JP4845087B2 - Formulation for oral administration - Google Patents
Formulation for oral administration Download PDFInfo
- Publication number
- JP4845087B2 JP4845087B2 JP2005155042A JP2005155042A JP4845087B2 JP 4845087 B2 JP4845087 B2 JP 4845087B2 JP 2005155042 A JP2005155042 A JP 2005155042A JP 2005155042 A JP2005155042 A JP 2005155042A JP 4845087 B2 JP4845087 B2 JP 4845087B2
- Authority
- JP
- Japan
- Prior art keywords
- component
- mass
- oral administration
- vitamin
- sodium
- 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.)
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Links
- 239000000203 mixture Substances 0.000 title claims description 15
- 238000009472 formulation Methods 0.000 title claims description 5
- 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 62
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 32
- 235000010323 ascorbic acid Nutrition 0.000 claims description 27
- 229960005070 ascorbic acid Drugs 0.000 claims description 27
- 239000011668 ascorbic acid Substances 0.000 claims description 26
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 21
- 238000002360 preparation method Methods 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- 230000008961 swelling Effects 0.000 claims description 16
- 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 claims description 15
- 235000019156 vitamin B Nutrition 0.000 claims description 15
- 239000011720 vitamin B Substances 0.000 claims description 15
- 229930003270 Vitamin B Natural products 0.000 claims description 13
- 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 claims description 11
- 229960002079 calcium pantothenate Drugs 0.000 claims description 11
- 238000004898 kneading Methods 0.000 claims description 10
- 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 9
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 8
- 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 8
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 229950008138 carmellose Drugs 0.000 claims description 7
- 239000011734 sodium Substances 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- 229920002472 Starch Polymers 0.000 claims description 6
- 235000019698 starch Nutrition 0.000 claims description 6
- 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 description 5
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- 150000003839 salts Chemical class 0.000 claims description 5
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- 238000005550 wet granulation Methods 0.000 claims description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- 229960000913 crospovidone Drugs 0.000 claims description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 4
- 239000004744 fabric Substances 0.000 claims 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 39
- 239000008187 granular material Substances 0.000 description 38
- 239000008213 purified water Substances 0.000 description 18
- 238000002156 mixing Methods 0.000 description 16
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 238000005469 granulation Methods 0.000 description 13
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- 238000000034 method Methods 0.000 description 10
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- 230000000052 comparative effect Effects 0.000 description 9
- 238000001125 extrusion Methods 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
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- 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 5
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 5
- 229930003268 Vitamin C Natural products 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 229920002785 Croscarmellose sodium Polymers 0.000 description 4
- 235000010724 Wisteria floribunda Nutrition 0.000 description 4
- -1 ascorbic acid alkali metal salts Chemical class 0.000 description 4
- 239000004503 fine granule Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- JZRWCGZRTZMZEH-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 4
- 229940088594 vitamin Drugs 0.000 description 4
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- 235000013343 vitamin Nutrition 0.000 description 4
- 239000011782 vitamin Substances 0.000 description 4
- ZGSZBVAEVPSPFM-FFHNEAJVSA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,5,6,7,7a,13-octahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;2,3-dihydroxybutanedioic acid Chemical compound OC(=O)C(O)C(O)C(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC ZGSZBVAEVPSPFM-FFHNEAJVSA-N 0.000 description 3
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 3
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 239000004480 active ingredient Substances 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 3
- 229960001948 caffeine Drugs 0.000 description 3
- 229940046978 chlorpheniramine maleate Drugs 0.000 description 3
- 229960001681 croscarmellose sodium Drugs 0.000 description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 3
- 229960000920 dihydrocodeine Drugs 0.000 description 3
- 229940073563 dl- methylephedrine hydrochloride Drugs 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 229960001680 ibuprofen Drugs 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- 150000003722 vitamin derivatives Chemical class 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-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
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 239000011230 binding agent Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 235000001465 calcium Nutrition 0.000 description 2
- 235000010376 calcium ascorbate Nutrition 0.000 description 2
- 229940047036 calcium ascorbate Drugs 0.000 description 2
- 239000011692 calcium ascorbate Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 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 2
- 239000002775 capsule Substances 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- 238000002845 discoloration Methods 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 229940055726 pantothenic acid Drugs 0.000 description 2
- 235000019161 pantothenic acid Nutrition 0.000 description 2
- 239000011713 pantothenic acid Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
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- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 2
- 235000010378 sodium ascorbate Nutrition 0.000 description 2
- 229960005055 sodium ascorbate Drugs 0.000 description 2
- 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 2
- 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 2
- 239000000126 substance Substances 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 1
- UHDPBLMLEMNPKP-UHFFFAOYSA-M 2-[3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4-methyl-1,3-thiazol-3-ium-5-yl]ethanol thiocyanate Chemical compound [S-]C#N.CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N UHDPBLMLEMNPKP-UHFFFAOYSA-M 0.000 description 1
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- YBJHBAHKTGYVGT-OOZYFLPDSA-N 5-[(3as,4r,6ar)-2-oxohexahydro-1h-thieno[3,4-d]imidazol-4-yl]pentanoic acid Chemical compound N1C(=O)N[C@@H]2[C@@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-OOZYFLPDSA-N 0.000 description 1
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- ASARMUCNOOHMLO-WLORSUFZSA-L cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2s)-1-[3-[(1r,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 Chemical compound [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 ASARMUCNOOHMLO-WLORSUFZSA-L 0.000 description 1
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- 229940074358 magnesium ascorbate Drugs 0.000 description 1
- AIOKQVJVNPDJKA-ZZMNMWMASA-L magnesium;(2r)-2-[(1s)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2h-furan-3-olate Chemical compound [Mg+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-] AIOKQVJVNPDJKA-ZZMNMWMASA-L 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000000978 natural dye Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 239000000820 nonprescription drug Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229940017794 potassium ascorbate Drugs 0.000 description 1
- 235000019275 potassium ascorbate Nutrition 0.000 description 1
- CONVKSGEGAVTMB-RXSVEWSESA-M potassium-L-ascorbate Chemical compound [K+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] CONVKSGEGAVTMB-RXSVEWSESA-M 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 235000008160 pyridoxine Nutrition 0.000 description 1
- 239000011677 pyridoxine Substances 0.000 description 1
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 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
- 229940085605 saccharin sodium Drugs 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 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 1
- 229940068459 sodium pantothenate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000005563 spheronization Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000979 synthetic dye Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000019157 thiamine Nutrition 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- 239000011721 thiamine 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
- 229960000344 thiamine hydrochloride Drugs 0.000 description 1
- 235000019190 thiamine hydrochloride Nutrition 0.000 description 1
- 239000011747 thiamine hydrochloride Substances 0.000 description 1
- 229960002663 thioctic acid Drugs 0.000 description 1
- 229940011671 vitamin b6 Drugs 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
本発明は、経口投与用製剤に関する。 The present invention relates to a preparation for oral administration.
