JP2006008667A - Stabilized solid preparation containing vitamin cs - Google Patents
Stabilized solid preparation containing vitamin cs Download PDFInfo
- Publication number
- JP2006008667A JP2006008667A JP2005149663A JP2005149663A JP2006008667A JP 2006008667 A JP2006008667 A JP 2006008667A JP 2005149663 A JP2005149663 A JP 2005149663A JP 2005149663 A JP2005149663 A JP 2005149663A JP 2006008667 A JP2006008667 A JP 2006008667A
- Authority
- JP
- Japan
- Prior art keywords
- ascorbic acid
- salt
- preparation according
- tablet
- hydrochloride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 44
- 239000007787 solid Substances 0.000 title claims abstract description 19
- 229940088594 vitamin Drugs 0.000 title abstract description 10
- 229930003231 vitamin Natural products 0.000 title abstract description 10
- 235000013343 vitamin Nutrition 0.000 title abstract description 10
- 239000011782 vitamin Substances 0.000 title abstract description 10
- 150000003722 vitamin derivatives Chemical class 0.000 title abstract description 9
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims abstract description 93
- 235000010323 ascorbic acid Nutrition 0.000 claims abstract description 35
- 239000011668 ascorbic acid Substances 0.000 claims abstract description 35
- 229960005070 ascorbic acid Drugs 0.000 claims abstract description 35
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 239000011230 binding agent Substances 0.000 claims abstract description 23
- 150000005846 sugar alcohols Chemical class 0.000 claims abstract description 13
- 239000007884 disintegrant Substances 0.000 claims abstract description 11
- 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 claims description 25
- 239000011692 calcium ascorbate Substances 0.000 claims description 24
- 235000010376 calcium ascorbate Nutrition 0.000 claims description 24
- 229940047036 calcium ascorbate Drugs 0.000 claims description 24
- 239000004386 Erythritol Substances 0.000 claims description 13
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 claims description 13
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 claims description 13
- 229940009714 erythritol Drugs 0.000 claims description 13
- 235000019414 erythritol Nutrition 0.000 claims description 13
- 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 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 12
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 12
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 11
- 229930003268 Vitamin C Natural products 0.000 claims description 11
- 239000004615 ingredient Substances 0.000 claims description 11
- 239000000845 maltitol Substances 0.000 claims description 11
- 235000010449 maltitol Nutrition 0.000 claims description 11
- 229940035436 maltitol Drugs 0.000 claims description 11
- 235000019154 vitamin C Nutrition 0.000 claims description 11
- 239000011718 vitamin C Substances 0.000 claims description 11
- 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 claims description 9
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 8
- 229940069328 povidone Drugs 0.000 claims description 8
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 7
- 239000011575 calcium Substances 0.000 claims description 7
- 229910052791 calcium Inorganic materials 0.000 claims description 7
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 6
- 235000010355 mannitol Nutrition 0.000 claims description 6
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 6
- 239000000811 xylitol Substances 0.000 claims description 6
- 235000010447 xylitol Nutrition 0.000 claims description 6
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 6
- 229960002675 xylitol Drugs 0.000 claims description 6
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 5
- 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 claims description 5
- 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 claims description 5
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 claims description 5
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 5
- 229950008138 carmellose Drugs 0.000 claims description 5
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 5
- 239000000600 sorbitol Substances 0.000 claims description 5
- 235000010356 sorbitol Nutrition 0.000 claims description 5
- 229960002920 sorbitol Drugs 0.000 claims description 5
- 238000009472 formulation Methods 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- 159000000003 magnesium salts Chemical class 0.000 claims description 3
- 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 claims 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical class OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011701 zinc Substances 0.000 claims 1
- 229910052725 zinc Inorganic materials 0.000 claims 1
- 238000002156 mixing Methods 0.000 abstract description 7
- 239000003826 tablet Substances 0.000 description 46
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 24
- 239000000843 powder Substances 0.000 description 24
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 22
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 18
- 229960001948 caffeine Drugs 0.000 description 15
- 229920002678 cellulose Polymers 0.000 description 14
- 235000010980 cellulose Nutrition 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- -1 sugar Chemical class 0.000 description 14
- 239000007864 aqueous solution Substances 0.000 description 13
- 239000001913 cellulose Substances 0.000 description 13
- 239000007888 film coating Substances 0.000 description 13
- 238000009501 film coating Methods 0.000 description 13
- 229920002261 Corn starch Polymers 0.000 description 12
- 229920002785 Croscarmellose sodium Polymers 0.000 description 12
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 12
- 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 12
- 229960003291 chlorphenamine Drugs 0.000 description 12
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 description 12
- 229960001681 croscarmellose sodium Drugs 0.000 description 12
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 12
- 229960000920 dihydrocodeine Drugs 0.000 description 12
- HFBYLYCMISIEMM-FFHNEAJVSA-N dihydrocodeine phosphate Chemical compound OP(O)(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC HFBYLYCMISIEMM-FFHNEAJVSA-N 0.000 description 12
- 229960001680 ibuprofen Drugs 0.000 description 12
- 229960005489 paracetamol Drugs 0.000 description 12
- 239000001100 (2S)-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chroman-4-one Substances 0.000 description 11
- QUQPHWDTPGMPEX-UHFFFAOYSA-N Hesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(COC4C(C(O)C(O)C(C)O4)O)O3)O)=CC(O)=C2C(=O)C1 QUQPHWDTPGMPEX-UHFFFAOYSA-N 0.000 description 11
- NTCYWJCEOILKNG-ROLPUNSJSA-N [(1r,2s)-1-hydroxy-1-phenylpropan-2-yl]-dimethylazanium;chloride Chemical compound Cl.CN(C)[C@@H](C)[C@H](O)C1=CC=CC=C1 NTCYWJCEOILKNG-ROLPUNSJSA-N 0.000 description 11
- QUQPHWDTPGMPEX-UTWYECKDSA-N aurantiamarin Natural products COc1ccc(cc1O)[C@H]1CC(=O)c2c(O)cc(O[C@@H]3O[C@H](CO[C@@H]4O[C@@H](C)[C@H](O)[C@@H](O)[C@H]4O)[C@@H](O)[C@H](O)[C@H]3O)cc2O1 QUQPHWDTPGMPEX-UTWYECKDSA-N 0.000 description 11
- APSNPMVGBGZYAJ-GLOOOPAXSA-N clematine Natural products COc1cc(ccc1O)[C@@H]2CC(=O)c3c(O)cc(O[C@@H]4O[C@H](CO[C@H]5O[C@@H](C)[C@H](O)[C@@H](O)[C@H]5O)[C@@H](O)[C@H](O)[C@H]4O)cc3O2 APSNPMVGBGZYAJ-GLOOOPAXSA-N 0.000 description 11
- 238000007906 compression Methods 0.000 description 11
- 230000006835 compression Effects 0.000 description 11
- 229940073563 dl- methylephedrine hydrochloride Drugs 0.000 description 11
- 229940025878 hesperidin Drugs 0.000 description 11
- QUQPHWDTPGMPEX-QJBIFVCTSA-N hesperidin Chemical compound C1=C(O)C(OC)=CC=C1[C@H]1OC2=CC(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO[C@H]4[C@@H]([C@H](O)[C@@H](O)[C@H](C)O4)O)O3)O)=CC(O)=C2C(=O)C1 QUQPHWDTPGMPEX-QJBIFVCTSA-N 0.000 description 11
- VUYDGVRIQRPHFX-UHFFFAOYSA-N hesperidin Natural products COc1cc(ccc1O)C2CC(=O)c3c(O)cc(OC4OC(COC5OC(O)C(O)C(O)C5O)C(O)C(O)C4O)cc3O2 VUYDGVRIQRPHFX-UHFFFAOYSA-N 0.000 description 11
- 235000019359 magnesium stearate Nutrition 0.000 description 11
- ARGKVCXINMKCAZ-UHFFFAOYSA-N neohesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(CO)O3)OC3C(C(O)C(O)C(C)O3)O)=CC(O)=C2C(=O)C1 ARGKVCXINMKCAZ-UHFFFAOYSA-N 0.000 description 11
- 238000010298 pulverizing process Methods 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 9
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- 229920002472 Starch Polymers 0.000 description 7
- 239000008107 starch Substances 0.000 description 7
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- 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 6
- 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 6
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- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 239000006188 syrup Substances 0.000 description 6
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- 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 5
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- 239000008101 lactose Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 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 5
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 4
- 235000019759 Maize starch Nutrition 0.000 description 4
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical class CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 4
- 229920003144 amino alkyl methacrylate copolymer Polymers 0.000 description 4
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 4
- 239000008298 dragée Substances 0.000 description 4
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- 239000008187 granular material Substances 0.000 description 4
- 229940057948 magnesium stearate Drugs 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 4
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- 239000011732 tocopherol Substances 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 3
- 239000004373 Pullulan Substances 0.000 description 3
- 229920001218 Pullulan Polymers 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
- 150000001720 carbohydrates Chemical class 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
- 238000001035 drying Methods 0.000 description 3
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- 238000005096 rolling process Methods 0.000 description 3
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- BALXUFOVQVENIU-GNAZCLTHSA-N Ephedrine hydrochloride Chemical compound Cl.CN[C@@H](C)[C@H](O)C1=CC=CC=C1 BALXUFOVQVENIU-GNAZCLTHSA-N 0.000 description 2
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 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
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- 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 2
- 229930003427 Vitamin E Natural products 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 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 2
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 2
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
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Landscapes
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Abstract
Description
本発明はビタミンＣ類を含む安定化された固形製剤に関する。 The present invention relates to a stabilized solid preparation containing vitamin Cs.
