JP5021210B2 - Compression molding - Google Patents
Compression molding Download PDFInfo
- Publication number
- JP5021210B2 JP5021210B2 JP2006007331A JP2006007331A JP5021210B2 JP 5021210 B2 JP5021210 B2 JP 5021210B2 JP 2006007331 A JP2006007331 A JP 2006007331A JP 2006007331 A JP2006007331 A JP 2006007331A JP 5021210 B2 JP5021210 B2 JP 5021210B2
- Authority
- JP
- Japan
- Prior art keywords
- mass
- compression
- bulk density
- cysteine
- crystalline cellulose
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000000748 compression moulding Methods 0.000 title description 22
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 90
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 67
- 235000010323 ascorbic acid Nutrition 0.000 claims description 52
- 238000002360 preparation method Methods 0.000 claims description 50
- 229920002678 cellulose Polymers 0.000 claims description 47
- 235000010980 cellulose Nutrition 0.000 claims description 47
- 235000013878 L-cysteine Nutrition 0.000 claims description 45
- 239000011668 ascorbic acid Substances 0.000 claims description 42
- 229960005070 ascorbic acid Drugs 0.000 claims description 41
- 239000001913 cellulose Substances 0.000 claims description 41
- 239000004201 L-cysteine Substances 0.000 claims description 33
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 16
- 229920000642 polymer Polymers 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 claims description 10
- 235000012239 silicon dioxide Nutrition 0.000 claims description 10
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 9
- 235000019359 magnesium stearate Nutrition 0.000 claims description 8
- 229920002472 Starch Polymers 0.000 claims description 5
- 239000000454 talc Substances 0.000 claims description 5
- 229910052623 talc Inorganic materials 0.000 claims description 5
- 235000012222 talc Nutrition 0.000 claims description 5
- 235000019698 starch Nutrition 0.000 claims description 4
- 239000008107 starch Substances 0.000 claims description 4
- 150000005846 sugar alcohols Chemical class 0.000 claims description 4
- 229920003169 water-soluble polymer Polymers 0.000 claims description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 2
- 229960000913 crospovidone Drugs 0.000 claims description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- 238000009495 sugar coating Methods 0.000 claims description 2
- 150000001720 carbohydrates Chemical class 0.000 claims 1
- 239000003826 tablet Substances 0.000 description 57
- 229960002433 cysteine Drugs 0.000 description 32
- 230000000052 comparative effect Effects 0.000 description 19
- 239000000843 powder Substances 0.000 description 16
- 150000008538 L-cysteines Chemical class 0.000 description 12
- 238000000576 coating method Methods 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 208000010201 Exanthema Diseases 0.000 description 10
- 150000000996 L-ascorbic acids Chemical class 0.000 description 10
- 201000005884 exanthem Diseases 0.000 description 10
- 206010037844 rash Diseases 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 239000011248 coating agent Substances 0.000 description 8
- 238000005469 granulation Methods 0.000 description 8
- 230000003179 granulation Effects 0.000 description 8
- 239000002245 particle Substances 0.000 description 8
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 description 7
- FAPWYRCQGJNNSJ-UBKPKTQASA-L calcium D-pantothenic acid Chemical compound [Ca+2].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O.OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O FAPWYRCQGJNNSJ-UBKPKTQASA-L 0.000 description 7
- 229960002079 calcium pantothenate Drugs 0.000 description 7
- 238000007906 compression Methods 0.000 description 7
- 230000006835 compression Effects 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- JZRWCGZRTZMZEH-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 7
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 6
- 206010014970 Ephelides Diseases 0.000 description 6
- 208000003351 Melanosis Diseases 0.000 description 6
- 206010042496 Sunburn Diseases 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 208000032843 Hemorrhage Diseases 0.000 description 5
- 208000012641 Pigmentation disease Diseases 0.000 description 5
- 230000000740 bleeding effect Effects 0.000 description 5
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 230000019612 pigmentation Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 241000278713 Theora Species 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 238000002845 discoloration Methods 0.000 description 4
- 206010025482 malaise Diseases 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 208000002874 Acne Vulgaris Diseases 0.000 description 3
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 3
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 3
- 201000004624 Dermatitis Diseases 0.000 description 3
- 206010019133 Hangover Diseases 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 3
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 3
- 208000024780 Urticaria Diseases 0.000 description 3
- 229930003268 Vitamin C Natural products 0.000 description 3
- 206010000496 acne Diseases 0.000 description 3
- 208000010668 atopic eczema Diseases 0.000 description 3
- 235000010376 calcium ascorbate Nutrition 0.000 description 3
- 229940047036 calcium ascorbate Drugs 0.000 description 3
- 239000011692 calcium ascorbate Substances 0.000 description 3
- BLORRZQTHNGFTI-ZZMNMWMASA-L calcium-L-ascorbate Chemical compound [Ca+2].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] BLORRZQTHNGFTI-ZZMNMWMASA-L 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- -1 etc. Chemical compound 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 230000006651 lactation Effects 0.000 description 3
- 229940055726 pantothenic acid Drugs 0.000 description 3
- 235000019161 pantothenic acid Nutrition 0.000 description 3
- 239000011713 pantothenic acid Substances 0.000 description 3
- 230000035935 pregnancy Effects 0.000 description 3
- 238000005096 rolling process Methods 0.000 description 3
- 235000010378 sodium ascorbate Nutrition 0.000 description 3
- 229960005055 sodium ascorbate Drugs 0.000 description 3
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 3
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000007940 sugar coated tablet Substances 0.000 description 3
- 230000009469 supplementation Effects 0.000 description 3
- 239000011721 thiamine Substances 0.000 description 3
- 229960003495 thiamine Drugs 0.000 description 3
- 235000019157 thiamine Nutrition 0.000 description 3
- UIERGBJEBXXIGO-UHFFFAOYSA-N thiamine mononitrate Chemical compound [O-][N+]([O-])=O.CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N UIERGBJEBXXIGO-UHFFFAOYSA-N 0.000 description 3
- 229960000984 tocofersolan Drugs 0.000 description 3
- 235000019154 vitamin C Nutrition 0.000 description 3
- 239000011718 vitamin C Substances 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- SNPLKNRPJHDVJA-ZETCQYMHSA-N D-panthenol Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCCO SNPLKNRPJHDVJA-ZETCQYMHSA-N 0.000 description 2
- 206010018276 Gingival bleeding Diseases 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 239000007941 film coated tablet Substances 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 208000011759 gum bleeding Diseases 0.000 description 2
- YOZNUFWCRFCGIH-BYFNXCQMSA-L hydroxocobalamin Chemical compound O[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O YOZNUFWCRFCGIH-BYFNXCQMSA-L 0.000 description 2
- 229960003512 nicotinic acid Drugs 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 2
- 229940101267 panthenol Drugs 0.000 description 2
- 235000020957 pantothenol Nutrition 0.000 description 2
- 239000011619 pantothenol Substances 0.000 description 2
- 239000002831 pharmacologic agent Substances 0.000 description 2
- 239000004014 plasticizer Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- GQTHJBOWLPZUOI-FJXQXJEOSA-M sodium D-pantothenate Chemical compound [Na+].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O GQTHJBOWLPZUOI-FJXQXJEOSA-M 0.000 description 2
- 229940068459 sodium pantothenate Drugs 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000002076 α-tocopherol Substances 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- RBCOYOYDYNXAFA-UHFFFAOYSA-L (5-hydroxy-4,6-dimethylpyridin-3-yl)methyl phosphate Chemical compound CC1=NC=C(COP([O-])([O-])=O)C(C)=C1O RBCOYOYDYNXAFA-UHFFFAOYSA-L 0.000 description 1
- IELOKBJPULMYRW-IKTKBOKFSA-N 4-oxo-4-[[(2S)-2,5,7,8-tetramethyl-2-[(4S,8S)-4,8,12-trimethyltridecyl]-3,4-dihydrochromen-6-yl]oxy]butanoic acid Chemical compound CC(C)CCC[C@H](C)CCC[C@H](C)CCC[C@@](C)(CC1)Oc(c(C)c2C)c1c(C)c2OC(CCC(O)=O)=O IELOKBJPULMYRW-IKTKBOKFSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 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
- IWXAZSAGYJHXPX-BCEWYCLDSA-N Bisbentiamine Chemical compound C=1C=CC=CC=1C(=O)OCC/C(SS\C(CCOC(=O)C=1C=CC=CC=1)=C(/C)N(CC=1C(=NC(C)=NC=1)N)C=O)=C(/C)N(C=O)CC1=CN=C(C)N=C1N IWXAZSAGYJHXPX-BCEWYCLDSA-N 0.000 description 1
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UHFFFAOYSA-N 0.000 description 1
