylose), polysaccharides of disaccharides and higher (such as sugar (granulated sugar, etc.), lactose, maltose, sucrose, trehalose, isomerized lactose, and various other oligosaccharides), and sugar alcohols ( palatinit, sorbitol, lactitol, erythritol, xylitol, maltitol, mannitol, etc.), starch syrup, isomerized sugars, reduced starch saccharides (reduced starch decomposition products), and the like.
Examples of fragrances include menthol, limonene, and vegetable essential oils (mentha oil, mint oil, lychee oil, orange oil, lemon oil, etc.).
Examples of the lubricant include magnesium stearate, calcium stearate, polyethylene glycol, sodium stearyl fumarate, sucrose fatty acid ester, light anhydrous silicic acid, hydrated silicon dioxide, and talc.
Examples of sweeteners include saccharin sodium, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, sucralose, mannitol, and erythritol.
Examples of the acidulant include citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, and salts thereof.
One type of other additives may be used alone, or two or more types may be used in combination.
錠剤が任意成分（Ｍ）を含有する場合、任意成分（Ｍ）の含有割合は、錠剤の総質量に対して５～９０質量％が好ましく、１０～８５質量％がより好ましい。任意成分（Ｍ）の含有割合が上記下限値以上であれば、錠剤の成形性がより向上する。任意成分（Ｍ）の含有割合が上記上限値以下であれば、崩壊性がより向上し、特に、経時に伴う崩壊遅延をより抑制できる。 When the tablet contains an optional component (M), the content of the optional component (M) is preferably 5 to 90% by mass, more preferably 10 to 85% by mass, based on the total mass of the tablet. If the content of the optional component (M) is at least the above lower limit, the formability of the tablet will be further improved. If the content rate of the optional component (M) is below the above upper limit, the disintegration properties will be further improved, and in particular, the delay in disintegration over time can be further suppressed.
＜錠剤の形態＞
錠剤の寸法は特に限定されないが、錠剤の取り扱いやすさと嚥下性の観点から錠剤の径φとして５～１４ｍｍが好ましく、６～１３ｍｍがより好ましく、７～１２ｍｍがさらに好ましい。また１錠当たりの錠剤質量は、１５０～５５０ｍｇが好ましい。
また、錠剤の形状としては特に限定されないが、スミ角平錠、スミ丸平錠、丸みを帯びたＲ錠もしくは２段階Ｒ錠が好ましい。
<Tablet form>
The size of the tablet is not particularly limited, but from the viewpoint of ease of handling and swallowing of the tablet, the diameter φ of the tablet is preferably 5 to 14 mm, more preferably 6 to 13 mm, and even more preferably 7 to 12 mm. Further, the mass of each tablet is preferably 150 to 550 mg.
Further, the shape of the tablet is not particularly limited, but preferably a square square tablet, a round flat tablet, a rounded R tablet, or a two-stage R tablet.
錠剤は、単層構造（単層錠）であってもよいし、積層構造（積層錠）であってもよい。
錠剤が単層錠の場合、錠剤は、上述した酸性の水難溶性薬物（Ａ）と、必要に応じて崩壊剤（Ｂ）、水溶性高分子（Ｃ）及び任意成分（Ｍ）の１つ以上とを含む薬物層で構成される。一方、錠剤が積層錠の場合、錠剤は、前記薬物層と、薬物層以外の層（任意層）とで構成される。
なお、錠剤が積層錠の場合、層の数は２層であってもよいし、３層以上であってもよい。本明細書において、２層の積層錠を特に「２層錠」ともいい、３層の積層錠を特に「３層錠」ともいう。
また、錠剤が積層錠の場合、任意層は、崩壊剤（Ｂ）及び水溶性高分子（Ｃ）のいずれか１つ以上を含んでいてもよいし、いずれも含まなくてもよい。任意層におけるこれらの成分の含有の有無及び含有割合等は、錠剤１錠当たりのこれらの成分の服用量等を勘案して適宜、選択することができる。また、上述した任意成分（Ｍ）は、薬物層のみに含まれていてもよいし、任意層のみに含まれていてもよいし、薬物層及び任意層の両方に含まれていてもよい。
錠剤が単層錠の場合、任意成分（Ｍ）は薬物層に含まれる。
なお、錠剤が酸性の水難溶性薬物（Ａ）としてイブプロフェン（ＩＢＰ）を含有し、任意成分（Ｍ）として乾燥水酸化アルミニウムゲル（ＡＬ）を含有する場合、乾燥水酸化アルミニウムゲルはイブプロフェンと異なる層、すなわち任意層に含まれることが好ましい。
The tablet may have a single-layer structure (single-layer tablet) or a laminated structure (layered tablet).
When the tablet is a single-layer tablet, the tablet contains the above-mentioned acidic poorly water-soluble drug (A), and optionally one or more of a disintegrant (B), a water-soluble polymer (C), and an optional ingredient (M). It consists of a drug layer containing. On the other hand, when the tablet is a laminated tablet, the tablet is composed of the drug layer and a layer (arbitrary layer) other than the drug layer.
In addition, when a tablet is a laminated tablet, the number of layers may be two layers, and three or more layers may be sufficient as it. In this specification, a two-layer laminated tablet is also particularly referred to as a "two-layer tablet", and a three-layer laminated tablet is also particularly referred to as a "three-layer tablet".
Further, when the tablet is a laminated tablet, the arbitrary layer may contain one or more of the disintegrant (B) and the water-soluble polymer (C), or may contain neither of them. The presence or absence of inclusion of these components in the arbitrary layer, their content ratio, etc. can be appropriately selected in consideration of the dosage of these components per tablet, etc. Further, the above-mentioned optional component (M) may be contained only in the drug layer, only in the arbitrary layer, or in both the drug layer and the arbitrary layer.
When the tablet is a single-layer tablet, the optional ingredient (M) is contained in the drug layer.
Note that when the tablet contains ibuprofen (IBP) as the acidic poorly water-soluble drug (A) and dry aluminum hydroxide gel (AL) as the optional component (M), the dry aluminum hydroxide gel has a layer different from that of ibuprofen. , that is, it is preferably included in an arbitrary layer.
＜製造方法＞
以下、本発明の錠剤の製造方法の一実施形態について説明する。
本実施形態の錠剤の製造方法は、少なくとも、以下に示す混合工程と、圧縮造粒工程と、打錠工程とを有し、好ましくは、圧縮造粒工程と打錠工程との間に篩過工程を有する。また、錠剤をコーティング錠とする場合は、打錠工程の後に以下に示すコーティング工程をさらに有することが好ましい。
<Manufacturing method>
Hereinafter, one embodiment of the method for manufacturing a tablet of the present invention will be described.
The tablet manufacturing method of the present embodiment includes at least the following mixing step, compression granulation step, and tableting step, and preferably, between the compression granulation step and the tableting step, sieving is performed. Has a process. Further, when the tablet is a coated tablet, it is preferable to further include a coating step shown below after the tableting step.
（混合工程）
混合工程は、（Ａ）成分を含有する粉体組成物を混合する工程である。
本発明の錠剤の製造方法では、後述の圧縮造粒工程の前に混合工程を２回以上行う。圧縮造粒工程の前に混合工程を２回以上行うことで、粉体組成物中の（Ａ）成分の含有量がより均一となり、密度も均一となる。その結果、粉体組成物の密度の均一性が維持された状態で、粉体組成物が圧縮造粒工程で用いる圧縮造粒装置（Ｙ）に備わるロール圧縮部（１対のロールの間）を通過できるため、圧縮状態が均一な造粒顆粒（Ｇ）が得られる。圧縮状態が均一な造粒顆粒（Ｇ）を用いることで、経時に伴う崩壊時間のばらつきが小さく、崩壊遅延が抑制された錠剤が得られる。
(Mixing process)
The mixing step is a step of mixing powder compositions containing component (A).
In the tablet manufacturing method of the present invention, the mixing step is performed two or more times before the compression granulation step described below. By performing the mixing step two or more times before the compression granulation step, the content of component (A) in the powder composition becomes more uniform, and the density also becomes more uniform. As a result, while the uniformity of the density of the powder composition is maintained, the powder composition is transferred to the roll compression section (between a pair of rolls) of the compression granulation device (Y) used in the compression granulation process. Since the granules can pass through the granules (G), uniformly compressed granules (G) can be obtained. By using granulated granules (G) that are uniformly compressed, tablets with small variations in disintegration time over time and suppressed delay in disintegration can be obtained.
圧縮造粒工程の前に行われる混合工程の回数は２回以上であれば特に制限されないが、回数が多くてもその効果は頭打ちとなる。また、回数が多くなるほど錠剤の生産性が低下することとなる。よって、生産性の観点から、圧縮造粒工程の前に行われる混合工程の回数は２～５回が好ましく、２～３回がより好ましく、２回がさらに好ましい。
なお、本発明において、「混合工程を２回以上行う」とは、混合操作を２回以上停止することを意味する。通常、混合工程では混合機を用いて粉体組成物を混合するが、混合操作の停止とは、混合機の運転を停止することを意味する。具体的には、粉体組成物の流動が止まった時点を混合操作が停止した（又は混合機の運転が停止した）、すなわち、Ｎ回目（Ｎは１以上の整数である）の混合工程が終了した、とみなす。
The number of times of the mixing step performed before the compression granulation step is not particularly limited as long as it is two or more times, but even if the number of times is large, the effect will reach a plateau. Moreover, the greater the number of times, the lower the productivity of tablets becomes. Therefore, from the viewpoint of productivity, the number of mixing steps performed before the compression granulation step is preferably 2 to 5 times, more preferably 2 to 3 times, and even more preferably 2 times.
In the present invention, "performing the mixing step twice or more" means stopping the mixing operation twice or more. Usually, in the mixing step, a powder composition is mixed using a mixer, and stopping the mixing operation means stopping the operation of the mixer. Specifically, the mixing operation stops (or the operation of the mixer stops) at the point when the flow of the powder composition stops, that is, the Nth mixing step (N is an integer of 1 or more) It is considered finished.
また、本明細書において、圧縮造粒工程の前に２回以上行われる混合工程のうち、Ｎ回目の混合工程を「第Ｎの混合工程」ともいう。例えば、１回目の混合工程を「第１の混合工程」ともいい、２回目の混合工程を「第２の混合工程」ともいう。
また、本明細書において、混合前の（Ａ）成分を含有する粉体組成物を「粉体組成物（α）」ともいい、第Ｎの混合工程で得られた粉体組成物を「粉体組成物（αＮ）」ともいう。例えば、第１の混合工程で得られた粉体組成物を「粉体組成物（α１）」ともいい、第２の混合工程で得られた粉体組成物を「粉体組成物（α２）」ともいう。また、最後の混合工程で得られた粉体組成物を「造粒前粉体」ともいう。
また、本明細書において、酸性の水難溶性薬物（Ａ）を含有しない粉体組成物を「粉体組成物（β）」ともいう。
Moreover, in this specification, among the mixing steps performed two or more times before the compression granulation step, the N-th mixing step is also referred to as the "Nth mixing step." For example, the first mixing step is also referred to as a "first mixing step," and the second mixing step is also referred to as a "second mixing step."
In addition, in this specification, the powder composition containing component (A) before mixing is also referred to as "powder composition (α)", and the powder composition obtained in the Nth mixing step is referred to as "powder composition (α)". Also called body composition (αN). For example, the powder composition obtained in the first mixing step is also referred to as "powder composition (α1)", and the powder composition obtained in the second mixing step is also referred to as "powder composition (α2)". ” is also called. Further, the powder composition obtained in the final mixing step is also referred to as "pre-granulation powder".
Further, in this specification, a powder composition that does not contain the acidic poorly water-soluble drug (A) is also referred to as a "powder composition (β)."
以下、圧縮造粒工程の前に混合工程を２回行う場合を例にとり、第１の混合工程と第２の混合工程の一例について説明する。 Hereinafter, an example of the first mixing step and the second mixing step will be described, taking as an example a case where the mixing step is performed twice before the compression granulation step.
第１の混合工程は、１回目の混合工程、すなわち最初の混合工程であり、粉体組成物（α）の一部又は全部を混合し、粉体組成物（α１）を得る工程である。
粉体組成物（α１）は、（Ａ）成分に加えて、（Ｂ）成分及び（Ｃ）成分の少なくとも一方を含有することが好ましい。また、粉体組成物（α１）は、必要に応じて任意成分（Ｍ）をさらに含有していてもよい。粉体組成物（α１）が（Ａ）成分と任意成分とを含有する場合、第１の混合工程は、（Ａ）成分と任意成分（例えば（Ｂ）成分、（Ｃ）成分及び任意成分（Ｍ）の１つ以上）とを混合する工程ともいえる。
第１の混合工程では、粉体組成物（α）の全部を混合することが好ましい。
なお、第１の混合工程で粉体組成物（α）の一部を混合する場合、この粉体組成物（α）の一部には、少なくとも（Ａ）成分が含まれていればよく、（Ａ）成分に加えて、（Ｂ）成分、（Ｃ）成分及び任意成分（Ｍ）の１つ以上が含まれていてもよい。
The first mixing step is the first mixing step, that is, the first mixing step, and is a step of mixing part or all of the powder composition (α) to obtain the powder composition (α1).