一般用医薬品は複数の有効成分を配合することが多く、一方、２種以上の薬物を配合すると配合変化が生じることが多い。例えば、ビタミン剤を２種以上混合した製剤は配合変化を生じ着色する。そのため、それぞれを顆粒分けして製剤化する方法、更に顆粒にコーティングする方法がとられている。例えば、Ｌ−アルコルビン酸を疎水性熱溶融性脂質で被覆してから水溶性ビタミン類と混合し外観色の変化を抑える方法が知られている（特許文献１）。しかしながら、この方法は、Ｌ−アスコルビン酸を疎水性熱溶融性脂質で被覆するため、製造工程が煩雑で、製造コストが高くなるという問題を生じ、更に有効成分の均一配合等にも問題がある。
また、本発明で使用する膨潤剤は、薬物の不快な味をマスキングできることは知られている（特許文献２、３）が、アスコルビン酸類とビタミンＢ群類を含有する製剤の変色を防ぐことは知られていない。
In addition, the swelling agent used in the present invention is known to be able to mask the unpleasant taste of the drug (Patent Documents 2 and 3), but prevents the discoloration of the preparation containing ascorbic acids and vitamin B groups. unknown.
本発明の目的は、ビタミンＣ類及びビタミンＢ群類を、顆粒分けすることなく1つの顆粒中で配合変化を起こさずに、有効成分が均一に配合され、簡易な製造方法で製造できる経口投与用製剤を提供することにある。 The purpose of the present invention is to administer vitamin Cs and vitamins B in a single granule without any granulation, and the active ingredient is uniformly blended and can be produced by a simple production method. It is to provide pharmaceutical preparations.
本発明は、（Ａ）ビタミンＣ類、（Ｂ）ビタミンＢ群類及び（Ｃ）膨潤剤を含有する組成物を湿式造粒することにより得られる経口投与用製剤を提供するものである。
また、本発明は、（Ａ）ビタミンＣ類、（Ｂ）ビタミンＢ群類及び（Ｃ）膨潤剤を含有する組成物を、水又はアルコールの含有量が３０質量％以下の含水アルコールと練合わせ、次いで湿式造粒する経口投与用製剤の製造方法を提供するものである。
The present invention provides a preparation for oral administration obtained by wet granulating a composition containing (A) vitamin Cs, (B) vitamin B group and (C) swelling agent.
Moreover, this invention kneads the composition containing (A) vitamin C, (B) vitamin B group, and (C) swelling agent with the hydrous alcohol whose content of water or alcohol is 30 mass% or less. Then, the manufacturing method of the formulation for oral administration which carries out wet granulation next is provided.
本発明の経口投与用製剤は、ビタミンＣ類及びビタミンＢ群類が1つの顆粒中に含有されているにもかかわらず、着色変化が抑制され配合変化を起こさず安定であって、有効成分は均一に配合されている。更に製造が簡便であって製造コストの低減が図られる。 The preparation for oral administration of the present invention is stable without causing a change in coloration and stable in spite of containing vitamin C and vitamin B group in one granule. It is blended uniformly. Further, the manufacturing is simple and the manufacturing cost can be reduced.
本発明で使用する成分（Ａ）ビタミンＣ類としては、アスコルビン酸；アスコルビン酸ナトリウム、アスコルビン酸カリウム等のアスコルビン酸アルカリ金属塩：アスコルビン酸カルシウム、アスコルビン酸マグネシウム等のアスコルビン酸アルカリ土類金属塩等が挙げられる。成分（Ａ）としては、アスコルビン酸、アスコルビン酸ナトリウム、アスコルビン酸カルシウムが好ましく、特にアスコルビン酸が好ましい。成分（Ａ）は粉末であって、平均粒径は、１〜５００μｍ、更に１０〜３５５μｍ、特に２０〜１５０μｍであるのが好ましい。平均粒径は、レーザ回折法で測定した値を用いる。
成分（Ａ）は、経口投与用製剤中に１〜９５質量％、更に５〜９０質量％含有するのが好ましい。
As component (A) vitamin C used in the present invention, ascorbic acid; ascorbic acid alkali metal salts such as sodium ascorbate and potassium ascorbate: ascorbic acid alkaline earth metal salts such as calcium ascorbate and magnesium ascorbate, etc. Is mentioned. As the component (A), ascorbic acid, sodium ascorbate, and calcium ascorbate are preferable, and ascorbic acid is particularly preferable. The component (A) is a powder, and the average particle size is preferably 1 to 500 μm, more preferably 10 to 355 μm, and particularly preferably 20 to 150 μm. As the average particle diameter, a value measured by a laser diffraction method is used.
Component (A) is preferably contained in the preparation for oral administration in an amount of 1 to 95% by mass, more preferably 5 to 90% by mass.
本発明で使用する成分（Ｂ）ビタミンＢ群類としては、チアミン（ビタミンＢ1）、リボフラビン（ビタミンＢ2）、ニコチン酸（ビタミンＢ3）、パントテン酸（ビタミンＢ5）、ピリドキシン（ビタミンＢ6）、コバラミン（Ｂ12）、ビオチン（ビタミンＢ7）、葉酸等が挙げられ、更にこれらの塩、エステル等も包含する。例えば、塩酸チアミン、硝酸チアミン、チオシアン酸チアミン、ビタミンＢ1ラウリル硫酸塩、ビタミンＢ1ロダン酸塩、ビタミンＢ2酪酸エステル、ビタミンＢ2リン酸エステルナトリウム、ニコチン酸アミド、パントテン酸ナトリウム、パントテン酸カルシウム、塩酸ピリドキシン、リポ酸等が挙げられる。成分（Ｂ）としては、硝酸チアミン及び／又はパントテン酸カルシウムが好ましい。ビタミンＢ群類は、１種又は２種以上を組み合わせて使用してもよい。
成分（Ｂ）は、粉末であればよく、平均粒径は、１〜５００μｍ、更に１０〜３５５μｍ、特に２０〜１５０μｍであるのが好ましい。
成分（Ｂ）は、経口投与用製剤中にそれぞれ１〜９５質量％、更に５〜９０質量％含有するのが好ましい。
The component (B) vitamin B group used in the present invention includes thiamine (vitamin B 1 ), riboflavin (vitamin B 2 ), nicotinic acid (vitamin B 3 ), pantothenic acid (vitamin B 5 ), pyridoxine (vitamin B) 6 ), cobalamin (B 12 ), biotin (vitamin B 7 ), folic acid, and the like, and salts and esters thereof are also included. For example, thiamine hydrochloride, thiamine nitrate, thiamine thiocyanate, vitamin B 1 lauryl sulfate, vitamin B 1 rhodanate, vitamin B 2 butyrate, sodium vitamin B 2 phosphate, nicotinamide, sodium pantothenate, pantothenic acid Examples include calcium, pyridoxine hydrochloride, lipoic acid and the like. As component (B), thiamine nitrate and / or calcium pantothenate are preferred. Vitamin B group may be used alone or in combination of two or more.
