WO2002087549A1 - Multiple unit type sustained-release tablets - Google Patents
Multiple unit type sustained-release tablets Download PDFInfo
- Publication number
- WO2002087549A1 WO2002087549A1 PCT/JP2002/004023 JP0204023W WO02087549A1 WO 2002087549 A1 WO2002087549 A1 WO 2002087549A1 JP 0204023 W JP0204023 W JP 0204023W WO 02087549 A1 WO02087549 A1 WO 02087549A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- release
- granules
- sustained
- immediate
- release granules
- Prior art date
Links
- 239000007939 sustained release tablet Substances 0.000 title claims abstract description 52
- 239000008187 granular material Substances 0.000 claims abstract description 210
- 238000013268 sustained release Methods 0.000 claims abstract description 75
- 239000012730 sustained-release form Substances 0.000 claims abstract description 75
- 239000011230 binding agent Substances 0.000 claims abstract description 55
- 238000004519 manufacturing process Methods 0.000 claims abstract description 16
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims description 74
- 239000002245 particle Substances 0.000 claims description 45
- 239000007884 disintegrant Substances 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 26
- 229940079593 drug Drugs 0.000 claims description 24
- 239000003814 drug Substances 0.000 claims description 24
- 239000000843 powder Substances 0.000 claims description 24
- 238000007906 compression Methods 0.000 claims description 15
- 230000006835 compression Effects 0.000 claims description 15
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 6
- 229960000913 crospovidone Drugs 0.000 claims description 6
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 6
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 6
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 6
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 6
- 239000000126 substance Substances 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 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 238000013270 controlled release Methods 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 239000003826 tablet Substances 0.000 description 45
- 238000005469 granulation Methods 0.000 description 28
- 230000003179 granulation Effects 0.000 description 28
- 239000000203 mixture Substances 0.000 description 19
- 239000004480 active ingredient Substances 0.000 description 15
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000011248 coating agent Substances 0.000 description 11
- 238000000576 coating method Methods 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 238000002156 mixing Methods 0.000 description 8
- 235000019359 magnesium stearate Nutrition 0.000 description 7
- 239000011812 mixed powder Substances 0.000 description 7
- 239000001856 Ethyl cellulose Substances 0.000 description 6
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 6
- 235000019325 ethyl cellulose Nutrition 0.000 description 6
- 229920001249 ethyl cellulose Polymers 0.000 description 6
- 239000008202 granule composition Substances 0.000 description 6
- 229920003023 plastic Polymers 0.000 description 6
- 239000004033 plastic Substances 0.000 description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- 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 5
- 239000000654 additive Substances 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 239000007921 spray Substances 0.000 description 5
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- 229920002785 Croscarmellose sodium Polymers 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 235000010980 cellulose Nutrition 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 229960001681 croscarmellose sodium Drugs 0.000 description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 3
- 239000003405 delayed action preparation Substances 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 229920003169 water-soluble polymer Polymers 0.000 description 3
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 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 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- DYWNLSQWJMTVGJ-KUSKTZOESA-N Phenylpropanolamine hydrochloride Chemical compound Cl.C[C@H](N)[C@H](O)C1=CC=CC=C1 DYWNLSQWJMTVGJ-KUSKTZOESA-N 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 2
- -1 acrylonol Chemical compound 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 229960001948 caffeine Drugs 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
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- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
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- 229960000541 cetyl alcohol Drugs 0.000 description 2
- 238000013329 compounding Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 239000007888 film coating Substances 0.000 description 2
- 238000009501 film coating Methods 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 239000001341 hydroxy propyl starch Substances 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229960002305 phenylpropanolamine hydrochloride Drugs 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- 239000001069 triethyl citrate Substances 0.000 description 2
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 2
- 235000013769 triethyl citrate Nutrition 0.000 description 2
- YQSHYGCCYVPRDI-UHFFFAOYSA-N (4-propan-2-ylphenyl)methanamine Chemical compound CC(C)C1=CC=C(CN)C=C1 YQSHYGCCYVPRDI-UHFFFAOYSA-N 0.000 description 1
- WHRZCXAVMTUTDD-UHFFFAOYSA-N 1h-furo[2,3-d]pyrimidin-2-one Chemical compound N1C(=O)N=C2OC=CC2=C1 WHRZCXAVMTUTDD-UHFFFAOYSA-N 0.000 description 1
- QNVKOSLOVOTXKF-UHFFFAOYSA-N 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexan-1-ol;hydron;chloride Chemical compound Cl.NC1=C(Br)C=C(Br)C=C1CNC1CCC(O)CC1 QNVKOSLOVOTXKF-UHFFFAOYSA-N 0.000 description 1
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 1
- RSWGJHLUYNHPMX-UHFFFAOYSA-N Abietic-Saeure Natural products C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 description 1
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- 229920001817 Agar Polymers 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 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 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
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- 108010010803 Gelatin Proteins 0.000 description 1
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- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
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- HOKDBMAJZXIPGC-UHFFFAOYSA-N Mequitazine Chemical compound C12=CC=CC=C2SC2=CC=CC=C2N1CC1C(CC2)CCN2C1 HOKDBMAJZXIPGC-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 description 1
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- KHPCPRHQVVSZAH-HUOMCSJISA-N Rosin Natural products O(C/C=C/c1ccccc1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 KHPCPRHQVVSZAH-HUOMCSJISA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930003451 Vitamin B1 Natural products 0.000 description 1
- QDPOOGQUCJJZAO-FCXRPNKRSA-N [(E)-3-(3,4-dihydroxyphenyl)prop-2-enoyl] (E)-3-(3,4-dihydroxyphenyl)prop-2-enoate Chemical compound C1=C(O)C(O)=CC=C1\C=C\C(=O)OC(=O)\C=C\C1=CC=C(O)C(O)=C1 QDPOOGQUCJJZAO-FCXRPNKRSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
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- 230000002411 adverse Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 1
- 229960000985 ambroxol hydrochloride Drugs 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 229960000456 carbinoxamine maleate Drugs 0.000 description 1
- GVNWHCVWDRNXAZ-BTJKTKAUSA-N carbinoxamine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(OCCN(C)C)C1=CC=C(Cl)C=C1 GVNWHCVWDRNXAZ-BTJKTKAUSA-N 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 229940046978 chlorpheniramine maleate Drugs 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
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- 230000001419 dependent effect Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 229960003782 dextromethorphan hydrobromide Drugs 0.000 description 1
- GUBNMFJOJGDCEL-UHFFFAOYSA-N dicyclomine hydrochloride Chemical compound [Cl-].C1CCCCC1C1(C(=O)OCC[NH+](CC)CC)CCCCC1 GUBNMFJOJGDCEL-UHFFFAOYSA-N 0.000 description 1
- 229940110321 dicyclomine hydrochloride Drugs 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
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- 238000010828 elution Methods 0.000 description 1
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- JTLXCMOFVBXEKD-FOWTUZBSSA-N fursultiamine Chemical compound C1CCOC1CSSC(\CCO)=C(/C)N(C=O)CC1=CN=C(C)N=C1N JTLXCMOFVBXEKD-FOWTUZBSSA-N 0.000 description 1
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- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 1
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- 235000019410 glycyrrhizin Nutrition 0.000 description 1
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 1
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- 229960001680 ibuprofen Drugs 0.000 description 1
- 230000009474 immediate action Effects 0.000 description 1
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- 229960003511 macrogol Drugs 0.000 description 1
- 229940018415 meclizine hydrochloride Drugs 0.000 description 1
- 150000004667 medium chain fatty acids Chemical class 0.000 description 1
- 229960005042 mequitazine Drugs 0.000 description 1
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- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
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- 238000012986 modification Methods 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 1
- 229960002646 scopolamine Drugs 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 229960003495 thiamine Drugs 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
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- 229960002622 triacetin Drugs 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 239000011691 vitamin B1 Substances 0.000 description 1
- 235000010374 vitamin B1 Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
Definitions
- the present invention relates to an improvement of a multiple unit type sustained release tablet. More specifically, in a multi-unit type sustained-release tablet comprising an immediate-release portion and a sustained-release portion of a drug. A multi-unit-type sustained-release tablet with an improved dissolution rate of components from the immediate-release portion. About. Background art
- Sustained-release preparations are dosage forms whose purpose is to reduce the number of doses by controlling the release rate of the drug and to reduce the burden of taking patients.
- the main forms of sustained-release preparations are single-unit type sustained-release tablets with a whole tablet coated with a sustained-release membrane, and multi-unit type sustained-release tablets consisting of a large number of drug-dependent particles coated with a sustained-release membrane. And are known. It is known that a multi-unit type preparation is excellent in reducing the dispersion of a drug within and between individuals.
- a portion capable of rapidly releasing a drug (immediate release portion) can be added together with a sustained release portion, so that an effective blood concentration of the drug can be obtained and maintained quickly. it can. For example, by rapidly and slowly releasing an analgesic component, pain can be rapidly suppressed in a patient having pain due to any cause, and the pain can be suppressed for a long time.
- sustained-release granules consist of drug substance granules coated with a sustained-release membrane as described above. Since it is manufactured, the particle size must be relatively large, and the immediate-release granules also need to use relatively large particles. Also, the sustained-release granules have a relatively uniform particle size, and are designed as hard granules to maintain the sustained-release properties. When molding into tablets, it is necessary to use quick-release granules with excellent moldability.
- granules prepared by the fluidized bed granulation method have better compression moldability than granules prepared by other granulation methods, but the tablet disintegration time obtained by compressing the granules into tablets Is often long, which impairs the significance of blending the immediate release portion.
- a large amount of a disintegrant is added to the immediate-release granules to enhance the disintegration properties of the tablet, it becomes difficult to increase the particle size of the granulated product (granules), and thus the sustained release with a relatively large particle size It is difficult to obtain immediate-release granules having a particle size comparable to that of the granules.
- the amount of the binder is increased, the particle size of the granulated product (granules) can be increased, but the disintegration of the tablet again deteriorates.
- the particle size of the sustained release granule and the quick release granule can be made substantially the same, Accordingly, it is an object of the present invention to provide a multi-unit type sustained release tablet which can obtain a good mixture of the two, can be sufficiently molded, and is excellent in disintegration, and a method for producing the same.
- the inventor of the present invention has found that, in a multiple-feed type sustained-release tablet containing a sustained-release granule and a rapid-release granule, the granulation method and components of the rapid-release granule are appropriately selected, and By adding the binder added to the release granules as a powder, it is possible to obtain quick release granules having the same particle size as the sustained release granules and excellent in moldability, and It has been found that a good mixing of the disintegrating granules and the quick-release granules can be obtained, and that a multi-unit type sustained-release tablet which can be sufficiently molded and has excellent disintegration properties can be obtained.
- the present invention relates to tableting granules that release a drug continuously (hereinafter, also referred to as “slow-release granules”) and tableting granules that release a drug quickly (hereinafter, “quick-release granules”). ), Wherein the immediate-release granules contain a disintegrant and a binder, and the binder is mixed in a powder state in the production of the quick-release granules. Provide a sustained release tablet.
- the binder mixed in a powder state in the production of immediate release granules preferably has an average particle size of 100 ⁇ m or less, more preferably 75 m or less. Powder.
- the disintegrant used in the production of the immediate release granules preferably has an average particle size of 100 ⁇ m or less, and has a low degree of substitution such as hydroxypropylcellulose, carboxymethylcellulose, and croscarmellose sodium. It is preferably one or more substances selected from the group consisting of chromium and crospovidone.
- the binder used for producing the immediate release granules is preferably one or more substances selected from the group consisting of hydroxypropylcellulose and hydroxypropylmethylcellulose.
- the amount of the disintegrant contained in the immediate-release granules is preferably 5 to the entire immediate-release granules.