It is preferable that the powder composition (α1) contains at least one of the component (B) and the component (C) in addition to the component (A). Moreover, the powder composition (α1) may further contain an optional component (M) as required. When the powder composition (α1) contains the component (A) and the optional component, the first mixing step includes the component (A) and the optional component (for example, the component (B), the component (C), and the optional component ( It can also be said to be a step of mixing one or more of M).
In the first mixing step, it is preferable to mix all of the powder composition (α).
In addition, when mixing a part of the powder composition (α) in the first mixing step, it is sufficient that the part of this powder composition (α) contains at least the component (A), In addition to component (A), one or more of component (B), component (C), and optional component (M) may be included.
粉体組成物（α１）を調製する際、各成分は公知の製造方法により製造したものを用いてもよいし、市販のものを用いてもよい。また、各成分は、原末をそのまま用いてもよいし、所望の中位径となるように混合前に原末を粉砕して用いてもよい。原末を粉砕する際、１種類の成分の原末を単独で粉砕してもよいし、他の成分の原末と共に粉砕して用いてもよい。特に、（Ａ）成分は、粉砕することにより、体内での溶出性（特に服用直後の溶出性）が向上するため、有用である。
原末の粉砕に使用する装置としては、例えばコーミル、ピンミル等の粉砕機が挙げられる。
なお、本明細書において、（Ａ）成分を粉砕する工程を「粉砕工程」ともいう。詳しくは後述するが、粉砕工程は第１の工程の前でもよいし、第２の工程の前又は第２の工程の後でもよい。
When preparing the powder composition (α1), each component may be produced by a known production method, or may be commercially available. Further, for each component, the bulk powder may be used as it is, or the bulk powder may be pulverized before mixing so as to have a desired median diameter. When pulverizing the bulk powder, the bulk powder of one type of component may be crushed alone or may be used together with the bulk powder of other components. In particular, component (A) is useful because pulverization improves dissolution in the body (particularly dissolution immediately after administration).
Examples of the device used for pulverizing the bulk powder include pulverizers such as Cormill and Pin Mill.
In addition, in this specification, the process of pulverizing component (A) is also referred to as a "pulverizing process." Although details will be described later, the pulverization step may be performed before the first step, before the second step, or after the second step.
第１の混合工程で用いる混合機としては、撹拌混合機、容器回転型混合機等が挙げられる。
経時に伴う崩壊時間のばらつきの抑制効果や、崩壊遅延の抑制効果が得られやすい点で、第１の混合工程では撹拌混合機を用いることが好ましく、高速撹拌混合機を用いることがより好ましい。
なお、本明細書において、混合工程で用いる混合機を総称して「混合機（Ｘ）」ともいう。
Examples of the mixer used in the first mixing step include a stirring mixer, a container rotating mixer, and the like.
In the first mixing step, it is preferable to use a stirring mixer, and it is more preferable to use a high-speed stirring mixer, since it is easy to obtain the effect of suppressing variations in disintegration time over time and the effect of suppressing delay in disintegration.
In addition, in this specification, the mixers used in the mixing process are also collectively referred to as "mixers (X)."
撹拌混合機としては、例えばスパルタンミキサー（株式会社ダルトン製）、ハイスピードミキサー（株式会社アーステクニカ製）、バーチカルグラニュレータ（株式会社パウレック製）等の高速撹拌混合機；リボンミキサー（株式会社ダルトン製）等の中低速撹拌混合機などが挙げられる。
容器回転型混合機としては、例えばボーレコンテナミキサー（株式会社広島メタル＆マシナリー製）、Ｖ型混合機（株式会社ダルトン製）等が挙げられる。
各混合機を用いた第１の混合工程の標準的な運転条件は以下の通りである。
Examples of stirring mixers include high-speed stirring mixers such as Spartan Mixer (manufactured by Dalton Co., Ltd.), High Speed Mixer (manufactured by Earth Technica Co., Ltd.), Vertical Granulator (manufactured by Powrec Co., Ltd.); Ribbon Mixer (manufactured by Dalton Co., Ltd.); ) and other medium-low speed stirring mixers.
Examples of the container rotary mixer include Bohle container mixer (manufactured by Hiroshima Metal & Machinery Co., Ltd.) and V-type mixer (manufactured by Dalton Co., Ltd.).
Standard operating conditions for the first mixing step using each mixer are as follows.
スパルタンミキサーを用いる場合、チョッパー回転速度は１００～２５００ｒｐｍが好ましく、ミキシングアームは３～３５ｒｐｍが好ましい。
ハイスピードミキサーを用いる場合、チョッパー回転速度は１００～３５００ｒｐｍが好ましく、ブレードは３～５００ｒｐｍが好ましい。
バーチカルグラニュレータを用いる場合、チョッパー回転速度は１００～３５００ｒｐｍが好ましく、ブレードは３～５００ｒｐｍが好ましい。
リボンミキサーを用いる場合、回転速度は１０～１００ｒｐｍが好ましい。
ボーレコンテナミキサーを用いる場合、回転速度は２～１５ｒｐｍが好ましい。
Ｖ型混合機を用いる場合、回転速度は２～１５ｒｐｍが好ましい。
When using a Spartan mixer, the chopper rotation speed is preferably 100 to 2500 rpm, and the mixing arm is preferably 3 to 35 rpm.
When using a high-speed mixer, the chopper rotation speed is preferably 100 to 3500 rpm, and the blade rotation speed is preferably 3 to 500 rpm.
When using a vertical granulator, the chopper rotation speed is preferably 100 to 3500 rpm, and the blade rotation speed is preferably 3 to 500 rpm.
When using a ribbon mixer, the rotation speed is preferably 10 to 100 rpm.
When using a Bohle container mixer, the rotation speed is preferably 2 to 15 rpm.
When using a V-type mixer, the rotation speed is preferably 2 to 15 rpm.
第１の混合工程は、下記式（１）より算出した工程能力指数（Ｃｐ）が１を超えるまで、粉体組成物（α）の一部又は全部を混合することが好ましい。すなわち、工程能力指数（Ｃｐ）が１を超えた後に、混合機の運転を停止することが好ましい。工程能力指数（Ｃｐ）が１を超えることは、粉体組成物（α１）中の（Ａ）成分の含有量が均一であることを意味する。
Ｃｐ＝（規格上限－規格下限）/（６個の検体中の（Ａ）成分の含有量の標準偏差） ・・・（１）
なお、規格は９０～１１０％として計算する（１００％は（Ａ）成分含有量の規格中央値）。すなわち、式（１）中の「規格上限－規格下限」は１１０％－９０％＝２０％である。
In the first mixing step, it is preferable to mix part or all of the powder composition (α) until the process capability index (Cp) calculated from the following formula (1) exceeds 1. That is, it is preferable to stop the operation of the mixer after the process capability index (Cp) exceeds 1. A process capability index (Cp) of more than 1 means that the content of component (A) in the powder composition (α1) is uniform.
Cp = (upper limit of specification - lower limit of specification) / (standard deviation of content of component (A) in 6 samples) ... (1)
Note that the specification is calculated as 90 to 110% (100% is the standard median value of the content of component (A)). That is, "upper limit of specification - lower limit of specification" in equation (1) is 110% - 90% = 20%.
式（１）中の「６個の検体中の（Ａ）成分の含有量の標準偏差」は、以下のようにして求める値である。
すなわち、粉体組成物（α１）を容器に投入し、容器内の粉体組成物（α１）の上面から１０ｃｍ下の領域における任意の３箇所から検体を採取する。同様に、容器内の粉体組成物（α１）の底面における任意の３箇所から検体を採取する。各検体中の（Ａ）成分の含有量を高速液体クロマトグラフィー等により測定し、６個の検体の（Ａ）成分の含有量の値から標準偏差を求める。
The "standard deviation of the content of component (A) in the six specimens" in formula (1) is a value determined as follows.
That is, the powder composition (α1) is put into a container, and samples are collected from three arbitrary locations in a region 10 cm below the top surface of the powder composition (α1) in the container. Similarly, samples are collected from three arbitrary locations on the bottom of the powder composition (α1) in the container. The content of component (A) in each sample is measured by high performance liquid chromatography or the like, and the standard deviation is determined from the content of component (A) in the six samples.
第１の混合工程の後、第２の混合工程を行う。
第２の混合工程は、粉体組成物（α１）又は粉体組成物（α１）を含む混合粉体（α１’）を混合し、粉体組成物（α２）を得る工程である。
圧縮造粒工程の前に混合工程を２回行う場合、第２の混合工程が最後の混合工程、すなわち圧縮造粒工程の直前の混合工程であり、第２の混合工程で粉体組成物（α）の全部を混合する。また、粉体組成物（α２）が造粒前粉体である。
After the first mixing step, a second mixing step is performed.
The second mixing step is a step of mixing the powder composition (α1) or a mixed powder (α1') containing the powder composition (α1) to obtain a powder composition (α2).
When the mixing step is performed twice before the compression granulation step, the second mixing step is the last mixing step, that is, the mixing step immediately before the compression granulation step, and the powder composition ( Mix all of α). Further, the powder composition (α2) is a pre-granulated powder.
第２の混合工程では、粉体組成物（α１）を混合してもよいし、粉体組成物（α１）を含む混合粉体（α１’）を混合してもよい。（Ａ）成分の均一性がより高まり、ロール圧縮部を通過する粉体の密度が均一になり易くなる点で、第２の混合工程では粉体組成物（α１）を混合することが好ましい。すなわち、第１の混合工程で粉体組成物（α）の全部を混合した後、第１の混合工程で得られた粉体組成物（α１）を第２の混合工程でさらに混合することが好ましい。
圧縮造粒工程の前に混合工程を２回行う場合であって、かつ、第１の混合工程で粉体組成物（α）の一部を混合した場合は、粉体組成物（α１）に残りの粉体組成物（α）を加えて混合粉体（α１’）を調製し、この混合粉体（α１’）を第２の混合工程で混合する。
In the second mixing step, the powder composition (α1) may be mixed, or a mixed powder (α1') containing the powder composition (α1) may be mixed. It is preferable to mix the powder composition (α1) in the second mixing step, since the uniformity of the component (A) is further increased and the density of the powder passing through the roll compression section is likely to be uniform. That is, after all of the powder composition (α) is mixed in the first mixing step, the powder composition (α1) obtained in the first mixing step may be further mixed in the second mixing step. preferable.
If the mixing step is performed twice before the compression granulation step, and part of the powder composition (α) is mixed in the first mixing step, the powder composition (α1) The remaining powder composition (α) is added to prepare a mixed powder (α1'), and this mixed powder (α1') is mixed in a second mixing step.
第２の混合工程で用いる混合機としては、撹拌混合機、容器回転型混合機等が挙げられる。
撹拌混合機としては、第１の混合工程で先に例示した撹拌混合機が挙げられる。
容器回転型混合機としては、第１の混合工程で先に例示した容器回転型混合機が挙げられる。
Examples of the mixer used in the second mixing step include a stirring mixer, a container rotating mixer, and the like.
Examples of the stirring mixer include the stirring mixer exemplified above in the first mixing step.
Examples of the container rotation type mixer include the container rotation type mixer exemplified above in the first mixing step.
第２の混合工程では、第１の混合工程と同一の混合機を用いてもよいし、異なる混合機を用いてもよい。経時に伴う崩壊時間のばらつきの抑制効果や、崩壊遅延の抑制効果が得られやすい点で、第２の混合工程では撹拌混合機を用いることが好ましく、高速撹拌混合機を用いることがより好ましい。
各混合機を用いた第２の混合工程の標準的な運転条件は、第１の混合工程の説明において先に例示した運転条件と同様である。
In the second mixing step, the same mixer as in the first mixing step may be used, or a different mixer may be used. In the second mixing step, it is preferable to use a stirring mixer, and it is more preferable to use a high-speed stirring mixer, since it is easy to obtain the effect of suppressing variations in disintegration time over time and the effect of suppressing delay in disintegration.
The standard operating conditions for the second mixing step using each mixer are the same as the operating conditions exemplified above in the description of the first mixing step.
圧縮造粒工程の前に混合工程を２回行う場合、第２の混合工程は、圧縮造粒工程の直前から６時間前の間に行うことが好ましく、直前から３時間前の間に行うことがより好ましく、直前から１時間前の間に行うことがさらに好ましい。最後の混合工程を上記のタイミングで行うことで、最後の混合工程から圧縮造粒工程の間で、造粒前粉体の凝集、高密度化、ブロッキングを抑制することができ、製造性が良好となる。 When performing the mixing step twice before the compression granulation step, the second mixing step is preferably performed between 6 hours before and 3 hours immediately before the compression granulation step. is more preferable, and it is even more preferable to carry out between immediately before and 1 hour before. By performing the final mixing process at the above timing, it is possible to suppress agglomeration, densification, and blocking of the powder before granulation between the final mixing process and the compression granulation process, resulting in good productivity. becomes.