- 241000209205 Coix Species 0.000 description 1
- 208000034656 Contusions Diseases 0.000 description 1
- 229920002261 Corn starch 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
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- IELOKBJPULMYRW-NJQVLOCASA-N D-alpha-Tocopheryl Acid Succinate Chemical compound OC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C IELOKBJPULMYRW-NJQVLOCASA-N 0.000 description 1
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- UYUXSRADSPPKRZ-UHFFFAOYSA-N D-glucuronic acid gamma-lactone Natural products O=CC(O)C1OC(=O)C(O)C1O UYUXSRADSPPKRZ-UHFFFAOYSA-N 0.000 description 1
- UYUXSRADSPPKRZ-SKNVOMKLSA-N D-glucurono-6,3-lactone Chemical compound O=C[C@H](O)[C@H]1OC(=O)[C@@H](O)[C@H]1O UYUXSRADSPPKRZ-SKNVOMKLSA-N 0.000 description 1
- 239000011627 DL-alpha-tocopherol Substances 0.000 description 1
- 235000001815 DL-alpha-tocopherol Nutrition 0.000 description 1
- 239000011626 DL-alpha-tocopherylacetate Substances 0.000 description 1
- 235000001809 DL-alpha-tocopherylacetate Nutrition 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- MJNIWUJSIGSWKK-BBANNHEPSA-N Riboflavin butyrate Chemical compound CCCC(=O)OC[C@@H](OC(=O)CCC)[C@@H](OC(=O)CCC)[C@@H](OC(=O)CCC)CN1C2=CC(C)=C(C)C=C2N=C2C1=NC(=O)NC2=O MJNIWUJSIGSWKK-BBANNHEPSA-N 0.000 description 1
- OHSHFZJLPYLRIP-BMZHGHOISA-M Riboflavin sodium phosphate Chemical compound [Na+].OP(=O)([O-])OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O OHSHFZJLPYLRIP-BMZHGHOISA-M 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- QEKBRBCVWVLFHH-QAKUKHITSA-L Tocopherol calcium succinate Chemical compound [Ca+2].[O-]C(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C.[O-]C(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C QEKBRBCVWVLFHH-QAKUKHITSA-L 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- VLSOAXRVHARBEQ-UHFFFAOYSA-N [4-fluoro-2-(hydroxymethyl)phenyl]methanol Chemical compound OCC1=CC=C(F)C=C1CO VLSOAXRVHARBEQ-UHFFFAOYSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- DAGINYYFSALQDF-UHFFFAOYSA-N acetyloxysulfonyl acetate Chemical compound CC(=O)OS(=O)(=O)OC(C)=O DAGINYYFSALQDF-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 230000000181 anti-adherent effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000002216 antistatic agent Substances 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- BTNNPSLJPBRMLZ-LGMDPLHJSA-N benfotiamine Chemical compound C=1C=CC=CC=1C(=O)SC(/CCOP(O)(O)=O)=C(/C)N(C=O)CC1=CN=C(C)N=C1N BTNNPSLJPBRMLZ-LGMDPLHJSA-N 0.000 description 1
- 229960002873 benfotiamine Drugs 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 229950009892 bisbentiamine Drugs 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- FDJOLVPMNUYSCM-UVKKECPRSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2,7, Chemical compound [Co+3].N#[C-].C1([C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)[N-]\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O FDJOLVPMNUYSCM-UVKKECPRSA-L 0.000 description 1
- 235000017471 coenzyme Q10 Nutrition 0.000 description 1
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000002826 coolant Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 235000000639 cyanocobalamin Nutrition 0.000 description 1
- 239000011666 cyanocobalamin Substances 0.000 description 1
- 229960002104 cyanocobalamin Drugs 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 229940099418 d- alpha-tocopherol succinate Drugs 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 238000005243 fluidization Methods 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 229920001002 functional polymer Polymers 0.000 description 1
- 229950006836 fursultiamine Drugs 0.000 description 1
- JTLXCMOFVBXEKD-FOWTUZBSSA-N fursultiamine Chemical compound C1CCOC1CSSC(\CCO)=C(/C)N(C=O)CC1=CN=C(C)N=C1N JTLXCMOFVBXEKD-FOWTUZBSSA-N 0.000 description 1
- FODTZLFLDFKIQH-FSVGXZBPSA-N gamma-Oryzanol (TN) Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)O[C@@H]2C([C@@H]3CC[C@H]4[C@]5(C)CC[C@@H]([C@@]5(C)CC[C@@]54C[C@@]53CC2)[C@H](C)CCC=C(C)C)(C)C)=C1 FODTZLFLDFKIQH-FSVGXZBPSA-N 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 229950002441 glucurolactone Drugs 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 235000004867 hydroxocobalamin Nutrition 0.000 description 1
- 239000011704 hydroxocobalamin Substances 0.000 description 1
- 229960001103 hydroxocobalamin Drugs 0.000 description 1
- 229960005469 hydroxocobalamin acetate Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- DQOCFCZRZOAIBN-WZHZPDAFSA-L hydroxycobalamin Chemical compound O.[Co+2].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O DQOCFCZRZOAIBN-WZHZPDAFSA-L 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960005321 mecobalamin Drugs 0.000 description 1
- JEWJRMKHSMTXPP-BYFNXCQMSA-M methylcobalamin Chemical compound C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O JEWJRMKHSMTXPP-BYFNXCQMSA-M 0.000 description 1
- 235000007672 methylcobalamin Nutrition 0.000 description 1
- 239000011585 methylcobalamin Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- GFEGEDUIIYDMOX-BMJUYKDLSA-N n-[(4-amino-2-methylpyrimidin-5-yl)methyl]-n-[(z)-3-[[(z)-2-[(4-amino-2-methylpyrimidin-5-yl)methyl-formylamino]-5-hydroxypent-2-en-3-yl]disulfanyl]-5-hydroxypent-2-en-2-yl]formamide Chemical compound C=1N=C(C)N=C(N)C=1CN(C=O)C(\C)=C(CCO)/SSC(/CCO)=C(/C)N(C=O)CC1=CN=C(C)N=C1N GFEGEDUIIYDMOX-BMJUYKDLSA-N 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 229960005010 orotic acid Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical compound CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 description 1
- 239000011589 pyridoxal 5'-phosphate Substances 0.000 description 1
- 229960004172 pyridoxine hydrochloride Drugs 0.000 description 1
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 description 1
- 239000011764 pyridoxine hydrochloride Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229960002477 riboflavin Drugs 0.000 description 1
- 235000019192 riboflavin Nutrition 0.000 description 1
- 239000002151 riboflavin Substances 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960001385 thiamine disulfide Drugs 0.000 description 1
- 229960000344 thiamine hydrochloride Drugs 0.000 description 1
- 235000019190 thiamine hydrochloride Nutrition 0.000 description 1
- 239000011747 thiamine hydrochloride Substances 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 229940042585 tocopherol acetate Drugs 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 229960004747 ubidecarenone Drugs 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 229940100445 wheat starch Drugs 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
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Inorganic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Description
本発明は、圧縮成型製剤に関し、さらに詳細には、薬効成分としてL−システインとアスコルビン酸を高含量含有した圧縮成型製剤に関する。 The present invention relates to a compression-molded preparation, and more particularly, to a compression-molded preparation containing a high content of L-cysteine and ascorbic acid as medicinal ingredients.
L−システインとアスコルビン酸を配合した製剤は、しみ、そばかす、日やけ、かぶれなどの色素沈着症、全身倦怠、二日酔、にきび、湿疹、じんましん、かぶれ、くすりまけ、歯ぐきからの出血、鼻出血の出血予防、肉体疲労時、妊娠・授乳期、病中病後の体力低下時、老年期のビタミンCの補給に対して用いられてきた。 Formulations containing L-cysteine and ascorbic acid include stains, freckles, sunburn, rashes, etc., general malaise, hangover, acne, eczema, hives, rashes, rashes, gum bleeding, nose It has been used for the prevention of bleeding, physical fatigue, pregnancy / lactation period, physical strength decline after illness, and supplementation of vitamin C in old age.
そして、例えば、しみ、そばかす、日やけなどの色素沈着症、全身倦怠、二日酔、にきび、湿疹、じんましん、かぶれ、くすりまけに対しては、1日当たりのL−システインの服用量が240mg、アスコルビン酸の服用量が300mgおよびパントテン酸カルシウムの服用量が24mgである糖衣錠が用いられている。また、しみ、そばかす、日やけ、かぶれによる色素沈着症、歯ぐきからの出血、鼻出血の出血予防、肉体疲労時、妊娠・授乳期、病中病後の体力低下時、老年期のビタミンCの補給に対しては、1日当たりのL−システインの服用量が30〜160mgおよびアスコルビン酸の服用量が300〜1200mgとなるL−システインとアスコルビン酸を配合した種々の製剤が用いられている。 For example, for pigmentation such as stains, freckles, sunburn, general malaise, hangover, acne, eczema, hives, rashes, and rashes, the dose of L-cysteine per day is 240 mg, Sugar-coated tablets with a dose of ascorbic acid of 300 mg and a dose of calcium pantothenate of 24 mg are used. In addition, pigmentation caused by spots, freckles, sunburn, rash, bleeding from gums, bleeding from nose bleeding, physical fatigue, pregnancy / lactation period, physical strength decline after sickness, supplementation of vitamin C in old age In contrast, various preparations in which L-cysteine and ascorbic acid are combined so that the dose of L-cysteine per day is 30 to 160 mg and the dose of ascorbic acid is 300 to 1200 mg are used.
しかし、L−システインとアスコルビン酸は共に1日当りの服用量が多いことに加え、特にL−システインは、流動性が悪く、圧縮成型性も悪いことから、錠剤として製剤化する場合には、賦形剤を大量に添加する必要があった。そして賦形剤を大量に用い、L−システインとアスコルビン酸の含量を多くすると、1錠当りの質量が多く大きな錠剤となるという問題があった。 However, both L-cysteine and ascorbic acid have high daily doses, and L-cysteine is particularly poor in fluidity and compression moldability. It was necessary to add a large amount of the dosage form. When a large amount of excipient is used and the contents of L-cysteine and ascorbic acid are increased, there is a problem in that the tablet has a large mass per tablet.