- the amount of the binder contained in the immediate-release granules is preferably 1 to the entire immediate-release granules.
- the sustained-release granules preferably have an average particle diameter of 100 to 100 m, more preferably 200 to 800 ⁇ m, and The sex granules preferably have an average particle size of 100 to: LOOO m, more preferably 15 Q to 800 m.
- the sustained release tablet of the present invention may contain a disintegrant in addition to the sustained release granules and the quick release granules.
- the disintegrant contained in the portion other than the sustained-release granules and the immediate-release granules the same disintegrants as those used in the above-mentioned immediate-release granules can be used.
- the present invention provides a multi-unit which comprises compression-tabletting granules for tableting (sustained-release granules) for continuously releasing a drug and granules for tableting (quick-release granules) for rapidly releasing a drug.
- a method for producing a sustained-release tablet characterized in that the immediate-release granules contain a disintegrant and a binder, and the binder is mixed in a powder state in the production of the immediate-release granules.
- a manufacturing method is provided. BEST MODE FOR CARRYING OUT THE INVENTION
- the multiple-unit type sustained release tablet of the present invention comprises tableting granules (sustained release granules) that continuously release the drug and tableting granules (quick release granules) that release the drug quickly.
- the quick release granules include a disintegrant and a binder, and the binder is mixed in a powder state in the production of the quick release granules.
- a binder is added in a solution state as in a usual fluidized-bed granulation method when the immediate-release granules are produced by a fluidized-bed granulation method or the like. Instead, it is characterized by being added as a powder. Otherwise, it can be produced in the same manner as a conventional multi-release sustained-release tablet comprising sustained-release granules and immediate-release granules. That is, a binder is added as a powder to an active ingredient such as a drug, a disintegrant, and other additives to prepare a mixed powder.
- immediate-release granules by a fluidized-bed granulation method.
- the multiple-unit sustained release tablet of the present invention can be produced by mixing the additives and compressing the granule mixture. By producing as described above, the immediate release granules can be produced to a relatively large particle size comparable to that of the sustained release granules, and the rapid release granules maintain good disintegration and compression moldability. Granules.
- the sustained-release granules and the quick-release granules are sufficiently mixed, and the multi-unit-type sustained-release tablets themselves have appropriate hardness, and Tablets with very short disintegration time. That is, in the conventional multiple unit type sustained release tablet, sufficient particle size and disintegration of the immediate release granules, which could not be achieved only by adjusting the blending amount of the disintegrant and the binder, could not be achieved. And compression moldability can be realized at the same time.
- the effects of the present invention as described above are mainly due to the rapid release prepared by a granulation method such as a fluidized bed granulation method having the above characteristics. It is considered that the distribution of the binder in the sexual granules is different from that in the granules produced by the conventional method. That is, when a binder is dissolved in a solvent and used as a solution as in the conventional fluidized bed granulation method, the binder is uniformly distributed inside the particles such as disintegrants and active ingredients and on the entire surface. As a result, particles such as disintegrants and active ingredients adhere to each other to grow granules.
- the amount of the binder becomes relatively large, and a large amount of the binder is present on the surface of the granules, so that dissolution and disintegration of the granules are inhibited, resulting in disintegration. It becomes granules lacking.
- the binder added in the form of powder is distributed as powder particles on the surface of the particles of the disintegrant, active ingredient, etc., and the particles of the disintegrant, active ingredient, etc. are adhered to form granules. grow up.
- adding a binder in a powder state means dissolving the binder in a solvent or the like.
- the powder is added as it is without any modification, and is not particularly limited as long as it is a powder, but is usually preferably 100 // // m or less, more preferably 75 ⁇ m or less as an average particle diameter.
- a powder having a particle size is used.
- Immediate release granules consist of at least a disintegrant, a binder and an active ingredient.
- Known disintegrants and binders constituting the immediate-release granules can be used.
- disintegrants examples include corn starch, hydroxypropyl starch, starches such as partially graphitized starch and carboxymethyl starch sodium, light anhydrous silicic acid, lactose, agar powder, microcrystalline cellulose, carboxymethylcellulose.
- binders include starches, dextrin, gum arabic, gelatin, sugars, hydroxypropyl starch, carboxymethylcellulose sodium, methylcellulose, hydroxypropylsenorelose, low-substituted hydroxypropinoresenorelose, and hydridone.
- Roxypropinolemethinoresenorelose, etinoresenorelose, polybutylpyrrolidone, macrogol and the like can be mentioned, and one or more of these can be used. Of these, hydroxypropynolecellulose and hydroxypropylmethylcellulose are particularly preferred.
- the active ingredient is not particularly limited as long as it is a substance which can be expected to improve dissolution by being compounded as the immediate-release part of the multiple-unit sustained-release tablet of the present invention, and various pharmaceutical compounds can be used. . Specific examples include peramide hydrochloride, acrylonol, creosote, caffeine, anhydrous caffeine, meclizine hydrochloride, diphthene hydrochloride.
- Examples include scopolamine, vera-donna extract, vitamin B1, fursultiamine, nicotinic acid amide, ibuprofen, acetaminophen, and pseudoephrine.
- the immediate-release granules of the multiple-unit type sustained-release tablet of the present invention may contain, if necessary, excipients such as lactose, mannite, corn starch, magnesium aluminate metasilicate, synthetic or natural gum, in addition to the above components.
- excipients such as lactose, mannite, corn starch, magnesium aluminate metasilicate, synthetic or natural gum, in addition to the above components.
- Lubricants such as talc, magnesium stearate, calcium stearate, etc .
- molding aids such as Avicel
- additives such as sugars.
- saccharide When a saccharide is used for the quick release granules of the multiple unit type sustained release tablet of the present invention, those having a high viscosity when dissolved can perform the same function as the binder and have a disintegration property. It is not preferable because it has an adverse effect, and it is preferable to use saccharides having a high dissolution rate of lac
- the amount of the disintegrant and the binder in the immediate-release granules is such that sufficient granule size, disintegration, and compression moldability can be obtained for the immediate-release granules produced as described above.
- the multiple unit type sustained release tablet obtained by use is not particularly limited as long as sufficient hardness and disintegration can be obtained.
- the amount of the disintegrant is preferably 5 to 50% by weight based on the entire immediate release granules. More preferably about 10 to 30% by weight, and the amount of the binder is preferably about 1 to 20% by weight, more preferably about 3 to 15% by weight.
- the above components are uniformly mixed to obtain a mixed powder, and the mixed powder is granulated to obtain quick-release granules.
- the granulation method and granulation conditions of the immediate-release granules are not particularly limited, and known granulation methods and granulation conditions generally used can be appropriately used, but granulation by a fluidized bed granulation method is preferable. .
- Granulation by the fluidized bed granulation method can be performed using a conventional fluidized bed granulator.In the present invention, however, only a solvent such as water is sprayed on the mixed powder already containing the binder.
- the amount of solvent such as water The same amount as when it is added as a binder solution in the subsequent fluidized-bed granulation method, or a slightly larger amount is preferable.
- the weight ratio between the solvent and the mixed powder used can be about 1: 2, but the weight ratio of the solvent and the mixed powder during granulation is usually About 1: 9 to 2: 8.
- the immediate-release granules produced as described above are produced in such a particle size that good mixing with the sustained-release granules can be obtained.
- the particle size of the immediate-release granules is similar to the particle size of the sustained-release granules, and is not particularly limited as long as good mixing with the sustained-release granules is obtained. It is preferably from 20 to 200%, more preferably from 50 to 100%, of the average particle size of the granules.
- the difference between the average particle size of the immediate release granules and the average particle size of the sustained release granules is preferably about 200 m or less, more preferably about 150 ⁇ m or less.
- the immediate-release granules preferably have an average particle diameter of about 100 to about 100 ⁇ , more preferably about 150 to 800 m, and the average particle diameter satisfies the above conditions. It is particularly preferred that granulation is performed so as to satisfy the conditions.
- the sustained-release granules usually have a particle diameter of about 300 to about I000 m.
- the tablet having a hardness of 1 mm when the immediate release granules alone are tableted with an 8 mm diameter, 24 Omg Z tablets, and a tableting pressure of 2.4 MPa. It is desirable that the disintegration time be 0 kp or more, preferably 14 kp or more, and the disintegration time in the disintegration test shown in the below-mentioned examples is 20 minutes or less, preferably 10 minutes or less.
- the sustained-release granules contained in the multi-unit type sustained-release tablet of the present invention can be the same as those used in conventional multi-unit type sustained-release tablets, and include, for example, an active ingredient and an optional ingredient.
- a sustained-release granule obtained by coating a sustained-release film on granules (elementary granules) comprising other additives can be obtained.
- the raw granules are optionally produced together with the active ingredient, using the same excipients, disintegrants, and lubricants as those mentioned above for the immediate-release granules, by a conventional method such as fluidized bed granulation. be able to.
- the elementary granules include crystalline cellulose spherical granules (trade name: Self Additives such as lactose and crystalline cellulose spherical granules (trade name: non-barrel) can be used.
- Examples of the active ingredients include the same drugs as mentioned for the immediate release granules.
- sustained-release base constituting the sustained-release film
- examples of the sustained-release base constituting the sustained-release film include ethyl cellulose, acrylic acid polymer and the like.
- Specific examples of the acrylic acid polymer include those sold under the trade name Eudragit NE30D, the same RS, and the same RL.
- ethyl cellulose is preferably used.
- These sustained-release bases may be used alone or in combination of two or more.
- a solvent for forming a solution or a dispersion for coating the above-mentioned sustained-release base on elementary granules a mixture of water and a lower alcohol or a lower alcohol is preferable. Ethyl alcohol is most preferred as the lower alcohol.
- the amount of the solvent used can be a suitable amount for the desired coating.
- the solution of the sustained-release base can be obtained by dissolving or dispersing in a solvent as described above by an ordinary method, but the sustained-release base is preferably uniformly dissolved or dispersed in the solvent. It is preferable to use a device such as a stirrer or the like to stir well.
- a coating aid such as hardened oil, stearic acid, and cetanol
- a plasticizer such as medium-chain fatty acid triglyceride, triacetin, triethyl citrate, and cetanol are added to the solution or dispersion of the sustained-release base.
- the desired dissolution rate of the active ingredient in the sustained release granules varies depending on the type of the active ingredient, but the compounding ratio of the active ingredient to the sustained release base, the sustained release film thickness, the type of the sustained release base, the molecular weight, etc.
- the dissolution rate can be adjusted by appropriately selecting For example, when the sustained release base is ethyl cellulose, the dissolution rate can be controlled by changing the molecular weight of the ethyl cellulose.
- a composite coating machine, a tumbling fluidized coating machine, a fluidized bed coating machine and the like can be used as a method for forming a film of the sustained-release base on the elementary granules. It is also effective to carry out curing as needed. The curing is preferably performed at a temperature equal to or higher than the softening point of the sustained-release base.
- the outer layer of the sustained-release granules is further coated with a water-soluble polymer protective film in order to further reduce the change in the elution rate of the active ingredient of the sustained-release granules by compression molding with the subsequent rapid-release granules. May be coated.
- water-soluble polymer used in this case examples include hydroxypropylmethylsenorellose, hydroxypropylcellulose and the like.
- the amount of the water-soluble polymer is preferably 15% by weight or less based on the sustained-release granules.
- the multiple-unit sustained-release tablet of the present invention is produced by compression-tabletting the above-mentioned quick-release granules and sustained-release granules by a usual method using a usual mixer and tableting machine. can do.
- the tableting pressure is not particularly limited as long as a tablet having an appropriate hardness is formed, but is usually about 0.5 to 4.0 MPa, preferably about 1.4 to 3.0 MPa.