The component (B) may be a powder, and the average particle diameter is preferably 1 to 500 μm, more preferably 10 to 355 μm, and particularly preferably 20 to 150 μm.
Component (B) is preferably contained in the preparation for oral administration in an amount of 1 to 95% by mass, and more preferably 5 to 90% by mass.
本発明の経口投与用製剤中の成分（Ａ）と成分（Ｂ）の含有質量比は、成分（Ａ）／成分（Ｂ）が０．５〜２０、更に０．５〜１５であるのが好ましい。 The content ratio of the component (A) to the component (B) in the preparation for oral administration of the present invention is such that the component (A) / component (B) is 0.5 to 20, more preferably 0.5 to 15. preferable.
本発明で使用する膨潤剤は、水を吸収して膨潤する物質である。膨潤剤に水又は含水アルコールを添加しビタミンＣ類とビタミンＢ群類とを練合し、造粒後、乾燥して水又は含水アルコールを除去する過程で、膨潤剤が収縮しビタミンＣ類とビタミンＢ群類を膨潤剤が隔離することにより、1顆粒中でビタミンＣ類とビタミンＢ群類が配合変化して変色せずに安定化する。 The swelling agent used in the present invention is a substance that swells by absorbing water. In the process of adding water or hydrous alcohol to the swelling agent, kneading vitamins C and vitamins B, granulating, drying and removing water or hydrous alcohol, the swelling agent shrinks and the vitamins C and By separating the vitamin B group by the swelling agent, the vitamin C group and the vitamin B group are mixed and changed in one granule and stabilized without discoloration.
膨潤剤としては、例えば低置換度ヒドロキシプロピルセルロース、カルメロース（カルボキシメチルセルロース）又はその塩、クロスカルメロースナトリウム（医薬品添加物規格記載：架橋型カルボキシメチルセルロースナトリウム）、カルボキシメチルスターチナトリウム、クロスポピドン（架橋型ポリビニルピロリドン）、結晶セルロース・カルメロースナトリウム等が挙げられる。カルメロースの塩としては、ナトリウム塩、カルシウム塩等が挙げられる。膨潤剤としては、低置換度ヒドロキシプロピルセルロース、カルメロースの塩、クロスカルメロースナトリウムが好ましく、特に低置換度ヒドロキシプロピルセルロースが好ましい。膨潤剤は、１種又は２種以上を併用してもよい。 Examples of the swelling agent include low-substituted hydroxypropylcellulose, carmellose (carboxymethylcellulose) or a salt thereof, croscarmellose sodium (description of pharmaceutical additives: crosslinked carboxymethylcellulose sodium), carboxymethyl starch sodium, crospovidone (crosslinked type) Polyvinylpyrrolidone), crystalline cellulose, carmellose sodium and the like. Examples of the salt of carmellose include sodium salt and calcium salt. As the swelling agent, low-substituted hydroxypropyl cellulose, carmellose salt, and croscarmellose sodium are preferable, and low-substituted hydroxypropyl cellulose is particularly preferable. A swelling agent may use together 1 type, or 2 or more types.
膨潤剤として低置換度ヒドロキシプロピルセルロースを使用する場合、そのヒドロキシプロピル基の含有量は、５．０〜１６．０質量％、更に１０．０〜１３．０質量％であるのが好ましい。 When low substituted hydroxypropylcellulose is used as the swelling agent, the hydroxypropyl group content is preferably 5.0 to 16.0% by mass, more preferably 10.0 to 13.0% by mass.
膨潤剤は本発明の経口投与用製剤中に５〜９５質量％、更に１０〜９０質量％含有するのが好ましい。また、膨潤剤はビタミンＣ類とビタミンＢ群類との質量比、成分（Ｃ）／（成分（Ａ）＋成分（Ｂ））が０．５〜１０、更に１〜９となる量で含有するのが好ましい。 The swelling agent is preferably contained in the preparation for oral administration of the present invention in an amount of 5 to 95% by mass, more preferably 10 to 90% by mass. The swelling agent is contained in such an amount that the mass ratio of vitamin C and vitamin B group, component (C) / (component (A) + component (B)) is 0.5 to 10, and further 1 to 9. It is preferable to do this.
本発明の経口投与用製剤には、成分（Ａ）〜（Ｃ）の他に、他の薬物、更に経口投与用製剤に通常使用される成分を適宜その目的に応じて配合してもよい。例えば、賦形剤（希釈剤）、結合剤、崩壊剤、甘味料、着香料、色素等が挙げられる。ここで、賦形剤としては、例えば乳糖、精製白糖、ブドウ糖等の糖類；Ｄ−マンニトール、ソルビトール、キシリトール、エリスリトール等の糖アルコール等が挙げられる。結合剤としては、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、メチルセルロース、ポリビニルピロリドン、デキストリン、アルファー化デンプン等が挙げられる。崩壊剤としては、トウモロコシデンプン等のデンプン類等が挙げられる。甘味料としては、サッカリンナトリウムやアスパルテーム等が挙げられる。香料としては、オレンジやレモン等の柑橘系香料やメントールやハッカ油等が挙げられる。色素としては、天然色素や合成色素等が挙げられる。 In addition to the components (A) to (C), the drug for oral administration of the present invention may be blended with other drugs and further components usually used in the drug for oral administration depending on the purpose. For example, excipients (diluents), binders, disintegrants, sweeteners, flavoring agents, pigments and the like can be mentioned. Examples of the excipient include sugars such as lactose, purified white sugar, and glucose; sugar alcohols such as D-mannitol, sorbitol, xylitol, and erythritol. Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, dextrin, pregelatinized starch and the like. Examples of the disintegrant include starches such as corn starch. Examples of the sweetener include saccharin sodium and aspartame. Examples of the fragrances include citrus fragrances such as orange and lemon, menthol and mint oil. Examples of the dye include natural dyes and synthetic dyes.
本発明の経口投与用製剤は、成分（Ａ）〜（Ｃ）を含有する組成物を、水又は３０質量％以下の含水アルコールと練合わせ、次いで湿式造粒することにより製造される。ここで使用するアルコールとしては、エタノール、イソプロパノール等の低級アルコールが好ましく、特にエタノールが好ましい。水としては、精製水、イオン交換水等が挙げられる。水又は含水アルコールのうち、水が好ましい。 The preparation for oral administration of the present invention is produced by kneading a composition containing the components (A) to (C) with water or a hydrous alcohol of 30% by mass or less, and then wet granulating. As the alcohol used here, lower alcohols such as ethanol and isopropanol are preferable, and ethanol is particularly preferable. Examples of water include purified water and ion exchange water. Of water and hydrous alcohol, water is preferred.