これに対し、1錠当たりの質量を少なくし、錠剤を小さくして服用することも考えられるが、この場合は1回に服用する錠剤の数が増えてしまい、患者にとって服用し難い物となってしまっていた。また、アスコルビン酸の流動性と圧縮成型性は比較的良いことから、一錠中のアスコルビン酸の含量を多くすることはできても、上記のようにL−システインの流動性が悪いため、この含量を多くすることは困難であった。 On the other hand, it is conceivable to reduce the mass per tablet and reduce the tablet size, but in this case the number of tablets to be taken at one time increases, making it difficult for patients to take. It was. Moreover, since the fluidity and compression moldability of ascorbic acid are relatively good, even though the content of ascorbic acid in one tablet can be increased, the fluidity of L-cysteine is poor as described above. It was difficult to increase the content.
上記のように、L−システインとアスコルビン酸を配合した製剤は、しみ、そばかす、日やけ、かぶれなどによる色素沈着症を治療するために用いられることが多いが、肌のターンオーバーに時間がかかり、個人によっても異なるが、その効果が現れるにはおおよそ3ヶ月続けて服用を続ける必要があり、このような長期間に渡り大きな錠剤あるいは多数の錠剤を服用することは、患者にとって利便性が悪いだけでなく、コンプライアンスの低下を招き、その効果を充分に発揮できない原因のひとつにもなっていた。 As described above, formulations containing L-cysteine and ascorbic acid are often used to treat pigmentation caused by spots, freckles, sunburn, rashes, etc., but it takes time to turn over the skin. Although it varies depending on the individual, it is necessary to continue taking approximately 3 months for the effect to appear, and taking such a large tablet or a large number of tablets over a long period of time is inconvenient for the patient. Not only that, it also caused a decline in compliance and was one of the reasons why the effect could not be fully demonstrated.
実際、特許文献1の製剤例2.2、製剤例2.3および製剤例2.4に示されるアスコルビン酸とL−システインを同時に含有する錠剤は、アスコルビン酸の含有量が18質量%前後、L−システインの含有量は9から15質量%と低くなってしまっている。また、特許文献2、特許文献3、特許文献4、特許文献5および特許文献6には、素錠1錠当りのアスコルビン酸とL−システインの含有量の合計が60質量%を超える素錠が開示されているが、これらの素錠では、アスコルビン酸の含有量が45〜56%と多いのにかかわらず、L−システインの含有量は、いずれも8〜19質量%と少ないものである。 Actually, the tablets containing ascorbic acid and L-cysteine at the same time shown in Formulation Example 2.2, Formulation Example 2.3 and Formulation Example 2.4 of Patent Document 1 have an ascorbic acid content of about 18% by mass, The content of L-cysteine is as low as 9 to 15% by mass. Patent Document 2, Patent Document 3, Patent Document 4, Patent Document 5 and Patent Document 6 include uncoated tablets in which the total content of ascorbic acid and L-cysteine per uncoated tablet exceeds 60% by mass. Although disclosed, these uncoated tablets have a low L-cysteine content of 8 to 19% by mass, regardless of the high ascorbic acid content of 45 to 56%.
更に、特許文献7には、L−システインの含有量が22質量%の素錠が明らかにされているが、このものはアスコルビン酸の含有量は28質量%と少なくなってしまっており、素錠中にL−システインを20質量%以上、且つ、アスコルビン酸を30質量%含み、製造性に優れた素錠は今まで提供されていなかった。 Furthermore, Patent Document 7 discloses an uncoated tablet having an L-cysteine content of 22% by mass, but this product has a content of ascorbic acid as low as 28% by mass. An uncoated tablet that contains 20% by mass or more of L-cysteine and 30% by mass of ascorbic acid and has excellent manufacturability has not been provided so far.
さらに、L−システインとアスコルビン酸を含む錠剤は、少量の打錠をすることはできても大量に生産を行なうと、配合する賦形剤等の製剤添加物によっては、流動性が悪く打錠できなかったり、ステッキングやキャッピングなどの打錠障害を引き起こしたり、或いは、成分含量のばらつきが多かったり、重量の偏差が大きくなったりして、効率的に製造できないこともあった。また、錠剤として打錠することができても、システイン臭を防止する目的で、素錠にフィルムコーティングや糖衣を施すと、成分含量の低下がなくても、保存中に変色やひび割れを生じてしまうこともあった。 Furthermore, tablets containing L-cysteine and ascorbic acid can be compressed in a small amount, but if they are produced in large quantities, depending on the formulation additives such as excipients to be blended, the flowability is poor. In some cases, it could not be produced efficiently, causing tableting troubles such as sticking and capping, or a large variation in the component content and a large deviation in weight. Even if it can be tableted as a tablet, film coating or sugar coating is applied to the uncoated tablet for the purpose of preventing the cysteine odor, causing discoloration and cracking during storage even if the content of the ingredient is not reduced. It sometimes happened.
従って本発明は、L−システインと、アスコルビン酸とをそれぞれ20質量%以上および30質量%以上という高含量で含有した、しみ、そばかす、日やけ、かぶれなどによる色素沈着症に対する治療効果を最大限に発揮するための小型でかつ高品質な錠剤を提供することをその課題とするものである。 Therefore, the present invention maximizes the therapeutic effect on pigmentation caused by stains, freckles, sunburn, rash, etc., containing L-cysteine and ascorbic acid at a high content of 20% by mass or more and 30% by mass or more, respectively. It is an object of the present invention to provide a small and high-quality tablet that can be used in the future.
本発明者らは、上記課題を解決すべく鋭意検討を重ねた結果、2種以上の結晶セルロ−スと高膨潤性高分子とを組み合わせた担体に、L−システイン若しくはその塩とアスコルビン酸若しくはその塩を配合し、これを圧縮成型することにより、L−システインとアスコルビン酸の含有量が高いにもかかわらず、錠剤の重量の偏差が少なく、成分含量のばらつきや打錠障害も無く、大量に生産し得る服用性に優れた小型の錠剤が得られることを見出し、本発明を完成した。 As a result of intensive studies to solve the above problems, the present inventors have added L-cysteine or a salt thereof and ascorbic acid or a carrier comprising a combination of two or more types of crystal cellulose and a highly swellable polymer. By blending the salt and compression-molding it, there is little deviation in the weight of the tablet despite the high contents of L-cysteine and ascorbic acid, there is no variation in the content of ingredients and no tableting problems, and a large amount The present invention was completed by finding that a small tablet excellent in dosage that can be produced was obtained.
すなわち本発明は、L−システイン若しくはその塩をL−システインに換算して20〜40質量%、アスコルビン酸若しくはその塩をアスコルビン酸に換算して30〜70質量%、複数の結晶セルロースを合計で7.5〜25質量%および高膨潤性高分子を1〜20質量%含有することを特徴とする圧縮成型製剤を提供するものである。 That is, in the present invention, L-cysteine or a salt thereof is converted into L-cysteine, 20 to 40% by mass, ascorbic acid or a salt thereof is converted into ascorbic acid, 30 to 70% by mass, and a plurality of crystalline celluloses in total. The present invention provides a compression-molded preparation containing 7.5 to 25% by mass and 1 to 20% by mass of a highly swellable polymer.
L−システインおよびアスコルビン酸等を薬効成分として含有する本発明の圧縮成型製剤は、複数の結晶セルロースおよび高膨潤性高分子の配合により、L−システインおよびアスコルビン酸を高濃度で含有しながら、製造性に優れた小型な圧縮成型製剤の提供が可能になった。 The compression-molded preparation of the present invention containing L-cysteine, ascorbic acid and the like as medicinal ingredients is produced while containing L-cysteine and ascorbic acid at a high concentration by blending a plurality of crystalline cellulose and a highly swellable polymer. It has become possible to provide a compact compression-molded preparation with excellent properties.
従って、L−システインおよびアスコルビン酸等の有する作用を有効に薬剤として使用することが可能になり、しみ、そばかす、日やけ、かぶれなどの色素沈着症、全身倦怠、二日酔、にきび、湿疹、じんましん、かぶれ、くすりまけ、歯ぐきからの出血、鼻出血の出血予防、肉体疲労時、妊娠・授乳期、病中病後の体力低下時、老年期のビタミンCの補給に対しての効果の発現が確実な服用し易い圧縮成型製剤の提供が可能となる。 Therefore, it becomes possible to effectively use the action of L-cysteine, ascorbic acid and the like as a drug, pigmentation such as spots, freckles, sunburn, rash, general malaise, hangover, acne, eczema, Efficacy of urticaria, rashes, bruises, gum bleeding, nose bleeding prevention, physical fatigue, pregnancy / lactation period, physical strength decline after disease, aging, vitamin C supplementation It is possible to provide a reliable compression-molded preparation that is easy to take.
本発明の圧縮成型製剤(以下、「本発明製剤」という)は、複数の結晶セルロースと高膨潤性高分子を含有する担体に、L−システイン若しくはその塩とアスコルビン酸若しくはその塩とを高含有量で配合し、これを圧縮成型することにより調製される。 The compression-molded preparation of the present invention (hereinafter referred to as “the preparation of the present invention”) contains a high amount of L-cysteine or a salt thereof and ascorbic acid or a salt thereof in a carrier containing a plurality of crystalline cellulose and a highly swellable polymer. It is prepared by blending in an amount and compression molding this.