- the hardness of the multiple-unit type sustained-release tablet of the present invention is usually 3 kp or more, preferably 4 kp or more when the diameter of the tablet is 8 mm.
- the compounding ratio of the immediate release granules and the sustained release granules in the multiple unit type sustained release tablets of the present invention varies depending on the rapid release and sustained release performance of the active ingredient, and both are used as tablets having appropriate hardness. There is no particular limitation as long as the tablet can be compressed, but usually, the weight ratio of the immediate release granules to the sustained release granules is about 1: 0.5 to 1: 3, preferably about 1: 0.5 to 1: 1. It is.
- the amount of the immediate-release granules is too small, the moldability of the tablet will be deteriorated, and if the amount of the rapid-release granules is too large, the tablet will become large and it will be difficult to take the drug, or the sustained-release granules will be released quickly. Problems such as hindering collapse may occur.
- the multiple unit type sustained release tablet of the present invention is characterized in that the binder is mixed in a powder state in the production of the quick release granules. Therefore, the present invention is directed to a multiple unit including compression and compression of granules for tableting (sustained-release granules) that continuously release a drug and granules for tableting (immediate-release granules) that release a drug rapidly.
- G A method for producing a sustained-release tablet, characterized in that the immediate-release granules contain a disintegrant and a binder, and the binder is mixed in a powder state in the production of the immediate-release granules. Manufacturing methods are also provided. Example
- a granulation liquid was prepared by dissolving 810 g of feninolepropanolenoamine hydrochloride and 608 g of ethyl cellulose in a mixture of 8586 g of ethanolanol and 2147 g of water.
- 800g selfie is put into a bottom spray type fluidized bed granulation coating machine with an inner cylinder, and the previously prepared granulation liquid is sprayed at an air supply temperature of 50 ° C and a spray speed of 20-30g / min, After spraying 12000 g of the granulation liquid, it was dried for about 30 minutes at an air supply temperature of 80 ° C to obtain elementary granules before coating.
- ethyl cellulose and 24.9 g of triethyl citrate were dissolved in a mixture of 7935 g of ethanol and 1983 g of water to obtain a sustained-release film coating solution.
- 810 g of the raw granules before coating are put into a bottom spray type fluidized bed granulation coating machine with an inner cylinder, and the air supply temperature is set at 35 ° C and the spray speed is adjusted within the range of 20 to 30 g / min to achieve sustained release.
- After spraying 10128 g of the film coating solution it was dried for about 20 minutes at a supply air temperature of 80 ° C. Agglomerates were removed by sieving to obtain sustained-release granules.
- the resulting sustained release granules had an average particle size of 378 / m.
- sustained release granules were used in the following Examples and Comparative Examples.
- immediate release granules were prepared in the same manner as in Example 1. However, the hydroxypropyl cellulose as a binder was added by spraying instead of the water sprayed in Example 1 as a 7% aqueous solution. The resulting immediate-release granules had an average particle size of 256 m.
- the rapid release granules 326 g, the sustained release granules 125. 5 g, magnesium stearate 2. 25 g were mixed in a plastic bag, to give granules for tableting mixture.
- This mixture was tableted using a tableting machine Collect 12 HU manufactured by Kikusui Seisakusho (compression pressure: 2.96 MPa) to obtain a tablet having a diameter of 8 mm and a tablet weight of about 185.5 mg.
- the hardness of the obtained tablet was about 4 kp.
- immediate-release granules were prepared in the same procedure as in Example 1. However, the hydroxypropyl cellulose as a binder was added by spraying instead of the water sprayed in Example 1 as a 7% aqueous solution. The resulting immediate-release granules had an average particle size of 21.3 m.
- Powders of the respective components of the formulation shown as Comparative Example 3 in Table 1 were weighed, mixed and charged into a Powrex Vertical Granulator, to which an appropriate amount of water was added and granulated. That is, granulation was performed from a powder containing a binder by a mixed granulation method. The obtained wet granules are dried using a fluid bed dryer manufactured by Huaint Int's Co., Ltd. Obtained. The resulting immediate-release granules had an average particle size of 212 m.
- Immediate release granules were prepared using the same formulation and procedure as in Example 1. The quick release obtained The granules had an average particle size of 211 m.
- Immediate release granules were prepared using the same formulation and procedure as in Example 1.
- the obtained immediate-release granules had an average particle size of 218 m.
- a multi-unit type sustained release tablet having a short disintegration time can be prepared, and a tablet which can be expected to have more rapid immediate action and sustained action can be obtained.
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Abstract
Multiple unit type sustained-release tablets composed of sustained-release granules and quick-release granules characterized in that the quick-release granules contain a disintegrating agent and a binder and the binder is mixed in a powdery state in the production of the quick-release granules. Thus, multiple unit type sustained-release tablets showing a short disintegration time are provided.
Description
明 細 書 マルチプルュニット型徐放性錠剤 技術分野 Description Multiunit type sustained release tablet Technical field
本発明はマルチプルユニッ ト型徐放性錠剤の改良に関する。 より詳細には、 薬 剤の速放性部分と徐放性部分からなるマルチプルュニッ ト型徐放性錠剤において. 速放性部分からの成分の溶出速度を向上させたマルチプルュニット型徐放性錠剤 に関する。 背景技術 The present invention relates to an improvement of a multiple unit type sustained release tablet. More specifically, in a multi-unit type sustained-release tablet comprising an immediate-release portion and a sustained-release portion of a drug. A multi-unit-type sustained-release tablet with an improved dissolution rate of components from the immediate-release portion. About. Background art
徐放性製剤は、 薬剤の放出速度を制御することにより投与回数を減らし、 患者 の服薬という負担を軽減させることを目的とした剤形である。 徐放性製剤の主要 な形態として、錠剤全体に徐放性膜を被覆したシングルユニット型徐放性錠剤と、 徐放性膜を被覆した多数の薬剤頼粒からなるマルチプルュニッ ト型徐放性錠剤と が知られている。 薬物の吸収について個体内及び個体間におけるバラツキを小さ くするためにはマルチプルュニッ ト型の製剤が優れていることが知られている。 またマルチプルュ-ッ ト型の製剤では徐放性部分とともに薬剤を速やかに放出 し得る部分 （速放性部分） を配合し得るので、 薬物の有効血中濃度を迅速に得、 かつ持続することができる。 例えば、 鎮痛成分を速やかに放出しかつ徐放するこ とにより、 何らかの原因により痛みを持つ患者において痛みを速やかに抑制する とともに長時間にわたって痛みを抑制することができる。 Sustained-release preparations are dosage forms whose purpose is to reduce the number of doses by controlling the release rate of the drug and to reduce the burden of taking patients. The main forms of sustained-release preparations are single-unit type sustained-release tablets with a whole tablet coated with a sustained-release membrane, and multi-unit type sustained-release tablets consisting of a large number of drug-dependent particles coated with a sustained-release membrane. And are known. It is known that a multi-unit type preparation is excellent in reducing the dispersion of a drug within and between individuals. In addition, in a multi-rupture type preparation, a portion capable of rapidly releasing a drug (immediate release portion) can be added together with a sustained release portion, so that an effective blood concentration of the drug can be obtained and maintained quickly. it can. For example, by rapidly and slowly releasing an analgesic component, pain can be rapidly suppressed in a patient having pain due to any cause, and the pain can be suppressed for a long time.
マルチプルュ-ッ ト型徐放性製剤に薬剤を速やかに放出する成分を配合する場 合、 上記のような薬剤の素顆粒に徐放性膜を被覆した徐放性顆粒と、 薬剤を速や かに放出する速放性顆粒とを配合することが一般的である。 これらの徐放性顆粒 と速放性顆粒とは良好な混合を得るためにできるだけ近い粒子寸法を有している ことが必要である。 徐放性顆粒は上記のように薬剤素顆粒に徐放性膜を被覆して
製造するので比較的粒子径が大きくならざるを得ず、 速放性顆粒もそれに合わせ て比較的大きな粒子を使用する必要がある。 また、 徐放性顆粒は比較的粒子径が 揃っており、 徐放性を保持させるため硬い顆粒として設計されるので圧縮成形性 に劣ることから、 徐放性顆粒と速放性顆粒とを打錠して成形する場合、 成形性に 優れた速放性顆粒を使用する必要がある。 When a component that rapidly releases a drug is compounded in a multi-cut type sustained-release preparation, the drug can be quickly released, as described above. It is common to mix the granules with immediate-release granules. It is necessary that these sustained-release granules and immediate-release granules have a particle size as close as possible in order to obtain good mixing. Sustained-release granules consist of drug substance granules coated with a sustained-release membrane as described above. Since it is manufactured, the particle size must be relatively large, and the immediate-release granules also need to use relatively large particles. Also, the sustained-release granules have a relatively uniform particle size, and are designed as hard granules to maintain the sustained-release properties. When molding into tablets, it is necessary to use quick-release granules with excellent moldability.
一般的に流動層造粒法により調製した顆粒は他の造粒法により調製した顆粒と 比較して圧縮成形性は優れているが、 その顆粒を圧縮して錠剤にすると得られる 錠剤の崩壊時間が長くなることが多く、 速放性部分を配合した意義が損なわれて しまう。 しかし、 錠剤の崩壊性を高くするために速放性顆粒に崩壊剤を多量に添 加すると造粒物 （顆粒） の粒子径を大きくすることが困難になり、 比較的粒子径 が大きい徐放性顆粒と同程度の粒子径の速放性顆粒を得にく くなる。 この場合、 結合剤を増量すると造粒物 （顆粒） の粒子径は大きくすることができるが、 再び 錠剤の崩壊性が悪くなる。 Generally, granules prepared by the fluidized bed granulation method have better compression moldability than granules prepared by other granulation methods, but the tablet disintegration time obtained by compressing the granules into tablets Is often long, which impairs the significance of blending the immediate release portion. However, if a large amount of a disintegrant is added to the immediate-release granules to enhance the disintegration properties of the tablet, it becomes difficult to increase the particle size of the granulated product (granules), and thus the sustained release with a relatively large particle size It is difficult to obtain immediate-release granules having a particle size comparable to that of the granules. In this case, when the amount of the binder is increased, the particle size of the granulated product (granules) can be increased, but the disintegration of the tablet again deteriorates.
このように従来の方法では、 徐放性顆粒と速放性顆粒とを配合したマルチプル ュニッ ト型徐放性錠剤において、 速放性顆粒の結合剤と崩壊剤の配合を調整する ことのみによっては、 徐放性顆粒及び速放性顆粒の粒子径を同程度のものとし、 十分に成形が可能で、 かつ崩壊性に優れた錠剤とするという 目的を同時に達成す ることは困難であった。 発明の開示 As described above, in the conventional method, in a multiple-unit type sustained-release tablet in which sustained-release granules and immediate-release granules are blended, only by adjusting the blending of the binder and disintegrant of the rapid-release granules. However, it has been difficult to simultaneously achieve the object of making the tablet size of the sustained-release granules and the immediate-release granules of the same size, sufficiently compactable, and excellent in disintegration. Disclosure of the invention
従って本発明は、 徐放性顆粒と速放性顆粒とを配合したマルチプルュニッ ト型 徐放性錠剤において、 徐放性顆粒及び速放性顆粒の粒子径を同程度のものとする ことができ、 従って両者の良好な混合が得られ、 また十分に成形が可能で、 かつ 崩壊性に優れたマルチプルュニッ ト型徐放性錠剤及びその製造方法を提供するこ とを目的とする。 Therefore, in the present invention, in a multi-unit type sustained release tablet containing a sustained release granule and a quick release granule, the particle size of the sustained release granule and the quick release granule can be made substantially the same, Accordingly, it is an object of the present invention to provide a multi-unit type sustained release tablet which can obtain a good mixture of the two, can be sufficiently molded, and is excellent in disintegration, and a method for producing the same.