湿式造粒としては、攪拌造粒、流動層造粒、押し出し造粒法等の通常医薬品等
に利用される湿式造粒法であれば特に限定されないが、好ましくは押し出し造粒
法である。
The wet granulation is not particularly limited as long as it is a wet granulation method commonly used for pharmaceuticals such as stirring granulation, fluidized bed granulation, extrusion granulation method, etc., but extrusion granulation method is preferable.
本発明の経口投与用製剤は、例えば次の如くして製造することができる。
成分（Ａ）及び成分（Ｂ）に、成分（Ｃ）及び必要に応じて添加する成分を加え、攪拌型混合機で混合後、膨潤剤の２〜５質量倍量の水又は３０質量％以下のアルコール水溶液で練合し膨潤状態とする。次いで、この練合物を押し出し造粒機にて造粒後、２〜５質量倍量の水又は含水アルコールを箱型乾燥機又は流動層造粒乾燥機で乾燥して顆粒を製造する。また、必要に応じて押し出し造粒後、篩を用いて目的の粒度の顆粒とすることもでき、更にマルメライザーで球形化処理を施し球形の顆粒としてもよい。
また、上記練合物を箱形乾燥機又は流動層造粒乾燥機にて乾燥し、必要により粉砕した後、篩を用いて所望の粒度の顆粒を得ることもできる。顆粒の粒度調節は、水又は含水アルコールの量を調節するか、押し出し造粒時のスクリーン径を０．３〜１．２ｍｍの範囲で変えて行ってもよい。得られた顆粒に、更に服用感や薬物の安定性等を考慮して糖類や高分子等でコーティングを行ってもよい。
The preparation for oral administration of the present invention can be produced, for example, as follows.
To component (A) and component (B), add component (C) and components to be added as necessary, and after mixing with a stirrer type mixer, 2 to 5 times the amount of swelling agent water or 30% by mass or less Kneading with an aqueous alcohol solution to obtain a swollen state. Next, the kneaded product is granulated with an extruding granulator, and then 2 to 5 times by mass of water or hydrous alcohol is dried with a box-type drier or fluidized bed granulating drier to produce granules. Moreover, after extrusion granulation as needed, it can also be used as a granule of the target particle size using a sieve, and also it may be made into a spherical granule by applying a spheronization treatment with a Malmerizer.
Moreover, after drying the said kneaded material with a box-type dryer or a fluidized-bed granulation dryer and grind | pulverizing as needed, the granule of a desired particle size can also be obtained using a sieve. The particle size of the granules may be adjusted by adjusting the amount of water or hydrous alcohol or changing the screen diameter during extrusion granulation within a range of 0.3 to 1.2 mm. The obtained granules may be further coated with saccharides, polymers, etc. in consideration of the feeling of administration and drug stability.
湿式造粒して得られた顆粒の平均粒径は、１００〜１０００μｍ、更に１５０〜９００μｍ、特に２００〜８００μｍであるのが着色変化の抑制、流動性改善の点で好ましい。なお、粒子の粒径は篩分け法で測定した値を用いる。 The average particle size of the granules obtained by wet granulation is preferably 100 to 1000 μm, more preferably 150 to 900 μm, and particularly preferably 200 to 800 μm from the viewpoint of suppressing color change and improving fluidity. In addition, the value measured by the sieving method is used for the particle size of the particles.
このようにして製造された顆粒状の経口投与用製剤は、着色変化が抑制され、しかも流動性が良いので、顆粒をそのまま散剤、細粒剤等として使用できるが、カプセル剤等にして使用してもよく、更に直接打錠して速溶性の錠剤型医薬製剤を容易に製造することがでる。従って、本発明の経口投与用製剤としては、顆粒剤、散剤、錠剤、カプセル剤等が挙げられる。これらの経口投与用製剤を調製するにあたっては、更に固形製剤に通常使用される成分、例えば、デンプン、炭酸カルシウム、硫酸カルシウム、結晶セルロース、植物末等の賦形剤、着色剤、矯味剤、矯臭剤、光線遮断剤、香味剤、甘味剤等を配合してもよい。 The granular preparation for oral administration thus produced is suppressed in color change and has good fluidity, so that the granule can be used as it is as a powder, fine granule, etc., but it can be used as a capsule or the like. Further, it is possible to easily produce a fast-dissolving tablet-type pharmaceutical preparation by direct tableting. Therefore, examples of the preparation for oral administration of the present invention include granules, powders, tablets, capsules and the like. In preparing these preparations for oral administration, further components usually used in solid preparations such as starch, calcium carbonate, calcium sulfate, crystalline cellulose, plant powder and other excipients, coloring agents, corrigents, flavoring An agent, a light blocking agent, a flavoring agent, a sweetening agent and the like may be blended.
実施例１
アスコルビン酸（１００Ｍ：武田薬品工業（株）製）５０ｇ、硝酸チアミン（武田薬品工業（株）製）５０ｇ、低置換度ヒドロキシプロピルセルロース（信越化学（株）製、Ｌ−ＨＰＣ ＬＨ３１）９００ｇをバーチカルグラニュレーターＶＧ−１０（パウレック（株）製）で混合後、精製水２７００ｇを添加し練合した後、ツインドームグランＴＤＧ−８０（不二パウダル（株）製）０．６ｍｍスクリーンで押し出し造粒後、流動層乾燥機ＷＳＧ−５（大川原製作所（株）製）にて乾燥し、１６号及び４２号篩を使用して１６〜４２号（粒子径５００〜３５５μｍ）の顆粒剤を製造した。
Example 1
Vertical ascorbic acid (100M: Takeda Pharmaceutical Co., Ltd.) 50g, thiamine nitrate (Takeda Pharmaceutical Co., Ltd.) 50g, low substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd., L-HPC LH31) 900g After mixing with a granulator VG-10 (manufactured by Paulek Co., Ltd.), 2700 g of purified water was added and kneaded, followed by extrusion granulation with a twin dome gran TDG-80 (manufactured by Fuji Powder Co., Ltd.) 0.6 mm screen. Then, it dried with the fluid bed dryer WSG-5 (made by Okawara Seisakusho Co., Ltd.), and manufactured the granule of 16-42 (particle diameter 500-355 micrometers) using the No. 16 and No. 42 sieve.