本発明製剤において、薬効成分として用いられるL−システイン若しくはその塩(以下、「L−システイン類」という)としては、L−システインそのもののほかに、L−塩酸システインなどL−システインの酸付加塩等を用いることができるが、L−システインを用いることが好ましい。このL−システイン類の投与量は、成人に対しては、L−システインに換算して通常1日に付き10〜1000mgの範囲であり、30〜480mgであることが好ましく、160〜240mgであることが特に好ましい。このL−システイン類は、1日1回または、2〜4回に分けて服用されるが、好適には2〜3回に分けて服用される。 In the preparation of the present invention, L-cysteine or a salt thereof (hereinafter referred to as “L-cysteines”) used as a medicinal ingredient is an acid addition salt of L-cysteine such as L-cysteine hydrochloride in addition to L-cysteine itself. Etc., but L-cysteine is preferably used. The dose of these L-cysteines is usually in the range of 10 to 1000 mg per day in terms of L-cysteine, preferably 30 to 480 mg, preferably 160 to 240 mg for adults. It is particularly preferred. These L-cysteines are taken once a day or in 2 to 4 divided doses, preferably in 2 to 3 divided doses.
本発明製剤中でのL−システイン類の含有割合は、L−システインに換算して20〜40質量%とすることが好ましく、さらに25〜35質量%、特に27.5〜32.5質量%とすることが好ましい。 The content ratio of L-cysteines in the preparation of the present invention is preferably 20 to 40% by mass, more preferably 25 to 35% by mass, particularly 27.5 to 32.5% by mass in terms of L-cysteine. It is preferable that
一方、本発明製剤において、薬効成分として用いられるアスコルビン酸若しくはその塩(以下、「アスコルビン酸類」という)としては、アスコルビン酸そのもののほかに、アスコルビン酸カルシウム、アスコルビン酸ナトリウムなどのアスコルビン酸塩や、直打用アスコルビン酸、直打用アスコルビン酸カルシウム、直打用アスコルビン酸ナトリウムのいずれも用いることができる。また、これらのアスコルビン酸類中でも、直打用アスコルビン酸、直打用アスコルビン酸カルシウム、直打用アスコルビン酸ナトリウムを用いることが好ましく、これらはBASF武田ビタミン(株)より入手することができる。本発明においては、このアスコルビン酸類の投与量は、成人に対しては、通常1日に付きアスコルビン酸に換算して50〜2000mgの範囲であり、50〜500mgであることが好ましく、200〜400mgであることが特に好ましい。このアスコルビン酸類は、L−システイン類と同様に、1日1回または、2〜4回に分けて服用されるが、2〜3回に分けて服用されることが好ましい。 On the other hand, in the preparation of the present invention, ascorbic acid or a salt thereof (hereinafter referred to as “ascorbic acid”) used as a medicinal component, ascorbic acid itself, ascorbate such as calcium ascorbate and sodium ascorbate, Ascorbic acid for direct hitting, calcium ascorbate for direct hitting, and sodium ascorbate for direct hitting can be used. Among these ascorbic acids, it is preferable to use direct hitting ascorbic acid, direct hitting calcium ascorbate, and direct hitting sodium ascorbate, and these can be obtained from BASF Takeda Vitamin Co., Ltd. In the present invention, the dose of these ascorbic acids is usually in the range of 50 to 2000 mg converted to ascorbic acid per day for adults, preferably 50 to 500 mg, preferably 200 to 400 mg. It is particularly preferred that The ascorbic acids are taken once a day or divided into 2 to 4 times like the L-cysteines, but are preferably taken divided into 2 to 3 times.
本発明製剤中でのアスコルビン酸類の含有割合は、アスコルビン酸に換算して30〜70質量%とすることが好ましく、さらに32.5〜60質量%、特に35〜40質量%とすることが好ましい。 The content of ascorbic acids in the preparation of the present invention is preferably 30 to 70% by mass in terms of ascorbic acid, more preferably 32.5 to 60% by mass, and particularly preferably 35 to 40% by mass. .
本発明製剤には、上記のL−システイン類およびアスコルビン酸類のほかにさらに他の薬理活性成分を配合しても良い。好ましい例としては、パントテン酸、パントテン酸カルシウム、パントテン酸ナトリウム、パンテノールなどのパントテン酸、コハク酸d−α−トコフェロール、コハク酸dl−α−トコフェロール、コハク酸dl−α−トコフェロールカルシウム、酢酸d−α−トコフェロール、酢酸dl−α−トコフェロール、d−α−トコフェロール、dl−α−トコフェロールなどのビタミンE、塩酸チアミン、硝酸チアミン、硝酸ビスチアミン、チアミンジスルフィド、チアミンジアセチル硫酸エステル、塩酸フルスルチアミン、塩酸ジセチアミン、オクトチアミン、シコチアミン、ビスイブチアミン、ビスベンチアミン、ベンフォチアミンなどのビタミンB1、リボフラビン、酪酸リボフラビン、リン酸リボフラビンナトリウムなどのビタミンB2、塩酸ピリドキシン、リン酸ピリドキサールなどのビタミンB6、シアノコバラミン、塩酸ヒドロキソコバラミン、酢酸ヒドロキソコバラミン、メコバラミンなどのビタミンB12、ニコチン酸、ニコチン酸アミドなどのニコチン酸、ヨクイニン、オロチン酸、ビオチン、ガンマーオリザノール、グルクロノラクトン、グルクロン酸アミド、ユビデカレノンなどを挙げることができる。このうち、特に好ましい例としては、パントテン酸、パントテン酸カルシウム、パントテン酸ナトリウム、パンテノールなどのパントテン酸を挙げることができ、その投与量は、成人に対しては、通常1日に付き5〜30mgであることが好ましい。 In addition to the above L-cysteines and ascorbic acids, the pharmaceutical preparation of the present invention may further contain other pharmacologically active ingredients. Preferred examples include pantothenic acid, calcium pantothenate, sodium pantothenate, panthenol, etc., d-α-tocopherol succinate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, d-acetate -Α-tocopherol, dl-α-tocopherol acetate, d-α-tocopherol, dl-α-tocopherol and other vitamin E, thiamine hydrochloride, thiamine nitrate, thiamine nitrate, thiamine nitrate, thiamine disulfide, thiamine diacetyl sulfate, fursultiamine hydrochloride, hydrochloric dicethiamine, oct thiamine, Shikochiamin, bis Eve thiamine, bisbentiamine, vitamin B 1, such as benfotiamine, riboflavin, riboflavin butyrate, vitamin B 2 such as riboflavin phosphate sodium Pyridoxine hydrochloride, vitamin B 6 such as pyridoxal phosphate, cyanocobalamin, hydrochloric hydroxocobalamin acetate hydroxocobalamin, vitamin B 12, nicotinic acid, such as mecobalamin, nicotinic acid, such as nicotinic acid amide, Coix, orotic acid, biotin, gamma oryzanol, Examples thereof include glucuronolactone, glucuronic acid amide, ubidecarenone and the like. Among these, particularly preferred examples include pantothenic acid such as pantothenic acid, calcium pantothenate, sodium pantothenate, panthenol and the like. 30 mg is preferred.
一方、本発明製剤には、担体として複数の結晶セルロースが用いられる。この複数の結晶セルロースの例としては、嵩密度0.3g/cm3以上の結晶セルロースと嵩密度0.3g/cm3未満の結晶セルロースの組み合わせを挙げることができる。 On the other hand, in the preparation of the present invention, a plurality of crystalline cellulose is used as a carrier. Examples of the plurality of crystalline celluloses include a combination of crystalline cellulose having a bulk density of 0.3 g / cm 3 or more and crystalline cellulose having a bulk density of less than 0.3 g / cm 3 .
このうち、嵩密度0.3g/cm3以上の結晶セルロースとしては、嵩密度0.6g/cm3程度までのものを好ましく使用することができ、その具体例としては、セオラスPH−301(嵩密度0.41g/cm3;旭化成ケミカルズ社製)、セオラスPH−301D(嵩密度0.41g/cm3;同上)、セオラスPH−301Z(嵩密度0.41g/cm3;同上)、セオラスPH−302(嵩密度0.43g/cm3;同上)、セオラスPH−200(嵩密度0.33g/cm3;同上)、セオラスPH−102(嵩密度0.30g/cm3;同上)、ビバプアー103(嵩密度0.32g/cm3;レッテンマイヤー社製)、ビバプアー301(嵩密度0.38g/cm3;同上)、ビバプアー102(嵩密度0.31g/cm3;同上)、ビバプアー112(嵩密度0.35g/cm3;同上)、ビバプアー12(嵩密度0.33g/cm3;同上)、ビバプアー200(嵩密度0.34g/cm3;同上)等があげられる。これらは、1種または2種以上を混合して用いることができる。このうちさらに好ましいものとしては、平均粒子径が90μm以上の結晶セルロース:セオラスPH−302、セオラスPH−200、セオラスPH−102、ビバプアー112、ビバプアー102、ビバプアー12、ビバプアー200等が挙げられ、よりさらに好ましくは、平均粒子径が120μm以上の結晶セルロース:ビバプアー12、ビバプアー200、セオラスPH−200等が挙げられる。 Among these, as crystalline cellulose having a bulk density of 0.3 g / cm 3 or more, those having a bulk density of up to about 0.6 g / cm 3 can be preferably used. Density 0.41 g / cm 3 ; manufactured by Asahi Kasei Chemicals Co., Ltd.), Theolas PH-301D (bulk density 0.41 g / cm 3 ; same as above), Theoras PH-301Z (bulk density 0.41 g / cm 3 ; same as above), Theolas PH -302 (bulk density 0.43 g / cm 3; ibid), CEOLUS PH-200 (bulk density 0.33 g / cm 3; ibid), CEOLUS PH-102 (bulk density 0.30 g / cm 3; ibid), Bibapua (; manufactured by Retten MAYER bulk density 0.32 g / cm 3), Bibapua 301 103 (bulk density 0.38 g / cm 3; ibid), Bibapua 102 (bulk density 0.31 g / cm 3; ibid), Bibapu Over 112 (bulk density 0.35 g / cm 3; ibid), Bibapua 12 (bulk density 0.33 g / cm 3; ibid), Bibapua 200 (bulk density 0.34 g / cm 3; ibid), and the like. These may be used alone or in combination of two or more. Among these, more preferred are crystalline celluloses having an average particle size of 90 μm or more: Theolas PH-302, Theolas PH-200, Theolas PH-102, Viva Poor 112, Viva Poor 102, Viva Poor 12, Viva Poor 200, and the like. More preferably, crystalline cellulose having an average particle size of 120 μm or more: Viva Poor 12, Viva Poor 200, Theola PH-200, or the like can be used.