アスコルビン酸は、水分の存在により変色することが知られている。そのため、ビタミンＣを含有する製剤の製造においては水分の厳密な管理が必要であり、水を透過しない包装材で包装することが要求される。また、アスコルビン酸は、他の成分との配合により変化しやすいため、アスコルビン酸が変色する場合が多い。そのため、ビタミンＣ含有製剤では、アスコルビン酸の安定性に留意しながら製剤を設計し、製造する必要がある。 Ascorbic acid is known to change color due to the presence of moisture. Therefore, in the manufacture of a preparation containing vitamin C, it is necessary to strictly control moisture, and packaging with a packaging material that does not transmit water is required. Moreover, since ascorbic acid is easy to change by mixing with other components, ascorbic acid is often discolored. Therefore, it is necessary to design and manufacture a vitamin C-containing preparation while paying attention to the stability of ascorbic acid.
特許文献１には、ビタミンＣ、ビタミンＥなどの薬効成分と、砂糖、澱粉糖、糖アルコ−ルなどの糖類と、前記糖類粒子が湿る程度の水分を含む混合物を打錠し、口腔内での崩壊性、溶解性が高く、適度な機械的強度を有する錠剤を得ることが開示されている。この特許文献１の実施例１には、アスコルビン酸、アスコルビン酸ナトリウム、ｄ−α−トコフェロールなどを薬効成分とし、キシリトールを糖類とした錠剤が記載されている。特許文献２には、アスコルビン酸とマルチトールとの流動性の高い混合粉末組成物の製造方法が開示されている。この製造方法により共存するマルチトールによってアスコルビン酸の分解が抑制されるとの記載があるが、これらの先行文献には具体的なビタミンＣの安定化について記載されていない。特許文献３には、ビタミンＣ類とエリスリトールを含む組成物を練合して、押出造粒することによりビタミンＣ類が安定化した製剤を得ることが開示されているが、錠剤については記載されていない。
本発明の目的は、アスコルビン酸またはその塩を安定に含有する組成物を提供することにある。本発明の他の目的はアスコルビン酸またはその塩を安定に含有する固形製剤およびその製造方法を提供することにある。 The objective of this invention is providing the composition which contains ascorbic acid or its salt stably. Another object of the present invention is to provide a solid preparation stably containing ascorbic acid or a salt thereof and a method for producing the same.
本発明者らは、アスコルビン酸またはその塩を含む製剤の安定化について種々検討を加えたところ、アスコルビン酸またはその塩としてアスコルビン酸カルシウム、特に、その造粒物である直打用アスコルビン酸カルシウムを用い、他の成分の群を造粒し、アスコルビン酸またはその塩と分離して配合すると安定化されること、さらには他の成分を造粒する際に用いる賦形剤、崩壊剤および結合剤として前記のものを選択することによって、さらにいっそう安定化することを見出した。
すなわち、本発明は、
The present inventors have made various studies on the stabilization of a preparation containing ascorbic acid or a salt thereof. Ascorbic acid or a salt thereof is calcium ascorbate, in particular, calcium ascorbate for direct hitting which is a granulated product thereof. Used, granulated in groups of other ingredients, stabilized when blended separately from ascorbic acid or its salts, and excipients, disintegrants and binders used in granulating other ingredients It has been found that further stabilization can be achieved by selecting the above as the above.
That is, the present invention
（１）アスコルビン酸またはその塩と、糖アルコール、崩壊剤および結合剤を含有する造粒物とを配合してなることを特徴とするビタミンＣ類を含む安定化された固形製剤；
（２）アスコルビン酸またはその塩が、造粒物である前記（１）記載の固形製剤；
（３）アスコルビン酸またはその塩が、アスコルビン酸およびアスコルビン酸のナトリウム塩、カリウム塩、カルシウム塩、亜鉛塩およびマグネシウム塩から選ばれる１種または２種以上である前記（１）記載の製剤；
（４）アスコルビン酸またはその塩がアスコルビン酸カルシウムである前記（１）記載の製剤；
（５）アスコルビン酸またはその塩が直打用アスコルビン酸カルシウムである前記（２）記載の製剤；
（６）糖アルコールがＤ−マンニトール、エリスリトール、キシリトール、マルチトールおよびソルビトールから選ばれる１種または２種以上である前記（１）記載の製剤；
（７）糖アルコールがマルチトールおよびエリスリトールから選ばれる１種または２種である前記（１）記載の製剤；
（８）崩壊剤が低置換度ヒドロキシプロピルメチルセルロースおよびカルメロースカルシウムから選ばれる１種または２種である前記（１）記載の製剤；
（９）結合剤がポビドン（ポリビニルピロリドン）である前記（１）記載の製剤；
（１０）糖アルコール、崩壊剤および結合剤を含有する造粒物中に他の薬効成分を含有する前記（１）記載の製剤；
（１１）固形製剤が錠剤である前記（１）記載の製剤などを提供する。
(1) A stabilized solid preparation containing vitamin C, comprising ascorbic acid or a salt thereof and a granulated product containing a sugar alcohol, a disintegrant and a binder;
(2) The solid preparation according to (1), wherein the ascorbic acid or a salt thereof is a granulated product;
(3) The preparation according to the above (1), wherein the ascorbic acid or a salt thereof is at least one selected from ascorbic acid and sodium salt, potassium salt, calcium salt, zinc salt and magnesium salt of ascorbic acid;
(4) The preparation according to (1), wherein ascorbic acid or a salt thereof is calcium ascorbate;
(5) The preparation according to the above (2), wherein the ascorbic acid or a salt thereof is calcium ascorbate for direct hitting;
(6) The preparation according to the above (1), wherein the sugar alcohol is one or more selected from D-mannitol, erythritol, xylitol, maltitol and sorbitol;
(7) The preparation according to (1), wherein the sugar alcohol is one or two selected from maltitol and erythritol;
(8) The preparation according to (1), wherein the disintegrant is one or two selected from low-substituted hydroxypropylmethylcellulose and carmellose calcium;
(9) The preparation according to the above (1), wherein the binder is povidone (polyvinylpyrrolidone);
(10) The preparation according to the above (1), which contains other medicinal ingredients in the granulated product containing a sugar alcohol, a disintegrant and a binder;
(11) The preparation according to (1) above, wherein the solid preparation is a tablet.