第２の混合工程は、粉体組成物（α２）中の密度差がなくなるまで、粉体組成物（α１）又は混合粉体（α１’）を混合することが好ましい。粉体組成物（α２）中の密度差は、混合時間（処理時間）が長くなるほど、小さくなる傾向にある。
処理時間は、混合機の運転条件にもよるが、通常は、１０秒～１０分が好ましく、２０秒～５分がより好ましい。処理時間が上記下限値以上であれば、経時に伴う崩壊時間のばらつきをより抑えることができる。処理時間が上記上限値以下であれば、製造時間を短縮することができる。
In the second mixing step, the powder composition (α1) or mixed powder (α1') is preferably mixed until there is no density difference in the powder composition (α2). The density difference in the powder composition (α2) tends to become smaller as the mixing time (processing time) becomes longer.
Although the treatment time depends on the operating conditions of the mixer, it is usually preferably 10 seconds to 10 minutes, more preferably 20 seconds to 5 minutes. When the treatment time is equal to or greater than the above lower limit, variations in disintegration time over time can be further suppressed. If the processing time is equal to or less than the above upper limit, the manufacturing time can be shortened.
（Ａ）成分の溶出性の向上や、造粒顆粒（Ｇ）の混合均一性の向上の点で、圧縮造粒工程の前に粉砕工程を行うことが好ましいが、粉砕工程は行わなくてもよい。粉砕工程を行う場合、粉砕工程は、第１の混合工程の前に行ってもよいし、第１の混合工程と第２の混合工程との間に行ってもよいし、第２の混合工程と圧縮造粒工程との間に行ってもよい。
圧縮造粒工程の前までの製造工程の一例としては、以下に示す（ｉ）～（iv）が挙げられる。
（ｉ）第１の混合工程→粉砕工程→第２の混合工程→圧縮造粒工程
（ii）粉砕工程→第１の混合工程→第２の混合工程→圧縮造粒工程
（iii）第１の混合工程→第２の混合工程→粉砕工程→圧縮造粒工程
（iv）第１の混合工程→第２の混合工程→圧縮造粒工程
(A) From the viewpoint of improving the dissolution of the component and improving the mixing uniformity of the granulated granules (G), it is preferable to perform a pulverizing step before the compression granulation step, but it is not necessary to perform the pulverizing step. good. When performing a crushing process, the crushing process may be performed before the first mixing process, between the first mixing process and the second mixing process, or after the second mixing process. and the compression granulation step.
Examples of manufacturing steps before the compression granulation step include (i) to (iv) shown below.
(i) First mixing process → Grinding process → Second mixing process → Compression granulation process (ii) Grinding process → First mixing process → Second mixing process → Compression granulation process (iii) First Mixing process → second mixing process → crushing process → compression granulation process (iv) first mixing process → second mixing process → compression granulation process
（ｉ）の場合、粉体組成物（α１）を粉砕した後に、粉砕後の粉体組成物（α１）又は粉砕後の粉体組成物（α１）を含む混合粉体（α１’）を第２の混合工程で混合すればよい。
（ii）の場合、粉砕した（Ａ）成分を用いて粉体組成物（α）を調製し、この粉体組成物（α）の一部又は全部を第１の混合工程で混合すればよい。
（iii）の場合、粉体組成物（α２）を粉砕した後に、粉砕後の粉体組成物（α２）（すなわち粉砕後の造粒前粉体）を圧縮造粒工程で圧縮造粒すればよい。
In the case of (i), after pulverizing the powder composition (α1), the pulverized powder composition (α1) or the mixed powder (α1') containing the pulverized powder composition (α1) is They may be mixed in step 2 of the mixing step.
In the case of (ii), a powder composition (α) may be prepared using the crushed component (A), and part or all of this powder composition (α) may be mixed in the first mixing step. .
In the case of (iii), after pulverizing the powder composition (α2), the pulverized powder composition (α2) (i.e., the pulverized powder before granulation) is compressed and granulated in a compression granulation step. good.
なお、混合工程を３回以上行う場合、圧縮造粒工程の直前の混合工程（すなわち最後の混合工程）で粉体組成物（α）の全部を混合するが、第１の混合工程で粉体組成物（α）の全部を混合した後、第１の混合工程で得られた粉体組成物（α１）を２回目以降の混合工程でさらに混合することが好ましい。
圧縮造粒工程の直前の混合工程は、圧縮造粒工程の直前から６時間前の間に行うことが好ましく、直前から３時間前の間に行うことがより好ましく、直前から１時間前の間に行うことがさらに好ましい。
また、３回目以降の混合工程で用いる混合機としては、撹拌混合機、容器回転型混合機等が挙げられる。
撹拌混合機としては、第１の混合工程で先に例示した撹拌混合機が挙げられる。
容器回転型混合機としては、第１の混合工程で先に例示した容器回転型混合機が挙げられる。
３回目以降の混合工程では、第１の混合工程と同一の混合機を用いてもよいし、異なる混合機を用いてもよい。また、３回目以降の混合工程では、第２の混合工程と同一の混合機を用いてもよいし、異なる混合機を用いてもよい。
３回目以降の混合工程における処理時間は、混合機の運転条件にもよるが、通常は、１０秒～１０分が好ましく、２０秒～５分がより好ましい。
In addition, when performing the mixing process three or more times, all of the powder composition (α) is mixed in the mixing process immediately before the compression granulation process (i.e., the last mixing process), but the powder composition (α) is mixed in the first mixing process. After all of the composition (α) is mixed, it is preferable that the powder composition (α1) obtained in the first mixing step is further mixed in the second and subsequent mixing steps.
The mixing step immediately before the compression granulation step is preferably carried out between 6 hours before the compression granulation step, more preferably between 3 hours immediately before the compression granulation step, and 1 hour before the compression granulation step. It is more preferable to carry out the
Further, examples of the mixer used in the third and subsequent mixing steps include a stirring mixer, a container rotation type mixer, and the like.
Examples of the stirring mixer include the stirring mixer exemplified above in the first mixing step.
Examples of the container rotation type mixer include the container rotation type mixer exemplified above in the first mixing step.
In the third and subsequent mixing steps, the same mixer as in the first mixing step may be used, or a different mixer may be used. Further, in the third and subsequent mixing steps, the same mixer as in the second mixing step may be used, or a different mixer may be used.
The treatment time in the third and subsequent mixing steps depends on the operating conditions of the mixer, but is usually preferably 10 seconds to 10 minutes, more preferably 20 seconds to 5 minutes.
（圧縮造粒工程）
圧縮造粒工程は、圧縮造粒装置（Ｙ）を用いて、混合工程において混合された粉体組成物を圧縮造粒し、造粒顆粒（Ｇ）を得る工程である。
圧縮造粒工程では、最後の混合工程で得られた粉体組成物である造粒前粉体を圧縮造粒する。
(Compression granulation process)
The compression granulation step is a step of compressing and granulating the powder composition mixed in the mixing step using a compression granulation device (Y) to obtain granules (G).
In the compression granulation step, the pre-granulation powder, which is the powder composition obtained in the last mixing step, is compressed and granulated.
圧縮造粒工程で用いる圧縮造粒装置（Ｙ）は、ロール圧縮部を備えた造粒装置である。
圧縮造粒工程では、圧縮造粒装置（Ｙ）として、ローラーコンパクター型圧縮造粒装置（例えばフロイント・ターボ株式会社製）又はブリケット型圧縮造粒装置（例えば新東工業株式会社製、ホソカワミクロン株式会社製）を用いる。
なお、これらの圧縮造粒装置は、通常、ロール圧縮部の上流にスクリューを有するホッパー部を備えている。ホッパー部には、スクリューに粉体を安定的に供給するための水平軸スクレーパーが附属されている場合があるが、本発明においては、水平軸スクレーパーによる粉体の撹拌は混合工程には含まれないものとする。すなわち、本発明における混合工程は、粉体組成物が圧縮造粒装置（Ｙ）に投入される前の工程である。
The compression granulation device (Y) used in the compression granulation step is a granulation device equipped with a roll compression section.
In the compression granulation process, the compression granulation device (Y) is a roller compactor type compression granulation device (for example, manufactured by Freund Turbo Co., Ltd.) or a briquette type compression granulation device (for example, manufactured by Shinto Kogyo Co., Ltd., Hosokawa Micron Co., Ltd.). (manufactured by).
Note that these compression granulation devices are usually equipped with a hopper section having a screw upstream of the roll compression section. The hopper section may be equipped with a horizontal scraper for stably supplying powder to the screw, but in the present invention, stirring of the powder by the horizontal scraper is not included in the mixing process. Make it not exist. That is, the mixing step in the present invention is a step before the powder composition is introduced into the compression granulator (Y).
圧縮造粒工程でローラーコンパクター型圧縮造粒装置を用いる場合の好ましい造粒条件は以下の通りである。
圧縮ロール幅１ｃｍ当たりの粉体処理速度は９０ｇ／分以上が好ましい。粉体処理速度が上記下限値以上であれば、高い生産効率が見込める。粉体処理速度の上限は特に制限されないが、速度が速すぎると造粒前粉体の圧縮が不十分となり、後述するフレーク状になりにくい場合がある。よって、粉体処理速度は９０～２５０ｇ／分が好ましく、１２０～２００ｇ／分がより好ましい。
ロール圧力は適宜選定されるが、３～１２ＭＰａが好ましい。ロール圧力が、上記下限値以上であれば造粒顆粒（Ｇ）の硬度が良好となり、上記上限値以下であれば崩壊性がより良好となる。
粉体供給スクリュー回転速度は２０～１００ｒｐｍが好ましい。粉体供給スクリュー回転速度が、上記下限値以上であれば高い生産効率が見込め、上記上限値以下であればロール圧縮部への造粒前粉体の供給性が良好となる。
Preferred granulation conditions when using a roller compactor type compression granulation device in the compression granulation step are as follows.
The powder processing speed per 1 cm of compression roll width is preferably 90 g/min or more. If the powder processing speed is equal to or higher than the above lower limit, high production efficiency can be expected. The upper limit of the powder processing speed is not particularly limited, but if the speed is too high, the powder before granulation may not be sufficiently compressed and may be difficult to form flakes as described below. Therefore, the powder processing speed is preferably 90 to 250 g/min, more preferably 120 to 200 g/min.
The roll pressure is appropriately selected, but is preferably 3 to 12 MPa. If the roll pressure is at least the above lower limit value, the hardness of the granulated granules (G) will be good, and if it is below the above upper limit value, the disintegrability will be better.
The rotation speed of the powder supply screw is preferably 20 to 100 rpm. If the powder supply screw rotation speed is equal to or higher than the above lower limit value, high production efficiency can be expected, and if it is equal to or less than the above upper limit value, the supply performance of the pre-granulated powder to the roll compression section will be good.
圧縮造粒工程でブリケット型圧縮造粒装置を用いる場合の好ましい造粒条件は、ローラーコンパクター型圧縮造粒装置を用いる場合と同様である。
ロールのポケット容積は約０．３～１２０ｃｃが好ましく、形状はピロー型やレンズ型、アーモンド形等の公知のものを使用できる。
Preferable granulation conditions when using a briquette type compression granulation device in the compression granulation step are the same as those when using a roller compactor type compression granulation device.
The pocket volume of the roll is preferably about 0.3 to 120 cc, and known shapes such as pillow, lens, and almond shapes can be used.
造粒前粉体が圧縮造粒装置（Ｙ）のロール圧縮部を通過することで造粒前粉体は、ローラーコンパクター型圧縮造粒機ではフレーク状となり、ブリケット型圧縮造粒装置ではペレット状となる。以下、ロール圧縮部を通過してフレーク状或いはペレット状となった造粒前粉体を「フレーク」ともいう。
圧縮成形された直後、すなわちロール圧縮部を通過した直後のフレーク温度は１０～５５℃が好ましく、１５～４５℃がより好ましく、２０～４０℃がさらに好ましい。フレーク温度が上記下限値以上であれば、ロール圧縮部やフレークの結露を防ぎ、製造性が良好となる。フレーク温度が上記上限値以下であれば、フレーク温度上昇に伴い生じる錠剤の崩壊遅延をより抑制することができる。
フレーク温度を制御するための冷却方法は限定されるものではなく、ロール圧縮部のロール内部に冷却水を流してもよいし、外部から冷風を当ててもよい。
なお、フレーク温度は、例えば、サーモグラフィカメラを用いて測定することができる。
When the powder before granulation passes through the roll compression part of the compression granulator (Y), the powder before granulation becomes flakes in a roller compactor type compression granulator, and becomes pellets in a briquette type compression granulator. becomes. Hereinafter, the pre-granulated powder that has passed through the roll compression section and has become flakes or pellets will also be referred to as "flakes."
The temperature of the flakes immediately after compression molding, that is, immediately after passing through the roll compression section, is preferably 10 to 55°C, more preferably 15 to 45°C, and even more preferably 20 to 40°C. If the flake temperature is equal to or higher than the above lower limit, dew condensation on the roll compression part and the flakes will be prevented and productivity will be improved. When the flake temperature is below the above upper limit, it is possible to further suppress the delay in tablet disintegration that occurs due to an increase in flake temperature.
The cooling method for controlling the flake temperature is not limited, and cooling water may be allowed to flow inside the roll of the roll compression section, or cold air may be applied from the outside.
Note that the flake temperature can be measured using, for example, a thermography camera.