一方、嵩密度0.3g/cm3未満の結晶セルロースとしては、嵩密度0.10g/cm3程度までのものを好ましく使用することができ、その具体例としては、セオラスKG−802(嵩密度0.21g/cm3;旭化成ケミカルズ社製)、セオラスPH−F20JP(嵩密度0.23g/cm3;同上)、セオラスPH−101(嵩密度0.29g/cm3;同上)、セオラスPH−101D(嵩密度0.29g/cm3;同上)、ビバプアー105(嵩密度0.23g/cm3;レッテンマイヤー社製)、ビバプアー101(嵩密度0.29g/cm3;同上)等があげられる。これらは、1種または2種以上を混合して用いることができる。このうちさらに好ましいものとしては、平均粒子径が50μm以上の結晶セルロース:セオラスKG−802、セオラスPH−101、セオラスPH−101D、ビバプアー101等が挙げられ、よりさらに好ましくは、嵩密度の最も小さいセオラスKG−802が挙げられる。 On the other hand, as the crystalline cellulose having a bulk density of less than 0.3 g / cm 3 , those having a bulk density of up to about 0.10 g / cm 3 can be preferably used. Specific examples thereof include Theola KG-802 (bulk density). 0.21 g / cm 3; manufactured by Asahi Kasei Chemicals Corporation), Ceolus PH-F20JP (bulk density 0.23 g / cm 3; ibid), CEOLUS PH-101 (bulk density 0.29 g / cm 3; ibid), CEOLUS PH- 101D (bulk density 0.29 g / cm 3; ibid), Bibapua 105 (bulk density 0.23 g / cm 3; manufactured by Retten MAYER), Bibapua 101 (bulk density 0.29 g / cm 3; ibid), and the like . These may be used alone or in combination of two or more. Among these, crystalline cellulose having an average particle diameter of 50 μm or more: Theoras KG-802, Theoras PH-101, Theoras PH-101D, Viva Poor 101, and the like are more preferable, and more preferably, the bulk density is the smallest. Theolaus KG-802 is exemplified.
これらの結晶セルロースの本発明製剤の全質量に対する添加量は、L−システインおよびアスコルビン酸等の含有量や錠剤の全質量により異なるが、嵩密度0.3g/cm3以上の結晶セルロースと嵩密度0.3g/cm3未満の結晶セルロースを合わせて、好ましくは7.5〜25質量%であり、より好ましくは15〜20質量%の範囲である。それぞれ別々では、嵩密度0.3g/cm3以上の結晶セルロースの本発明製剤の全質量に対する添加量は好ましくは5〜23質量%であり、より好ましくは10〜15質量%の範囲であり、嵩密度0.3g/cm3未満の結晶セルロースの本発明製剤の全質量に対する添加量は好ましくは1〜20質量%であり、より好ましくは2.5〜10質量%の範囲である。 The addition amount of these crystalline celluloses with respect to the total mass of the preparation of the present invention varies depending on the contents of L-cysteine and ascorbic acid and the total mass of the tablet, but the crystalline cellulose having a bulk density of 0.3 g / cm 3 or more and the bulk density The combined crystal cellulose of less than 0.3 g / cm 3 is preferably 7.5 to 25% by mass, more preferably 15 to 20% by mass. Separately, the addition amount of crystalline cellulose having a bulk density of 0.3 g / cm 3 or more with respect to the total mass of the preparation of the present invention is preferably 5 to 23% by mass, more preferably 10 to 15% by mass, The amount of crystalline cellulose having a bulk density of less than 0.3 g / cm 3 is preferably 1 to 20% by mass, more preferably 2.5 to 10% by mass, based on the total mass of the preparation of the present invention.
本発明においては、嵩密度0.3g/cm3以上の結晶セルロースと嵩密度0.3g/cm3未満の結晶セルロースとを8:1〜1:4の質量比で組み合わせて用いることが好ましく、更に4:1〜1:1の質量比で組み合わせて用いることが好ましく、特に2.5:1〜1.5:1とすることが最良である。上記の結晶セルロースのうち、嵩密度0.3g/cm3以上のものは、成型性を良好に保ちながら、L−システイン類を高濃度で含有する打錠用粉末の打錠時の流動性を向上させるものであり、嵩密度0.3g/cm3未満の結晶セルロースは、打錠時の圧縮時の成型性を著しく向上させ、錠剤硬度の向上にも寄与するものである。 In the present invention, it is preferable to use crystalline cellulose having a bulk density of 0.3 g / cm 3 or more and crystalline cellulose having a bulk density of less than 0.3 g / cm 3 in a mass ratio of 8: 1 to 1: 4. Furthermore, it is preferable to use in combination at a mass ratio of 4: 1 to 1: 1, and it is particularly best to use 2.5: 1 to 1.5: 1. Among the above crystalline celluloses, those having a bulk density of 0.3 g / cm 3 or more exhibit fluidity at the time of tableting of a tableting powder containing L-cysteines at a high concentration while maintaining good moldability. Crystalline cellulose having a bulk density of less than 0.3 g / cm 3 remarkably improves moldability during compression during tableting and contributes to improvement in tablet hardness.
更に、本発明製剤に用いる高膨潤性高分子は、水に不溶でかつ膨潤性が大きいものである。この高膨潤性高分子は、L−システイン類およびアスコルビン酸類等との配合で、打錠前には流動性を保ち、圧縮成型性に優れ、成型した後には変色等が起こらず、反応性の低いものである。このような高膨潤性高分子の具体例としては、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルセルロース、クロスポピドン等があげられ、これらは、1種または2種以上を混合して用いることができる。これらの中で最適な具体例としては、低置換度ヒドロキシプロピルセルロース(L−HPC)が挙げられ、特に平均粒子径50μmのL−HPC(LH−11およびLH−B1)が好ましく、特に繊維状の紛体であるL−HPC(LH−11)がさらに好ましい。 Furthermore, the highly swellable polymer used in the preparation of the present invention is insoluble in water and has a high swellability. This highly swellable polymer is blended with L-cysteines, ascorbic acids, etc., maintains fluidity before tableting, has excellent compression moldability, does not cause discoloration after molding, and has low reactivity. Is. Specific examples of such a highly swellable polymer include croscarmellose sodium, low-substituted hydroxypropylcellulose, crospovidone, and the like, and these can be used alone or in combination of two or more. . Among these, the most suitable specific examples include low-substituted hydroxypropylcellulose (L-HPC), and L-HPC (LH-11 and LH-B1) having an average particle diameter of 50 μm is particularly preferred, and is particularly fibrous. L-HPC (LH-11) which is a powder of
この高膨潤性高分子の本発明製剤の全質量に対する添加量は、全質量に対し、1〜20質量%が好ましく、さらに好ましくは2.5〜10質量%の範囲である。 The addition amount of the highly swellable polymer with respect to the total mass of the preparation of the present invention is preferably from 1 to 20 mass%, more preferably from 2.5 to 10 mass%, based on the total mass.
本発明製剤は、上記したL−システイン類およびアスコルビン酸類等の薬理活性成分、結晶セルロースおよび高膨潤性高分子に、必要に応じて公知の医薬用添加剤、例えば、賦形剤、結合剤、崩壊剤、滑沢剤、安定剤、界面活性剤、溶解補助剤、還元剤、緩衝剤、吸着剤、流動化剤、帯電防止剤、コーティング剤、可塑剤、付着防止剤、遮光剤、光沢化剤、抗酸化剤、甘味剤、矯味剤、清涼化剤、着色剤、着香剤、香料、芳香剤等を加え、圧縮成型用の粉粒体を調整し、常法に従って圧縮成型することにより製造される。 The preparation of the present invention may be prepared by adding known pharmaceutical additives such as excipients, binders, and the like to the above-described pharmacologically active ingredients such as L-cysteines and ascorbic acids, crystalline cellulose and highly swellable polymers. Disintegrant, lubricant, stabilizer, surfactant, solubilizer, reducing agent, buffer, adsorbent, fluidizer, antistatic agent, coating agent, plasticizer, anti-adhesive agent, light-shielding agent, glossing By adding powders, antioxidants, sweeteners, flavoring agents, cooling agents, coloring agents, flavoring agents, fragrances, fragrances, etc., adjusting the powder granules for compression molding, and compression molding according to conventional methods Manufactured.