本発明者は、 徐放性顆粒と速放性顆粒とを配合したマルチプルュ-ッ ト型徐放 性錠剤において、 その速放性顆粒の造粒方法及び成分を適切に選択し、 さらに速
放性顆粒に添加される結合剤を粉末として添加することにより、 徐放性顆粒と同 程度の粒子径を有し、 かつ成形性に優れた速放性顆粒を得ることができ、 従って 徐放性顆粒と速放性顆粒との良好な混合が得られ、 また十分に成形が可能で、 か つ崩壊性に優れたマルチプルュニッ ト型徐放性錠剤が得られることを見出した。 すなわち本発明は、 薬物を持続的に放出する打錠用顆粒 （以下、 「徐放性顆粒」 ともいう） と薬物を速やかに放出する打錠用顆粒 （以下、 「速放性顆粒」 ともい う） からなるマルチプルユニッ ト型徐放性錠剤において、 速放性顆粒が崩壊剤及 び結合剤を含み、 速放性顆粒の製造において結合剤が粉末の状態で混合されるこ とを特徴とする徐放性錠剤を提供する。 The inventor of the present invention has found that, in a multiple-feed type sustained-release tablet containing a sustained-release granule and a rapid-release granule, the granulation method and components of the rapid-release granule are appropriately selected, and By adding the binder added to the release granules as a powder, it is possible to obtain quick release granules having the same particle size as the sustained release granules and excellent in moldability, and It has been found that a good mixing of the disintegrating granules and the quick-release granules can be obtained, and that a multi-unit type sustained-release tablet which can be sufficiently molded and has excellent disintegration properties can be obtained. That is, the present invention relates to tableting granules that release a drug continuously (hereinafter, also referred to as “slow-release granules”) and tableting granules that release a drug quickly (hereinafter, “quick-release granules”). ), Wherein the immediate-release granules contain a disintegrant and a binder, and the binder is mixed in a powder state in the production of the quick-release granules. Provide a sustained release tablet.
上記本発明の徐放性錠剤においては、 速放性顆粒の製造において粉末の状態で 混合される結合剤は、 好ましくは 1 0 0 μ m以下、 より好ましくは 7 5 m以下 の平均粒子径を有する粉末である。 In the above-mentioned sustained release tablet of the present invention, the binder mixed in a powder state in the production of immediate release granules preferably has an average particle size of 100 μm or less, more preferably 75 m or less. Powder.
速放性顆粒の製造に使用される崩壊剤は、 1 0 0 μ m以下の平均粒子径を有す ることが好ましく、 また低置換度ヒ ドロキシプロピルセルロース、 カルボキシメ チルセルロース、 クロスカルメ ロースナトリ ウム及ぴクロスポビドンからなる群 から選択される一種または二種以上の物質であることが好ましい。 The disintegrant used in the production of the immediate release granules preferably has an average particle size of 100 μm or less, and has a low degree of substitution such as hydroxypropylcellulose, carboxymethylcellulose, and croscarmellose sodium. It is preferably one or more substances selected from the group consisting of chromium and crospovidone.
速放性顆粒の製造に使用される結合剤は、 ヒ ドロキシプロピルセルロース及び ヒ ドロキシプロピルメチルセルロースからなる群から選択される一種または二種 以上の物質であることが好ましい。 The binder used for producing the immediate release granules is preferably one or more substances selected from the group consisting of hydroxypropylcellulose and hydroxypropylmethylcellulose.
上記速放性顆粒に含まれる崩壊剤の量は、速放性顆粒全体に対して好ましくは 5 The amount of the disintegrant contained in the immediate-release granules is preferably 5 to the entire immediate-release granules.
〜50重量％、 より好ましくは 10〜30重量％程度である。 About 50% by weight, more preferably about 10 to 30% by weight.
上記速放性顆粒に含まれる結合剤の量は、速放性顆粒全体に対して好ましくは 1 The amount of the binder contained in the immediate-release granules is preferably 1 to the entire immediate-release granules.
〜20重量％、 より好ましくは 3〜15重量％程度である。 -20% by weight, more preferably about 3-15% by weight.
本発明の徐放性錠剤においては、 徐放性顆粒は、 好ましくは 1 0 0〜 1 0 0 0 m、 より好ましくは 2 0 0〜8 0 0 μ mの平均粒子径を有し、 速放性顆粒は、 好ましくは 1 0 0〜： L O O O m、 より好ましくは 1 5 Q〜8 0 0 mの平均粒 子径を有する。
本発明の徐放性錠剤は、 徐放性顆粒及び速放性顆粒に加えて崩壊剤を含んでも よい。 この徐放性顆粒及び速放性顆粒以外の部分に含まれる崩壊剤としては、 上 記速放性顆粒に使用されるものと同様の崩壊剤を使用することができ、 その量は 徐放性錠剤全体に対して好ましくは 1〜25重量％、 より好ましくは？〜 15重量％程 度である。 In the sustained-release tablet of the present invention, the sustained-release granules preferably have an average particle diameter of 100 to 100 m, more preferably 200 to 800 μm, and The sex granules preferably have an average particle size of 100 to: LOOO m, more preferably 15 Q to 800 m. The sustained release tablet of the present invention may contain a disintegrant in addition to the sustained release granules and the quick release granules. As the disintegrant contained in the portion other than the sustained-release granules and the immediate-release granules, the same disintegrants as those used in the above-mentioned immediate-release granules can be used. Preferably 1 to 25% by weight based on the whole tablet, more preferably? About 15% by weight.
さらに本発明は、 薬物を持続的に放出する打錠用顆粒 （徐放性顆粒） と薬物を 速やかに放出する打錠用顆粒 （速放性顆粒） を圧縮打錠することを含むマルチプ ルュニッ ト型徐放性錠剤の製造方法において、 速放性顆粒が崩壊剤及び結合剤を 含み、 速放性顆粒の製造において結合剤を粉末の状態で混合することを特徴とす る徐放性錠剤の製造方法を提供する。 発明を実施するための最良の形態 Further, the present invention provides a multi-unit which comprises compression-tabletting granules for tableting (sustained-release granules) for continuously releasing a drug and granules for tableting (quick-release granules) for rapidly releasing a drug. A method for producing a sustained-release tablet, characterized in that the immediate-release granules contain a disintegrant and a binder, and the binder is mixed in a powder state in the production of the immediate-release granules. A manufacturing method is provided. BEST MODE FOR CARRYING OUT THE INVENTION
以下、 本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail.
本発明のマルチプルュニッ ト型徐放性錠剤は、 薬物を持続的に放出する打錠用 顆粒 （徐放性顆粒） と薬物を速やかに放出する打錠用顆粒 （速放性顆粒） からな り、 速放性顆粒が崩壊剤及び結合剤を含み、 速放性顆粒の製造において結合剤が 粉末の状態で混合されることを特徴とする。 The multiple-unit type sustained release tablet of the present invention comprises tableting granules (sustained release granules) that continuously release the drug and tableting granules (quick release granules) that release the drug quickly. The quick release granules include a disintegrant and a binder, and the binder is mixed in a powder state in the production of the quick release granules.
すなわち本発明のマルチプルュニッ ト型徐放性錠剤は、 その製造において速放 性顆粒を流動層造粒法等により製造する際に、 結合剤を通常の流動層造粒法のよ うに溶液状態で添加するのではなく、 粉末として添加することを特徴とし、 それ 以外は従来の徐放性顆粒と速放性顆粒とからなるマルチプルュ-ッ ト型徐放性錠 剤と同様に製造することができる。 すなわち、 薬物等の活性成分、 崩壊剤、 その 他の添加剤に結合剤を粉末で添加し、 混合した混合粉末を調製する。 そしてその 混合粉末に水分を噴霧することにより流動層造粒法により速放性顆粒を得、 その 速放性顆粒と別途調製した徐放性顆粒及び必要に応じて滑沢剤や崩壊剤等の添加 剤を混合し、 その顆粒混合物を圧縮することにより、 本発明のマルチプルュニッ ト型徐放性錠剤を製造することができる。
上記のようにして製造することにより、 速放性顆粒は徐放性顆粒と同程度の比 較的大きな粒子寸法に製造することができ、 しかも良好な崩壊性と圧縮成形性を 維持した速放性顆粒とすることができる。 従って、 製造されるマルチプルュニッ ト型徐放性錠剤においては、徐放性顆粒と速放性顆粒とが十分に混合されており、 マルチプルュニッ ト型徐放性錠剤自体は適切な硬度を保有し、 かつ崩壊時間の非 常に短い錠剤となる。 すなわち、 従来のマルチプルユニッ ト型徐放性錠剤におい て、 崩壊剤と結合剤の配合量を調節することのみによっては達成することができ なかった、 速放性顆粒の十分な粒子寸法、 崩壊性及び圧縮成形性を同時に実現し 得るものである。 That is, in the multiple-unit type sustained-release tablet of the present invention, a binder is added in a solution state as in a usual fluidized-bed granulation method when the immediate-release granules are produced by a fluidized-bed granulation method or the like. Instead, it is characterized by being added as a powder. Otherwise, it can be produced in the same manner as a conventional multi-release sustained-release tablet comprising sustained-release granules and immediate-release granules. That is, a binder is added as a powder to an active ingredient such as a drug, a disintegrant, and other additives to prepare a mixed powder. Then, water is sprayed on the mixed powder to obtain immediate-release granules by a fluidized-bed granulation method. The immediate-release granules and separately prepared sustained-release granules and, if necessary, a lubricant, a disintegrant, etc. The multiple-unit sustained release tablet of the present invention can be produced by mixing the additives and compressing the granule mixture. By producing as described above, the immediate release granules can be produced to a relatively large particle size comparable to that of the sustained release granules, and the rapid release granules maintain good disintegration and compression moldability. Granules. Therefore, in the manufactured multi-unit type sustained-release tablets, the sustained-release granules and the quick-release granules are sufficiently mixed, and the multi-unit-type sustained-release tablets themselves have appropriate hardness, and Tablets with very short disintegration time. That is, in the conventional multiple unit type sustained release tablet, sufficient particle size and disintegration of the immediate release granules, which could not be achieved only by adjusting the blending amount of the disintegrant and the binder, could not be achieved. And compression moldability can be realized at the same time.
本発明はいかなる理論にも拘束されるものではないが、 上記のような本発明の 効果は、 主として、 上記のような特徴を有する流動層造粒法等の造粒法により調 製した速放性顆粒における結合剤の分布が従来法により製造した顆粒におけるも のとは異なることによると考えられる。 すなわち、 従来の流動層造粒法のように 結合剤を溶剤に溶解して溶液として用いた場合、 結合剤は崩壊剤、 活性成分等の 粒子の内部と表面全体とに均一に分布され、 それにより崩壊剤、 活性成分等の粒 子が接着され顆粒が成長する。 このような状態で比較的大きな顆粒を得るために は結合剤の量が相対的に多くなり、 また顆粒の表面に結合剤が多く存在して顆粒 の溶解や崩壊が阻害され、 結果として崩壊性に欠ける顆粒となってしまう。 これ に対し本発明によれば、粉末状で添加された結合剤は、粉末の粒子として崩壊剤、 活性成分等の粒子の表面に分布し、 崩壊剤、 活性成分等の粒子が接着され顆粒が 成長する。 これにより結合剤は顆粒の内部に多く存在し、 顆粒の表面に存在する 結合剤は少なくなり、 場合により顆粒がそれ以上成長しない程度まで顆粒の表面 に存在する結合剤は少なくなり得る。 このように結合剤を溶液として用いて得ら れる顆粒よりも顆粒表面上に存在する結合剤が少ない顆粒とすることにより、 顆 粒の溶解や崩壊が阻害されることがなく、 崩壊性に優れ、 圧縮成形性にも優れた 顆粒が得られる。 Although the present invention is not limited by any theory, the effects of the present invention as described above are mainly due to the rapid release prepared by a granulation method such as a fluidized bed granulation method having the above characteristics. It is considered that the distribution of the binder in the sexual granules is different from that in the granules produced by the conventional method. That is, when a binder is dissolved in a solvent and used as a solution as in the conventional fluidized bed granulation method, the binder is uniformly distributed inside the particles such as disintegrants and active ingredients and on the entire surface. As a result, particles such as disintegrants and active ingredients adhere to each other to grow granules. In order to obtain relatively large granules in such a state, the amount of the binder becomes relatively large, and a large amount of the binder is present on the surface of the granules, so that dissolution and disintegration of the granules are inhibited, resulting in disintegration. It becomes granules lacking. In contrast, according to the present invention, the binder added in the form of powder is distributed as powder particles on the surface of the particles of the disintegrant, active ingredient, etc., and the particles of the disintegrant, active ingredient, etc. are adhered to form granules. grow up. This allows the binder to be more abundant inside the granules, less binder present on the surface of the granules, and possibly less binder present on the surfaces of the granules to such an extent that the granules do not grow any further. By making the granules having less binder present on the surface of the granules than the granules obtained by using the binder as a solution, dissolution and disintegration of the condyles are not hindered and the disintegration is excellent. Granules with excellent compression moldability can be obtained.