本発明に従って、アスコルビン酸またはその塩を、他の成分を造粒し、アスコルビン酸とまたはその塩と分離して配合すること、さらには他の成分を造粒する際に用いる賦形剤、崩壊剤および結合剤として特定のものを選択することによって、非常に安定化されたアスコルビン酸またはその塩を含有する固形製剤、特に錠剤を製造することができる。 In accordance with the present invention, ascorbic acid or a salt thereof is granulated from other ingredients and blended separately from ascorbic acid or a salt thereof, and further, an excipient used for granulating other ingredients, disintegration By selecting specific agents and binders, it is possible to produce solid formulations, particularly tablets, containing highly stabilized ascorbic acid or salts thereof.
本発明におけるアスコルビン酸またはその塩（以下、単にビタミンＣ類と称する場合がある）は、医薬品上許容されるものであれば特に限定されるものではない。アスコルビン酸の塩としては、例えば、ナトリウム塩、カリウム塩、カルシウム塩、亜鉛塩、マグネシウム塩等が挙げられ、これらは１種または２種以上を用いることができる。好ましくは、アスコルビン酸カルシウムが用いられる。
本発明では、好ましくは、ビタミンＣ類は造粒して使用する。例えば、造粒したアスコルビン酸カルシウムとしては、特開平３−４７１２１号公報に記載されるような、α化デンプン、水溶性セルロース類、水溶性高分子化合物などの水溶性結合剤を用いて、常法により造粒したアスコルビン酸カルシウム造粒物が好ましい。特に、造粒物１０ｇを１００ｍｌの水に溶解した場合の水溶液のｐＨが５．０〜７．０となる量の酒石酸、クエン酸等の有機固体酸（好ましくは脂肪族カルボン酸）を含有してなるアスコルビン酸カルシウム造粒物が好ましく、該造粒物の平均粒子径が約２００〜４００μｍのものがより好ましい。さらに好ましくは、直打用アスコルビン酸カルシウムが好ましい。直打用アスコルビン酸カルシウムとは、直接打錠することができる粒状アスコルビン酸カルシウムを意味し、このような直打用アスコルビン酸カルシウムは商業的にも入手可能である。また、特開平３−４７１２１号公報の記載に準じて製造することも可能である。
製剤中のビタミンＣ類の配合量は特に限定するものではなく、通常、ビタミンＣ類含有の固形製剤に使用される量でよく、例えば、製剤に対して１〜３０重量％、好ましくは、４〜２０重量％配合される。
Ascorbic acid or a salt thereof (hereinafter sometimes simply referred to as vitamin C) in the present invention is not particularly limited as long as it is pharmaceutically acceptable. Examples of the salt of ascorbic acid include sodium salt, potassium salt, calcium salt, zinc salt, magnesium salt, and the like, and one or more of these can be used. Preferably, calcium ascorbate is used.
In the present invention, vitamin C is preferably used after being granulated. For example, as granulated calcium ascorbate, water-soluble binders such as pregelatinized starch, water-soluble celluloses, water-soluble polymer compounds, etc., as described in JP-A-3-47121, are usually used. A calcium ascorbate granulated product granulated by the method is preferred. In particular, it contains an organic solid acid (preferably an aliphatic carboxylic acid) such as tartaric acid and citric acid in such an amount that the pH of the aqueous solution becomes 5.0 to 7.0 when 10 g of the granulated product is dissolved in 100 ml of water. A calcium ascorbate granulated product is preferable, and an average particle size of the granulated product is more preferably about 200 to 400 μm. More preferably, direct ascorbic calcium ascorbate is preferred. Direct calcium ascorbate means granular calcium ascorbate that can be directly compressed, and such direct calcium ascorbate is also commercially available. Further, it can be produced according to the description in JP-A-3-47121.
The blending amount of vitamin C in the preparation is not particularly limited, and may be an amount usually used for a solid preparation containing vitamin C, for example, 1 to 30% by weight, preferably 4%. -20% by weight is blended.
本発明の製剤では、ビタミンＣ類を安定化させるために、他の成分をビタミンＣ類と分離して造粒し、配合する。
かかる造粒は、公知の賦形剤を用い、例えば、流動層造粒、押出造粒等の常法に従って行うことができる。本発明においては、この造粒を行う際に賦形剤として、特に、糖アルコール、崩壊剤および結合剤を用いる。好ましくは、糖アルコールとしては、Ｄ−マンニトール、エリスリトール、キシリトール、マルチトールおよびソルビトールから選ばれる１種または２種以上、とりわけマルチトールまたはエリスリトールから選ばれる１種または２種を用いる。このような糖アルコールは、例えば、市販品（東和化成工業（株）の粉末還元麦芽糖水飴アマルティMR-100、日研化成（株）のエリスリトールなど）として入手できる。崩壊剤としては、低置換度ヒドロキシプロピルメチルセルロース、カルメロースカルシウムから選ばれる１種または２種を用いる。このような崩壊剤は、例えば、市販品（信越化学（株）の低置換度ヒドロキシプロピルメチルセルロース、五徳薬品のECG-505など）として入手できる。また、結合剤としては、ポビドン（ポリビニルピロリドン）を用い、市販品（BASFのコリドンなど）として入手できる。このように賦形剤を選択することによって、ビタミンＣ類の経日的分解と製剤の外観変化が顕著に抑制され、製品の品質保証期間が長く、製品価値の高い固形製剤を得ることができる。
これら、賦形剤の配合量も特に限定するものではなく、通常、ビタミンＣ類含有の固形製剤に使用される量でよい。
In the preparation of the present invention, in order to stabilize vitamin Cs, other ingredients are separated from vitamin Cs, granulated and blended.
Such granulation can be performed using a known excipient according to a conventional method such as fluidized bed granulation or extrusion granulation. In the present invention, a sugar alcohol, a disintegrant, and a binder are used as excipients when performing this granulation. Preferably, as the sugar alcohol, one or more selected from D-mannitol, erythritol, xylitol, maltitol and sorbitol, especially one or two selected from maltitol or erythritol are used. Such sugar alcohols are available as, for example, commercially available products (such as powder reduced maltose syrup amalty MR-100 from Towa Kasei Kogyo Co., Ltd., erythritol from Nikken Kasei Co., Ltd.). As the disintegrant, one or two kinds selected from low-substituted hydroxypropylmethylcellulose and carmellose calcium are used. Such disintegrants can be obtained as, for example, commercially available products (low-substituted hydroxypropylmethylcellulose from Shin-Etsu Chemical Co., Ltd., ECG-505 from Gotoku Pharmaceutical, etc.) As the binder, povidone (polyvinylpyrrolidone) is used, and it can be obtained as a commercial product (BASF's corridone, etc.). By selecting excipients in this way, the daily degradation of vitamin Cs and the appearance change of the preparation are remarkably suppressed, and the product quality assurance period is long and a solid preparation with high product value can be obtained. .
The blending amount of these excipients is not particularly limited, and may be an amount usually used for a vitamin C-containing solid preparation.
本発明では、他の配合成分の造粒物に、所望により、他の薬効成分を含有させてもよい。かかる他の薬効成分は治療学的に有効な活性成分、あるいは予防学的に有効な活性成分であれば特に限定するものではなく、通常、ビタミンＣ類と併用される薬効成分の１種または２種以上が通常採用される配合量で用いられる。
このような薬効成分としては、例えば、イブプロフェン、アセトアミノフェン、ジクロフェナック、ジクロフェナックナトリウム、ロキソプロフェンナトリウム、アスピリン、アスピリンアルミニウム、エテンザミド、アミノピリン、サリチルアミド、ラクチルフェネチジン、イソプロピルアンチピリン、サザピリン、サリチル酸ナトリウム、フェニルブタゾン、ケトフェニルブタゾン、オキシフェンブタゾン、インドメタシン、フェナセチン、臭化ブチルスコポラミン、モルヒネ、エトミドリン、ペンタゾシン、フェノプロフェンカルシウム、ナプロキセン、セレコキシブ、バルデコキシブ、トラマドール、イブフェナック、セラチオペプチダーゼ、塩化リゾチーム、メフェナム酸、トラネキサム酸、ベラドンナ総アルカロイドなどの解熱、鎮痛及び/又は消炎剤;
In the present invention, other medicinal components may be contained in the granulated product of other blending components as desired. Such other medicinal ingredients are not particularly limited as long as they are therapeutically effective active ingredients or prophylactically effective active ingredients, and usually one or two medicinal ingredients used in combination with vitamin Cs. More than the seeds are used in the compounding amounts usually employed.