ロール圧縮部により得られたフレークを解砕・整粒機等を用いて、解砕・整粒してもよく、これにより目的とする平均粒子径の造粒顆粒（Ｇ）を得ることができる。
造粒顆粒（Ｇ）の平均粒子径は製造性に問題がない範囲で任意に設定できるが、例えば４５～９００μｍが好ましく、１５０～８５０μｍがより好ましく、２５０～８００μｍがさらに好ましい。造粒顆粒（Ｇ）の平均粒子径が上記下限値以上であれば、（Ａ）成分に起因する打錠時に充填不良や付着等の障害を抑制できる。造粒顆粒（Ｇ）の平均粒子径が上記上限値以下であれば、打錠時に臼へ充填される粉体重量のばらつきをより抑制できる。
なお、造粒顆粒（Ｇ）の平均粒子径は個数平均径を意味し、レーザー回折式粒度分布測定装置（例えばＢＥＣＫＭＡＮ ＣＯＵＬＴＥＲ社製、製品名「ＬＳ１３ ３２０」）を使用して個数％（メディアン径）により算出することができる。
The flakes obtained by the roll compression section may be crushed and sized using a crushing and sizing machine, etc., thereby making it possible to obtain granulated granules (G) with the desired average particle size. .
The average particle diameter of the granules (G) can be arbitrarily set within a range that does not cause problems in manufacturability, but is preferably 45 to 900 μm, more preferably 150 to 850 μm, and even more preferably 250 to 800 μm. If the average particle diameter of the granulated granules (G) is equal to or larger than the above lower limit, problems such as filling defects and adhesion during tableting caused by the component (A) can be suppressed. If the average particle diameter of the granulated granules (G) is below the above-mentioned upper limit, variations in the weight of powder filled into a die during tabletting can be further suppressed.
The average particle diameter of the granules (G) means the number average diameter, and the number % (median diameter ) can be calculated.
圧縮造粒工程で得られる造粒顆粒（Ｇ）は（Ａ）成分を含む。造粒前粉体（Ｇ）が（Ａ）成分に加えて（Ｂ）成分及び（Ｃ）成分の少なくとも一方を含有する場合、造粒顆粒（Ｇ）も（Ａ）成分に加えて（Ｂ）成分及び（Ｃ）成分の少なくとも一方を含有することとなる。また、造粒前粉体が任意成分（Ｍ）を含有していれば、造粒顆粒（Ｇ）も任意成分（Ｍ）を含有することとなる。
なお、（Ａ）成分としてイブプロフェンを含む造粒顆粒（Ｇ）を特に「ＩＢＰ造粒顆粒」ともいう。
Granulated granules (G) obtained in the compression granulation step contain component (A). When the pre-granulated powder (G) contains at least one of the (B) component and (C) component in addition to the (A) component, the granulated granules (G) also contain (B) in addition to the (A) component. It contains at least one of the component and the component (C). Moreover, if the powder before granulation contains the optional component (M), the granulated granules (G) will also contain the optional component (M).
Note that the granules (G) containing ibuprofen as the component (A) are also particularly referred to as "IBP granules."
（Ａ）成分の含有割合は、造粒顆粒（Ｇ）の総質量に対して２４～９０質量％が好ましく、４０～６７質量％がより好ましい。（Ａ）成分の含有割合が上記下限値以上であれば、錠剤を小型化でき、服用性が良好となる。（Ａ）成分の含有割合が上記上限値以下であれば、経時に伴う崩壊遅延をより抑制できる。加えて、粉砕機や打錠機への造粒顆粒（Ｇ）（主に（Ａ）成分）の付着を抑制できる。 The content of component (A) is preferably 24 to 90% by mass, more preferably 40 to 67% by mass, based on the total mass of the granules (G). If the content ratio of the component (A) is equal to or higher than the above lower limit, the tablet can be made smaller and easier to take. If the content ratio of the component (A) is below the above upper limit, the delay in disintegration over time can be further suppressed. In addition, adhesion of granulated granules (G) (mainly component (A)) to a crusher or tablet machine can be suppressed.
（Ｂ）成分の含有割合は、造粒顆粒（Ｇ）の総質量に対して８～２７質量％が好ましく、１６～２４質量％がより好ましい。（Ｂ）成分の含有割合が上記下限値以上であれば、崩壊性がより向上し、特に、経時に伴う崩壊遅延をより抑制できる。加えて、粉砕機や打錠機への造粒顆粒（Ｇ）（主に（Ａ）成分）の付着を抑制できる。（Ｂ）成分の含有割合が上記上限値以下であれば、錠剤を小型化でき、服用性が良好となる。 The content of component (B) is preferably 8 to 27% by mass, more preferably 16 to 24% by mass, based on the total mass of the granules (G). If the content ratio of the component (B) is equal to or higher than the above lower limit, the disintegration properties will be further improved, and in particular, the delay in disintegration over time can be further suppressed. In addition, adhesion of granulated granules (G) (mainly component (A)) to a crusher or tablet machine can be suppressed. If the content ratio of the component (B) is below the above upper limit, the tablet can be made smaller and easier to take.
（Ｃ）成分の含有割合は、造粒顆粒（Ｇ）の総質量に対して１．４～５．５質量％が好ましく、２～３．１質量％がより好ましい。（Ｃ）成分の含有割合が上記下限値以上であれば、（Ａ）成分の溶出性が向上する。加えて、フレークの成形性が良好となる。（Ｃ）成分の含有割合が上記上限値以下であれば、崩壊性がより向上し、特に、経時に伴う崩壊遅延をより抑制できる。 The content of component (C) is preferably 1.4 to 5.5% by mass, more preferably 2 to 3.1% by mass, based on the total mass of the granules (G). If the content ratio of the component (C) is equal to or higher than the above lower limit, the dissolution of the component (A) will be improved. In addition, the moldability of the flakes is improved. If the content ratio of component (C) is below the above upper limit, the disintegration properties will be further improved, and in particular, the delay in disintegration over time can be further suppressed.
（篩過工程）
篩過工程は、圧縮造粒工程の後に、造粒顆粒（Ｇ）中の粒子径が２５０μｍ以下である粒子の含有割合が３０質量％未満となるように、造粒顆粒（Ｇ）を篩過する工程である。
造粒顆粒（Ｇ）中の粒子径が２５０μｍ以下である粒子の含有割合は、造粒顆粒（Ｇ）の総質量に対して３０質量％未満が好ましく、２５質量％以下がより好ましい。粒子径が２５０μｍ以下である粒子の割合が上記上限値以下であれば、崩壊性がより向上し、特に、経時に伴う崩壊遅延をより抑制できる。加えて、打錠工程における臼への造粒顆粒（Ｇ）の充填性が良好となる。
(sieving process)
In the sieving step, after the compression granulation step, the granules (G) are sieved so that the content of particles with a particle size of 250 μm or less in the granules (G) is less than 30% by mass. This is the process of
The content ratio of particles having a particle size of 250 μm or less in the granules (G) is preferably less than 30% by mass, more preferably 25% by mass or less based on the total mass of the granules (G). If the proportion of particles having a particle diameter of 250 μm or less is below the above upper limit, the disintegration properties will be further improved, and in particular, the delay in disintegration over time can be further suppressed. In addition, the filling properties of the granules (G) into the mortar in the tableting process are improved.
なお、粒子径が２５０μｍ以下である粒子とは、目開き２５０μｍの篩を通過する粒子を指し、粒子径が２５０μｍ以下の粒子の含有割合は、目開き１０００μｍ、８５０μｍ、５００μｍ、３５５μｍ、２５０μｍの篩を用い、サンプル量１００ｇで、第十八改正日本薬局方に記載の「粒度測定法」第２法に基づいて操作を行った際の、目開き２５０μｍを通過した粉体の質量基準百分率を算出することで求められる。 In addition, particles with a particle size of 250 μm or less refer to particles that pass through a sieve with an opening of 250 μm, and the content ratio of particles with a particle size of 250 μm or less passes through a sieve with an opening of 1000 μm, 850 μm, 500 μm, 355 μm, and 250 μm. Calculate the mass-based percentage of powder that has passed through an opening of 250 μm when the sample amount is 100 g and the operation is performed based on Method 2 of "Particle size measurement method" described in the 18th revised Japanese Pharmacopoeia. It is required by doing.
（打錠工程）
打錠工程は、圧縮造粒工程で得られた造粒顆粒（Ｇ）又は造粒顆粒（Ｇ）を含む混合粉体（Ｇ’）を打錠して、錠剤を得る工程である。
打錠工程では、造粒顆粒（Ｇ）を打錠してもよいし、造粒顆粒（Ｇ）に任意成分（例えば崩壊剤（Ｂ）、水溶性高分子（Ｃ）及び任意成分（Ｍ）の１つ以上）を添加して打錠してもよい。
なお、本明細書において、造粒顆粒（Ｇ）に任意成分を添加したものを「混合粉体（Ｇ’）」という。
(Tableting process)
The tableting process is a process of obtaining tablets by compressing the granules (G) obtained in the compression granulation process or the mixed powder (G') containing the granules (G).
In the tableting step, the granulated granules (G) may be compressed into tablets, or optional ingredients (for example, a disintegrant (B), a water-soluble polymer (C), and an optional ingredient (M)) may be added to the granulated granules (G). (one or more of these) may be added to the tablet.
In this specification, the granulated granules (G) to which optional components are added are referred to as "mixed powder (G')."
造粒顆粒（Ｇ）又は混合粉体（Ｇ’）を打錠する方法としては、例えば臼と杵とを備えた打錠機を用いて打錠する方法が挙げられる。
打錠機としては、ロータリー式の打錠機（例えば、株式会社菊水製作所製、製品名「アクエリアス３－Ｊ」；株式会社畑鐵工所製、製品名「Ｌ－４１型」等）が挙げられるが、高い生産効率を有するロータリー式の打錠機（例えば、株式会社菊水製作所製、製品名「アクエリアス３－Ｋ」等）が好ましい。
Examples of the method for tabletting the granulated granules (G) or the mixed powder (G') include a method of tabletting using a tableting machine equipped with a mortar and a punch.
Examples of the tablet press include rotary tablet presses (for example, manufactured by Kikusui Seisakusho Co., Ltd., product name "Aquarius 3-J"; manufactured by Hata Iron Works Co., Ltd., product name "L-41 type", etc.). However, a rotary tablet press having high production efficiency (for example, manufactured by Kikusui Seisakusho Co., Ltd., product name "Aquarius 3-K", etc.) is preferable.
打錠条件としては特に制限されず、錠剤に求める硬度等を勘案して適宜決定される。
ロータリー式の打錠機は、回転盤を備える。回転盤の回転速度は適宜調整可能だが、１０～１００ｒｐｍが好ましく、２０～６０ｒｐｍがより好ましい。回転盤の回転速度が上記下限値以上であれば、生産効率を高められる。回転盤の回転速度が上記上限値以下であれば、臼への造粒顆粒（Ｇ）又は混合粉体（Ｇ’）の充填量が安定する。
The tableting conditions are not particularly limited and are appropriately determined taking into consideration the hardness required for the tablet.
A rotary tablet press is equipped with a rotating disk. The rotation speed of the rotary disk can be adjusted as appropriate, but is preferably 10 to 100 rpm, more preferably 20 to 60 rpm. If the rotational speed of the rotary disk is equal to or higher than the above lower limit value, production efficiency can be improved. If the rotational speed of the rotating disk is below the above upper limit value, the amount of granulated granules (G) or mixed powder (G') filled into the mortar will be stabilized.
単層錠を製造する場合、造粒顆粒（Ｇ）又は混合粉体（Ｇ’）を臼に充填して打錠を行うが、打錠を行う際は、予圧で打錠した後に、本圧で打錠することが好ましい。以下の明細書において、予圧で打錠する工程を「予圧工程」といい、本圧で打錠する工程を「本圧工程」ともいう。すなわち、打錠工程は、予圧工程と本圧工程とを有することが好ましい。予圧は１０ｋＮ以下が好ましく、０．１～８ｋＮがより好ましい。予圧を上記範囲内とすることでキャッピングを抑制できる。本圧は６～２０ｋＮが好ましく、８～１４ｋＮが好ましい。本圧を上記下限値以上とすることで十分な硬度が得られ、上記上限値以下とすることで錠剤の崩壊性が向上する。 When manufacturing single-layer tablets, granules (G) or mixed powder (G') are filled into a mortar and then compressed. It is preferable to compress the tablet with In the following specification, the process of compressing tablets with pre-pressure is referred to as "pre-pressure process", and the process of compressing tablets with main pressure is also referred to as "main-pressure process". That is, the tableting process preferably includes a pre-pressing process and a main-pressing process. The preload is preferably 10 kN or less, more preferably 0.1 to 8 kN. By setting the preload within the above range, capping can be suppressed. The main pressure is preferably 6 to 20 kN, preferably 8 to 14 kN. By setting the main pressure to the above lower limit value or more, sufficient hardness can be obtained, and by setting the main pressure to below the above upper limit value, the disintegration property of the tablet can be improved.