本発明において、 結合剤を粉末の状態で添加するとは、 結合剤を溶剤等に溶解
することなく原粉末のまま添加することを意味し、 粉末であれば特に限定されな いが、 通常は平均粒子径として好ましくは 1 0 0 // m以下、 より好ましくは 7 5 μ m以下の粒子径を有する粉末を使用する。 このよ うな粒子径を有する結合剤を 使用することにより、 崩壊性に優れ、 かつ比較的大きい粒子径の速放性顆粒を製 造することができる。 In the present invention, adding a binder in a powder state means dissolving the binder in a solvent or the like. Means that the powder is added as it is without any modification, and is not particularly limited as long as it is a powder, but is usually preferably 100 // // m or less, more preferably 75 μm or less as an average particle diameter. A powder having a particle size is used. By using a binder having such a particle size, quick-release granules having excellent disintegration properties and a relatively large particle size can be produced.
速放性顆粒は、 少なく とも崩壊剤、 結合剤及び活性成分とからなる。 速放性顆 粒を構成する崩壊剤及び結合剤は従来から知られているものを使用することがで さる。 Immediate release granules consist of at least a disintegrant, a binder and an active ingredient. Known disintegrants and binders constituting the immediate-release granules can be used.
崩壊剤の例としては、 コーンスターチ、 ヒ ドロキシプロピルスターチ、 部分ァ ルファー化デンプン及びカルボキシメチルスターチナトリ ゥム等のデンプン類、 軽質無水ケィ酸、 乳糖、 カンテン末、 微結晶セルロース、 カルボシキメチルセル ロース、 低置換度ヒ ドロキシプロピノレセノレロース、 ヒ ドロキシプロピノレセノレ口一 ス、 カノレボキシメチノレセノレロースカノレシゥム、 クロスカノレメ ロースナト リ ウム、 ク ロスポビドン等が挙げられ、 これらの 1種以上を使用することができる。 これ らのうち、 低置換度ヒ ドロキシプロピルセルロース、 カノレボキシメチルセノレロー ス、 クロスカルメロースナトリ ゥム及びクロスポビドンが特に好ましい。 Examples of disintegrants include corn starch, hydroxypropyl starch, starches such as partially graphitized starch and carboxymethyl starch sodium, light anhydrous silicic acid, lactose, agar powder, microcrystalline cellulose, carboxymethylcellulose. Loose, low-substituted hydroxypropinoresenololose, hydroxypropinoresorenolose, canoleboximetinoresenorelosecanolecum, croscanoleme rosin sodium, clospovidone and the like. More than one species can be used. Of these, low-substituted hydroxypropylcellulose, canoleboxymethylcenorellose, croscarmellose sodium and crospovidone are particularly preferred.
結合剤の例としては、 デンプン類、 デキス トリン、 アラビアゴム末、 ゼラチン、 糖類、 ヒ ドロキシプロピルスターチ、 カルボキシメチルセルロースナトリ ウム、 メチルセルロース、 ヒ ドロキシプロピルセノレロース、 低置換度ヒ ドロキシプロピ ノレセノレロース、 ヒ ドロキシプロピノレメチノレセノレロース、 ェチノレセノレロース、 ポリ ビュルピロリ ドン、 マクロゴール等が挙げられ、 これらの 1種以上を使用するこ とができる。 これらのうち、 ヒ ドロキシプロピノレセルロース及びヒ ドロキシプロ ピルメチルセルロースが特に好ましい。 Examples of binders include starches, dextrin, gum arabic, gelatin, sugars, hydroxypropyl starch, carboxymethylcellulose sodium, methylcellulose, hydroxypropylsenorelose, low-substituted hydroxypropinoresenorelose, and hydridone. Roxypropinolemethinoresenorelose, etinoresenorelose, polybutylpyrrolidone, macrogol and the like can be mentioned, and one or more of these can be used. Of these, hydroxypropynolecellulose and hydroxypropylmethylcellulose are particularly preferred.
活性成分としては、 本発明のマルチプルュニッ ト型徐放性錠剤の速放部として 配合して溶出性の向上が期待できる物質であれば特に限定されず、 種々の医薬品 化合物等を使用することができる。 具体例としては、 塩酸口ペラミ ド、 ァクリノ ール、 ク レオソー ト、 カフェイン、 無水カフェイン、 塩酸メクリジン、 塩酸ジフ
ェンヒ ドラミン、 塩酸フエニルプロパノールァミン、 リ ン酸ジヒ ドロコディン、 臭化水素酸デキス トロメ トルファン、 ノス力ピン、 塩酸アンブロキソール、 メキ タジン、 マレイン酸クロルフエ二ラミン、 塩酸ジサイクロ ミン、 臭化水素酸スコ ポラミン、 ベラ ドンナエキス、 ビタミン B 1、 フルスルチアミ ン、 ニコチン酸ァ ミ ド、 イブプロフェン、 ァセ トァミノフェン、 プソィ ドエフエ ドリン等を挙げる ことができる。 The active ingredient is not particularly limited as long as it is a substance which can be expected to improve dissolution by being compounded as the immediate-release part of the multiple-unit sustained-release tablet of the present invention, and various pharmaceutical compounds can be used. . Specific examples include peramide hydrochloride, acrylonol, creosote, caffeine, anhydrous caffeine, meclizine hydrochloride, diphthene hydrochloride. Phenhydramine, phenylpropanolamine hydrochloride, dihydrocodine phosphate, dextromethorphan hydrobromide, noseptin, ambroxol hydrochloride, mequitazine, chlorpheniramine maleate, dicyclomine hydrochloride, hydrobromide Examples include scopolamine, vera-donna extract, vitamin B1, fursultiamine, nicotinic acid amide, ibuprofen, acetaminophen, and pseudoephrine.
本発明のマルチプルュニッ ト型徐放性錠剤の速放性顆粒は、 上記の成分の他、 必要に応じて乳糖、 マンニッ ト、 トウモロコシデンプン、 メタケイ酸アルミン酸 マグネシウム、 合成もしくは天然ガム等の賦形剤、 タルク、 ステアリン酸マグネ シゥム、 ステアリン酸カルシウム等の滑沢剤等、 アビセル等のような成形助剤、 糖類等の添加剤を含んでいてもよい。 尚、 本発明のマルチプルユニッ ト型徐放性 錠剤の速放性顆粒に糖類を使用する場合は、 溶解した際に溶液が高い粘性を示す ものは結合剤と同様の機能を果たし、崩壊性に悪影響を与えるので好ましくなく、 乳糖、 マンニッ ト等の溶解速度が速く、 溶解した際の溶液の粘性が低い糖類を使 用することが好ましい。 The immediate-release granules of the multiple-unit type sustained-release tablet of the present invention may contain, if necessary, excipients such as lactose, mannite, corn starch, magnesium aluminate metasilicate, synthetic or natural gum, in addition to the above components. Lubricants such as talc, magnesium stearate, calcium stearate, etc .; molding aids such as Avicel; and additives such as sugars. When a saccharide is used for the quick release granules of the multiple unit type sustained release tablet of the present invention, those having a high viscosity when dissolved can perform the same function as the binder and have a disintegration property. It is not preferable because it has an adverse effect, and it is preferable to use saccharides having a high dissolution rate of lactose, mannite, etc., and a low viscosity of the solution when dissolved.
速放性顆粒中の崩壊剤及び結合剤の量は、 上記のようにして製造される速放性 顆粒について十分な顆粒寸法、 崩壊性、 圧縮成形性が得られ、 さらにその速放性 顆粒を使用して得られるマルチプルユニッ ト型徐放性錠剤について十分な硬度と 崩壊性が得られる限り特に限定されないが、 速放性顆粒全体に対して、 崩壊剤の 量は好ましくは 5〜50重量％、 より好ましくは 10〜30重量％程度であり、結合剤の 量は好ましくは 1〜20重量％、 より好ましくは 3〜15重量％程度である。 The amount of the disintegrant and the binder in the immediate-release granules is such that sufficient granule size, disintegration, and compression moldability can be obtained for the immediate-release granules produced as described above. The multiple unit type sustained release tablet obtained by use is not particularly limited as long as sufficient hardness and disintegration can be obtained. The amount of the disintegrant is preferably 5 to 50% by weight based on the entire immediate release granules. More preferably about 10 to 30% by weight, and the amount of the binder is preferably about 1 to 20% by weight, more preferably about 3 to 15% by weight.
上記のような成分を均一に混合して混合粉末を得、 その混合粉末を造粒するこ とにより速放性顆粒を得る。 速放性顆粒の造粒方法、 造粒条件等は特に限定され ず、 通常用いられる公知の造粒方法、 造粒条件等が適宜使用できるが、 流動層造 粒法により造粒することが好ましい。 流動層造粒法による造粒は、 従来の流動層 造粒機を用いて行うことができるが、 本発明においては上記結合剤を既に含む混 合粉末に対し水等の溶媒のみを噴霧することによって行う。 水等の溶媒の量は従
来の流動層造粒法において結合剤の溶液として添加される場合と同様の量あるい は若干多い量が好ましい。 例えば使用される溶媒と混合粉末の重量比は約 1 ： 2 程度とすることができるが、 流動層造粒法においては溶媒が蒸発するため、 造粒 中における溶媒と混合粉末の重量比は通常約 1 ： 9 ~ 2 ： 8程度である。 The above components are uniformly mixed to obtain a mixed powder, and the mixed powder is granulated to obtain quick-release granules. The granulation method and granulation conditions of the immediate-release granules are not particularly limited, and known granulation methods and granulation conditions generally used can be appropriately used, but granulation by a fluidized bed granulation method is preferable. . Granulation by the fluidized bed granulation method can be performed using a conventional fluidized bed granulator.In the present invention, however, only a solvent such as water is sprayed on the mixed powder already containing the binder. Done by The amount of solvent such as water The same amount as when it is added as a binder solution in the subsequent fluidized-bed granulation method, or a slightly larger amount is preferable. For example, the weight ratio between the solvent and the mixed powder used can be about 1: 2, but the weight ratio of the solvent and the mixed powder during granulation is usually About 1: 9 to 2: 8.