実施例２
アスコルビン酸（１００Ｍ：武田薬品工業（株）製）５０ｇ、硝酸チアミン（武田薬品工業（株）製）５０ｇ、低置換度ヒドロキシプロピルセルロース（Ｌ−ＨＰＣ ＬＨ３１：信越化学（株）製、）７００ｇ、Ｄ−マンニトール（マンニットＰ：東和化成工業（株）製）２００ｇをバーチカルグラニュレーターＶＧ−１０（パウレック（株）製）で混合後、精製水２１００ｇを添加し練合した後、実施例１と同様にして顆粒剤を製造した。
Example 2
Ascorbic acid (100M: Takeda Pharmaceutical Co., Ltd.) 50g, Thiamine nitrate (Takeda Pharmaceutical Co., Ltd.) 50g, Low-substituted hydroxypropylcellulose (L-HPC LH31: Shin-Etsu Chemical Co., Ltd.) 700g, After mixing 200 g of D-mannitol (Mannit P: manufactured by Towa Kasei Kogyo Co., Ltd.) with a vertical granulator VG-10 (Paulec Co., Ltd.), 2100 g of purified water was added and kneaded. Granules were produced in the same manner.
実施例３
アスコルビン酸（１００Ｍ：武田薬品工業（株）製）５０ｇ、硝酸チアミン（武田薬品工業（株）製）５０ｇ、低置換度ヒドロキシプロピルセルロース（Ｌ−ＨＰＣ ＬＨ３１：信越化学（株）製）５００ｇ、Ｄ−マンニトール（マンニットＰ：東和化成工業（株）製）４００ｇをバーチカルグラニュレーターＶＧ−１０（パウレック（株）製）で混合後、精製水１５００ｇを添加し練合した後、実施例１と同様にして顆粒剤を製造した。
Example 3
Ascorbic acid (100M: Takeda Pharmaceutical Co., Ltd.) 50g, Thiamine nitrate (Takeda Pharmaceutical Co., Ltd.) 50g, Low-substituted hydroxypropyl cellulose (L-HPC LH31: Shin-Etsu Chemical Co., Ltd.) 500g, D -Mannitol (Mannit P: manufactured by Towa Kasei Kogyo Co., Ltd.) 400 g was mixed with a vertical granulator VG-10 (Paulec Co., Ltd.), purified water 1500 g was added and kneaded, and the same as in Example 1 Thus, a granule was produced.
実施例４
アスコルビン酸（１００Ｍ：武田薬品工業（株）製）５０ｇ、硝酸チアミン（武田薬品工業（株）製）５０ｇ、低置換度ヒドロキシプロピルセルロース（Ｌ−ＨＰＣ ＬＨ３１：信越化学（株）製）３００ｇ、Ｄ−マンニトール（マンニットＰ：東和化成工業（株）製）６００ｇをバーチカルグラニュレーターＶＧ−１０（パウレック（株）製）で混合後、精製水９００ｇを添加し練合した後、実施例１と同様にして顆粒剤を製造した。
Example 4
Ascorbic acid (100M: Takeda Pharmaceutical Co., Ltd.) 50 g, Thiamine nitrate (Takeda Pharmaceutical Co., Ltd.) 50 g, Low-substituted hydroxypropylcellulose (L-HPC LH31: Shin-Etsu Chemical Co., Ltd.) 300 g, D -Mannitol (Mannit P: manufactured by Towa Kasei Kogyo Co., Ltd.) (600 g) was mixed with a vertical granulator VG-10 (Paulec Co., Ltd.), and then purified water (900 g) was added and kneaded. Thus, a granule was produced.
実施例５
アスコルビン酸（１００Ｍ：武田薬品工業（株）製）５０ｇ、硝酸チアミン（武田薬品工業（株）製）５０ｇ、低置換度ヒドロキシプロピルセルロース（Ｌ−ＨＰＣ ＬＨ３１：信越化学（株）製）２００ｇ、Ｄ−マンニトール（マンニットＰ：東和化成工業（株）製）７００ｇをバーチカルグラニュレーターＶＧ−１０（パウレック（株）製）で混合後、精製水６００ｇを添加し練合した後、実施例１と同様にして顆粒剤を製造した。
Example 5
Ascorbic acid (100M: Takeda Pharmaceutical Co., Ltd.) 50g, Thiamine nitrate (Takeda Pharmaceutical Co., Ltd.) 50g, Low-substituted hydroxypropylcellulose (L-HPC LH31: Shin-Etsu Chemical Co., Ltd.) 200g, D -After mixing 700 g of mannitol (Mannit P: manufactured by Towa Kasei Kogyo Co., Ltd.) with a vertical granulator VG-10 (manufactured by Paulek Co., Ltd.), adding 600 g of purified water and kneading, the same as in Example 1 Thus, a granule was produced.
実施例６
アスコルビン酸（１００Ｍ：武田薬品工業（株）製）５０ｇ、硝酸チアミン（武田薬品工業（株）製）５０ｇ、低置換度ヒドロキシプロピルセルロース（Ｌ−ＨＰＣ ＬＨ３１：信越化学（株）製）１００ｇ、Ｄ−マンニトール（マンニットＰ：東和化成工業（株）製）８００ｇをバーチカルグラニュレーターＶＧ−１０（パウレック（株）製）で混合後、精製水３００ｇを添加し練合した後、実施例１と同様にして顆粒剤を製造した。
Example 6
Ascorbic acid (100M: Takeda Pharmaceutical Co., Ltd.) 50g, Thiamine nitrate (Takeda Pharmaceutical Co., Ltd.) 50g, Low-substituted hydroxypropylcellulose (L-HPC LH31: Shin-Etsu Chemical Co., Ltd.) 100g, D -After mixing 800 g of mannitol (Mannit P: Towa Kasei Kogyo Co., Ltd.) with a vertical granulator VG-10 (Powrec Co., Ltd.), adding 300 g of purified water and kneading, the same as in Example 1 Thus, a granule was produced.
比較例１
アスコルビン酸（１００Ｍ：武田薬品工業（株）製）５０ｇ、硝酸チアミン（武田薬品工業（株）製）５０ｇ、Ｄ−マンニトール（マンニットＰ：東和化成工業（株）製）９００ｇをバーチカルグラニュレーターＶＧ−１０（パウレック（株）製）で混合後、精製水１５０ｇを添加し練合した後、実施例１と同様にして顆粒剤を製造した。
Comparative Example 1
50 g of ascorbic acid (100M: Takeda Pharmaceutical Co., Ltd.), 50 g of thiamine nitrate (manufactured by Takeda Pharmaceutical Co., Ltd.) and 900 g of D-mannitol (Mannit P: Towa Kasei Kogyo Co., Ltd.) are used as a vertical granulator VG. After mixing with -10 (manufactured by Paulec Co., Ltd.), 150 g of purified water was added and kneaded, and then granules were produced in the same manner as in Example 1.
試験例１
実施例１〜６及び比較例１で製造した顆粒剤１．０ｇをアルミヒートシール（０．０１２μｍ）に分包して、加速条件下において着色変化ΔＥを測定した。
Test example 1
1.0 g of the granules prepared in Examples 1 to 6 and Comparative Example 1 were packaged in an aluminum heat seal (0.012 μm), and the color change ΔE was measured under accelerated conditions.