２層錠を製造する場合、薬物層を構成する造粒顆粒（Ｇ）又は混合粉体（Ｇ’）（以下、これらを総称して「薬物層用成分」ともいう。）は、臼に最初に充填されてもよく、任意層を構成する成分（以下、「任意層用成分」ともいう。）よりも後に充填されてもよい。薬物層用成分の安定性の観点から、薬物層用成分を臼に充填した後に任意層用成分を充填することが好ましい。
なお、任意層用成分としては、酸性の水難溶性薬物（Ａ）を含有しない粉体組成物（β）、粉体組成物（β）の造粒物（造粒顆粒）、粉体組成物（β）の造粒物に任意成分（例えば崩壊剤（Ｂ）、水溶性高分子（Ｃ）及び任意成分（Ｍ）の１つ以上）を添加した混合粉体などが挙げられる。粉体組成物（β）は、崩壊剤（Ｂ）及び水溶性高分子（Ｃ）の少なくとも一方を含んでいてもよい。また、粉体組成物（β）は、任意成分（Ｍ）を含んでいてもよい。
また、任意成分（Ｍ）として乾燥水酸化アルミニウムゲルを含む粉体組成物（β）の造粒物を特に「ＡＬ造粒顆粒」ともいう。
When manufacturing two-layer tablets, the granules (G) or mixed powder (G') constituting the drug layer (hereinafter also collectively referred to as "components for drug layer") are first placed in a mortar. It may be filled in after the components constituting the arbitrary layer (hereinafter also referred to as "component for arbitrary layer"). From the viewpoint of stability of the drug layer components, it is preferable to fill the drug layer components into a mortar and then fill the optional layer components.
The optional layer components include a powder composition (β) that does not contain the acidic poorly water-soluble drug (A), a granulated product (granulated granules) of the powder composition (β), and a powder composition ( Examples include a mixed powder obtained by adding an optional component (for example, one or more of a disintegrant (B), a water-soluble polymer (C), and an optional component (M)) to the granules of β). The powder composition (β) may contain at least one of a disintegrant (B) and a water-soluble polymer (C). Moreover, the powder composition (β) may contain an optional component (M).
Furthermore, the granulated product of the powder composition (β) containing dry aluminum hydroxide gel as the optional component (M) is also particularly referred to as "AL granules."
打錠を行う際は、１つ目の成分（例えば薬物層用成分）を臼に充填し、その上に２つ目の成分（例えば任意層用成分）を充填した後に予圧工程及び本圧工程を順次行ってもよい。また、１つ目の成分を臼に充填した後に１度目の予圧工程（第一の予圧工程）を行い、次いで２つ目の成分を臼に充填した後に必要に応じて２度目の予圧工程（第二の予圧工程）を行い、さらに本圧工程を行ってもよい。打錠障害をより抑制する観点では、各層の成分を臼に充填する毎に予圧工程を行うことが好ましい。
予圧は１０ｋＮ以下が好ましく、０．１～８ｋＮがより好ましい。予圧を上記範囲内とすることでキャッピングを抑制できる。本圧は６～２０ｋＮが好ましく、８～１４ｋＮが好ましい。本圧を上記下限値以上とすることで十分な硬度が得られ、上記上限値以下とすることで錠剤の崩壊性が向上する。
When tabletting, the first component (e.g. drug layer component) is filled into a mortar, the second component (e.g. arbitrary layer component) is filled on top of it, and then a pre-compression step and a main pressure step are performed. may be performed sequentially. In addition, after filling the mortar with the first component, a first preloading step (first preloading step) is performed, and then after filling the mortar with the second component, a second preloading step ( A second pre-pressure step) may be performed, and then a main-pressure step may be performed. From the viewpoint of further suppressing tableting failure, it is preferable to perform a pre-compression step every time the components of each layer are filled into a die.
The preload is preferably 10 kN or less, more preferably 0.1 to 8 kN. By setting the preload within the above range, capping can be suppressed. The main pressure is preferably 6 to 20 kN, preferably 8 to 14 kN. By setting the main pressure to the above lower limit value or more, sufficient hardness can be obtained, and by setting the main pressure to below the above upper limit value, the disintegration property of the tablet can be improved.
３層錠を製造する場合、例えば、薬物層用成分を二つに分け、薬物層用成分、任意層用成分、薬物層用成分の順に臼に充填した後に、打錠してもよく、任意層用成分を二つに分け、任意層用成分、薬物層用成分、任意層用成分の順に臼に充填した後に、打錠してもよい。打錠障害をより抑止する観点では、薬物層用成分、任意層用成分、薬物層用成分の順に臼に充填することが好ましい。また、任意層を構成する成分を含み粉体組成物（β）と組成が異なる粉体組成物（γ）又はその造粒物（造粒顆粒）を調製し、各層を構成する成分を任意の順に臼に充填した後に、打錠してもよい。打錠障害をより抑止する観点及び薬物層用成分の安定性の観点では、薬物層用成分を最初に臼に充填することが好ましい。なお、予圧工程及び本圧工程については、上記２層錠を製造する場合と同様である。 When manufacturing a three-layer tablet, for example, the drug layer component may be divided into two parts, and the drug layer component, optional layer component, and drug layer component may be filled in a mortar in this order, and then tableted. The layer components may be divided into two parts, the optional layer component, the drug layer component, and the optional layer component filled in a mortar in this order, and then tableted. From the viewpoint of further suppressing tableting failure, it is preferable to fill the mortar with the drug layer component, the optional layer component, and the drug layer component in this order. In addition, a powder composition (γ) or a granulated product thereof (granulated granules) containing components constituting any layer and having a different composition from the powder composition (β) is prepared, and the components constituting each layer are optionally The tablets may be compressed after being filled in a mortar in order. From the viewpoint of further suppressing tableting failure and the stability of the drug layer components, it is preferable to first fill the drug layer components into a mortar. Note that the pre-pressing step and the main-pressing step are the same as in the case of manufacturing the above-mentioned two-layer tablet.
打錠工程では、滑沢剤を外部滑沢法により添加してもよい。
外部滑沢法は、滑沢剤を打錠機の杵及び臼に噴霧（塗布）して薬物層用成分等を打錠することで、杵及び臼と接触する錠剤の表面に滑沢剤を添加する方法である。
滑沢剤の杵及び臼への噴霧（塗布）は、従来の公知の方法に基づき、あるいは市販の機械を用いて行うことができる。市販の機械としては、例えば外部滑沢噴霧システムＥＬＳ－Ｐ１（株式会社菊水製作所製）、外部滑沢装置ＥＸＴＡＬＵＢ（株式会社畑鐵工所製）等が挙げられる。
外部滑沢法によって添加される滑沢剤の量は、錠剤の崩壊性の観点から、最初に臼に充填する成分（例えば薬物層用成分）の総質量に対して１質量％未満が好ましく、０．５質量％以下がより好ましく、０．１質量％以下がさらに好ましい。
なお、外部滑沢法により、薬物層の表面に付着した滑沢剤も薬物層の一部とみなす。単層錠の場合、錠剤の表面に付着した滑沢剤の全てが薬物層の一部とみなされる。２層錠の場合、例えば薬物層用成分を充填した後に第一の予圧工程を行った場合は、薬物層の表面に付着した滑沢剤の全てが薬物層の一部とみなされる。１つ目の成分を臼に充填し、予圧工程を行わずにその上に２つ目の成分を充填した後に予圧工程及び本圧工程を行う場合、外部滑沢法により添加された滑沢剤の半分が薬物層の一部とみなされ、残りの半分が任意層の一部とみなされる。３層錠の場合は、２層錠と同様である。ただし、外部滑沢法により薬物層の表面に付着する滑沢剤は、噴霧量の総質量に対して約１質量％であるため、噴霧量が１錠あたり３ｍｇ未満の場合、外部滑沢法によって噴霧された滑沢剤が錠剤の表面に付着する量は極僅かである。
In the tableting process, lubricants may be added by external lubrication.
In the external lubrication method, a lubricant is sprayed (applied) onto the punches and dies of a tableting machine and the ingredients for the drug layer are compressed into tablets. This is a method of adding
Spraying (application) of the lubricant onto the punch and die can be performed based on conventionally known methods or using a commercially available machine. Commercially available machines include, for example, the external lubricant spray system ELS-P1 (manufactured by Kikusui Seisakusho Co., Ltd.) and the external lubricant device EXTALUB (manufactured by Hata Iron Works Co., Ltd.).
From the viewpoint of tablet disintegration, the amount of lubricant added by the external lubrication method is preferably less than 1% by mass based on the total mass of the components (e.g. drug layer components) initially filled into the die. The content is more preferably 0.5% by mass or less, and even more preferably 0.1% by mass or less.
Note that the lubricant attached to the surface of the drug layer by the external lubrication method is also considered to be part of the drug layer. In the case of single-layer tablets, all of the lubricant attached to the surface of the tablet is considered part of the drug layer. In the case of a two-layer tablet, for example, if the first precompression step is performed after filling the drug layer components, all of the lubricant attached to the surface of the drug layer is considered to be part of the drug layer. If the first component is filled into the mortar and the second component is filled on top of it without the pre-compression process, then the pre-compression process and the main compression process are performed, the lubricant added by the external lubrication method. half is considered part of the drug layer and the other half is considered part of the optional layer. In the case of a 3-layer tablet, the same applies as for a 2-layer tablet. However, since the lubricant that adheres to the surface of the drug layer by the external lubrication method is approximately 1% by mass based on the total mass of the sprayed amount, if the amount of sprayed is less than 3 mg per tablet, the lubricant attached to the surface of the drug layer by the external lubrication method The amount of lubricant sprayed by the method that adheres to the surface of the tablet is extremely small.
こうして得られた錠剤は、造粒顆粒（Ｇ）又は混合粉体（Ｇ’）を打錠して得られる、（Ａ）成分を含む薬物層を有する。
薬物層中の造粒顆粒（Ｇ）の含有割合は、薬物層の総質量に対して３０質量％以上が好ましく、３３質量％以上がより好ましい。造粒顆粒（Ｇ）の含有割合が上記下限値以上であれば、錠剤を小型化でき、服用性が良好となる。
The tablet thus obtained has a drug layer containing the component (A) obtained by tableting the granules (G) or mixed powder (G').
The content of the granules (G) in the drug layer is preferably 30% by mass or more, more preferably 33% by mass or more based on the total mass of the drug layer. If the content of the granulated granules (G) is at least the above lower limit, the tablet can be made smaller and easier to take.
錠剤は、服用性の向上等を目的として、必要に応じてコーティング剤によりコーティング処理が施されてもよい。
なお、本明細書において、コーティング前の錠剤を「素錠」ともいう。また、コーティング後の錠剤を「コーティング錠」ともいう。
また、本明細書において、コーティング処理により薬物層の表面に形成されたコーティング層は、薬物層の一部とみなす。
Tablets may be coated with a coating agent, if necessary, for the purpose of improving ease of administration.
In addition, in this specification, the tablet before coating is also referred to as a "plain tablet." The coated tablet is also referred to as a "coated tablet."
Further, in this specification, a coating layer formed on the surface of a drug layer by coating treatment is considered to be a part of the drug layer.
（コーティング工程）
コーティング工程は、素錠をコーティング処理する工程である。
コーティング剤としては、崩壊性を著しく損なわないものを選択することが好ましく、中でも被膜形成剤、可塑剤及び着色剤の１つ以上を含有することが好ましく、少なくとも被膜形成剤を含有することがより好ましい。
コーティング剤は、１種を単独で用いてもよく、２種以上を組み合わせて用いてもよい。
(Coating process)
The coating process is a process of coating the uncoated tablet.
As the coating agent, it is preferable to select one that does not significantly impair disintegration properties, and among them, it is preferable that it contains one or more of a film forming agent, a plasticizer, and a coloring agent, and it is more preferable that it contains at least a film forming agent. preferable.
One type of coating agent may be used alone, or two or more types may be used in combination.
被膜形成剤としては、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、ヒドロキシメチルセルロース、メチルセルロース、エチルセルロース等のセルロース類；アラビアゴム、カルボキシビニルポリマー、ポビドン、ポリビニルアルコール、ポリアクリル酸等が挙げられる。
可塑剤としては、例えばマクロゴール、クエン酸トリエチル、トリアセチン、カルナウバロウ等の日本薬局方（広川書店）及び医薬品添加物規格（株式会社薬事日報社）等の公定書に記載されているものが挙げられる。
着色剤としては、例えば酸化チタン、タルク、三二酸化鉄、黄色５号アルミニウムレーキ等が挙げられる。
被膜形成剤、可塑剤及び着色剤は、それぞれ１種を単独で用いてもよく、２種以上を組み合わせて用いてもよい。
Examples of the film forming agent include celluloses such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, methylcellulose, and ethylcellulose; gum arabic, carboxyvinyl polymer, povidone, polyvinyl alcohol, and polyacrylic acid.
Examples of plasticizers include those listed in official documents such as the Japanese Pharmacopoeia (Hirokawa Shoten) and Pharmaceutical Excipient Standards (Yakuji Nippo Co., Ltd.), such as macrogol, triethyl citrate, triacetin, and carnauba wax. .
Examples of the coloring agent include titanium oxide, talc, iron sesquioxide, and yellow No. 5 aluminum lake.
The film forming agent, plasticizer, and coloring agent may each be used singly or in combination of two or more.