Examples of such medicinal ingredients include ibuprofen, acetaminophen, diclofenac, diclofenac sodium, loxoprofen sodium, aspirin, aspirin aluminum, ethenamide, aminopyrine, salicylamide, lactylphenetidine, isopropylantipyrine, sazapyrine, sodium salicylate, phenylbuta Zon, ketophenylbutazone, oxyphenbutazone, indomethacin, phenacetin, butylscopolamine bromide, morphine, etmidrin, pentazocine, fenoprofen calcium, naproxen, celecoxib, valdecoxib, tramadol, ibufenac, seratiopeptidase, lysozyme chloride, mefenam Antipyretic acids such as acid, tranexamic acid, belladonna total alkaloids Analgesic and / or anti-inflammatory agent;
ジフェンヒドラミン又はその塩(例えば、塩酸塩など)、クロルフェニラミン又はその塩(例えば、D一マレイン酸塩など)、メキタジン、塩酸プロメタジン、酒石酸アリメマジン、塩酸イソチペンジル、テオクル酸ジフェニルピラリン、塩酸シプロヘプタジン、塩酸トリプロリジン、塩酸ホモクロルシクリジン、ナパジシル酸メブヒドロリン、フマル酸クレマスチン、マレイン酸ジメチンデン、塩酸イプロヘプチン、テルフェナジンなどの抗ヒスタミン薬；
塩酸クロペラスチン、コデイン類(例えば、リン酸ジヒドロコデイン及びリン酸コデインなど)、オキシメテバノール、塩酸エプラジノン、チペピジン、クエン酸チペピジン、塩酸エフェドリン、塩酸アロクラミド、フェン酸カルベタペンタン、ジブナートナトリウム、ヒベンズ酸チペピジン、フェンジゾ酸クロペラスチン、塩酸メトキシフェナミン、ノスカピン、塩酸ノスカピン、ジメモルファン又はその塩(例えば、リン酸塩、硫酸塩など)、塩酸ブロムヘキシン、デキストロメトルファンとその塩（例えば、臭化水素酸デキストロメトルファン、デキストロメトルファン・フェノールフタリン塩など）、グアイフェネシンなどの鎮咳及び/又は去疾剤;
フェニルプロパノールアミン、塩酸エフェドリン、プソイドエフェドリン又はその塩（例えば、塩酸塩、硫酸塩）などの抗うっ血薬；
d1一塩酸メチルエフェドリン、テオフィリン、アミノフィリン、フマル酸ホルモテロール、塩酸トリメトキノールなどの気管支拡張剤;
カフェインとその誘導体、例えば、無水カフェイン、カフェイン(1水和物)、カフェインサイトレート、安息香酸ナトリウムカフェインなどのカフェイン類；
甘草(カンゾウGlycyrrhizaeRadix)、セネガ、柴胡(サイコBupleuriRadix)、桂皮
(CinnamomiCortex)、葛根(PherariaeRadix)、麻黄(EphedraeHerba)、ケイガイ(SchizonepetaeHerba)、レンギョウ(ForsythiaeFructus)、キョウニン
(AmeniacaeSemen)、半夏(ハンゲPinellaeTuber)、シャクヤク(PaeoniaeRadix)、細辛(サイシンAsiasriRadix)、生姜(ショウキョウZingiberisRhizoma)、五味子(ゴミシSchisandraeFructus)、蘇葉(PerillaeHerba)、人参(GinsengRadix)、陳皮(AurantiiNobilisPericarpicm)などの漢方薬エキス;
ビタミンB1誘導体(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、ベンフォチアミン等)、ビタミンB1(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、チアミンジセチル硫酸エステル塩等)、ビタミンB2(リボフラビン、リン酸リボフラビンナトリウム、酪酸リボフラビン等)、ビタミンB6(塩酸ピリドキシン、リン酸ピリドキサール等)、ビタミンB12(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、メコバラミン等)、ビタミンE(コハク酸d一α一トコフェロール、コハク酸d1一α一トコフェロールカルシウム、酢酸d一α一トコフェロール、酢酸d1一α一トコフェロール等)、ニコチン酸、ニコチン酸アミド、パントテン酸カルシウム、パントテン酸カルシウムタイプS、ビオチン、ガンマーオリザノール、オロチン酸、グルクロノラクトン、グルクロン酸アミド、ヨクイニンなどのビタミン類;
水酸化マグネシウム、酸化マグネシウム、水酸化アルミニウム、硫酸アルミニウ
ム、メタケイ酸アルミン酸マグネシウム[例えば、ノイシリン(商品名)]、ケイ酸アルミン酸マグネシウム、合成ヒドロタルサイト[例えば、アルカマック(商品名)]、水酸化アルミニウム・炭酸水素ナトリウムの共沈生成物[例えば、クムライト(商品名)]、スクラルファートなどの制酸剤や粘膜保護剤;ミネラル;アミノ酸類などが挙げられる。
Diphenhydramine or a salt thereof (e.g., hydrochloride), chlorpheniramine or a salt thereof (e.g., D-maleate), mequitazine, promethazine hydrochloride, alimemazine tartrate, istipendyl hydrochloride, diphenylpyraline teolate, cyproheptadine hydrochloride, triprotate hydrochloride Antihistamines such as lysine, homochlorocyclidine hydrochloride, mebuhydroline napadisylate, clemastine fumarate, dimethinedene maleate, iproheptin hydrochloride, terfenadine;
Cloperastine hydrochloride, codeines (e.g., dihydrocodeine phosphate and codeine phosphate), oxymethavanol, eprazinone hydrochloride, tipepidine, tipepidine citrate, ephedrine hydrochloride, aloclamide hydrochloride, carbetapentane phenate, sodium dibunate, tipepidine hibenzate Cloperastine fendizate, methoxyphenamine hydrochloride, noscapine, noscapine hydrochloride, dimemorphan or its salts (eg, phosphate, sulfate, etc.), bromhexine hydrochloride, dextromethorphan and its salts (eg, dextromethorphan hydrobromide) Dextromethorphan / phenolphthaline salt, etc.), antitussive and / or expectorant such as guaifenesin;
An anti-congestive agent such as phenylpropanolamine, ephedrine hydrochloride, pseudoephedrine or a salt thereof (eg, hydrochloride, sulfate);
d1 bronchodilators such as methylephedrine monohydrochloride, theophylline, aminophylline, formoterol fumarate, trimethquinol hydrochloride;
Caffeine and its derivatives, for example, anhydrous caffeine, caffeine (monohydrate), caffeine citrate, caffeine such as sodium benzoate caffeine;
Licorice (licorice GlycyrrhizaeRadix), Senega, Shiba (Psycho BupleuriRadix), cinnamon
(CinnamomiCortex), Pakaria (PherariaeRadix), Mao (EphedraeHerba), Keichi (SchizonepetaeHerba), ForsythiaeFructus, Kyonin
(AmeniacaeSemen), Half-summer (Hangue PinellaeTuber), Peonies (PaeoniaeRadix), Spicy (AsiasriRadix), Ginger (ZingiberisRhizoma), Gomi (SchisandraeFructus), Suyo (PerillaeHerba), Rad ) And other herbal medicine extracts;
Vitamin B 1 derivatives (fursultiamine hydrochloride, dicetiamine hydrochloride, octothiamine, chicotiamine, bisbutiamine, bisbenchamine, benfotiamine, etc.), vitamin B 1 (thiamine hydrochloride, thiamine nitrate, bisthiamine nitrate, thiamine disulfide, thiamine disulfide) Cetyl sulfate, etc.), vitamin B 2 (riboflavin, sodium riboflavin phosphate, riboflavin butyrate, etc.), vitamin B 6 (pyridoxine hydrochloride, pyridoxal phosphate, etc.), vitamin B 12 (cyanocobalamin, hydroxocobalamin hydrochloride, hydroxocobalamin acetate, Mecobalamin, etc.), vitamin E (succinic acid d 1 α 1 tocopherol, succinic acid d 1 1 α 1 tocopherol calcium, acetic acid d 1 α 1 tocopherol, acetic acid d 1 α 1 tocopherol, etc.), nicotinic acid, nicotinic acid amide, pantothenic acid Siumu, calcium pantothenate type S, biotin, gamma oryzanol, orotic acid, glucuronolactone, glucuronic acid amide, vitamins such as Coix Seed;