着色変化測定：加速条件；６０℃、３日静置保存
測定法；測定器 色差計（ＳＱ２０００：日本電色工業（株）製）顆粒を丸セル（３０×１５ｍｍ）に入れて測定した。測定値は、３回の平均値で示す。
Color change measurement: accelerated condition; stored at 60 ° C. for 3 days
Measuring method: Measuring device Color difference meter (SQ2000: manufactured by Nippon Denshoku Industries Co., Ltd.) granules were placed in a round cell (30 × 15 mm) and measured. A measured value is shown by the average value of 3 times.
その結果を表１に示す。 The results are shown in Table 1.
本発明の顆粒剤は、いずれも配合変化を起こさず経時的に安定であったのに対し、比較例１の顆粒剤は着色が激しかった。 All of the granules of the present invention were stable over time with no change in composition, whereas the granules of Comparative Example 1 were intensely colored.
実施例７
アスコルビン酸（１００Ｍ：武田薬品工業（株）製）５０ｇ、パントテン酸カルシウム（アルプス薬品工業（株）製）５０ｇ、低置換度ヒドロキシプロピルセルロース（Ｌ−ＨＰＣ ＬＨ３１：信越化学（株）製）９００ｇをバーチカルグラニュレーターＶＧ−１０（パウレック（株）製）で混合後、精製水２７００ｇを添加し練合した後、ツインドームグランＴＤＧ−８０（不二パウダル（株）製）０．６ｍｍスクリーンで押し出し造粒後、流動層乾燥機ＷＳＧ−５（大川原製作所（株）製）にて乾燥し、１６号及び４２号篩を使用して１６〜４２号の顆粒剤を製造した。
Example 7
Ascorbic acid (100M: Takeda Pharmaceutical Co., Ltd.) 50g, calcium pantothenate (Alps Pharmaceutical Co., Ltd.) 50g, low-substituted hydroxypropylcellulose (L-HPC LH31: Shin-Etsu Chemical Co., Ltd.) 900g After mixing with a vertical granulator VG-10 (manufactured by POWREC Co., Ltd.), 2700 g of purified water was added and kneaded, and then extruded with a twin dome gran TDG-80 (manufactured by Fuji Paudal Co., Ltd.) 0.6 mm screen. After granulation, it was dried with a fluidized bed dryer WSG-5 (manufactured by Okawara Seisakusho Co., Ltd.), and Nos. 16 and 42 sieves were used to produce Nos. 16 to 42 granules.
実施例８
アスコルビン酸（１００Ｍ：武田薬品工業（株）製）５０ｇ、パントテン酸カルシウム（アルプス薬品工業（株）製）５０ｇ、低置換度ヒドロキシプロピルセルロース（Ｌ−ＨＰＣ ＬＨ３１：信越化学（株）製）７００ｇ、Ｄ−マンニトール（マンニットＰ：東和化成工業（株）製）２００ｇをバーチカルグラニュレーターＶＧ−１０（パウレック（株）製）で混合後、精製水２１００ｇを添加し練合した後、実施例７と同様にして顆粒剤を製造した。
Example 8
Ascorbic acid (100M: Takeda Pharmaceutical Co., Ltd.) 50g, calcium pantothenate (Alps Pharmaceutical Co., Ltd.) 50g, low-substituted hydroxypropyl cellulose (L-HPC LH31: Shin-Etsu Chemical Co., Ltd.) 700g, After mixing 200 g of D-mannitol (Mannit P: manufactured by Towa Kasei Kogyo Co., Ltd.) with a vertical granulator VG-10 (Paulec Co., Ltd.), 2100 g of purified water was added and kneaded. Granules were produced in the same manner.
実施例９
アスコルビン酸（１００Ｍ：武田薬品工業（株）製）５０ｇ、パントテン酸カルシウム（アルプス薬品工業（株）製）５０ｇ、低置換度ヒドロキシプロピルセルロース（Ｌ−ＨＰＣ ＬＨ３１：信越化学（株）製）５００ｇ、Ｄ−マンニトール（マンニットＰ：東和化成工業（株）製）４００ｇをバーチカルグラニュレーターＶＧ−１０（パウレック（株）製）で混合後、精製水１５００ｇを添加し練合した後、実施例７と同様にして顆粒剤を製造した。
Example 9
Ascorbic acid (100M: Takeda Pharmaceutical Co., Ltd.) 50 g, calcium pantothenate (Alps Pharmaceutical Co., Ltd.) 50 g, low-substituted hydroxypropyl cellulose (L-HPC LH31: Shin-Etsu Chemical Co., Ltd.) 500 g, After mixing 400 g of D-mannitol (Mannit P: manufactured by Towa Kasei Kogyo Co., Ltd.) with a vertical granulator VG-10 (manufactured by Paulec Co., Ltd.), adding 1500 g of purified water and kneading, Example 7 and Granules were produced in the same manner.
実施例１０
アスコルビン酸（１００Ｍ：武田薬品工業（株）製）５０ｇ、パントテン酸カルシウム（アルプス薬品工業（株）製）５０ｇ、低置換度ヒドロキシプロピルセルロース（Ｌ−ＨＰＣ ＬＨ３１：信越化学（株）製）３００ｇ、Ｄ−マンニトール（マンニットＰ：東和化成工業（株）製）６００ｇをバーチカルグラニュレーターＶＧ−１０（パウレック（株）製）で混合後、精製水９００ｇを添加し練合した後、実施例７と同様にして顆粒剤を製造した。
Example 10
Ascorbic acid (100M: Takeda Pharmaceutical Co., Ltd.) 50g, Calcium pantothenate (Alps Pharmaceutical Co., Ltd.) 50g, Low-substituted hydroxypropylcellulose (L-HPC LH31: Shin-Etsu Chemical Co., Ltd.) 300g, After mixing 600 g of D-mannitol (Mannit P: Towa Kasei Kogyo Co., Ltd.) with a vertical granulator VG-10 (Powrec Co., Ltd.), adding 900 g of purified water and kneading, Example 7 and Granules were produced in the same manner.