また、コーティング剤として、これらの成分が混合された市販のプレミックス品を用いてもよく、例えば、日本カラコン合同会社製の商品名「オパドライ」等が挙げられる。
これらの中でも、コーティング剤としてはポリビニルアルコールを含有するものが好ましく、市販品としては、例えば日本カラコン合同会社製の商品名「オパドライＡＭＢII」が挙げられる。
Further, as a coating agent, a commercially available premix product in which these components are mixed may be used, such as "Opadry", a trade name manufactured by Nippon Colorcon LLC.
Among these, coating agents containing polyvinyl alcohol are preferable, and commercially available products include, for example, "Opadry AMB II" manufactured by Nippon Colorcon LLC under the trade name.
コーティング錠におけるコーティング剤の使用量（被覆量）は、本発明の効果を損なわない範囲で適宜設定される。例えば、コーティングされていない錠剤（素錠）１００質量部に対し、０．１～５質量部が好ましく、０．５～２質量部がより好ましい。コーティング剤の使用量が、上記下限値以上であれば錠剤の服用性を良好に維持でき、上記上限値以下であれば崩壊性を良好に維持できる。 The amount of coating agent used in the coated tablet (coating amount) is appropriately set within a range that does not impair the effects of the present invention. For example, it is preferably 0.1 to 5 parts by weight, more preferably 0.5 to 2 parts by weight, per 100 parts by weight of an uncoated tablet (uncoated tablet). If the usage amount of the coating agent is at least the above lower limit value, the ease of taking the tablet can be maintained well, and when it is below the above upper limit value, the disintegrability can be maintained well.
素錠をコーティング処理する方法特に限定されず、従来公知の方法を用いることができる。コーティング処理に使用する装置としては、例えばハイコーター（フロイント産業株式会社製）、アクアコーター（フロイント産業株式会社製）等のパン型コーティング装置が挙げられる。 The method for coating uncoated tablets is not particularly limited, and conventionally known methods can be used. Examples of the apparatus used for the coating treatment include pan-type coating apparatuses such as Hi-Coater (manufactured by Freund Sangyo Co., Ltd.) and Aqua Coater (manufactured by Freund Sangyo Co., Ltd.).
＜作用効果＞
本発明の錠剤の製造方法によれば、圧縮造粒工程の前に上述した混合工程を２回以上行うので、密度の均一性が維持された状態で粉体組成物が圧縮造粒装置（Ｙ）に備わるロール圧縮部を通過でき、圧縮状態が均一な造粒顆粒（Ｇ）が得られる。圧縮状態が均一な造粒顆粒（Ｇ）を用いることで、経時に伴う崩壊時間のばらつきが小さく、崩壊遅延が抑制された錠剤が得られる。
しかも、圧縮造粒法は、例えば流動層造粒法に比べて加水工程や乾燥工程を省略可能であり、生産効率が高い。よって、本発明の錠剤の製造方法によれば、経時に伴う崩壊時間のばらつきが小さく、崩壊遅延が抑制された、酸性の水難溶性薬物（Ａ）を含有する錠剤を生産性よく製造できる。
<Effect>
According to the tablet manufacturing method of the present invention, the above-mentioned mixing step is performed two or more times before the compression granulation step, so the powder composition is mixed with the compression granulation device (Y ) can pass through the roll compression part provided in ), and granules (G) with a uniform compression state can be obtained. By using granulated granules (G) that are uniformly compressed, tablets with small variations in disintegration time over time and suppressed delay in disintegration can be obtained.
Furthermore, the compression granulation method can omit the water addition step and the drying step compared to, for example, the fluidized bed granulation method, and has high production efficiency. Therefore, according to the tablet manufacturing method of the present invention, tablets containing the acidic, poorly water-soluble drug (A) can be manufactured with high productivity, with little variation in disintegration time over time and suppressed delay in disintegration.
以下、実施例を示して本発明を詳細に説明するが、本発明は以下の記載によって限定されるものではない。
各例で使用した原料、打錠条件及び評価方法は、以下の通りである。
EXAMPLES Hereinafter, the present invention will be explained in detail with reference to Examples, but the present invention is not limited to the following description.
The raw materials, tableting conditions, and evaluation methods used in each example are as follows.
「使用原料」
使用原料として、以下に示す化合物を用いた。
・イブプロフェン：ＢＡＳＦ社製、商品名「イブプロフェン２５」。
・低置換度ヒドロキシプロピルセルロース：信越化学工業株式会社製、商品名「ＬＨ－３１」。
・カルメロース：五徳薬品株式会社製、商品名「カルメロース ＮＳ-３００」。
・メチルセルロース：信越化学工業株式会社製、商品名「メトローズ ＳＭ－４」。
・ヒドロキシプロピルセルロース：日本曹達式会社製、商品名「ＨＰＣ－ＳＳＬ」。
・アセトアミノフェン：ノバシル社製、商品名「ＲＨＯＤＡＰＡＰＡＰ ＰＯＷＤＥＲ」。
・軽質無水ケイ酸：富士シリシア株式会社製、商品名「サイリシア３５０」。
・結晶セルロース：旭化成株式会社製、商品名「セオラス ＵＦ－７０２」。
・乾燥水酸化アルミニウムゲル：協和化学工業株式会社製、商品名「Ｓ－１００」。
・リン酸二水素カリウム：太平化学産業株式会社製、商品名「日本薬局方外医薬品規格リン酸二水素カリウム」。
・ステアリン酸マグネシウム：太平化学産業株式会社製、商品名「ステアリン酸マグネシウム」、植物性 一般（外部滑沢時）、軽質（内部添加時）。
・無水カフェイン：三菱ケミカルフーズ株式会社製、商品名「日本薬局方無水カフェイン」。
・Ｄ－マンニトール：ロケットジャパン株式会社製、商品名「ペアリトール５０Ｃ」。
"Raw materials used"
The compounds shown below were used as raw materials.
- Ibuprofen: manufactured by BASF, product name "Ibuprofen 25".
- Low-substituted hydroxypropyl cellulose: manufactured by Shin-Etsu Chemical Co., Ltd., trade name "LH-31".
- Carmellose: Manufactured by Gotoku Pharmaceutical Co., Ltd., product name "Carmellose NS-300".
- Methylcellulose: Manufactured by Shin-Etsu Chemical Co., Ltd., product name "Metrose SM-4".
・Hydroxypropyl cellulose: Manufactured by Nippon Soda Shiki Kaisha, product name "HPC-SSL".
- Acetaminophen: Manufactured by Novacil, product name "RHODAPAPAP POWDER".
-Light silicic anhydride: manufactured by Fuji Silysia Co., Ltd., product name "Silysia 350".
・Crystalline cellulose: Manufactured by Asahi Kasei Corporation, product name "CEOLUS UF-702".
- Dry aluminum hydroxide gel: manufactured by Kyowa Chemical Industry Co., Ltd., product name "S-100".
・Potassium dihydrogen phosphate: Manufactured by Taihei Kagaku Sangyo Co., Ltd., product name: “Potassium dihydrogen phosphate, non-Japanese Pharmacopoeia drug standard.”
・Magnesium stearate: Manufactured by Taihei Kagaku Sangyo Co., Ltd., product name "Magnesium Stearate", vegetable-based, general (when externally lubricated), light (when added internally).
・Anhydrous caffeine: Manufactured by Mitsubishi Chemical Foods Co., Ltd., product name "Japanese Pharmacopoeia Anhydrous Caffeine".
- D-Mannitol: Manufactured by Rocket Japan Co., Ltd., product name "Pairitol 50C".
［測定・評価方法］
＜崩壊試験＞
錠剤をＰＴＰ（Ｐｒｅｓｓ Ｔｈｒｏｕｇｈ Ｐａｃｋａｇｅ）包装材料（住友ベークライト株式会社製、商品名「ＶＳＬ－４６１０Ｎ」）を用いてＰＴＰ包装した。ＰＴＰ包装が施された錠剤を５０℃、７５％ＲＨで４週間保存した。
製造直後と、５０℃、７５％ＲＨで４週間保存した後の錠剤各１０錠について、それぞれ崩壊時間を第十八改正日本薬局方に準じて試験して測定し、その平均値を求めた。また、１０錠の崩壊時間の値から標準偏差を求め、崩壊時間のばらつきを求めた。
製造直後の錠剤の崩壊時間の平均値を「初期の崩壊時間」とし、崩壊時間の標準偏差を「初期の崩壊時間のばらつき」とした。一方、５０℃、７５％ＲＨで４週間保存した後の錠剤の崩壊時間の平均値を「保存後の崩壊時間」とし、崩壊時間の標準偏差を「保存後の崩壊時間のばらつき」とした。また、保存後の崩壊時間から初期の崩壊時間を差し引いた値を「崩壊時間の差」とした。
[Measurement/evaluation method]
<Disintegration test>
The tablets were packaged using PTP (Press Through Package) packaging material (manufactured by Sumitomo Bakelite Co., Ltd., trade name "VSL-4610N"). The PTP-packaged tablets were stored at 50° C. and 75% RH for 4 weeks.
The disintegration time of each of the 10 tablets immediately after manufacture and after storage at 50° C. and 75% RH for 4 weeks was tested and measured in accordance with the 18th edition of the Japanese Pharmacopoeia, and the average value was determined. Further, the standard deviation was determined from the values of the disintegration time of the 10 tablets, and the dispersion of the disintegration time was determined.
The average value of the disintegration time of the tablets immediately after manufacture was defined as the "initial disintegration time", and the standard deviation of the disintegration time was defined as the "variation in the initial disintegration time". On the other hand, the average value of the disintegration time of the tablets after storage for 4 weeks at 50° C. and 75% RH was defined as the "disintegration time after storage", and the standard deviation of the disintegration time was defined as "variation in disintegration time after storage". In addition, the value obtained by subtracting the initial disintegration time from the disintegration time after storage was defined as the "difference in disintegration time."
［実施例１～１８、２２～２５］
＜ＩＢＰ造粒顆粒の製造＞
１錠当たりの組成が表１～５に示す組成となるように、（Ａ）成分、（Ｂ）成分、（Ｃ）成分及び任意成分（Ｍ）を含有する粉体組成物（α）の全部を高速撹拌混合機（株式会社ダルトン製、製品名「スパルタンミキサーＳＰＭ－１６０ＧＨＣＮ」）を用い、チョッパー回転速度：１４００ｒｐｍ、ミキシングアーム：２０ｒｐｍ、処理時間：２分の条件で混合し、粉体組成物（α１）を得た（第１の混合工程）。
次いで、粉体組成物（α１）を高速撹拌混合機から取り出し、ピンミル粉砕機（株式会社パウレック製、製品名「コロプレックス１６０Ｚ」）を用いて粉砕した。
[Examples 1-18, 22-25]
<Manufacture of IBP granules>
All of the powder composition (α) containing component (A), component (B), component (C) and optional component (M) so that the composition per tablet is as shown in Tables 1 to 5. were mixed using a high-speed stirring mixer (manufactured by Dalton Co., Ltd., product name "Spartan Mixer SPM-160GHCN") under the conditions of chopper rotation speed: 1400 rpm, mixing arm: 20 rpm, and processing time: 2 minutes to obtain a powder composition. (α1) was obtained (first mixing step).
Next, the powder composition (α1) was taken out from the high-speed stirring mixer and pulverized using a pin mill pulverizer (manufactured by Powrex Co., Ltd., product name “Coloplex 160Z”).
粉砕後の粉体組成物（α１）をピンミル粉砕機から取り出し、容器に投入した。容器内の粉体組成物（α１）の上面から１０ｃｍ下の領域における任意の３箇所から検体を採取した。同様に、容器内の粉体組成物（α１）の底面における任意の３箇所から検体を採取した。各検体中の（Ａ）成分の含有量を、高速液体クロマトグラフィーを用い、以下の測定条件でそれぞれ測定した。測定には、検体の濃度が０．１ｍｇ／ｍＬとなるように適宜、移動相に溶解させたものをサンプルとして用いた。
<<測定条件>>
・測定装置：株式会社島津製作所製、製品名「一体型ＨＰＬＣ Ｐｒｏｍｉｎｅｎｃｅ－ｉ」。
・分離カラム：ジーエルサイエンス株式会社製、商品名「Ｉｎｅｒｔｓｉｌ ＯＤＳ－３（５．０μｍ、１５０ｍｍ×４．６ｍｍ）」。
・移動相：アセトニトリル／ｐＨ２．６の０．０５ｍоｌ／Ｌリン酸二水素ナトリウム試液混液＝３／２（体積比）。ｐＨ２．６の０．０５ｍоｌ／Ｌリン酸二水素ナトリウム試液は第十八改正日本薬局方に準じて調製した。
・移動相の流量：１．０ｍＬ／分。
・サンプルの注入量：５０μＬ。
・測定温度：４０℃。
The powder composition (α1) after pulverization was taken out from the pin mill pulverizer and put into a container. Specimens were collected from three arbitrary locations in a region 10 cm below the top surface of the powder composition (α1) in the container. Similarly, samples were collected from three arbitrary locations on the bottom of the powder composition (α1) in the container. The content of component (A) in each specimen was measured using high performance liquid chromatography under the following measurement conditions. For the measurements, samples were used that were dissolved in an appropriate mobile phase so that the concentration of the specimen was 0.1 mg/mL.