上記のようにして製造される速放性顆粒は、 徐放性顆粒との良好な混合が得ら れるような粒子径に製造する。 速放性顆粒の粒子径は、 徐放性顆粒の粒子径と同 程度で、 徐放性顆粒との良好な混合が得られる限り特に限定されないが、 速放性 顆粒の平均粒子径が徐放性顆粒の平均粒子径の 2 0〜 2 0 0 %であることが好ま しく、 より好ましくは 5 0〜 1 0 0 %である。 また速放性顆粒の平均粒子径と徐 放性顆粒の平均粒子径の差は、 好ましくは約 2 0 0 m以下、 より好ましくは約 1 5 0 μ m以下である。 速放性顆粒は、 好ましくは 1 0 0〜： 1 0 0 0 μ πι、 より 好ましくは 1 5 0〜8 0 0 m程度の平均粒子径を有し、 かつその平均粒子径が 上記の条件を満たすように造粒されることが特に好ましい。 尚、 徐放性顆粒は通 常 3 0 0〜： I 0 0 0 m程度の粒子径を有する。 The immediate-release granules produced as described above are produced in such a particle size that good mixing with the sustained-release granules can be obtained. The particle size of the immediate-release granules is similar to the particle size of the sustained-release granules, and is not particularly limited as long as good mixing with the sustained-release granules is obtained. It is preferably from 20 to 200%, more preferably from 50 to 100%, of the average particle size of the granules. The difference between the average particle size of the immediate release granules and the average particle size of the sustained release granules is preferably about 200 m or less, more preferably about 150 μm or less. The immediate-release granules preferably have an average particle diameter of about 100 to about 100 μππι, more preferably about 150 to 800 m, and the average particle diameter satisfies the above conditions. It is particularly preferred that granulation is performed so as to satisfy the conditions. The sustained-release granules usually have a particle diameter of about 300 to about I000 m.
本発明のマルチプルユニッ ト型徐放性錠剤においては、 前記速放性顆粒のみを 8 m m径、 2 4 O m g Z錠、打錠圧 2. 4 MPaで打錠した場合の錠剤の硬度が 1 0 k p以上、 好ましくは 1 4 k p以上で、 後述の実施例に示した崩壊試験における崩 壊時間が 2 0分以内、 好ましくは 1 0分以内であることが望ましい。 このような 硬度及び崩壊度とすることにより、 速放性顆粒に求められる綻剤圧縮成形性と活 性薬剤の速い放出性とが十分に両立される。 In the multiple unit type sustained release tablet of the present invention, the tablet having a hardness of 1 mm when the immediate release granules alone are tableted with an 8 mm diameter, 24 Omg Z tablets, and a tableting pressure of 2.4 MPa. It is desirable that the disintegration time be 0 kp or more, preferably 14 kp or more, and the disintegration time in the disintegration test shown in the below-mentioned examples is 20 minutes or less, preferably 10 minutes or less. By setting the hardness and the disintegration degree in such a manner, both the compressibility of the disintegrant required for the immediate release granules and the rapid release of the active agent are sufficiently compatible.
本発明のマルチプルュニッ ト型徐放性錠剤に含まれる徐放性顆粒は、 従来のマ ルチプルュニッ ト型徐放性錠剤に使用されるものと同様のものとすることができ、 例えば、 活性成分及び任意にその他の添加剤からなる顆粒 （素顆粒） に徐放性膜 をコーティングした徐放性顆粒とすることができる。 The sustained-release granules contained in the multi-unit type sustained-release tablet of the present invention can be the same as those used in conventional multi-unit type sustained-release tablets, and include, for example, an active ingredient and an optional ingredient. In addition, a sustained-release granule obtained by coating a sustained-release film on granules (elementary granules) comprising other additives can be obtained.
素顆粒は活性成分とともに任意に上記速放性顆粒について挙げたものと同様の 賦形剤、 崩壊剤、 滑沢剤等の添加剤を使用して流動層造粒法等の常法により製造 することができる。 また素顆粒には、 結晶セルロース球形顆粒 （商品名 ： セルフ
ィァ） 、 乳糖 '結晶セルロース球形顆粒 （商品名 ： ノンバレル） 等の添加剤を用 いることができる。 活性成分の例としては、 上記速放性顆粒について挙げたもの と同様の薬剤が挙げられる。 The raw granules are optionally produced together with the active ingredient, using the same excipients, disintegrants, and lubricants as those mentioned above for the immediate-release granules, by a conventional method such as fluidized bed granulation. be able to. The elementary granules include crystalline cellulose spherical granules (trade name: Self Additives such as lactose and crystalline cellulose spherical granules (trade name: non-barrel) can be used. Examples of the active ingredients include the same drugs as mentioned for the immediate release granules.
徐放性膜を構成する徐放化基剤としては、 ェチルセルロース、 アクリル酸ポリ マー等が挙げられる。 アクリル酸ポリマーの具体例としては、 商品名オイ ドラギ ッ ト N E 3 0 D、 同 R S、 同 R Lで販売されているもの等が例示される。 本発明 においては、 ェチルセルロースが好ましく使用される。 これらの徐放化基剤はそ れぞれ単独で用いてもよく、 2種以上を併せて用いてもよい。 Examples of the sustained-release base constituting the sustained-release film include ethyl cellulose, acrylic acid polymer and the like. Specific examples of the acrylic acid polymer include those sold under the trade name Eudragit NE30D, the same RS, and the same RL. In the present invention, ethyl cellulose is preferably used. These sustained-release bases may be used alone or in combination of two or more.
上記徐放化基剤を素顆粒に被覆するための溶液または分散物を形成するための 溶剤としては、水と低級アルコールとの混合物または低級アルコールが好ましレ、。 低級アルコールとしてはエチルアルコールが最も好ましい。 溶剤の使用量は所望 の被覆に適した使用量とすることができる。 徐放化基剤の溶液は上記のような溶 媒中に通常の方法により溶解あるいは分散することにより得られるが、 徐放化基 剤は溶媒中に均一に溶解または分散されていることが好ましく、 撹拌機等の装置 を用い、 十分撹拌して製造することが好ましい。 また、 徐放化基剤の溶液または 分散物には硬化油、 ステアリン酸、 セタノール等のコーティング助剤、 中鎖脂肪 酸トリグリセリ ド、 トリァセチン、 クェン酸トリェチル、 セタノ一ル等の可塑剤 等を添加してもよレ、。 As a solvent for forming a solution or a dispersion for coating the above-mentioned sustained-release base on elementary granules, a mixture of water and a lower alcohol or a lower alcohol is preferable. Ethyl alcohol is most preferred as the lower alcohol. The amount of the solvent used can be a suitable amount for the desired coating. The solution of the sustained-release base can be obtained by dissolving or dispersing in a solvent as described above by an ordinary method, but the sustained-release base is preferably uniformly dissolved or dispersed in the solvent. It is preferable to use a device such as a stirrer or the like to stir well. In addition, a coating aid such as hardened oil, stearic acid, and cetanol, and a plasticizer such as medium-chain fatty acid triglyceride, triacetin, triethyl citrate, and cetanol are added to the solution or dispersion of the sustained-release base. You can.
有効成分の種類により徐放性顆粒に望まれる活性成分の溶出速度は異なるが、 有効成分と徐放化基剤との配合比、 徐放性膜厚、 徐放性基剤の種類、 分子量等を 適当に選択することにより溶出速度を調節することができる。 例えば、 徐放化基 剤がェチルセルロースである場合は、 ェチルセルロースの分子量を変えることに より溶出速度を制御することができる。 The desired dissolution rate of the active ingredient in the sustained release granules varies depending on the type of the active ingredient, but the compounding ratio of the active ingredient to the sustained release base, the sustained release film thickness, the type of the sustained release base, the molecular weight, etc. The dissolution rate can be adjusted by appropriately selecting For example, when the sustained release base is ethyl cellulose, the dissolution rate can be controlled by changing the molecular weight of the ethyl cellulose.
素顆粒上に徐放化基剤の皮膜を形成させる方法としては、 複合型コーティング 機、 転動流動コーティング機及び流動層コーティング機等を利用することができ る。 また、 必要に応じキュアリングを行うことも効果的である。 キュアリングは 徐放化基剤の軟化点以上で行うことが好ましい。
本発明においては、 その後の速放性顆粒との圧縮成形による徐放性顆粒の活性 成分の溶出速度の変化をより少なくするために、 徐放性顆粒の外層をさらに水溶 性高分子の保護皮膜で被覆してもよい。 この場合に用いられる水溶性高分子とし ては、 ヒ ドロキシプロピルメチルセノレロース、 ヒ ドロキシプロピルセルロース等 を挙げることができる。 水溶性高分子の量は徐放性顆粒に対して 1 5重量％以下 とすることが好ましい。 As a method for forming a film of the sustained-release base on the elementary granules, a composite coating machine, a tumbling fluidized coating machine, a fluidized bed coating machine and the like can be used. It is also effective to carry out curing as needed. The curing is preferably performed at a temperature equal to or higher than the softening point of the sustained-release base. In the present invention, the outer layer of the sustained-release granules is further coated with a water-soluble polymer protective film in order to further reduce the change in the elution rate of the active ingredient of the sustained-release granules by compression molding with the subsequent rapid-release granules. May be coated. Examples of the water-soluble polymer used in this case include hydroxypropylmethylsenorellose, hydroxypropylcellulose and the like. The amount of the water-soluble polymer is preferably 15% by weight or less based on the sustained-release granules.
本発明のマルチプルュニッ ト型徐放性錠剤は、 上記のような速放性顆粒と徐放 性顆粒とを、 通常の混合機、 打錠機を用い、 通常の方法により圧縮打錠すること により製造することができる。 打錠圧は適度な硬度の錠剤が形成される限り特に 制限されないが、 通常 0. 5〜4. 0 MPa、 好ましくは 1. 4〜3. 0 MPa程度である。 本発 明のマルチプルュニッ ト型徐放性錠剤の硬度は、 例えば錠剤の直径が 8 m mの場 合は、 通常 3 k p以上、 好ましくは 4 k p以上である。 The multiple-unit sustained-release tablet of the present invention is produced by compression-tabletting the above-mentioned quick-release granules and sustained-release granules by a usual method using a usual mixer and tableting machine. can do. The tableting pressure is not particularly limited as long as a tablet having an appropriate hardness is formed, but is usually about 0.5 to 4.0 MPa, preferably about 1.4 to 3.0 MPa. The hardness of the multiple-unit type sustained-release tablet of the present invention is usually 3 kp or more, preferably 4 kp or more when the diameter of the tablet is 8 mm.
本発明のマルチプルュニッ ト型徐放性錠剤における速放性顆粒と徐放性顆粒と の配合割合は、 活性成分の速放及び徐放性能によっても変化し、 両者を適度な硬 度を有する錠剤として打錠できる限り特に制限されないが、 通常は、 速放性顆粒 と徐放性顆粒との重量比で 1 : 0 . 5〜： 1 : 3、 好ましくは 1 : 0 . 5〜： 1 : 1 程度である。 速放性顆粒の量が少なすぎると錠剤の成形性の悪化などを招き、 速 放性顆粒の量が多すぎると錠剤が大きくなり服薬しにく くなる、 あるいは徐放性 顆粒を速やかに放出するための崩壊が妨げられる等の問題が起こり得る。 The compounding ratio of the immediate release granules and the sustained release granules in the multiple unit type sustained release tablets of the present invention varies depending on the rapid release and sustained release performance of the active ingredient, and both are used as tablets having appropriate hardness. There is no particular limitation as long as the tablet can be compressed, but usually, the weight ratio of the immediate release granules to the sustained release granules is about 1: 0.5 to 1: 3, preferably about 1: 0.5 to 1: 1. It is. If the amount of the immediate-release granules is too small, the moldability of the tablet will be deteriorated, and if the amount of the rapid-release granules is too large, the tablet will become large and it will be difficult to take the drug, or the sustained-release granules will be released quickly. Problems such as hindering collapse may occur.