Magnesium hydroxide, magnesium oxide, aluminum hydroxide, aluminum sulfate, magnesium aluminate metasilicate [e.g., neusilin (trade name)], magnesium silicate aluminate, synthetic hydrotalcite [e.g., Alkamak (trade name)], Examples thereof include coprecipitation products of aluminum hydroxide and sodium hydrogen carbonate [for example, cumulite (trade name)], antacids such as sucralfate and mucosal protective agents; minerals;
本発明の固形製剤は、常法により、例えば、細粒剤、顆粒剤、丸剤、錠剤（フィルムコーティング錠、薄層糖衣錠、糖衣錠等を含む）、カプセル剤等剤形とすることができ、前記の各成分と共に、滑沢剤や、必要に応じて、溶解補助剤、緩衝剤、保存剤、可溶化剤、抗酸化剤、矯味剤、香料、着色剤等の慣用の製剤添加剤を適当量含有することができる。
本発明の固形製剤としては、特に錠剤が好ましく、例えば、フィルムコーティング錠の場合、フィルムコーティング基剤として、メチルセルロース、エチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、アミノアルキルメタアクリレートコポリマーＥ、アミノアルキルメタアクリレートコポリマーＬ、アミノアルキルメタアクリレートコポリマーＲＳ、アミノアルキルメタアクリレートコポリマーＳ、カルボキシビニルポリマー、ポリビニルアルコール、ポリビニルアセタールジエチルアミンアセテート、プルラン等が用いられる。
薄層糖衣錠の場合、薄層糖衣基剤として、ショ糖、トレハロース、乳糖、マンニトール、ソルビトール、キシリトール、マルチトール、エリスリトール、粉末還元麦芽糖水飴、プルラン、酸化チタン、ポリエチレングリコール等が用いられる。
糖衣錠の場合、糖衣基剤としては、ショ糖、トレハロース、乳糖、マンニトール、ソルビトール、キシリトール、マルチトール、エリスリトール、粉末還元麦芽糖水飴、プルラン等が用いられる。
以下、実施例、比較例および試験例を挙げて本発明をさらに詳しく説明するが、これらは本発明を限定するものではない。
The solid preparation of the present invention can be made into dosage forms such as fine granules, granules, pills, tablets (including film-coated tablets, thin-layer sugar-coated tablets, sugar-coated tablets, etc.), capsules and the like by conventional methods. Along with the above-mentioned components, lubricants and, if necessary, conventional formulation additives such as solubilizing agents, buffering agents, preservatives, solubilizers, antioxidants, flavoring agents, flavoring agents, and coloring agents are appropriately used. It can be contained in an amount.
The solid preparation of the present invention is particularly preferably a tablet. For example, in the case of a film-coated tablet, as a film coating base, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, aminoalkyl methacrylate copolymer E, amino Alkyl methacrylate copolymer L, aminoalkyl methacrylate copolymer RS, aminoalkyl methacrylate copolymer S, carboxyvinyl polymer, polyvinyl alcohol, polyvinyl acetal diethylamine acetate, pullulan and the like are used.
In the case of a thin-layer sugar-coated tablet, sucrose, trehalose, lactose, mannitol, sorbitol, xylitol, maltitol, erythritol, powdered reduced maltose starch syrup, pullulan, titanium oxide, polyethylene glycol and the like are used.
In the case of sugar-coated tablets, sucrose, trehalose, lactose, mannitol, sorbitol, xylitol, maltitol, erythritol, powdered reduced maltose starch syrup, pullulan and the like are used.
EXAMPLES Hereinafter, although an Example, a comparative example, and a test example are given and this invention is demonstrated further in detail, these do not limit this invention.
表１に示すようにアセトアミノフェン、イブプロフェン、ｄ−マレイン酸クロルフェニラミン、リン酸ジヒドロコデイン、ｄｌ−塩酸メチルエフェドリン、無水カフェイン、ヘスペリジンに結晶セルロース、低置換度ヒドロキシプロピルセルロース、粉末還元麦芽糖水飴、トウモロコシデンプンを加えて転動流動層造粒機（パウレック製、MP-10型転動流動層造粒機）に入れ、給気温度70℃で、結合剤としてポビドン6％水溶液を噴霧して造粒後、乾燥して造粒末を製造した。
パワーミル（昭和化学機械製、スクリーンサイズ1.5mmφ）で粉砕して整粒末を得た後、直打用アスコルビン酸カルシウム、トウモロコシデンプン、低置換度ヒドロキシプロピルセルロース、ステアリン酸マグネシウムを加えて粗混合後、タンブラー混合機（昭和化学機械製、TM-60S型）に入れ、15rpmで3分間混合した。そして、コレクト12HUK打錠機（菊水製作所製、30rpm）で13.5×6.8mm杵で1錠当たり405mgの重量、圧縮圧1000kg/杵当たりの条件で打錠して素錠を得た。
得られた素錠をフィルムコーティング装置（パウレック製、ドリアコーターDRC-500型）に入れ、調製したフィルムコーティング液を、回転数8rpm、給気温度70℃、給気量4m3/min、液供給速度13g/min、スプレー空気量4000Nl/hr、の条件で操作してフィルムコーティング錠を得た。
After pulverization with a power mill (Showa Kagaku Kikai Co., Ltd., screen size 1.5mmφ) to obtain a sized powder, after roughly mixing with calcium ascorbate, maize starch, low-substituted hydroxypropylcellulose and magnesium stearate for direct hitting The mixture was placed in a tumbler mixer (TM-60S, manufactured by Showa Chemical Machinery Co., Ltd.) and mixed at 15 rpm for 3 minutes. Then, it was tableted with a collect 12HUK tableting machine (manufactured by Kikusui Seisakusho Co., Ltd., 30 rpm) at 13.5 × 6.8 mm 杵 under the conditions of a weight of 405 mg per tablet and a compression pressure of 1000 kg / 杵 to obtain an uncoated tablet.
The obtained uncoated tablet is put into a film coating device (Powrec, Doria Coater DRC-500 type), and the prepared film coating solution is rotated at 8 rpm, air supply temperature 70 ° C, air supply amount 4 m 3 / min, liquid supply Film-coated tablets were obtained by operating at a speed of 13 g / min and a spray air amount of 4000 Nl / hr.