<<Measurement conditions>>
- Measuring device: Manufactured by Shimadzu Corporation, product name: "Integrated HPLC Prominence-i".
- Separation column: manufactured by GL Sciences Co., Ltd., trade name "Inertsil ODS-3 (5.0 μm, 150 mm x 4.6 mm)".
- Mobile phase: acetonitrile/pH 2.6 0.05 mol/L sodium dihydrogen phosphate test solution mixture = 3/2 (volume ratio). A 0.05 mol/L sodium dihydrogen phosphate test solution with a pH of 2.6 was prepared according to the 18th edition of the Japanese Pharmacopoeia.
- Mobile phase flow rate: 1.0 mL/min.
・Sample injection volume: 50 μL.
・Measurement temperature: 40℃.
６個の検体の（Ａ）成分の含有量の値から標準偏差を求め、下記式（１）より算出した工程能力指数（Ｃｐ）が１を超え、容器内の粉体組成物（α１）中の（Ａ）成分であるイブプロフェンの含有量が均一であることを確認した。なお、規格は９０～１１０％として計算した。
Ｃｐ＝（規格上限－規格下限）/（６個の検体中の（Ａ）成分の含有量の標準偏差） ・・・（１）
The standard deviation was calculated from the content of component (A) of the six samples, and the process capability index (Cp) calculated from the following formula (1) exceeded 1, and the powder composition (α1) in the container It was confirmed that the content of ibuprofen, component (A), was uniform. Note that the calculation was performed assuming that the standard is 90% to 110%.
Cp = (upper limit of specification - lower limit of specification) / (standard deviation of content of component (A) in 6 samples) ... (1)
次いで、粉砕後の粉体組成物（α１）を表１～５に示す種類の混合機を用いてさらに混合し、粉体組成物（α２）を得た（第２の混合工程）。本実施例では、得られた粉体組成物（α２）を造粒前粉体とした。
なお、第２の混合工程では、混合機として以下に示す高速撹拌混合機、中低速撹拌混合機、容器回転型混合機のいずれかを用いた。また、各混合機における運転条件を以下に示す。
<<高速撹拌混合機>>
・ＳＰＭ：スパルタンミキサーＳＰＭ－１６０ＧＨＣＮ（株式会社ダルトン製）、チョッパー回転速度：１４００ｒｐｍ、ミキシングアーム：２０ｒｐｍ、処理時間：２分。
・ＨＳＭ：ハイスピードミキサーＦＳ．ＧＳ．１０Ｊ（株式会社アーステクニカ製）、チョッパー回転速度：２０００ｒｐｍ、ブレード：２００ｒｐｍ、処理時間：２分。
・ＶＧ：バーチカルグラニュレータＶＧ－２５（株式会社パウレック製）、チョッパー回転速度：２０００ｒｐｍ、ブレード：２００ｒｐｍ、処理時間：２分。
<<中低速撹拌混合機>>
・ＲＭ：リボン型混合機Ｒ－５（株式会社徳寿工作所製）、回転速度：４５ｒｐｍ、処理時間：２分。
<<容器回転型混合機>>
・ＢＣＭ：ボーレコンテナミキサーＰＭ－１００（株式会社広島メタル＆マシナリー製）、回転速度：８ｒｐｍ、処理時間：５分。
Next, the powder composition (α1) after pulverization was further mixed using the types of mixers shown in Tables 1 to 5 to obtain a powder composition (α2) (second mixing step). In this example, the obtained powder composition (α2) was used as a powder before granulation.
In the second mixing step, any one of the following high-speed stirring mixer, medium-low speed stirring mixer, and container rotating type mixer was used as the mixer. In addition, the operating conditions for each mixer are shown below.
<<High-speed stirring mixer>>
- SPM: Spartan mixer SPM-160GHCN (manufactured by Dalton Co., Ltd.), chopper rotation speed: 1400 rpm, mixing arm: 20 rpm, processing time: 2 minutes.
・HSM: High speed mixer FS. G.S. 10J (manufactured by Earth Technica Co., Ltd.), chopper rotation speed: 2000 rpm, blade: 200 rpm, processing time: 2 minutes.
- VG: Vertical granulator VG-25 (manufactured by Powrec Co., Ltd.), chopper rotation speed: 2000 rpm, blade: 200 rpm, processing time: 2 minutes.
<<Medium-low speed stirring mixer>>
・RM: Ribbon type mixer R-5 (manufactured by Tokuju Kosho Co., Ltd.), rotation speed: 45 rpm, processing time: 2 minutes.
<<Container rotating mixer>>
- BCM: Bohle Container Mixer PM-100 (manufactured by Hiroshima Metal & Machinery Co., Ltd.), rotation speed: 8 rpm, processing time: 5 minutes.
次いで、造粒前粉体を混合機から取り出し、ローラーコンパクター型圧縮造粒装置（フロイント・ターボ株式会社製、製品名「ローラーコンパクターＦＰ１６０×６０Ｓ」）に投入して圧縮造粒し、イブプロフェンを含む造粒顆粒（ＩＢＰ造粒顆粒）を得た（圧縮造粒工程）。なお、圧縮ロール幅１ｃｍ当たりの粉体処理速度が表１～５に示す速度となるように調節しながら圧縮造粒を行った。また、ロール圧縮部を通過した直後のフレーク温度が表１～５に示す温度になるよう、循環式低温恒温水槽（トーマス科学器械株式会社製、製品名「ＴＲＬ７５０ＨＳ」）を用い、冷却水をローラーコンパクター型圧縮造粒装置のロール圧縮部のロール内部に循環させることでロールを冷却した。また、フレーク温度についてはサーモグラフィカメラ（ＦＬＩＲ社製、製品名「ＦＬＩＲ Ｅ５－ＸＴ」）を用い、ロール圧縮部を通過した直後のフレーク温度を測定した。
必要に応じ目開き２５０μｍの篩により篩過を行い（篩過工程）、篩を通過した粒子径が２５０μｍ以下の粉体と、篩を通過しなかった粒子径が２５０μｍ超の粉体とを混合して、ＩＢＰ造粒顆粒中の粒子径が２５０μｍ以下である粒子の割合が表１～５に示す値となるように調整した。
Next, the powder before granulation is taken out from the mixer and put into a roller compactor type compression granulation device (manufactured by Freund Turbo Co., Ltd., product name "Roller Compactor FP160 x 60S") for compression granulation to contain ibuprofen. Granulated granules (IBP granulated granules) were obtained (compression granulation process). The compression granulation was performed while adjusting the powder processing speed per 1 cm of compression roll width to be as shown in Tables 1 to 5. In addition, a circulating low-temperature constant temperature water bath (manufactured by Thomas Scientific Instruments Co., Ltd., product name "TRL750HS") was used to supply cooling water to the rollers so that the temperature of the flakes immediately after passing through the roll compression section was the temperature shown in Tables 1 to 5. The roll was cooled by circulating it inside the roll of the roll compression section of a compactor-type compression granulator. Furthermore, the temperature of the flakes was measured using a thermography camera (manufactured by FLIR, product name: "FLIR E5-XT") immediately after passing through the roll compression section.
If necessary, sieve through a sieve with an opening of 250 μm (sieving step), and mix the powder with a particle size of 250 μm or less that passed through the sieve and the powder with a particle size of more than 250 μm that did not pass through the sieve. The proportion of particles having a particle size of 250 μm or less in the IBP granules was adjusted to the values shown in Tables 1 to 5.
＜ＡＬ造粒顆粒の製造＞
１錠当たりの組成が表１～５に示す組成となるように、崩壊剤（Ｂ）及び任意成分（Ｍ）を含有する粉体組成物（β）の全部を高速撹拌混合機（株式会社ダルトン製、製品名「スパルタンミキサーＳＰＭ-１６０ＧＨＣＮ」）を用い、チョッパー回転速度１４００ｒｐｍ、ミキシングアーム２０ｒｐｍ、処理時間１分の条件で混合した。
次いで、混合後の粉体組成物（β１）を高速撹拌混合機から取り出し、ローラーコンパクター型圧縮造粒装置（フロイント・ターボ株式会社製、製品名「ローラーコンパクターＦＰ１６０×６０Ｓ」）に投入して圧縮造粒し、乾燥水酸化アルミニウムゲルを含む造粒顆粒（ＡＬ造粒顆粒）を得た。
<Manufacture of AL granules>
The entire powder composition (β) containing the disintegrant (B) and optional ingredients (M) was mixed with a high-speed stirring mixer (Dalton Co., Ltd.) so that the composition per tablet was as shown in Tables 1 to 5. The mixture was mixed using a chopper rotation speed of 1400 rpm, a mixing arm of 20 rpm, and a processing time of 1 minute using a Spartan Mixer SPM-160GHCN (manufactured by Manufacturer, Inc., product name: "Spartan Mixer SPM-160GHCN").
Next, the powder composition (β1) after mixing was taken out from the high-speed stirring mixer and put into a roller compactor-type compression granulator (manufactured by Freund Turbo Co., Ltd., product name "Roller Compactor FP160x60S") for compression. Granulation was performed to obtain granules containing dried aluminum hydroxide gel (AL granules).
＜錠剤の製造＞
ＩＢＰ造粒顆粒をロータリー式の打錠機（株式会社菊水製作所製、製品名「アクエリアス３－Ｋ」）の臼に充填し、予圧０．３ｋＮにて打錠した後（第一の予圧工程）、ＡＬ造粒顆粒をさらに充填し、予圧６ｋＮにて打錠した後（第二の予圧工程）に、本圧１０ｋＮにて打錠し（本圧工程）、イブプロフェンを含む層（ＩＢＰ層）と乾燥水酸化アルミニウムゲルを含む層（ＡＬ層）とを有する錠剤（積層錠）を得た。ＩＢＰ層が薬物層であり、ＡＬ層が任意層である。なお、打錠には、実施例１～１５、１７～１８、２０～２５では直径φが８．０ｍｍの臼及び杵を用い、実施例１６では直径φが１０．０ｍｍの臼及び杵を用いた。また、杵としては、杵先の形状が２段Ｒ（直径φが８．０ｍｍの場合：Ｒ１＝３．２ｍｍ、Ｒ２＝９．５ｍｍ、直径φが１０．０ｍｍの場合：Ｒ１＝４．０ｍｍ、Ｒ２＝１１．５ｍｍ）を用いた。また、打錠時にはＩＢＰ造粒顆粒の充填前に外部滑沢噴霧システムＥＬＳ－Ｐ１（株式会社菊水製作所製）により、１錠当たり０．０５質量％のステアリン酸マグネシウムを上下杵、臼に噴霧し打錠した。
得られた錠剤について、崩壊試験を行った。結果を表１～５に示す。
<Manufacture of tablets>
After filling the IBP granules into the mortar of a rotary tabletting machine (manufactured by Kikusui Seisakusho Co., Ltd., product name "Aquarius 3-K") and compressing into tablets with a preload of 0.3 kN (first preloading step) , the AL granules were further filled and tableted with a pre-pressure of 6 kN (second pre-pressure step), and then tableted with a main pressure of 10 kN (main-pressure step) to form a layer containing ibuprofen (IBP layer). A tablet (laminated tablet) having a layer containing dry aluminum hydroxide gel (AL layer) was obtained. The IBP layer is the drug layer and the AL layer is the optional layer. For tabletting, a mortar and punch with a diameter φ of 8.0 mm were used in Examples 1 to 15, 17 to 18, and 20 to 25, and a mortar and punch with a diameter φ of 10.0 mm was used in Example 16. there was. In addition, as for the punch, the shape of the punch tip is 2 steps R (when the diameter φ is 8.0 mm: R1 = 3.2 mm, R2 = 9.5 mm, when the diameter φ is 10.0 mm: R1 = 4.0 mm , R2=11.5 mm) was used. In addition, during tabletting, before filling the IBP granules, 0.05% by mass of magnesium stearate per tablet was sprayed onto the upper and lower punches and die using an external lubricant spray system ELS-P1 (manufactured by Kikusui Seisakusho Co., Ltd.). I pressed the tablets.
A disintegration test was conducted on the obtained tablets. The results are shown in Tables 1 to 5.
［実施例１９～２１］
１錠当たりの組成が表４に示す組成となるように変更した以外は、実施例１～１８、２２～２５と同様にしてＩＢＰ造粒顆粒を製造した。
１錠当たりの組成が表４に示す組成となるように、得られたＩＢＰ造粒顆粒と崩壊剤（Ｂ）と任意成分（Ｍ）を混合し、ＩＢＰ層用の混合粉体を調製した。
[Examples 19-21]
IBP granules were produced in the same manner as Examples 1 to 18 and 22 to 25, except that the composition per tablet was changed to the composition shown in Table 4.
The obtained IBP granules, a disintegrant (B), and an optional component (M) were mixed so that the composition per tablet was as shown in Table 4 to prepare a mixed powder for the IBP layer.