本発明製剤に用いる医薬用添加剤としては、L−システイン類およびアスコルビン酸類等との配合で、圧縮成型した後、変色を起こさない水溶性高分子、軽質無水ケイ酸、糖、糖アルコール、澱粉、タルク、ステアリン酸マグネシウムから選ばれる1種または2種以上を配合することが好ましい。 The pharmaceutical additive used in the preparation of the present invention includes a water-soluble polymer, light anhydrous silicic acid, sugar, sugar alcohol, starch, which does not cause discoloration after compression molding by blending with L-cysteines and ascorbic acids It is preferable to blend one or more selected from talc and magnesium stearate.
これらのうち、L−システイン類およびアスコルビン酸類等と配合して、圧縮成型した後に変色を起こさない水溶性高分子としては、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、ポリエチレングリコール等が挙げられる。また澱粉としては、アルファー化デンプン、部分アルファー化デンプン、コーンスターチ、馬鈴薯でんぷん、小麦でんぷん、米でんぷん等が、糖・糖アルコールとしては、乳糖、マンニトール、キシリット、デキストリン、ソルビトール等がそれぞれ挙げられる。これら水溶性高分子、澱粉、糖・糖アルコールの添加量は、圧縮成型製剤の大きさや圧縮成型用粉体の製造方法により異なるため、その量は特定できないが、圧縮成型製剤全質量に対し、およそ0〜40質量%である。 Among these, examples of water-soluble polymers that are blended with L-cysteines and ascorbic acids and do not cause discoloration after compression molding include hydroxypropylmethylcellulose, hydroxypropylcellulose, polyethylene glycol, and the like. Examples of starch include pregelatinized starch, partially pregelatinized starch, corn starch, potato starch, wheat starch, and rice starch. Examples of sugar / sugar alcohol include lactose, mannitol, xylit, dextrin, and sorbitol. The amount of these water-soluble polymers, starch, sugar / sugar alcohol added varies depending on the size of the compression molding preparation and the method for producing the powder for compression molding, so the amount cannot be specified, It is approximately 0 to 40% by mass.
また、上記医薬用添加剤のうち、軽質無水ケイ酸は、圧縮成型用紛体の流動性を増加させると共に、圧縮成型製剤の湿潤や固着を防止する作用を有するものである。この軽質無水ケイ酸は、平均粒子径2〜10μmのものが好ましく、平均粒子径2〜4μmの軽質無水ケイ酸を用いることがさらに望ましい。その添加量は、本発明製剤全質量に対し、0.1〜3質量%を用いることが望ましく、0.2〜1質量%を用いることが特に好ましい。 Among the above-mentioned pharmaceutical additives, light anhydrous silicic acid has the effect of increasing the fluidity of the powder for compression molding and preventing the compression molding preparation from getting wet and sticking. The light anhydrous silicic acid preferably has an average particle diameter of 2 to 10 μm, and more preferably light anhydrous silicic acid having an average particle diameter of 2 to 4 μm. As for the addition amount, it is desirable to use 0.1-3 mass% with respect to this invention formulation total mass, and it is especially preferable to use 0.2-1 mass%.
さらに、タルクおよびステアリン酸マグネシウムは、両方を又はそのどちらか一方を、圧縮成型製剤全質量に対し、0.1〜3質量%を添加することが望ましく、0.5〜1.5質量%を用いることが特に好ましい。 Furthermore, it is desirable to add 0.1 to 3% by mass of talc and magnesium stearate, or both of them, based on the total mass of the compression-molded preparation, and 0.5 to 1.5% by mass. It is particularly preferable to use it.
圧縮成型用の粉粒体は、上記成分を混合した粉末のままで、あるいは、その一部またはすべてを造粒末として用いても良い。この粉体を造粒末とするに当たっては、一般に利用される造粒法、例えば、水や有機溶媒を含む溶液又は分散液を用いる噴霧造粒法、撹拌造粒法、流動造粒法、転動造粒法、転動流動造粒法等の湿式造粒法、粉粒状の結合剤を用いる圧密造粒法などの乾式造粒法等が利用できる。 The powder for compression molding may remain as a powder mixed with the above components, or a part or all of the powder may be used as the granulated powder. In making this powder into a granulated powder, generally used granulation methods such as spray granulation method using a solution or dispersion containing water or an organic solvent, stirring granulation method, fluidized granulation method, rolling granulation method, A wet granulation method such as a dynamic granulation method or a rolling fluidization granulation method, a dry granulation method such as a compaction granulation method using a powdery binder can be used.
本発明製剤は、単発式打錠機、ロータリー式打錠機等を用いて圧縮成型することにより製造される。このときの圧縮成型時の圧力は、200kg/cm2以上に調製することが好ましく、より好ましくは400〜2000kg/cm2である。また、本発明製剤の質量は制限されるものではないが、通常約50〜約400mgであり、約100〜約200mgがより好ましい。この質量は、服用1回当たりの1投与単位あるいはその整数分の1に対応したもの(例えば1回当たり1錠〜3錠服用等を可能とする成分含量)とすることが好ましい。また、本発明製剤の大きさは、例えば円形の錠剤に成型した場合、その直径は通常約4〜約12mmであり、より好ましくは約6〜約10mm程度である。 The preparation of the present invention is produced by compression molding using a single-type tablet press, a rotary tablet press or the like. Pressure during compression molding at this time, it is preferable to prepare the 200 kg / cm 2 or more, more preferably 400~2000kg / cm 2. The mass of the preparation of the present invention is not limited, but is usually about 50 to about 400 mg, more preferably about 100 to about 200 mg. This mass is preferably one corresponding to a single dosage unit per dose or a fraction of that (for example, a component content enabling 1 to 3 tablets per dose). Further, the size of the preparation of the present invention is, for example, about 4 to about 12 mm, more preferably about 6 to about 10 mm when molded into a round tablet.
上記のようにして得られた圧縮成型製剤は、パンコーティング法、流動層コーティング法、転動コーティング法、ドライコーティング法や、これらの方法を組み合わせること等により速溶性のコーティング製剤や糖衣製剤とすることもできる。この際、水溶性或は胃溶性の皮膜剤を水や有機溶媒に溶解又は分散させ、スプレーコーティングすることや、これらの皮膜剤を直接散布し、熱や圧力を加えドライコーティングすることもできる。更に、皮膜剤には可塑剤、付着防止剤、遮光剤、増量剤、着色剤、着香料等を添加しても良い。 The compression-molded preparation obtained as described above is made into a fast-dissolving coating preparation or sugar-coated preparation by combining the pan coating method, fluidized bed coating method, rolling coating method, dry coating method, and these methods. You can also At this time, a water-soluble or gastric-soluble film agent can be dissolved or dispersed in water or an organic solvent and spray-coated, or these film agents can be directly sprayed and dried by applying heat or pressure. Furthermore, a plasticizer, an adhesion preventive agent, a light shielding agent, an extender, a colorant, a flavoring agent, and the like may be added to the film agent.
以上説明した本発明の圧縮成型製剤の最良の実施形態は、L−システインを27.5〜32.5質量%、アスコルビン酸を35〜40質量%含有し、嵩密度0.3g/cm3以上で平均粒子径が120μm以上の結晶セルロースを全質量中15〜20質量%、嵩密度0.3g/cm3未満で平均粒子径が50μm以上の結晶セルロースを2.5〜10質量%、高膨潤性高分子として低置換度ヒドロキシプロピルセルロースを0.1〜5質量%、軽質無水ケイ酸を1〜10質量%、タルクおよび/又はステアリン酸マグネシウムを0.1〜3質量%配合して得た圧縮成型用粉体を用い、製剤1個当たりの質量を約100〜約200mg、直径約6〜約10mmとなるように圧縮成型時の圧力400〜2000kg/cm2以上で圧縮成型した圧縮成型製剤である。 The best embodiment of the compression-molded preparation of the present invention described above contains 27.5 to 32.5% by mass of L-cysteine and 35 to 40% by mass of ascorbic acid, and has a bulk density of 0.3 g / cm 3 or more. 15 to 20% by mass of crystalline cellulose having an average particle size of 120 μm or more, 2.5 to 10% by mass of crystalline cellulose having a bulk density of less than 0.3 g / cm 3 and an average particle size of 50 μm or more, and high swelling As a functional polymer, 0.1 to 5% by mass of low-substituted hydroxypropylcellulose, 1 to 10% by mass of light anhydrous silicic acid, and 0.1 to 3% by mass of talc and / or magnesium stearate were obtained. A compression-molded preparation using a powder for compression-molding and compression-molded at a pressure of 400-2000 kg / cm 2 or more during compression molding so that the mass per preparation is about 100 to about 200 mg and the diameter is about 6 to about 10 mm. so is there.
本発明製剤の製造に用いられる打錠用粉末は、L−システイン類とアスコルビン酸類の含有量が多いにもかかわらず、嵩密度の異なる2種の結晶セルロースおよび高膨潤性高分子を含有するため、流動性が非常に良好で、圧縮成型性が優れたものである。 The powder for tableting used for the production of the preparation of the present invention contains two kinds of crystalline celluloses having different bulk densities and a highly swellable polymer in spite of the high contents of L-cysteines and ascorbic acids. The fluidity is very good and the compression moldability is excellent.
従って、この打錠用粉末を用い、高速打錠機により製造される本発明製剤は、大量に生産を行なっても打錠障害を引き起こさず、成分含量のばらつきや重量の偏差が少なく、服用性に優れた小型の錠剤となる。 Accordingly, the preparation of the present invention produced by a high-speed tableting machine using this tableting powder does not cause tableting troubles even when mass-produced, has little variation in component content and weight deviation, and is ingestible. It becomes an excellent small tablet.