表２に示すようにアセトアミノフェン、イブプロフェン、ｄ−マレイン酸クロルフェニラミン、リン酸ジヒドロコデイン、ｄｌ−塩酸メチルエフェドリン、無水カフェイン、ヘスペリジンに結晶セルロース、低置換度ヒドロキシプロピルセルロース、エリスリトール、トウモロコシデンプンを加えて転動流動層造粒機（パウレック製、MP-10型流動層造粒機）にて結合剤としてポビドン6％水溶液を噴霧して造粒後、乾燥して造粒末を製造した。
パワーミル（昭和化学機械製、スクリーンサイズ1.5mmφ）で粉砕して整粒末を得た後、直打用アスコルビン酸カルシウム、トウモロコシデンプン、低置換度ヒドロキシプロピルセルロース、ステアリン酸マグネシウムを加えて粗混合後、タンブラー混合機（昭和化学機械製、TM-60S型）に入れ、15rpmで3分間混合した。そして、コレクト12HUK打錠機（菊水製作所製、30rpm）で8.5mmφR面杵で1錠当たり270mgの重量、圧縮圧1000kg/杵当たりの条件で打錠して素錠を得た。
その後、実施例１と同様の操作を行ってフィルムコーティング錠を製した。
After pulverization with a power mill (Showa Kagaku Kikai Co., Ltd., screen size 1.5mmφ) to obtain a sized powder, after roughly mixing with calcium ascorbate, maize starch, low-substituted hydroxypropylcellulose and magnesium stearate for direct hitting The mixture was placed in a tumbler mixer (TM-60S, manufactured by Showa Chemical Machinery Co., Ltd.) and mixed at 15 rpm for 3 minutes. Then, it was tableted with a collect 12HUK tableting machine (manufactured by Kikusui Seisakusho Co., Ltd., 30 rpm) with a 8.5 mmφR face weight under the conditions of a weight of 270 mg per tablet and a compression pressure of 1000 kg / kg to obtain an uncoated tablet.
Then, operation similar to Example 1 was performed and the film coating tablet was manufactured.
表３に示すようにアセトアミノフェン、イブプロフェン、ｄ−マレイン酸クロルフェニラミン、リン酸ジヒドロコデイン、ｄｌ−塩酸メチルエフェドリン、無水カフェイン、ヘスペリジンに結晶セルロース、カルメロースカルシウム、エリスリトール、トウモロコシデンプンを加えて転動流動層造粒機（パウレック製、MP-10型流動層造粒機）にて結合剤としてポビドン6％水溶液を噴霧して造粒後、乾燥して造粒末を製造した。
パワーミル（昭和化学機械製、スクリーンサイズ1.5mmφ）で粉砕して整粒末を得た後、直打用アスコルビン酸カルシウム、トウモロコシデンプン、カルメロースカルシウム、ステアリン酸マグネシウムを加えて粗混合後、タンブラー混合機（昭和化学機械製、TM-60S型）に入れ、15rpmで3分間混合した。そして、コレクト12HUK打錠機（菊水製作所製、30rpm）で8.5mmφR面杵で1錠当たり270mgの重量、圧縮圧1000kg/杵当たりの条件で打錠して素錠を得た。
その後、実施例１と同様の操作を行ってフィルムコーティング錠を製した。
After pulverizing with a power mill (Showa Kagaku Kikai, screen size 1.5mmφ) to obtain a sized powder, add calcium ascorbate, maize starch, carmellose calcium, magnesium stearate for direct hitting, and roughly mix, then tumbler mix The machine (Showa Chemical Machinery, TM-60S type) was mixed at 15 rpm for 3 minutes. Then, it was tableted with a collect 12HUK tableting machine (manufactured by Kikusui Seisakusho Co., Ltd., 30 rpm) with a 8.5 mmφR face weight under the conditions of a weight of 270 mg per tablet and a compression pressure of 1000 kg / kg to obtain an uncoated tablet.
Then, operation similar to Example 1 was performed and the film coating tablet was manufactured.
表４に示すようにアセトアミノフェン、イブプロフェン、ｄ−マレイン酸クロルフェニラミン、リン酸ジヒドロコデイン、ｄｌ−塩酸メチルエフェドリン、無水カフェイン、ヘスペリジンに結晶セルロース、低置換度ヒドロキシプロピルセルロース、粉末還元麦芽糖水飴、トウモロコシデンプンを加えて流動層造粒機（パウレック製、FD-5S型流動層造粒機）にて結合剤としてポビドン6％水溶液を噴霧して造粒後、乾燥して造粒末を製造した。
パワーミル（昭和化学機械製、スクリーンサイズ2.0mmφ）で粉砕して整粒末を得た後、直打用アスコルビン酸カルシウム、トウモロコシデンプン、結晶セルロース、ステアリン酸マグネシウムを加えて粗混合後、タンブラー混合機（昭和化学機械製、TM-60S型）に入れ、15rpmで3分間混合した。そして、コレクト12HUK打錠機（菊水製作所製、30rpm）で13.5×6.8mm杵で1錠当たり405mgの重量、圧縮圧1000kg/杵当たりの条件で打錠して素錠を得た。
その後、実施例１と同様の操作を行ってフィルムコーティング錠を得た。
After pulverizing with a power mill (Showa Kagaku Kikai Co., Ltd., screen size: 2.0 mmφ) to obtain a sized powder, calcium ascorbate, maize starch, crystalline cellulose and magnesium stearate for direct hitting are added and roughly mixed, then a tumbler mixer (TM-60S, manufactured by Showa Chemical Machinery Co., Ltd.) and mixed for 3 minutes at 15 rpm. Then, it was tableted with a collect 12HUK tableting machine (manufactured by Kikusui Seisakusho Co., Ltd., 30 rpm) at 13.5 × 6.8 mm 杵 under the conditions of a weight of 405 mg per tablet and a compression pressure of 1000 kg / 杵 to obtain an uncoated tablet.
Then, operation similar to Example 1 was performed and the film coating tablet was obtained.
表５に示すようにアセトアミノフェン、イブプロフェン、ｄ−マレイン酸クロルフェニラミン、リン酸ジヒドロコデイン、ｄｌ−塩酸メチルエフェドリン、無水カフェイン、ヘスペリジンに結晶セルロース、低置換度ヒドロキシプロピルセルロース、粉末還元麦芽糖水飴、トウモロコシデンプンを加えて流動層造粒機（パウレック製、MP-10型流動層造粒機）にて結合剤としてポビドン6％水溶液を噴霧して造粒後、乾燥して造粒末を製造した。
同様にアスコルビン酸カルシウムに結合剤として酒石酸を溶かしたヒドロキシプロピルセルロース2910水溶液を噴霧して造粒後、乾燥して造粒末を製造した。
パワーミル（昭和化学機械製、スクリーンサイズ2.0mmφ）で各造粒末を粉砕して整粒末を得た後、トウモロコシデンプン、結晶セルロース、ステアリン酸マグネシウムを加えて粗混合後、タンブラー混合機（昭和化学機械製、TM-60S型）に入れ、15rpmで3分間混合した。そして、コレクト19KAWC打錠機（菊水製作所製、30rpm）で8.5mmφR面杵で1錠当たり270mgの重量、圧縮圧1000kg/杵当たりの条件で打錠して素錠を得た。
その後、実施例１と同様の操作を行ってフィルムコーティング錠を得た。
Similarly, a hydroxypropylcellulose 2910 aqueous solution in which tartaric acid was dissolved as a binder in calcium ascorbate was sprayed and granulated, followed by drying to produce a granulated powder.
After pulverizing each granulated powder with a power mill (Showa Kagaku Kikai Co., Ltd., screen size 2.0 mmφ) to obtain a sized powder, corn starch, crystalline cellulose and magnesium stearate are added and roughly mixed, and then a tumbler mixer (Showa) (Made by Chemical Machinery, TM-60S type) and mixed at 15 rpm for 3 minutes. Then, it was tableted with a collect 19KAWC tableting machine (manufactured by Kikusui Seisakusho Co., Ltd., 30 rpm) with a 8.5 mmφR surface weight under the conditions of a weight of 270 mg per tablet and a compression pressure of 1000 kg / kg to obtain an uncoated tablet.
Then, operation similar to Example 1 was performed and the film coating tablet was obtained.