ＩＢＰ層用の混合粉体をロータリー式の打錠機（株式会社菊水製作所製、製品名「アクエリアス３－Ｋ」）の臼に充填し、予圧０．３ｋＮにて打錠した後（予圧工程）に、本圧１０ｋＮにて打錠し（本圧工程）、ＩＢＰ層からなる錠剤（単層錠）を得た。なお、打錠には、実施例１９では直径φが１０．０ｍｍの臼及び杵を用い、実施例２０～２１では直径φが８．０ｍｍの臼及び杵を用いた。また、杵としては、杵先の形状が２段Ｒ（直径φが８．０ｍｍの場合：Ｒ１＝３．２ｍｍ、Ｒ２＝９．５ｍｍ、直径φが１０．０ｍｍの場合：Ｒ１＝４．０ｍｍ、Ｒ２＝１１．５ｍｍ）を用いた。また、打錠時にはＩＢＰ層用の混合粉体の充填前に外部滑沢噴霧システムＥＬＳ－Ｐ１（株式会社菊水製作所製）により、１錠当たり０．０５質量％のステアリン酸マグネシウムを上下杵、臼に噴霧し打錠した。
得られた錠剤について、崩壊試験を行った。結果を表４に示す。
The mixed powder for the IBP layer was filled into the mortar of a rotary tabletting machine (manufactured by Kikusui Seisakusho Co., Ltd., product name "Aquarius 3-K"), and the tablets were compressed with a preload of 0.3 kN (preloading process). Then, tableting was performed at a main pressure of 10 kN (main pressure step) to obtain a tablet consisting of an IBP layer (single-layer tablet). For tabletting, a mortar and punch with a diameter φ of 10.0 mm were used in Example 19, and a mortar and punch with a diameter φ of 8.0 mm were used in Examples 20 to 21. In addition, as for the punch, the shape of the punch tip is 2 steps R (when the diameter φ is 8.0 mm: R1 = 3.2 mm, R2 = 9.5 mm, when the diameter φ is 10.0 mm: R1 = 4.0 mm , R2=11.5 mm) was used. In addition, during tabletting, before filling the mixed powder for the IBP layer, 0.05% by mass of magnesium stearate per tablet was applied using an external lubricating spray system ELS-P1 (manufactured by Kikusui Seisakusho Co., Ltd.) using upper and lower punches and dies. It was sprayed onto the tablets and compressed into tablets.
A disintegration test was conducted on the obtained tablets. The results are shown in Table 4.
［比較例１、３、４］
１錠当たりの組成が表６に示す組成となるように変更した以外は、実施例１～１８、２２～２５と同様にして第１の混合工程及び粉砕工程を行い、粉砕後の粉体組成物（α１）を得た。なお、実施例１～１８、２２～２５と同様にして工程能力指数（Ｃｐ）を求め、工程能力指数（Ｃｐ）が１を超え、容器内の粉体組成物（α１）中の（Ａ）成分であるイブプロフェンの含有量が均一であることを確認した。
得られた粉砕後の粉体組成物（α１）を造粒前粉体として用いた以外は、実施例１～１８、２２～２５と同様にして圧縮造粒工程を行い、ＩＢＰ造粒顆粒を得た。
[Comparative Examples 1, 3, 4]
The first mixing step and grinding step were carried out in the same manner as in Examples 1 to 18 and 22 to 25, except that the composition per tablet was changed to the composition shown in Table 6, and the powder composition after grinding was A product (α1) was obtained. The process capability index (Cp) was determined in the same manner as Examples 1 to 18 and 22 to 25, and the process capability index (Cp) exceeded 1, indicating that (A) in the powder composition (α1) in the container It was confirmed that the content of the ingredient ibuprofen was uniform.
The compression granulation step was carried out in the same manner as in Examples 1 to 18 and 22 to 25, except that the obtained powder composition after pulverization (α1) was used as the pre-granulation powder, and the IBP granules were Obtained.
別途、１錠当たりの組成が表６に示す組成となるように変更した以外は、実施例１～１８、２２～２５と同様にしてＡＬ造粒顆粒を製造した。 AL granules were produced in the same manner as in Examples 1 to 18 and 22 to 25, except that the composition per tablet was changed to the composition shown in Table 6.
ＩＢＰ造粒顆粒をロータリー式の打錠機（株式会社菊水製作所製、製品名「アクエリアス３－Ｋ」）の臼に充填し、予圧０．３ｋＮにて打錠した後（第一の予圧工程）、ＡＬ造粒顆粒をさらに充填し、予圧６ｋＮにて打錠した後（第二の予圧工程）に、本圧１０ｋＮにて打錠し（本圧工程）、ＩＢＰ層とＡＬ層とを有する錠剤（積層錠）を得た。なお、打錠には、直径φが８．０ｍｍの臼及び杵を用いた。また、杵としては、杵先の形状が２段Ｒ（Ｒ１＝３．２ｍｍ、Ｒ２＝９．５ｍｍ）を用いた。また、打錠時にはＩＢＰ造粒顆粒の充填前に外部滑沢噴霧システムＥＬＳ－Ｐ１（株式会社菊水製作所製）により、１錠当たり０．０５質量％のステアリン酸マグネシウムを上下杵、臼に噴霧し打錠した。
得られた錠剤について、崩壊試験を行った。結果を表６に示す。
After filling the IBP granules into the mortar of a rotary tabletting machine (manufactured by Kikusui Seisakusho Co., Ltd., product name "Aquarius 3-K") and compressing into tablets with a preload of 0.3 kN (first preloading step) , the AL granules are further filled and tableted with a pre-pressure of 6 kN (second pre-compression step), and then tableted with a main pressure of 10 kN (main-pressure step), resulting in a tablet having an IBP layer and an AL layer. (laminated tablets) were obtained. For tabletting, a mortar and punch with a diameter φ of 8.0 mm were used. Further, the punch used had a two-step R shape at the tip (R1 = 3.2 mm, R2 = 9.5 mm). In addition, during tabletting, before filling the IBP granules, 0.05% by mass of magnesium stearate per tablet was sprayed onto the upper and lower punches and die using an external lubricant spray system ELS-P1 (manufactured by Kikusui Seisakusho Co., Ltd.). I pressed the tablets.
A disintegration test was conducted on the obtained tablets. The results are shown in Table 6.
［比較例２］
１錠当たりの組成が表６に示す組成となるように変更した以外は、実施例１～１８、２２～２５と同様にしてＩＢＰ造粒顆粒を製造した。
１錠当たりの組成が表６に示す組成となるように、得られたＩＢＰ造粒顆粒と崩壊剤（Ｂ）と任意成分（Ｍ）を混合し、ＩＢＰ層用の混合粉体を調製した。
[Comparative example 2]
IBP granules were produced in the same manner as Examples 1 to 18 and 22 to 25, except that the composition per tablet was changed to the composition shown in Table 6.
The obtained IBP granules, a disintegrant (B), and an optional component (M) were mixed so that the composition per tablet was as shown in Table 6 to prepare a mixed powder for the IBP layer.
ＩＢＰ層用の混合粉体をロータリー式の打錠機（株式会社菊水製作所製、製品名「アクエリアス３－Ｋ」）の臼に充填し、予圧０．３ｋＮにて打錠した後（予圧工程）に、本圧１０ｋＮにて打錠し（本圧工程）、ＩＢＰ層からなる錠剤（単層錠）を得た。なお、打錠には、直径φが８．０ｍｍの臼及び杵を用いた。また、杵としては、杵先の形状が２段Ｒ（Ｒ１＝３．２ｍｍ、Ｒ２＝９．５ｍｍ）を用いた。また、打錠時にはＩＢＰ層用の混合粉体の充填前に外部滑沢噴霧システムＥＬＳ－Ｐ１（株式会社菊水製作所製）により、１錠当たり０．０５質量％のステアリン酸マグネシウムを上下杵、臼に噴霧し打錠した。
得られた錠剤について、崩壊試験を行った。結果を表６に示す。
The mixed powder for the IBP layer was filled into the mortar of a rotary tabletting machine (manufactured by Kikusui Seisakusho Co., Ltd., product name "Aquarius 3-K"), and the tablets were compressed with a preload of 0.3 kN (preloading process). Then, tableting was performed at a main pressure of 10 kN (main pressure step) to obtain a tablet consisting of an IBP layer (single-layer tablet). For tabletting, a mortar and punch with a diameter φ of 8.0 mm were used. Further, the punch used had a two-step R shape at the tip (R1 = 3.2 mm, R2 = 9.5 mm). In addition, during tabletting, before filling the mixed powder for the IBP layer, 0.05% by mass of magnesium stearate per tablet was applied using an external lubricating spray system ELS-P1 (manufactured by Kikusui Seisakusho Co., Ltd.) using upper and lower punches and dies. It was sprayed onto the tablets and compressed into tablets.
A disintegration test was conducted on the obtained tablets. The results are shown in Table 6.
表１～５の結果より、圧縮造粒工程の前に混合工程を２回行った各実施例で得られた錠剤は、経時に伴う崩壊時間のばらつきが小さく、かつ、崩壊遅延が抑制されていた。
一方、表６の結果より、圧縮造粒工程の前に混合工程を１回行った各比較例で得られた錠剤は、経時に伴う崩壊時間のばらつきが大きく、また、崩壊遅延が発生した。
From the results in Tables 1 to 5, the tablets obtained in each example in which the mixing step was performed twice before the compression granulation step had small variations in disintegration time over time, and the delay in disintegration was suppressed. Ta.
On the other hand, from the results in Table 6, the tablets obtained in each comparative example in which the mixing step was performed once before the compression granulation step had large variations in disintegration time over time, and delayed disintegration occurred.
Claims (6)
前記酸性の水難溶性薬物（Ａ）を含有する粉体組成物を混合する混合工程と、
圧縮造粒装置（Ｙ）を用いて、前記混合工程において混合された前記粉体組成物を圧縮造粒し、造粒顆粒を得る圧縮造粒工程と、
を有し、
前記圧縮造粒装置（Ｙ）が、ローラーコンパクター型圧縮造粒装置又はブリケット型圧縮造粒装置であり、
前記圧縮造粒工程の前に前記混合工程を２回以上行い、１回目の混合工程で前記粉体組成物の一部又は全部を混合し、少なくとも前記圧縮造粒工程の直前の混合工程で前記粉体組成物の全部を混合する、錠剤の製造方法。 A method for producing a tablet containing an acidic poorly water-soluble drug (A), comprising:
a mixing step of mixing a powder composition containing the acidic poorly water-soluble drug (A);
A compression granulation step in which the powder composition mixed in the mixing step is compressed and granulated using a compression granulation device (Y) to obtain granules;
has
The compression granulation device (Y) is a roller compactor type compression granulation device or a briquette type compression granulation device,
The mixing step is performed twice or more before the compression granulation step, and part or all of the powder composition is mixed in the first mixing step, and at least the mixing step immediately before the compression granulation step is performed. A method for manufacturing tablets, which involves mixing all of the powder composition.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2022082851A JP2023170811A (en) | 2022-05-20 | 2022-05-20 | Method for producing tablet |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2022082851A JP2023170811A (en) | 2022-05-20 | 2022-05-20 | Method for producing tablet |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2023170811A true JP2023170811A (en) | 2023-12-01 |
Family
ID=88927654
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2022082851A Pending JP2023170811A (en) | 2022-05-20 | 2022-05-20 | Method for producing tablet |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2023170811A (en) |
-
2022
- 2022-05-20 JP JP2022082851A patent/JP2023170811A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106943355B (en) | Pharmaceutical composition | |
| US20130172374A1 (en) | Solid composition for controlled release of ionizable active agents with poor aqueous solubility at low ph and methods of use thereof | |
| US20090098211A1 (en) | Solid dosage forms | |
| JP5208729B2 (en) | Method for producing sustained-release tablets | |
| JP5974469B2 (en) | Tablet manufacturing method | |
| US20240156740A1 (en) | Novel ibuprofen and acetaminophen composition | |
| JP5663238B2 (en) | Oral solid preparation and method for producing the same | |
| JP4329947B1 (en) | Tablets for internal use | |
| US20180344648A1 (en) | Clobazam tablet formulation and process for its preparation | |
| JP2023170811A (en) | Method for producing tablet | |
| JP7274825B2 (en) | Tablet and its manufacturing method | |
| JP2012046454A (en) | Tablet for internal use and method for producing the same | |
| JP7346404B2 (en) | Fixed-dose combination tablet formulation of acarbose and metformin and method for manufacturing the same | |
| JP2023095091A (en) | Tablet comprising dry aluminum hydroxide gel | |
| JP6552088B2 (en) | Granulated granules and method for producing the same, tablet and method for producing the same | |
| US20130165459A1 (en) | Pharmaceutical composition and dosage forms of elinogrel and methods of use thereof | |
| JP6407085B2 (en) | Tablet and production method thereof | |
| JP2023087862A (en) | Acetaminophen-containing tablet | |
| KR102620329B1 (en) | Tablet and method for manufacturing tablet | |
| JP7109255B2 (en) | Method for producing pulverized material and method for producing tablet | |
| JP6895856B2 (en) | Method for manufacturing solid preparations and tablets | |
| JP6757596B2 (en) | Oral solid tablets | |
| TW202224681A (en) | Single dosage form of a pharmaceutical composition for the treatment or prevention of hypertension and hypercholesterolemia | |
| JP2023173283A (en) | Granule and manufacturing method thereof, and tablet | |
| JP5801266B2 (en) | Method for producing tablets containing hydrophobic drugs |