上記のように、 本発明のマルチプルユニッ ト型徐放性錠剤は、 その速放性顆粒 の製造において結合剤が粉末の状態で混合されることを特徴とする。 従って本発 明は、 薬物を持続的に放出する打錠用顆粒 （徐放性顆粒） と薬物を速やかに放出 する打錠用顆粒 （速放性顆粒） を圧縮打錠することを含むマルチプルユニッ ト型 徐放性錠剤の製造方法において、 速放性顆粒が崩壊剤及び結合剤を含み、 速放性 顆粒の製造において結合剤を粉末の状態で混合することを特徴とする徐放性錠剤 の製造方法も提供する。
実施例 As described above, the multiple unit type sustained release tablet of the present invention is characterized in that the binder is mixed in a powder state in the production of the quick release granules. Therefore, the present invention is directed to a multiple unit including compression and compression of granules for tableting (sustained-release granules) that continuously release a drug and granules for tableting (immediate-release granules) that release a drug rapidly. G. A method for producing a sustained-release tablet, characterized in that the immediate-release granules contain a disintegrant and a binder, and the binder is mixed in a powder state in the production of the immediate-release granules. Manufacturing methods are also provided. Example
以下の実施例及び試験例により本発明をさらに詳細に説明するが、 本発明は以 下の実施例及び試験例により限定されるものではない。 徐放性顆粒の調製 The present invention will be described in more detail with reference to the following examples and test examples, but the present invention is not limited to the following examples and test examples. Preparation of sustained release granules
塩酸フエ二ノレプロパノーノレアミン 810g、 ェチルセルロース 608gをエタノーノレ 85 86g、 水 2147gの混合液に溶解し造粒液とした。 セルフィァ 800gを内筒付きボトム スプレー型流動層造粒コーティング機に投入し、先に調製した造粒液を給気温度 5 0°C、 スプレー速度を 20〜30g/mi nの範囲でスプレーし、 造粒液 12000gをスプレー した後、 給気温度 80°Cで約 30分乾燥しコーティング前の素顆粒を得た。 A granulation liquid was prepared by dissolving 810 g of feninolepropanolenoamine hydrochloride and 608 g of ethyl cellulose in a mixture of 8586 g of ethanolanol and 2147 g of water. 800g selfie is put into a bottom spray type fluidized bed granulation coating machine with an inner cylinder, and the previously prepared granulation liquid is sprayed at an air supply temperature of 50 ° C and a spray speed of 20-30g / min, After spraying 12000 g of the granulation liquid, it was dried for about 30 minutes at an air supply temperature of 80 ° C to obtain elementary granules before coating.
次に、ェチルセルロース 497g及びクェン酸ト リェチル 24. 9gをエタノール 7935g、 水 1983gの混合液に溶解し、徐放性膜塗布液とした。 前記コーティング前の素顆粒 810gを内筒付きボトムスプレー型流動層造粒コーティング機に投入し、給気温度 3 5°C、 スプレー速度を 20〜30g/mi nの範囲で調整して徐放性膜塗布液 10128gをスプ レーした後、 給気温度 80°Cで約 20分乾燥した。 凝集物を篩過により除去して徐放 性顆粒を得た。 得られた徐放性顆粒は 3 7 8 / mの平均粒子径を有していた。 Next, 497 g of ethyl cellulose and 24.9 g of triethyl citrate were dissolved in a mixture of 7935 g of ethanol and 1983 g of water to obtain a sustained-release film coating solution. 810 g of the raw granules before coating are put into a bottom spray type fluidized bed granulation coating machine with an inner cylinder, and the air supply temperature is set at 35 ° C and the spray speed is adjusted within the range of 20 to 30 g / min to achieve sustained release. After spraying 10128 g of the film coating solution, it was dried for about 20 minutes at a supply air temperature of 80 ° C. Agglomerates were removed by sieving to obtain sustained-release granules. The resulting sustained release granules had an average particle size of 378 / m.
この徐放性顆粒を以下の実施例及び比較例に用いた。 The sustained release granules were used in the following Examples and Comparative Examples.
(実施例 1 ) (Example 1)
表 1に示す処方で、 無水カフェイン 100g、 塩酸フエニルプロパノ一ルァミン 32 g、 マレイン酸カルビノキサミン 12 g、 グリチルリチン 30g、 乳糖 180g、 軽質無水ケ ィ酸 14g、 クロスカルメ ロースナ トリ ウム 130g、 ヒ ドロキシプロピノレセルロース 4 0gを混合し、 フロイント産業社製流動層造粒機に投入した。 給気温度 70°C、 スプ レー速度 5〜8g/mi nの範囲で 278gの水をスプレーし、速放性顆粒を得た。得られた 速放性顆粒は 2 0 5 μ mの平均粒子径を有していた。 Based on the formulation shown in Table 1, 100 g of anhydrous caffeine, 32 g of phenylpropanolamine hydrochloride, 12 g of carbinoxamine maleate, 30 g of glycyrrhizin, 180 g of lactose, 14 g of light caffeic anhydride, 130 g of croscarmellose sodium, 130 g of hydroxypropynole 40 g of cellulose was mixed and charged into a fluidized bed granulator manufactured by Freund Corporation. 278 g of water was sprayed at an air supply temperature of 70 ° C and a spray speed of 5 to 8 g / min to obtain quick-release granules. The obtained immediate-release granules had an average particle size of 205 μm.
この速放性顆粒 430g、 前記徐放性顆粒 160g、 ステアリン酸マグネシウム 2. 7gを ビニール袋に入れて混合し、 打錠用顆粒混合物とした。 この混合物を菊水製作所 製打錠機コレク ト 1 2 HUを用いて打錠し （圧縮圧 2. 96MPa) 、 直径 8ram、 1錠重量
約 185. 5mgの錠剤を得た。 得られた錠剤の硬度は約 4kpであった。 (比較例 1 ) 430 g of the immediate release granules, 160 g of the sustained release granules, and 2.7 g of magnesium stearate were put in a plastic bag and mixed to obtain a granule mixture for tableting. This mixture was tableted using a tablet machine, Collect 12 HU, manufactured by Kikusui Seisakusho (compression pressure: 2.96 MPa), diameter 8 ram, weight 1 tablet About 185.5 mg tablets were obtained. The hardness of the obtained tablet was about 4 kp. (Comparative Example 1)
表 1に比較例 1 として示す処方を使用し、 実施例 1 と同様の手順で速放性顆粒 を調製した。 但し結合剤のヒ ドロキシプロピルセルロースは、 7%水溶液として実 施例 1でスプレーした水に代えてスプレーすることにより添加した。 得られた速 放性顆粒は 2 5 6 mの平均粒子径を有していた。 Using the formulation shown in Table 1 as Comparative Example 1, immediate release granules were prepared in the same manner as in Example 1. However, the hydroxypropyl cellulose as a binder was added by spraying instead of the water sprayed in Example 1 as a 7% aqueous solution. The resulting immediate-release granules had an average particle size of 256 m.
この速放性顆粒 326g、 前記徐放性顆粒 125. 5g、 ステアリン酸マグネシウム 2. 25 gをビニール袋に入れて混合し、 打錠用顆粒混合物とした。 この混合物を菊水製作 所製打錠機コレク ト 1 2 HUを用いて打錠し （圧縮圧 2. 96MPa) 、 直径 8mm、 1錠重 量約 185. 5mgの錠剤を得た。 得られた錠剤の硬度は約 4kpであった。 The rapid release granules 326 g, the sustained release granules 125. 5 g, magnesium stearate 2. 25 g were mixed in a plastic bag, to give granules for tableting mixture. This mixture was tableted using a tableting machine Collect 12 HU manufactured by Kikusui Seisakusho (compression pressure: 2.96 MPa) to obtain a tablet having a diameter of 8 mm and a tablet weight of about 185.5 mg. The hardness of the obtained tablet was about 4 kp.
(比較例 2 ) (Comparative Example 2)
表 1に比較例 2として示す処方を使用し、 実施例 1 と同様の手順で速放性顆粒 を調製した。 但し結合剤のヒ ドロキシプロピルセルロースは、 7%水溶液として実 施例 1でスプレーした水に代えてスプレーすることにより添加した。 得られた速 放性顆粒は 2 1 3 mの平均粒子径を有していた。 Using the formulation shown in Table 1 as Comparative Example 2, immediate-release granules were prepared in the same procedure as in Example 1. However, the hydroxypropyl cellulose as a binder was added by spraying instead of the water sprayed in Example 1 as a 7% aqueous solution. The resulting immediate-release granules had an average particle size of 21.3 m.
この速放性顆粒 326g、 前記徐放性顆粒 125. 5g、 ステアリン酸マグネシウム 2. 25 gをビニール袋に入れて混合し、打錠用顆粒混合物とした。 この混合物を菊水製作 所製打錠機コレク ト 1 2 HUを用いて打錠し （圧縮圧 2. 96MPa) 、 直径 8mtn、 1錠重 量約 185. 5mgの錠剤を得た。 得られた錠剤の硬度は約 4kpであった。 326 g of the immediate release granules, 125.5 g of the sustained release granules, and 2.25 g of magnesium stearate were put in a plastic bag and mixed to obtain a granule mixture for tableting. The mixture was tableted using a tablet machine Collect 12 HU manufactured by Kikusui Seisakusho (compression pressure: 2.96 MPa) to obtain tablets having a diameter of 8 mtn and a tablet weight of about 185.5 mg. The hardness of the obtained tablet was about 4 kp.
(比較例 3 ) (Comparative Example 3)
表 1に比較例 3として示す処方の各成分の粉末を各々秤量し、 混合してパウレ ック社製バーチカルグラ二ユレ一ターに投入し、 適量の水を添加して造粒した。 すなわち、 混合造粒法により結合剤を含む粉末から造粒した。 得られた湿粒をフ 口イント産社製流動層乾燥機を用いて乾燥し、 24号篩を通過させて速放性顆粒を
得た。 得られた速放性顆粒は 2 1 2 mの平均粒子径を有していた。 この速放性顆粒 424g、 前記徐放性顆粒 140g、 ステアリン酸マグネシウム 2. 8gを ビニール袋に入れて混合し、 打錠用顆粒混合物とした。 この混合物を菊水製作所 製打錠機コレク ト 1 2 HUを用いて打錠し （圧縮圧 2. 96MPa) 、 直径 8mm 1錠重量 約 202. 5mgの錠剤を得た。 得られた錠剤の硬度は約 4kpであった。 速放性顆粒の処方 （g)Powders of the respective components of the formulation shown as Comparative Example 3 in Table 1 were weighed, mixed and charged into a Powrex Vertical Granulator, to which an appropriate amount of water was added and granulated. That is, granulation was performed from a powder containing a binder by a mixed granulation method. The obtained wet granules are dried using a fluid bed dryer manufactured by Huaint Int's Co., Ltd. Obtained. The resulting immediate-release granules had an average particle size of 212 m. 424 g of the immediate release granules, 140 g of the sustained release granules and 2.8 g of magnesium stearate were put in a plastic bag and mixed to obtain a granule mixture for tableting. The mixture was tableted using a tableting machine Collect 12 HU manufactured by Kikusui Seisakusho (compression pressure: 2.96 MPa) to obtain a tablet having a diameter of 8 mm and a tablet weight of about 202.5 mg. The hardness of the obtained tablet was about 4 kp. Formulation of immediate release granules (g)
* ；水に溶解 （7%水溶液） して添加した。 *: Dissolved in water (7% aqueous solution) and added.
* * ；処方中に粉末として添加した。 **: Added as a powder in the formulation.