表６に示すようにアセトアミノフェン、イブプロフェン、ｄ−マレイン酸クロルフェニラミン、リン酸ジヒドロコデイン、ｄｌ−塩酸メチルエフェドリン、無水カフェイン、ヘスペリジン、アスコルビン酸に結晶セルロース、クロスカルメロースナトリウム、乳糖、トウモロコシデンプンを加えて転動流動層造粒機（パウレック製、MP-10型流動層造粒機）にて結合剤としてヒドロキシプロピルセルロース6％水溶液を噴霧して造粒後、乾燥して造粒末を製造した。
パワーミル（昭和化学機械製、スクリーンサイズ1.5mmφ）で粉砕して整粒末を得た後、クロスカルメロースナトリウム、ステアリン酸マグネシウムを加えて粗混合後、タンブラー混合機（昭和化学機械製、TM-60S型）に入れ、15rpmで3分間混合した。そして、コレクト12HUK打錠機（菊水製作所製、30rpm）で8.5mmφR面杵で1錠当たり270mgの重量、圧縮圧1000kg/杵当たりの条件で打錠して素錠を得た。
その後、実施例１と同様の操作を行ってフィルムコーティング錠を製した。
After pulverizing with a power mill (Showa Kagaku Kikai, screen size 1.5mmφ) to obtain a sized powder, croscarmellose sodium and magnesium stearate were added and roughly mixed, then a tumbler mixer (Made by Showa Kagaku Kikai, TM- 60S type) and mixed at 15 rpm for 3 minutes. Then, it was tableted with a collect 12HUK tableting machine (manufactured by Kikusui Seisakusho Co., Ltd., 30 rpm) with a 8.5 mmφR face weight under the conditions of a weight of 270 mg per tablet and a compression pressure of 1000 kg / kg to obtain an uncoated tablet.
Then, operation similar to Example 1 was performed and the film coating tablet was manufactured.
表７に示すようにアセトアミノフェン、イブプロフェン、ｄ−マレイン酸クロルフェニラミン、リン酸ジヒドロコデイン、ｄｌ−塩酸メチルエフェドリン、無水カフェイン、ヘスペリジン、アスコルビン酸カルシウムに結晶セルロース、クロスカルメロースナトリウム、乳糖、トウモロコシデンプンを加えて転動流動層造粒機（パウレック製、MP-10型流動層造粒機）にて結合剤としてヒドロキシプロピルセルロース6％水溶液を噴霧して造粒後、乾燥して造粒末を製造した。
パワーミル（昭和化学機械製、スクリーンサイズ1.5mmφ）で粉砕して整粒末を得た後、クロスカルメロースナトリウム、ステアリン酸マグネシウムを加えて粗混合後、タンブラー混合機（昭和化学機械製、TM-60S型）に入れ、15rpmで3分間混合した。そして、コレクト12HUK打錠機（菊水製作所製、30rpm）で8.5mmφR面杵で1錠当たり270mgの重量、圧縮圧1000kg/杵当たりの条件で打錠して素錠を得た。
その後、実施例１と同様の操作を行ってフィルムコーティング錠を製した。
After pulverizing with a power mill (Showa Kagaku Kikai, screen size 1.5mmφ) to obtain a sized powder, croscarmellose sodium and magnesium stearate were added and roughly mixed, then a tumbler mixer (Made by Showa Kagaku Kikai, TM- 60S type) and mixed at 15 rpm for 3 minutes. Then, it was tableted with a collect 12HUK tableting machine (manufactured by Kikusui Seisakusho Co., Ltd., 30 rpm) with a 8.5 mmφR face weight under the conditions of a weight of 270 mg per tablet and a compression pressure of 1000 kg / kg to obtain an uncoated tablet.
Then, operation similar to Example 1 was performed and the film coating tablet was manufactured.
表８に示すようにアセトアミノフェン、イブプロフェン、ｄ−マレイン酸クロルフェニラミン、リン酸ジヒドロコデイン、ｄｌ−塩酸メチルエフェドリン、無水カフェイン、ヘスペリジンに結晶セルロース、クロスカルメロースナトリウム、乳糖、トウモロコシデンプンを加えて転動流動層造粒機（パウレック製、MP-10型流動層造粒機）にて結合剤としてヒドロキシプロピルセルロース6％水溶液を噴霧して造粒後、乾燥して造粒末を製造した。
パワーミル（昭和化学機械製、スクリーンサイズ1.5mmφ）で粉砕して整粒末を得た後、直打用アスコルビン酸カルシウム、クロスカルメロースナトリウム、ステアリン酸マグネシウムを加えて粗混合後、タンブラー混合機（昭和化学機械製、TM-60S型）に入れ、15rpmで3分間混合した。そして、コレクト12HUK打錠機（菊水製作所製、30rpm）で8.5mmφR面杵で1錠当たり280mgの重量、圧縮圧1000kg/杵当たりの条件で打錠して素錠を得た。
その後、実施例１と同様の操作を行ってフィルムコーティング錠を製した。
After pulverizing with a power mill (Showa Kagaku Kikai, screen size 1.5mmφ) to obtain a sized powder, calcium ascorbate, croscarmellose sodium and magnesium stearate for direct hitting are added and roughly mixed, and then a tumbler mixer ( Showa Chemical Machinery, TM-60S type) and mixed at 15 rpm for 3 minutes. Then, the tablet was tableted with a collect 12HUK tableting machine (manufactured by Kikusui Seisakusho Co., Ltd., 30 rpm) with a 8.5 mmφR surface weight under the conditions of a weight of 280 mg per tablet and a compression pressure of 1000 kg / kg.
Then, operation similar to Example 1 was performed and the film coating tablet was manufactured.
表９に示すようにアセトアミノフェン、イブプロフェン、ｄ−マレイン酸クロルフェニラミン、リン酸ジヒドロコデイン、ｄｌ−塩酸メチルエフェドリン、無水カフェイン、ヘスペリジンに結晶セルロース、クロスカルメロースナトリウム、マンニトールを加えて転動流動層造粒機（パウレック製、MP-10型流動層造粒機）にて結合剤としてヒドロキシプロピルセルロース6％水溶液を噴霧して造粒後、乾燥して造粒末を製造した。
パワーミル（昭和化学機械製、スクリーンサイズ1.5mmφ）で粉砕して整粒末を得た後、直打用アスコルビン酸カルシウム、クロスカルメロースナトリウム、ステアリン酸マグネシウムを加えて粗混合後、タンブラー混合機（昭和化学機械製、TM-60S型）に入れ、15rpmで3分間混合した。そして、コレクト12HUK打錠機（菊水製作所製、30rpm）で8.5mmφR面杵で1錠当たり270mgの重量、圧縮圧1000kg/杵当たりの条件で打錠して素錠を得た。
その後、実施例１と同様の操作を行ってフィルムコーティング錠を製した。
After pulverizing with a power mill (Showa Kagaku Kikai, screen size 1.5mmφ) to obtain a sized powder, calcium ascorbate, croscarmellose sodium and magnesium stearate for direct hitting are added and roughly mixed, and then a tumbler mixer ( Showa Chemical Machinery, TM-60S type) and mixed at 15 rpm for 3 minutes. Then, it was tableted with a collect 12HUK tableting machine (manufactured by Kikusui Seisakusho Co., Ltd., 30 rpm) with a 8.5 mmφR face weight under the conditions of a weight of 270 mg per tablet and a compression pressure of 1000 kg / kg to obtain an uncoated tablet.
Then, operation similar to Example 1 was performed and the film coating tablet was manufactured.
表１０に示すようにアセトアミノフェン、イブプロフェン、ｄ−マレイン酸クロルフェニラミン、リン酸ジヒドロコデイン、ｄｌ−塩酸メチルエフェドリン、無水カフェイン、ヘスペリジンに結晶セルロース、クロスカルメロースナトリウム、マルチトールを加えて転動流動層造粒機（パウレック製、MP-10型流動層造粒機）にて結合剤としてヒドロキシプロピルセルロース6％水溶液を噴霧して造粒後、乾燥して造粒末を製造した。
パワーミル（昭和化学機械製、スクリーンサイズ1.5mmφ）で粉砕して整粒末を得た後、直打用アスコルビン酸カルシウム、クロスカルメロースナトリウム、ステアリン酸マグネシウムを加えて粗混合後、タンブラー混合機（昭和化学機械製、TM-60S型）に入れ、15rpmで3分間混合した。そして、コレクト12HUK打錠機（菊水製作所製、30rpm）で8.5mmφR面杵で1錠当たり270mgの重量、圧縮圧1000kg/杵当たりの条件で打錠して素錠を得た。
その後、実施例１と同様の操作を行ってフィルムコーティング錠を製した。
After pulverizing with a power mill (Showa Kagaku Kikai, screen size 1.5mmφ) to obtain a sized powder, calcium ascorbate, croscarmellose sodium and magnesium stearate for direct hitting are added and roughly mixed, and then a tumbler mixer ( Showa Chemical Machinery, TM-60S type) and mixed at 15 rpm for 3 minutes. Then, it was tableted with a collect 12HUK tableting machine (manufactured by Kikusui Seisakusho Co., Ltd., 30 rpm) with a 8.5 mmφR face weight under the conditions of a weight of 270 mg per tablet and a compression pressure of 1000 kg / kg to obtain an uncoated tablet.