実施例１１
アスコルビン酸（１００Ｍ：武田薬品工業（株）製）５０ｇ、パントテン酸カルシウム（アルプス薬品工業（株）製）５０ｇ、低置換度ヒドロキシプロピルセルロース（Ｌ−ＨＰＣ ＬＨ３１：信越化学（株）製）２００ｇ、Ｄ−マンニトール（マンニットＰ：東和化成工業（株）製）７００ｇをバーチカルグラニュレーターＶＧ−１０（パウレック（株）製）で混合後、精製水６００ｇを添加し練合した後、実施例７と同様にして顆粒剤を製造した。
Example 11
Ascorbic acid (100M: Takeda Pharmaceutical Co., Ltd.) 50g, Calcium pantothenate (Alps Pharmaceutical Co., Ltd.) 50g, Low-substituted hydroxypropylcellulose (L-HPC LH31: Shin-Etsu Chemical Co., Ltd.) 200g, 700 g of D-mannitol (Mannit P: manufactured by Towa Kasei Kogyo Co., Ltd.) was mixed with a vertical granulator VG-10 (manufactured by Paulek Co., Ltd.), and 600 g of purified water was added and kneaded. Granules were produced in the same manner.
実施例１２
アスコルビン酸（１００Ｍ：武田薬品工業（株）製）５０ｇ、パントテン酸カルシウム（アルプス薬品工業（株）製）５０ｇ、低置換度ヒドロキシプロピルセルロース（Ｌ−ＨＰＣ ＬＨ３１：信越化学（株）製）１００ｇ、Ｄ−マンニトール（マンニットＰ：東和化成工業（株）製）８００ｇをバーチカルグラニュレーターＶＧ−１０（パウレック（株）製）で混合後、精製水３００ｇを添加し練合した後、実施例７と同様にして顆粒剤を製造した。
Example 12
Ascorbic acid (100M: Takeda Pharmaceutical Co., Ltd.) 50g, calcium pantothenate (Alps Pharmaceutical Co., Ltd.) 50g, low-substituted hydroxypropyl cellulose (L-HPC LH31: Shin-Etsu Chemical Co., Ltd.) 100g, After mixing 800 g of D-mannitol (Mannit P: manufactured by Towa Kasei Kogyo Co., Ltd.) with a vertical granulator VG-10 (manufactured by Pauleck Co., Ltd.), 300 g of purified water was added and kneaded. Granules were produced in the same manner.
比較例２
アスコルビン酸（１００Ｍ：武田薬品工業（株）製）５０ｇ、パントテン酸カルシウム（アルプス薬品工業（株）製）５０ｇ、Ｄ−マンニトール（マンニットＰ：東和化成工業（株）製）９００ｇをバーチカルグラニュレーターＶＧ−１０（パウレック（株）製）で混合後、精製水１５０ｇを添加し練合した後、実施例７と同様にして顆粒剤を製造した。
Comparative Example 2
Vertical granulator of ascorbic acid (100M: Takeda Pharmaceutical Co., Ltd.) 50g, calcium pantothenate (Alps Pharmaceutical Co., Ltd.) 50g, D-mannitol (Mannit P: Towa Kasei Kogyo Co., Ltd.) 900g After mixing with VG-10 (manufactured by Paulec Co., Ltd.), 150 g of purified water was added and kneaded, and then granules were produced in the same manner as in Example 7.
試験例２
実施例７〜１２及び比較例２で製造した顆粒剤を用いて、試験例１と同方法で、着色変化ΔＥを測定した。
結果を表２に示す。
Test example 2
Using the granules prepared in Examples 7 to 12 and Comparative Example 2, the color change ΔE was measured in the same manner as in Test Example 1.
The results are shown in Table 2.
本発明の顆粒剤は、いずれも配合変化を起こさず経時的に安定であったのに対し、比較例２の顆粒剤は着色が激しかった。 All of the granules of the present invention were stable over time with no change in composition, whereas the granules of Comparative Example 2 were intensely colored.
実施例１３
アスコルビン酸１５０ｇ、硝酸チアミン１２ｇ、イブプロフェン２２５ｇ、マレイン酸クロルフェニラミン３ｇ、リン酸ジヒドロコデイン１２ｇ、ｄＬ−塩酸メチルエフェドリン３０ｇ、無水カフェイン３８ｇ、低置換度ヒドロキシプロピルセルロース（Ｌ−ＨＰＣ ＬＨ３１：信越化学（株）製）１０３０ｇをバーチカルグラニュレーターＶＧ−２５（パウレック（株）製）で混合後、精製水３１００ｇを添加し練合した後、ツインドームグランＴＤＧ−８０（不二パウダル（株）製）０．６ｍｍスクリーンで押し出し造粒後、流動層乾燥機ＷＳＧ−５（大川原製作所（株）製）にて乾燥し、クアドロ コーミル（（株）パウレック製 スクリーン径：６１０μｍ）整粒して顆粒剤（細粒剤）を製造した。
Example 13
Ascorbic acid 150 g, thiamine nitrate 12 g, ibuprofen 225 g, chlorpheniramine maleate 3 g, dihydrocodeine phosphate 12 g, dL-methylephedrine hydrochloride 30 g, anhydrous caffeine 38 g, low-substituted hydroxypropylcellulose (L-HPC LH31: Shin-Etsu Chemical ( 1030 g) was mixed with a vertical granulator VG-25 (Paurec Co., Ltd.), and after adding 3100 g of purified water and kneading, Twin Dome Gran TDG-80 (Fuji Paudal Co., Ltd.) 0 After extrusion granulation with a 6 mm screen, it is dried with a fluid bed dryer WSG-5 (Okawara Seisakusho Co., Ltd.), quadrocomil (Pauleck Co., Ltd., screen diameter: 610 μm), and granulated (fine Granule).
実施例１４
アスコルビン酸１５９ｇ、硝酸チアミン１２ｇ、マレイン酸クロルフェニラミン３ｇ、イブプロフェン２２５ｇ、リン酸ジヒドロコデイン１２ｇ、ｄＬ−塩酸メチルエフェドリン３０ｇ、無水カフェイン３８ｇ、カルメロースカルシウム（ＥＣＧ−５０５：五徳薬品（株）製）１０３０ｇをバーチカルグラニュレーターＶＧ−２５（パウレック（株）製）で混合後、精製水３６００ｇを添加し練合した後、ツインドームグランＴＤＧ−８０（不二パウダル（株）製）０．６ｍｍスクリーンで押し出し造粒後、流動層乾燥機ＷＳＧ−５（大川原製作所（株）製）にて乾燥し、クアドロ コーミル（（株）パウレック製 スクリーン径：６１０μｍ）整粒して細粒剤を製造した。
Example 14
159 g of ascorbic acid, 12 g of thiamine nitrate, 3 g of chlorpheniramine maleate, 225 g of ibuprofen, 12 g of dihydrocodeine phosphate, 30 g of dL-methylephedrine hydrochloride, 38 g of anhydrous caffeine, carmellose calcium (ECG-505, manufactured by Gotoku Pharmaceutical Co., Ltd.) After mixing 1030 g with Vertical Granulator VG-25 (manufactured by POWREC Co., Ltd.), 3600 g of purified water was added and kneaded, then Twin Dome Gran TDG-80 (manufactured by Fuji Paudal Co., Ltd.) 0.6 mm screen After extrusion granulation, it was dried with a fluidized bed dryer WSG-5 (Okawara Seisakusho Co., Ltd.), and quadrocomil (Pauleck Co., Ltd., screen diameter: 610 μm) was sized to produce a fine granule.