(実施例 2 ) (Example 2)
実施例 1 と同じ処方及び手順を使用して速放性顆粒を調製した。 得られた速放
性顆粒は 2 1 1 mの平均粒子径を有していた。 Immediate release granules were prepared using the same formulation and procedure as in Example 1. The quick release obtained The granules had an average particle size of 211 m.
この速放性顆粒 430. 6g、 前記徐放性顆粒 160. 6g、 ステアリン酸マグネシウム 2. 69g、 クロスポビドン 96gをビニール袋に入れて混合し、打錠用顆粒混合物とした。 この混合物を菊水製作所製打錠機コレク ト 1 2 HUを用いて打錠し （圧縮圧 2. 96MP a) 、 直径 8rara、 1錠重量約 215. 5ragの錠剤を得た。 得られた錠剤の硬度は約 4kpで めつ 7こ。 430.6 g of the immediate release granules, 160.6 g of the sustained release granules, 2.69 g of magnesium stearate, and 96 g of crospovidone were put in a plastic bag and mixed to obtain a granule mixture for tableting. This mixture was tableted using a tableting machine Collect 12 HU manufactured by Kikusui Seisakusho (compression pressure: 2.96 MPa) to obtain tablets having a diameter of 8rara and a tablet weight of about 215.5 rag. The hardness of the obtained tablet is about 4 kp and it is 7 pieces.
(実施例 3 ) (Example 3)
実施例 1 と同じ処方及び手順を使用して速放性顆粒を調製した。 得られた速放 性顆粒は 2 1 8 mの平均粒子径を有していた。 Immediate release granules were prepared using the same formulation and procedure as in Example 1. The obtained immediate-release granules had an average particle size of 218 m.
この速放性顆粒 430g、 前記徐放性顆粒 160g、 ステアリン酸マグネシウム 2. 7g、 クロスポビドン 64gをビニール袋に入れて混合し、打錠用顆粒混合物とした。 この 混合物を菊水製作所製打錠機コレク ト 1 2 HUを用いて打錠し （圧縮圧 2. 96MPa) 、 直径 8mm、 1錠重量約 205. 5mgの錠剤を得た。 得られた錠剤の硬度は約 4kpであった。 (試験例 1 ) 430 g of the immediate release granules, 160 g of the sustained release granules, 2.7 g of magnesium stearate, and 64 g of crospovidone were put in a plastic bag and mixed to obtain a granule mixture for tableting. This mixture was tableted using a Kikusui Seisakusho tablet press collection preparative 1 2 HU (compression pressure 2. 96 MPa), to obtain tablets with a diameter of 8 mm, 1 tablet weight of about 205. 5 m g. The hardness of the obtained tablet was about 4 kp. (Test Example 1)
実施例及び比較例で得られた錠剤について第十三改正日本薬局方に記載の方法 により崩壊試験を行った。 The tablets obtained in the Examples and Comparative Examples were subjected to a disintegration test according to the method described in the thirteenth revised Japanese Pharmacopoeia.
すなわち、 第十三改正日本薬局方に記載の装置及び方法で、 36. 5°Cの水を試験 液として用い、 各錠剤が崩壊するまでの時間 （崩壊した錠剤片の全てが試験装置 底面の 2mmの網を通過するまでの時間） を測定した。 結果を表 2に示す。 In other words, using the device and method described in the 13th Revised Japanese Pharmacopoeia, using water at 36.5 ° C as a test solution, the time until each tablet disintegrates (all the disintegrated tablet pieces are on the bottom of the test device The time to pass through a 2 mm net) was measured. Table 2 shows the results.
表 2 Table 2
試験結果
試験結果から、 実施例 1 〜 3の錠剤は比較例 1 〜 3ものと比較して崩壊時間が 明らかに短くなつている。 特に実施例 1 と比較例 2を比較すると、 結合剤は実施
例 1の方が多いため通常ならば崩壊時間は実施例 1の方が長くなると考えられる が、試験結果では実施例 1は崩壊時間が 2. 6分であり、比較例 2は 4. 2分であった。 これらの結果より、本発明の結合剤の添加方法の効果が明確に示されている。 尚、 各錠剤の硬度 （約 4kp) は錠剤として適切な硬度である。 産業上の利用可能性 Test results From the test results, the disintegration times of the tablets of Examples 1 to 3 are clearly shorter than those of Comparative Examples 1 to 3. In particular, comparing Example 1 with Comparative Example 2, the binder Although the disintegration time is usually longer in Example 1 because Example 1 is more common, the disintegration time in Example 1 is 2.6 minutes in the test results and 4.2 minutes in Comparative Example 2 Met. From these results, the effect of the method for adding the binder of the present invention is clearly shown. The hardness of each tablet (approx. 4 kp) is appropriate for tablets. Industrial applicability
本発明によれば、崩壊時間の短いマルチプルュニッ ト型徐放性錠剤が調製でき、 より迅速な即効性と持効性とを期待できる錠剤が得られる。
According to the present invention, a multi-unit type sustained release tablet having a short disintegration time can be prepared, and a tablet which can be expected to have more rapid immediate action and sustained action can be obtained.
Claims
1 . 薬物を持続的に放出する打錠用顆粒 （徐放性顆粒） と薬物を速やかに放出 する打錠用顆粒 （速放性顆粒） からなるマルチプルユニッ ト型徐放性錠剤におい て、 速放性顆粒が崩壊剤及び結合剤を含み、 速放性顆粒の製造において結合剤が 粉末の状態で混合されることを特徴とする徐放性錠剤。 1. In a multiple unit type sustained release tablet consisting of granules for tableting (sustained release granules) that release the drug continuously and granules for tableting (quick release granules) that release the drug quickly, A sustained-release tablet, characterized in that the release granules comprise a disintegrant and a binder, and the binder is mixed in a powder form in the production of the immediate-release granules.
2 . 結合剤の粉末が、 1 0 0 // m以下の平均粒子径を有する粉末であることを 特徴とする請求項 1に記載の徐放性錠剤。 2. The sustained-release tablet according to claim 1, wherein the binder powder is a powder having an average particle diameter of 100 // m or less.
3 . 崩壊剤が 1 0 0 m以下の平均粒子径を有し、 低置換度ヒ ドロキシプロピ ノレセノレロース、 カノレボキシメチノレセノレロース、 クロスカノレメ ロースナ ト リ ウム及 びクロスポビドンからなる群から選択される一種または二種以上の物質からなる ことを特徴とする請求項 1または 2に記載の徐放性錠剤。 3. A disintegrant having an average particle size of 100 m or less, and selected from the group consisting of low-substituted hydroxypropinoresenorelose, canoleboximetinoresenorelose, croscanoleme sodium and crospovidone. 3. The sustained-release tablet according to claim 1, wherein the sustained-release tablet is composed of two or more substances.
4 . 結合剤がヒ ドロキシプロピルセルロース及びヒ ドロキシプロピノレメチルセ ルロースからなる群から選択される一種または二種以上の物質であることを特徴 とする請求項 1〜 3のいずれかに記載の徐放性綻剤。 4. The binder according to any one of claims 1 to 3, wherein the binder is one or more substances selected from the group consisting of hydroxypropylcellulose and hydroxypropinolemethylcellulose. Controlled release drug.
5 . 速放性顆粒が 5〜50重量％の崩壊剤を含むことを特徴とする請求項 1〜4の いずれかに記載の徐放性錠剤。 5. The sustained-release tablet according to any one of claims 1 to 4, wherein the immediate-release granules contain 5 to 50% by weight of a disintegrant.
6 . 速放性顆粒が 1〜20重量％の結合剤を含むことを特徴とする請求項 1〜 5の いずれかに記載の徐放性錠剤。 6. The sustained-release tablet according to any one of claims 1 to 5, wherein the immediate-release granules contain 1 to 20% by weight of a binder.
7 . 徐放性顆粒及び速放性顆粒が 1 0 0〜 1 0 0 0 μ mの平均粒子径を有する ことを特徴とする請求項 1〜 6のいずれかに記載の徐放性錠剤。 7. The sustained release tablet according to any one of claims 1 to 6, wherein the sustained release granules and the quick release granules have an average particle diameter of 100 to 1000 µm.
8 . 徐放性顆粒及び速放性顆粒に加えて崩壊剤を含むことを特徴とする請求項 1〜 7のいずれかに記載の徐放性錠剤。 8. The sustained-release tablet according to any one of claims 1 to 7, comprising a disintegrant in addition to the sustained-release granules and the immediate-release granules.
9 . 徐放性顆粒及び速放性顆粒に加えて含まれる崩壊剤が、 低置換度ヒ ドロキ シプロピルセノレロース、 カノレボキシメチルセノレロース、 クロス力ノレメ ロ一スナト リ ゥム及びクロスポビドンからなる群から選択される一種または二種以上の物質 からなることを特徴とする請求項 8に記載の徐放性錠剤。
9. Disintegrants contained in addition to sustained-release granules and immediate-release granules include low-substituted hydroxypropylsenorellose, canoleboxymethylsenorellose, cross-force norename sodium and crospovidone. 9. The sustained-release tablet according to claim 8, comprising one or more substances selected from the group consisting of:
1 0 . 徐放性顆粒及び速放性顆粒に加えて含まれる崩壊剤が、 徐放性錠剤に対 して 1〜25重量％の量で含まれることを特徴とする請求項 8または 9に記載の徐 放性錠剤。 10. The method according to claim 8 or 9, wherein the disintegrant contained in addition to the sustained-release granules and the immediate-release granules is contained in an amount of 1 to 25% by weight based on the sustained-release tablet. The sustained-release tablet described.
1 1 . 薬物を持続的に放出する打錠用顆粒 （徐放性顆粒） と薬物を速やかに放 出する打錠用顆粒 （速放性顆粒） を圧縮打錠することを含むマルチプルユニッ ト 型徐放性錠剤の製造方法において、 速放性顆粒が崩壊剤及び結合剤を含み、 速放 性顆粒の製造において結合剤を粉末の状態で混合することを特徴とする徐放性錠 剤の製造方法。
1 1. Multiple unit type including compression and compression of tableting granules (sustained-release granules) that continuously release the drug and tableting granules (quick-release granules) that release the drug quickly. A method for producing a sustained-release tablet, wherein the immediate-release granules comprise a disintegrant and a binder, and the binder is mixed in a powder state in the production of the immediate-release granules. Method.
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| JP2001126891 | 2001-04-25 |
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| WO2007114376A1 (en) * | 2006-03-30 | 2007-10-11 | Nippon Zoki Pharmaceutical Co., Ltd. | Solid pharmaceutical preparation |
| JP2009524651A (en) * | 2006-01-27 | 2009-07-02 | シージェイ チェイルジェダン コーポレイション | Multiple unit type sustained release oral preparation and method for producing the same |
| JP2009161495A (en) * | 2008-01-09 | 2009-07-23 | Everest Pharm Industrial Co Ltd | Kind of quickly disintegrable oral tablet containing slow-dissolving microparticle ascorbic acid |
| JP2012224641A (en) * | 2005-09-22 | 2012-11-15 | Intermune Inc | Capsule formulation of pirfenidone and pharmaceutically acceptable excipient |
| JP2013507356A (en) * | 2009-10-09 | 2013-03-04 | ユンジン・ファーム・カンパニー・リミテッド | Pharmaceutical composition having both rapid action and durability |
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| US10188637B2 (en) | 2016-03-29 | 2019-01-29 | Hoffmann-La Roche Inc. | Granulate formulation of 5-methyl-1-phenyl-2-(1H)-pyridone and method of making the same |
| JP2020532548A (en) * | 2017-08-29 | 2020-11-12 | コンリグ ファーマ エーピーエス | Compositions Containing Splatast Tosylate |
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Also Published As
| Publication number | Publication date |
|---|---|
| JP4280074B2 (en) | 2009-06-17 |
| JPWO2002087549A1 (en) | 2004-08-12 |
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