Then, operation similar to Example 1 was performed and the film coating tablet was manufactured.
表１１に示すようにアセトアミノフェン、イブプロフェン、ｄ−マレイン酸クロルフェニラミン、リン酸ジヒドロコデイン、ｄｌ−塩酸メチルエフェドリン、無水カフェイン、ヘスペリジンに結晶セルロース、クロスカルメロースナトリウム、エリスリトールを加えて転動流動層造粒機（パウレック製、MP-10型流動層造粒機）にて結合剤としてヒドロキシプロピルセルロース6％水溶液を噴霧して造粒後、乾燥して造粒末を製造した。
パワーミル（昭和化学機械製、スクリーンサイズ1.5mmφ）で粉砕して整粒末を得た後、直打用アスコルビン酸カルシウム、クロスカルメロースナトリウム、ステアリン酸マグネシウムを加えて粗混合後、タンブラー混合機（昭和化学機械製、TM-60S型）に入れ、15rpmで3分間混合した。そして、コレクト12HUK打錠機（菊水製作所製、30rpm）で8.5mmφR面杵で1錠当たり270mgの重量、圧縮圧1000kg/杵当たりの条件で打錠して素錠を得た。
その後、実施例１と同様の操作を行ってフィルムコーティング錠を製した。
After pulverizing with a power mill (Showa Kagaku Kikai, screen size 1.5mmφ) to obtain a sized powder, calcium ascorbate, croscarmellose sodium and magnesium stearate for direct hitting are added and roughly mixed, and then a tumbler mixer ( Showa Chemical Machinery, TM-60S type) and mixed at 15 rpm for 3 minutes. Then, it was tableted with a collect 12HUK tableting machine (manufactured by Kikusui Seisakusho Co., Ltd., 30 rpm) with a 8.5 mmφR face weight under the conditions of a weight of 270 mg per tablet and a compression pressure of 1000 kg / kg to obtain an uncoated tablet.
Then, operation similar to Example 1 was performed and the film coating tablet was manufactured.
錠剤の評価は外観変化の判定がしやすい素錠にて実施した。
実施例１〜５及び比較例１〜６で得られた素錠をガラス瓶に入れ、温度50℃で２週間、40℃４週間または８週間保存した時の錠剤の外観変化を色差計（スガ試験機製、S＆Mカラーコンピューター）により測色を行い、ハンターの式より白色度（ΔＥ）を算出することで評価した。
その結果を表１２に示す。
表１２に示すごとく、本発明の製剤はいずれの条件下においても比較例と比べてΔＥが５以下と小さく、外観変化も小さかった。
The evaluation of the tablet was carried out with an uncoated tablet that was easy to determine the appearance change.
The uncoated tablets obtained in Examples 1 to 5 and Comparative Examples 1 to 6 were placed in a glass bottle and the appearance change of the tablets when stored at 50 ° C. for 2 weeks, 40 ° C. for 4 weeks or 8 weeks was measured with a color difference meter (Suga test). The color was measured with an S & M color computer (manufactured by Koki Co., Ltd.) and evaluated by calculating the whiteness (ΔE) from the Hunter equation.
The results are shown in Table 12.
As shown in Table 12, the formulation of the present invention had a small ΔE of 5 or less and the change in appearance under the conditions of any of the comparative examples.
以上記載したごとく、本発明によれば、アスコルビン酸またはその塩を含む安定化された固形製剤、特に、錠剤を提供することができる。
As described above, according to the present invention, a stabilized solid preparation containing ascorbic acid or a salt thereof, particularly a tablet, can be provided.
Claims (11)
The preparation according to claim 1, wherein the solid preparation is a tablet.
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Cited By (6)
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| JP2008107212A (en) * | 2006-10-26 | 2008-05-08 | Sawai Pharmaceutical Co Ltd | New sticking evaluating method |
| JP2010111589A (en) * | 2008-11-04 | 2010-05-20 | Lion Corp | Solid preparation comprising clemastine fumarate and method for inhibiting lowering of clemastine fumarate content |
| WO2010092828A1 (en) * | 2009-02-12 | 2010-08-19 | 富士化学工業株式会社 | Disintegrating particle composition and rapidly disintegrating compression-molded material comprising same |
| JP2011132214A (en) * | 2009-09-28 | 2011-07-07 | Kowa Co | Loxoprofen-containing medicinal preparation |
| JP2012120441A (en) * | 2010-12-06 | 2012-06-28 | Sunstar Inc | Composition containing stably blended ascorbic acid and analog thereof |
| JP2013253077A (en) * | 2012-05-11 | 2013-12-19 | Shionogi & Co Ltd | Solid preparation containing ascorbic acid, sucralose and aspartame |
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| JPH08325145A (en) * | 1995-05-26 | 1996-12-10 | Sumitomo Pharmaceut Co Ltd | Stable isopropylantipyrine-containing preparation |
| JPH11335279A (en) * | 1998-05-26 | 1999-12-07 | Toa Yakuhin Kk | Ibuprofen-containing granule |
| WO2000071097A1 (en) * | 1999-05-20 | 2000-11-30 | Takeda Chemical Industries, Ltd. | Composition containing ascorbic acid salt |
| JP2001031567A (en) * | 1999-05-20 | 2001-02-06 | Takeda Chem Ind Ltd | Ascorbic acid-containing composition |
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| JPH05201858A (en) * | 1992-01-29 | 1993-08-10 | Ss Pharmaceut Co Ltd | Solid pharmaceutical preparation |
| JPH08325145A (en) * | 1995-05-26 | 1996-12-10 | Sumitomo Pharmaceut Co Ltd | Stable isopropylantipyrine-containing preparation |
| JPH11335279A (en) * | 1998-05-26 | 1999-12-07 | Toa Yakuhin Kk | Ibuprofen-containing granule |
| WO2000071097A1 (en) * | 1999-05-20 | 2000-11-30 | Takeda Chemical Industries, Ltd. | Composition containing ascorbic acid salt |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2008107212A (en) * | 2006-10-26 | 2008-05-08 | Sawai Pharmaceutical Co Ltd | New sticking evaluating method |
| JP2010111589A (en) * | 2008-11-04 | 2010-05-20 | Lion Corp | Solid preparation comprising clemastine fumarate and method for inhibiting lowering of clemastine fumarate content |
| WO2010092828A1 (en) * | 2009-02-12 | 2010-08-19 | 富士化学工業株式会社 | Disintegrating particle composition and rapidly disintegrating compression-molded material comprising same |
| JPWO2010092828A1 (en) * | 2009-02-12 | 2012-08-16 | 富士化学工業株式会社 | Disintegrating particle composition and fast disintegrating compression molding using the same |
| JP5637624B2 (en) * | 2009-02-12 | 2014-12-10 | 富士化学工業株式会社 | Disintegrating particle composition and fast disintegrating compression molding using the same |
| JP2011132214A (en) * | 2009-09-28 | 2011-07-07 | Kowa Co | Loxoprofen-containing medicinal preparation |
| JP2012120441A (en) * | 2010-12-06 | 2012-06-28 | Sunstar Inc | Composition containing stably blended ascorbic acid and analog thereof |
| JP2013253077A (en) * | 2012-05-11 | 2013-12-19 | Shionogi & Co Ltd | Solid preparation containing ascorbic acid, sucralose and aspartame |
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