比較例３
アスコルビン酸１５０ｇ、硝酸チアミン１２ｇ、マレイン酸クロルフェニラミン３ｇ、イブプロフェン２２５ｇ、リン酸ジヒドロコデイン１２ｇ、ｄＬ−塩酸メチルエフェドリン３０ｇ、無水カフェイン３８ｇ、Ｄ−マンニトール（製マンニットＰ：東和化成工業（株））１０３０ｇをバーチカルグラニュレーターＶＧ−２５（パウレック（株）製）で混合後、精製水３００ｇを添加し練合した後、ツインドームグランＴＤＧ−８０（不二パウダル（株）製）０．４ｍｍスクリーンで押し出し造粒後、流動層乾燥機ＷＳＧ−５（大川原製作所（株）製）にて乾燥し、クアドロ コーミル（（株）パウレック製 スクリーン径：６１０μｍ）整粒して細粒剤を製造した。
Comparative Example 3
150 g of ascorbic acid, 12 g of thiamine nitrate, 3 g of chlorpheniramine maleate, 225 g of ibuprofen, 12 g of dihydrocodeine phosphate, 30 g of dL-methylephedrine hydrochloride, 38 g of anhydrous caffeine, D-mannitol (manufactured by Maniwa P: Towa Kasei Kogyo Co., Ltd.) ) After mixing 1030 g with Vertical Granulator VG-25 (manufactured by POWREC Co., Ltd.), adding 300 g of purified water and kneading, Twin Dome Gran TDG-80 (Fuji Paudal Co., Ltd.) 0.4 mm screen After extrusion granulation, the mixture was dried with a fluidized bed dryer WSG-5 (Okawara Seisakusho Co., Ltd.), and quadrocomill (Pauleck Co., Ltd., screen diameter: 610 μm) was sized to produce a fine granule.
試験例３
実施例１３、１４及び比較例３で製造した細粒剤１．０ｇをアルミヒートシール（０．０１２μｍ）に分包して加速条件（５０℃ 1ヶ月）下での着色変化ΔＥを色差計（ＳＱ
２０００：日本電色工業（株）製）で測定した。
外観変化を、次の評価基準で評価した結果を表３に示す。製造時の対する成分の安定性を残存率（％）で測定した結果を表４に示す。
Test example 3
1.0 g of the fine granules prepared in Examples 13 and 14 and Comparative Example 3 were packaged in an aluminum heat seal (0.012 μm), and the color change ΔE under acceleration conditions (50 ° C. for 1 month) was measured with a color difference meter ( SQ
2000: measured by Nippon Denshoku Industries Co., Ltd.
Table 3 shows the results of evaluating the appearance change according to the following evaluation criteria. Table 4 shows the results of measuring the stability of the components with respect to the production rate by the residual ratio (%).
外観変化： − 変化なし
± 有意な変化を認めず
＋ わずかに黄色
＋＋ 黄色
＋＋＋ 褐色
Appearance change:-No change
± No significant change
+ Slightly yellow
++ yellow
+++ brown
本発明の細粒剤は、いずれも安定で外観変化も少なく着色も少なかった。更にアスコルビン酸、硝酸チアミンも安定であった。 All of the fine granules of the present invention were stable with little change in appearance and little coloring. Furthermore, ascorbic acid and thiamine nitrate were also stable.
実施例１５
実施例１の低置換度ヒドロキシプロピルセルロースに代えて、カルメロースナトリウム（ＥＣＧ−５０５：五徳薬品（株）製）、クロスカルメロースナトリウム（Ａｃ−Ｄｉ−ｓｏｌ：旭化成工業（株）製）、カルボキシメチルスターチナトリウム（プリモジェル：松谷化学工業（株）製）、クロスポピドン（コリドンＣＬ：ＢＡＳＦ武田（株）製）又は結晶セルロース・カルメロースナトリウム（アビセルＲＣ−Ａ５９１ＮＦ：旭化成工業（株）製）を用いて、同方法で顆粒剤を製造した。これらの顆粒剤は、５０℃、７５％ＲＨに３０日静置させても、いずれも安定で外観変化も少なく着色も少なかった。
Example 15
Instead of the low-substituted hydroxypropyl cellulose of Example 1, carmellose sodium (ECG-505: manufactured by Gotoku Pharmaceutical Co., Ltd.), croscarmellose sodium (Ac-Di-sol: manufactured by Asahi Kasei Kogyo Co., Ltd.), carboxy Methyl starch sodium (Primogell: manufactured by Matsutani Chemical Co., Ltd.), crospovidone (Collidon CL: manufactured by BASF Takeda Co., Ltd.) or crystalline cellulose carmellose sodium (Avicel RC-A591NF: manufactured by Asahi Kasei Kogyo Co., Ltd.) And granules were produced in the same manner. Even when these granules were allowed to stand at 50 ° C. and 75% RH for 30 days, all of them were stable, little changed in appearance, and little colored.
比較例４
アスコルビン酸（１００Ｍ：武田薬品工業（株）製）５０ｇ、パントテン酸カルシウム（アルプス薬品工業（株）製）５０ｇ、低置換度ヒドロキシプロピルセルロース（Ｌ−ＨＰＣ ＬＨ３１：信越化学（株）製）５００ｇ、Ｄ−マンニトール（マンニットＰ：東和化成工業（株）製）４００ｇをバーチカルグラニュレーターＶＧ−１０（パウレック（株）製）で混合後、打錠機（ＲＳ−Ｔ１５−Ｓ３５：菊水製作所）を用いて径９ｍｍ、１錠２５０ｍｇの錠剤を製造した。錠剤をアルミヒートシール（１２μｍ）に入れて６０℃、３日間静置保存した。錠剤の表面は黄色に変色していた。
Comparative Example 4
Ascorbic acid (100M: Takeda Pharmaceutical Co., Ltd.) 50 g, calcium pantothenate (Alps Pharmaceutical Co., Ltd.) 50 g, low-substituted hydroxypropyl cellulose (L-HPC LH31: Shin-Etsu Chemical Co., Ltd.) 500 g, After mixing 400 g of D-mannitol (Mannit P: manufactured by Towa Kasei Kogyo Co., Ltd.) with a vertical granulator VG-10 (Paulec Co., Ltd.), a tableting machine (RS-T15-S35: Kikusui Seisakusho) was used. A tablet with a diameter of 9 mm and one tablet of 250 mg was manufactured. The tablet was placed in an aluminum heat seal (12 μm) and stored at 60 ° C. for 3 days. The surface of the tablet turned yellow.
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