以下実施例を挙げ、本発明をさらに具体的に説明するが、本発明はこれらの実施例に何ら制約されるものではない。 EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.
実 施 例 1
素錠の製造(1)
L−システイン960g、直打用アスコルビン酸1237.2g、パントテン酸カルシウム96g、結晶セルロース(ビバプアー12:レッテンマイヤー社製)458.8g、結晶セルロース(セオラスKG−802:旭化成ケミカルズ社製)200g、低置換度ヒドロキシプロピルセルロース(LH−11:信越化学工業社製)200g、軽質無水ケイ酸(アドソリダー101:フロイント産業社製)16gを15分混合し、さらにステアリン酸マグネシウム32gを加えて1分混合し、得られた圧縮成型用顆粒をロータリー式打錠機で圧縮成型し、直径8mm、厚さ4.3mm、質量200mgの素錠(圧縮成型製剤)を得た。
Example 1
Manufacture of uncoated tablets (1)
960 g of L-cysteine, 1237.2 g of ascorbic acid for direct hitting, 96 g of calcium pantothenate, 458.8 g of crystalline cellulose (Vivapuer 12: manufactured by Rettenmeier), 200 g of crystalline cellulose (Theolus KG-802: manufactured by Asahi Kasei Chemicals), low Substitution degree hydroxypropyl cellulose (LH-11: manufactured by Shin-Etsu Chemical Co., Ltd.) 200 g, light anhydrous silicic acid (Adsolider 101: manufactured by Freund Sangyo Co., Ltd.) 16 g are mixed for 15 minutes, and further magnesium stearate 32 g is added and mixed for 1 minute. The obtained granules for compression molding were compression-molded with a rotary tableting machine to obtain an uncoated tablet (compression-molded preparation) having a diameter of 8 mm, a thickness of 4.3 mm, and a mass of 200 mg.
実 施 例 2
素錠の製造(2)
L−システイン960g、直打用アスコルビン酸1237.2g、パントテン酸カルシウムタイプS 147.6g、結晶セルロース(ビバプアー12:レッテンマイヤー)336.4g、結晶セルロース(セオラスKG−802:旭化成ケミカルズ)196g、低置換度ヒドロキシプロピルセルロース(LH−11:信越化学工業)196g、軽質無水ケイ酸(アドソリダー101:フロイント産業)15.6gを15分混合し、さらにステアリン酸マグネシウム31.2gを加えて1分混合し、得られた圧縮成型用顆粒をロータリー式打錠機で圧縮成型し、直径7mm、厚さ3.8mm、質量130mgの素錠(圧縮成型製剤)を得た。
Example 2
Manufacture of uncoated tablets (2)
960 g of L-cysteine, 1237.2 g of ascorbic acid for direct hitting, 147.6 g of calcium pantothenate type S, 336.4 g of crystalline cellulose (Vibapuer 12: Rettenmeier), 196 g of crystalline cellulose (Theorus KG-802: Asahi Kasei Chemicals), low 196 g of substituted hydroxypropylcellulose (LH-11: Shin-Etsu Chemical Co., Ltd.) and 15.6 g of light anhydrous silicic acid (Adsolider 101: Freund Industries) are mixed for 15 minutes, and 31.2 g of magnesium stearate is further added and mixed for 1 minute. The obtained granules for compression molding were compression-molded with a rotary tableting machine to obtain an uncoated tablet (compression-molded preparation) having a diameter of 7 mm, a thickness of 3.8 mm, and a mass of 130 mg.
実 施 例 3
フィルムコーティング錠の製造
L−システイン960g、直打用アスコルビン酸1237.2g、パントテン酸カルシウムタイプS 147.6g、結晶セルロース(ビバプアー12:レッテンマイヤー)407.2g、結晶セルロース(セオラスKG−802:旭化成ケミカルズ)200g、低置換度ヒドロキシプロピルセルロース(LH−11:信越化学工業)200g、軽質無水ケイ酸(アドソリダー101:フロイント産業)16gを15分混合し、さらにステアリン酸マグネシウム32gを加えて1分混合し、得られた圧縮成型用顆粒をロータリー式打錠機で圧縮成型し、直径8mm、厚さ4.3mm、質量200mgの素錠(圧縮成型製剤)を得た。
Example 3
Manufacture of film-coated tablets 960 g of L-cysteine, 1237.2 g of ascorbic acid for direct compression, 147.6 g of calcium pantothenate type S, 407.2 g of crystalline cellulose (Vibapua 12: Rettenmeier), crystalline cellulose (Theolas KG-802: Asahi Kasei) Chemicals) 200g, low-substituted hydroxypropylcellulose (LH-11: Shin-Etsu Chemical) 200g, light anhydrous silicic acid (ADSOLIDER 101: Freund Sangyo) 16g is mixed for 15 minutes, then magnesium stearate 32g is added and mixed for 1 minute. The obtained granules for compression molding were compression-molded with a rotary tableting machine to obtain an uncoated tablet (compression-molded preparation) having a diameter of 8 mm, a thickness of 4.3 mm, and a mass of 200 mg.
つぎに、この素錠をコーティングパンに入れ、5質量%のヒドロキシプロピルメチルセルロースを含有するエチルアルコール:精製水=1:1のコーティング液を用いて、1錠当りの重量増が10mgになるまでコーティングを行ない、フィルムコーティング錠を得た。 Next, this uncoated tablet is put in a coating pan and coated with a coating solution of ethyl alcohol: purified water = 1: 1 containing 5% by mass of hydroxypropylmethylcellulose until the weight increase per tablet becomes 10 mg. And film-coated tablets were obtained.
実 施 例 4
糖衣錠の製造
L−システイン960g、直打用アスコルビン酸1237.2g、パントテン酸カルシウム96g、結晶セルロース(ビバプアー12:レッテンマイヤー)388g、結晶セルロース(セオラスKG−802:旭化成ケミカルズ)196g、低置換度ヒドロキシプロピルセルロース(LH−11:信越化学工業)196g、軽質無水ケイ酸(アドソリダー101:フロイント産業)15.6gを15分混合し、さらにステアリン酸マグネシウム
31.2gを加えて1分混合し、得られた圧縮成型用顆粒をロータリー式打錠機で圧縮成型し、直径7mm、厚さ3.8mm、質量130mgの素錠(圧縮成型製剤)を得た。
Example 4
Manufacture of sugar-coated tablets L-cysteine 960 g, direct ascorbic acid 1237.2 g, calcium pantothenate 96 g, crystalline cellulose (Vivapua 12: Rettenmeier) 388 g, crystalline cellulose (Theorus KG-802: Asahi Kasei Chemicals) 196 g, low substituted hydroxy 196 g of propyl cellulose (LH-11: Shin-Etsu Chemical Co., Ltd.) and 15.6 g of light anhydrous silicic acid (Adsolider 101: Freund Sangyo) are mixed for 15 minutes, and then 31.2 g of magnesium stearate is added and mixed for 1 minute. The granules for compression molding were compression molded with a rotary tableting machine to obtain a plain tablet (compression molded preparation) having a diameter of 7 mm, a thickness of 3.8 mm, and a mass of 130 mg.
つぎに、この素錠をコーティングパンに入れ、5質量%のヒドロキシプロピルメチルセルロースを含有するエチルアルコール:精製水=1:1のコーティング液を用いて、1錠当りの重量増が10mgになるまでコーティングを行なった。 Next, this uncoated tablet is put in a coating pan and coated with a coating solution of ethyl alcohol: purified water = 1: 1 containing 5% by mass of hydroxypropylmethylcellulose until the weight increase per tablet becomes 10 mg. Was done.
引き続き、2質量%のタルク、2質量%の酸化チタン、3質量%の炭酸カルシウム、1質量%のアラビアゴム末および60質量%の精製白糖を含む水溶液で1錠当りの重量増が85mgになるまでコーティングを行なった。その後、60質量%の精製白糖を含む水溶液で1錠当りの重量増が15mgになるまでコーティングを行ない、糖衣錠を得た。 Subsequently, the weight increase per tablet is 85 mg with an aqueous solution containing 2% by mass of talc, 2% by mass of titanium oxide, 3% by mass of calcium carbonate, 1% by mass of gum arabic powder and 60% by mass of purified white sugar. Coating was carried out. Thereafter, coating was performed with an aqueous solution containing 60% by mass of purified sucrose until the increase in weight per tablet was 15 mg, whereby sugar-coated tablets were obtained.
比 較 例 1
比較素錠の製造(1)
実施例1の結晶セルロース(ビバプアー12:レッテンマイヤー)458.8gおよび結晶セルロース(セオラスKG−802:旭化成ケミカルズ)200gを結晶セルロース(セオラスKG−802:旭化成ケミカルズ)658.8gに変え、他は実施例1と同様にして比較素錠(比較圧縮成型製剤)を製造した。
Comparative Example 1
Production of comparative uncoated tablets (1)
458.8 g of crystalline cellulose (Vivapuer 12: Rettenmeier) and 200 g of crystalline cellulose (Theorus KG-802: Asahi Kasei Chemicals) in Example 1 were changed to 658.8 g of crystalline cellulose (Theorus KG-802: Asahi Kasei Chemicals), and others were carried out. Comparative uncoated tablets (comparative compression molding preparations) were produced in the same manner as in Example 1.
比 較 例 2
比較素錠の製造(2)
実施例1の結晶セルロース(ビバプアー12:レッテンマイヤー)458.8gおよび結晶セルロース(セオラスKG−802:旭化成ケミカルズ)200gを結晶セルロース(ビバプアー12:レッテンマイヤー)658.8gに変え、他は実施例1と同様にして比較素錠(比較圧縮成型製剤)を製造した。
Comparative Example 2
Manufacture of comparative uncoated tablets (2)
458.8 g of crystalline cellulose (Vivapuer 12: Rettenmeier) and 200 g of crystalline cellulose (Theorus KG-802: Asahi Kasei Chemicals) in Example 1 were changed to 658.8 g of crystalline cellulose (Vibapuer 12: Rettenmeier). In the same manner, a comparative uncoated tablet (comparative compression molding preparation) was produced.
比 較 例 3
比較素錠の製造(3)
実施例1の結晶セルロース(ビバプアー12:レッテンマイヤー)458.8gおよび低置換度ヒドロキシプロピルセルロース(LH−11:信越化学工業)200gを結晶セルロース(ビバプアー12:レッテンマイヤー)658.8gに変え、他は実施例1と同様にして比較素錠(比較圧縮成型製剤)を製造したが、キャッピングを生じた。
Comparative Example 3
Production of comparative uncoated tablets (3)
458.8 g of crystalline cellulose (Vivapuer 12: Rettenmeier) and 200 g of low-substituted hydroxypropylcellulose (LH-11: Shin-Etsu Chemical Co., Ltd.) of Example 1 were changed to 658.8 g of crystalline cellulose (Vivapuer 12: Rettenmeier), etc. Produced a comparative uncoated tablet (comparative compression-molded preparation) in the same manner as in Example 1, but capping occurred.
試 験 例 1
質量偏差試験:
実施例1〜4の素錠並びに比較例1および2の比較素錠各20錠について、個々の質量を測定し、質量偏差を調べた。その結果を表1にCV値(%)で示した。本発明製剤の素錠はいずれも質量偏差が小さいが、比較例1の素錠は質量偏差が大きかった。
Test example 1
Mass deviation test:
About each uncoated tablet of Examples 1-4 and the comparative uncoated tablet of Comparative Examples 1 and 2, each 20 mass was measured and the mass deviation was investigated. The results are shown in Table 1 as CV values (%). All the uncoated tablets of the preparation of the present invention had a small mass deviation, but the uncoated tablet of Comparative Example 1 had a large mass deviation.
試 験 例 2
錠剤硬度:
実施例1〜4の素錠並びに比較例1および2の比較素錠各10錠について、個々の錠剤硬度を錠剤硬度計(TH−303MP型錠剤破壊強度測定器;富山産業(株)製)を用い測定した。その結果を表2に示した。比較例2の比較素錠は同じ大きさである実施例1および3の素錠に比べはるかに硬度が小さかった。
Test example 2
Tablet hardness:
For each of the uncoated tablets of Examples 1 to 4 and the comparative uncoated tablets of Comparative Examples 1 and 2, each tablet hardness was measured using a tablet hardness meter (TH-303MP type tablet breaking strength measuring instrument; manufactured by Toyama Sangyo Co., Ltd.). Used and measured. The results are shown in Table 2. The comparative uncoated tablet of Comparative Example 2 was much smaller in hardness than the uncoated tablets of Examples 1 and 3 having the same size.
Claims (6)
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2006007331A JP5021210B2 (en) | 2006-01-16 | 2006-01-16 | Compression molding |
TW095139056A TWI414287B (en) | 2006-01-16 | 2006-10-23 | Compression molded preparation |
KR1020060108839A KR101364561B1 (en) | 2006-01-16 | 2006-11-06 | Compression molded preparation |
CN2006101564628A CN101002765B (en) | 2006-01-16 | 2006-12-31 | Compressed formed preparation |
HK07112670.5A HK1104234A1 (en) | 2006-01-16 | 2007-11-20 | Compression molded preparation |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2006007331A JP5021210B2 (en) | 2006-01-16 | 2006-01-16 | Compression molding |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2007186470A JP2007186470A (en) | 2007-07-26 |
JP2007186470A5 JP2007186470A5 (en) | 2009-02-05 |
JP5021210B2 true JP5021210B2 (en) | 2012-09-05 |
Family
ID=38341887
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2006007331A Active JP5021210B2 (en) | 2006-01-16 | 2006-01-16 | Compression molding |
Country Status (5)
Country | Link |
---|---|
JP (1) | JP5021210B2 (en) |
KR (1) | KR101364561B1 (en) |
CN (1) | CN101002765B (en) |
HK (1) | HK1104234A1 (en) |
TW (1) | TWI414287B (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SI2407166T1 (en) | 2009-03-13 | 2013-12-31 | Toyama Chemical Co., Ltd. | Tablet and granulated powder containing 6-fluoro-3-hydroxy-2-pyrazinecarboxamide |
JP5733930B2 (en) * | 2009-09-09 | 2015-06-10 | 武田薬品工業株式会社 | Solid preparation |
EP2946780B1 (en) * | 2013-01-15 | 2017-03-01 | FUJIFILM Corporation | Tablet containing 5-hydroxy-1h-imidazole-4-carboxamide |
JP6327237B2 (en) * | 2014-12-05 | 2018-05-23 | 大正製薬株式会社 | Solid composition |
JP7330716B2 (en) * | 2019-02-21 | 2023-08-22 | アサヒグループ食品株式会社 | Method for suppressing discoloration of composition containing amino acid or its salt and vitamin C, powder composition, granules, and tablet |
JP6676816B1 (en) * | 2019-05-31 | 2020-04-08 | シオノギヘルスケア株式会社 | L-cysteine-containing vitamin C-rich compression molded preparation |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001322927A (en) * | 2000-05-12 | 2001-11-20 | Shin Etsu Chem Co Ltd | Solid preparation including hydroxypropyl cellulose of low substitution degree and method for preparation of the same |
JP2002179559A (en) * | 2000-10-06 | 2002-06-26 | Takeda Chem Ind Ltd | Thin-layer sugar-coated tablet and method for producing the same |
JP2004026786A (en) * | 2002-05-10 | 2004-01-29 | Takeda Chem Ind Ltd | Vitamin preparation |
CN1593411A (en) * | 2004-01-15 | 2005-03-16 | 范敏华 | Speckle removing pharmaceutical composition |
-
2006
- 2006-01-16 JP JP2006007331A patent/JP5021210B2/en active Active
- 2006-10-23 TW TW095139056A patent/TWI414287B/en active
- 2006-11-06 KR KR1020060108839A patent/KR101364561B1/en active IP Right Grant
- 2006-12-31 CN CN2006101564628A patent/CN101002765B/en active Active
-
2007
- 2007-11-20 HK HK07112670.5A patent/HK1104234A1/en unknown
Also Published As
Publication number | Publication date |
---|---|
CN101002765B (en) | 2011-10-12 |
JP2007186470A (en) | 2007-07-26 |
TW200744572A (en) | 2007-12-16 |
CN101002765A (en) | 2007-07-25 |
HK1104234A1 (en) | 2008-01-11 |
KR20070076388A (en) | 2007-07-24 |
TWI414287B (en) | 2013-11-11 |
KR101364561B1 (en) | 2014-02-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR101612137B1 (en) | Orally disintegrating tablets | |
JP5366233B2 (en) | Orally disintegrating tablets | |
CN106943355B (en) | Pharmaceutical composition | |
JP5401327B2 (en) | Tablets with improved dissolution | |
EP2815752B1 (en) | Oral pharmaceutical composition | |
NZ536046A (en) | High dosage tablet forms of imatinib mesylate | |
JP5421945B2 (en) | Pharmaceutical composition containing irbesartan and amlodipine or a salt thereof | |
US20060222703A1 (en) | Pharmaceutical composition and preparation method thereof | |
JPWO2006123678A1 (en) | Stable tablets containing droxidopa | |
JP5021210B2 (en) | Compression molding | |
EP2335698B1 (en) | Pharmaceutical solid preparation having active ingredients separated by boundary therein | |
JP2010024181A (en) | Solid preparation and method for producing the same | |
WO2015008825A1 (en) | Orally disintegrating tablet | |
JP2007197373A (en) | Method for producing intraorally quickly disintegrating tablet | |
EP3238712B1 (en) | Very rapidly disintegrating tablet, and method for producing same | |
JP2021028326A (en) | Tablet comprising levetiracetam | |
JP2008037853A (en) | Rapidly disintegrating solid drug preparation containing isomaltose | |
JP5576006B2 (en) | Oral dosage form twice a day | |
JP7250305B2 (en) | Pharmaceutical composition containing memantine or a pharmaceutically acceptable salt thereof and method for producing the same | |
JP6846312B2 (en) | Solid preparation, tablet manufacturing method and coated tablet manufacturing method | |
JP2008201712A (en) | Film-coated preparation | |
JPWO2004091600A1 (en) | Oral solid preparation | |
JP6676816B1 (en) | L-cysteine-containing vitamin C-rich compression molded preparation | |
JP5226732B2 (en) | Compression molding for hypnosis | |
JP6982290B2 (en) | Solid pharmaceutical formulation for internal use containing Onji extract |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20081215 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20081215 |
|
RD02 | Notification of acceptance of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7422 Effective date: 20081215 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20120110 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20120312 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20120312 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20120522 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20120614 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5021210 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20150622 Year of fee payment: 3 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
S531 | Written request for registration of change of domicile |
Free format text: JAPANESE INTERMEDIATE CODE: R313531 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |