CN1048395C - 药物颗粒及其片剂的制备方法 - Google Patents
药物颗粒及其片剂的制备方法 Download PDFInfo
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- CN1048395C CN1048395C CN89101157A CN89101157A CN1048395C CN 1048395 C CN1048395 C CN 1048395C CN 89101157 A CN89101157 A CN 89101157A CN 89101157 A CN89101157 A CN 89101157A CN 1048395 C CN1048395 C CN 1048395C
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- cellulose
- water
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- Expired - Lifetime
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- 239000008187 granular material Substances 0.000 title claims abstract description 52
- 239000000203 mixture Substances 0.000 claims abstract description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 27
- 229920002678 cellulose Polymers 0.000 claims abstract description 23
- 239000001913 cellulose Substances 0.000 claims abstract description 23
- 239000011230 binding agent Substances 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims description 26
- 235000010980 cellulose Nutrition 0.000 claims description 22
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 17
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 17
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 17
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 10
- 238000005550 wet granulation Methods 0.000 claims description 10
- 239000002245 particle Substances 0.000 claims description 9
- 229940079593 drug Drugs 0.000 claims description 6
- 238000005469 granulation Methods 0.000 claims description 5
- 230000003179 granulation Effects 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 4
- 239000003782 beta lactam antibiotic agent Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000002132 β-lactam antibiotic Substances 0.000 claims description 2
- 229940124586 β-lactam antibiotics Drugs 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 20
- YMDYLBWLYFQCEJ-UHFFFAOYSA-I [Mg+2].[Al+3].OC([O-])=O.OC([O-])=O.OC([O-])=O.OC([O-])=O.OC([O-])=O Chemical compound [Mg+2].[Al+3].OC([O-])=O.OC([O-])=O.OC([O-])=O.OC([O-])=O.OC([O-])=O YMDYLBWLYFQCEJ-UHFFFAOYSA-I 0.000 claims 1
- 239000007864 aqueous solution Substances 0.000 claims 1
- 229940072172 tetracycline antibiotic Drugs 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 12
- 239000004615 ingredient Substances 0.000 description 8
- 229920003084 Avicel® PH-102 Polymers 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 5
- -1 hydroxypropyl Chemical group 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 4
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 4
- 229960003022 amoxicillin Drugs 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000000796 flavoring agent Substances 0.000 description 4
- 235000013355 food flavoring agent Nutrition 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 3
- FZKWRPSUNUOXKJ-CVHRZJFOSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydrate Chemical compound O.C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O FZKWRPSUNUOXKJ-CVHRZJFOSA-N 0.000 description 2
- CUMCMYMKECWGHO-UHFFFAOYSA-N 3-methyl-1,2-oxazole Chemical compound CC=1C=CON=1 CUMCMYMKECWGHO-UHFFFAOYSA-N 0.000 description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 2
- 229960003722 doxycycline Drugs 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- 229910000836 magnesium aluminium oxide Inorganic materials 0.000 description 2
- QWDJLDTYWNBUKE-UHFFFAOYSA-L magnesium bicarbonate Chemical compound [Mg+2].OC([O-])=O.OC([O-])=O QWDJLDTYWNBUKE-UHFFFAOYSA-L 0.000 description 2
- 229960005489 paracetamol Drugs 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229960003387 progesterone Drugs 0.000 description 2
- 239000000186 progesterone Substances 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- IMLJLCJZQLGHJS-JEKSYDDFSA-N (4s,4ar,5s,5ar,6s,12ar)-4-(dimethylamino)-1,5,6,10,11,12a-hexahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide;dihydrate Chemical compound O.O.C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O IMLJLCJZQLGHJS-JEKSYDDFSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- HYSALCMXIKJFNX-UHFFFAOYSA-N 2-benzyl-3-methylpyridine Chemical class CC1=CC=CN=C1CC1=CC=CC=C1 HYSALCMXIKJFNX-UHFFFAOYSA-N 0.000 description 1
- UXKKFPGAZIINBX-UHFFFAOYSA-N 3-chloro-1h-quinolin-2-one Chemical class C1=CC=C2NC(=O)C(Cl)=CC2=C1 UXKKFPGAZIINBX-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- XMFXTXKSWIDMER-UHFFFAOYSA-N 7-chloro-1h-quinolin-4-one Chemical compound ClC1=CC=C2C(O)=CC=NC2=C1 XMFXTXKSWIDMER-UHFFFAOYSA-N 0.000 description 1
- DPSPPJIUMHPXMA-UHFFFAOYSA-N 9-fluoro-5-methyl-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid Chemical compound C1CC(C)N2C=C(C(O)=O)C(=O)C3=C2C1=CC(F)=C3 DPSPPJIUMHPXMA-UHFFFAOYSA-N 0.000 description 1
- ITPDYQOUSLNIHG-UHFFFAOYSA-N Amiodarone hydrochloride Chemical compound [Cl-].CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCC[NH+](CC)CC)C(I)=C1 ITPDYQOUSLNIHG-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 239000004100 Oxytetracycline Substances 0.000 description 1
- 229930195708 Penicillin V Natural products 0.000 description 1
- 229920003081 Povidone K 30 Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 238000004026 adhesive bonding Methods 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- IYIKLHRQXLHMJQ-UHFFFAOYSA-N amiodarone Chemical compound CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCCN(CC)CC)C(I)=C1 IYIKLHRQXLHMJQ-UHFFFAOYSA-N 0.000 description 1
- 229960005260 amiodarone Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- 229940097572 chloromycetin Drugs 0.000 description 1
- 229960001380 cimetidine Drugs 0.000 description 1
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000005343 cylinder glass Substances 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229960004434 doxycycline monohydrate Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 229960000702 flumequine Drugs 0.000 description 1
- PLHJDBGFXBMTGZ-WEVVVXLNSA-N furazolidone Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)OCC1 PLHJDBGFXBMTGZ-WEVVVXLNSA-N 0.000 description 1
- 229960001625 furazolidone Drugs 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000003754 machining Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 229960000625 oxytetracycline Drugs 0.000 description 1
- 235000019366 oxytetracycline Nutrition 0.000 description 1
- 229960003924 oxytetracycline dihydrate Drugs 0.000 description 1
- 229940056367 penicillin v Drugs 0.000 description 1
- BPLBGHOLXOTWMN-MBNYWOFBSA-N phenoxymethylpenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)COC1=CC=CC=C1 BPLBGHOLXOTWMN-MBNYWOFBSA-N 0.000 description 1
- JOHZPMXAZQZXHR-UHFFFAOYSA-N pipemidic acid Chemical class N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CN=C1N1CCNCC1 JOHZPMXAZQZXHR-UHFFFAOYSA-N 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 229950000126 proligestone Drugs 0.000 description 1
- MQSDUYIXZDSLSZ-QSDCUGRSSA-N proligestone[ban:inn] Chemical compound C([C@@H]12)CC3=CC(=O)CC[C@]3(C)[C@H]2CC[C@]2(C)[C@@]3(C(C)=O)CC[C@]21OC(CC)O3 MQSDUYIXZDSLSZ-QSDCUGRSSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了对在水中的溶解度为10wt%或以下的有效物质和微晶或微细纤维素或二者的混合物，不使用大量粘合剂而制备药物颗粒的方法。
本发明也公开了用所述的药物颗粒制成的压片混合物制备快速崩解药片的方法。
Description
本发明涉及通过湿法制粒制备药物颗粒的方法以及制备
快速崩解的药片的方法。
药物的作用是根据有效成分(在治疗上有效的物质)的存在。通常有效成分应当与另外的物质混合，这些物质本身可能就是有疗效的或者是在适宜剂型的生产中所必须的辅助剂。对粉状药物的操作来说，重要的问题是粉末要有好的流动性。然而，许多有效的药物，由于其固有的不能会人满意的流动性能，不易加工成剂型，特别是片剂或胶囊。因此，按照充分确认的制剂惯例，在压片以前，首先将所需物质转换成颗粒，以使其具有所希望的流动性能。本发明包括湿成粒法，在这种情况下，有效成分与通常为水的制粒液体相混合，同时可加特殊的颗粒辅助剂。根据已知的方法，把所得湿团状物通过筛网、干燥、压碎、过筛。所产生的颗粒可用于压片混合物的组成部分，剂型为胶囊时也可应用。
为了提供均匀的固体颗粒，按照标准操作，应当将湿粘合物质(湿粘合剂)加入制粒混合剂中，特别是当颗粒含有比较大量的有效成分时。有关这方面的进一步资料可在H.A.Lieberman和L.Lachman的药物剂型(1980)，第I卷，113-116页(“湿成粒法”)或者L.Lachman，H.A.Lieberman及J.L.Kanig的“工业制药理论及实践”，第三版，320-324页(“湿成粒法”)中找到。湿粘合剂为阿拉伯树胶、明胶、聚乙烯吡咯烷酮、淀粉(淀粉糊和预胶凝淀粉)，藻酸钠和藻酸盐衍生物、山梨醇、葡萄糖和其它糖、黄蓍胶和可溶性纤维素，如甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠和羟丙基纤维素。在颗粒混合物中，湿粘合剂的用量常为有效成分重量的1-10％。虽然为得到好的颗粒必须考虑制粒时使用粘合剂，但也显示出由这种颗粒制成的片剂浸在水中时，崩解度较差。这从生物吸收的观点看可能是不利的。在极短时间内，有效物质由快速崩解的药片中释放，因而体内的吸收和治疗作用开始得早，起始药物浓度也较高。
本发明的目的是提供优良质量的颗粒(虽然含大量有效成分)以进一步加工成有满意崩解性能的坚实片剂。
通过应用湿成粒法意外地发现，可由高浓度的治疗上有效的物质(在水中的溶解度限制在10wt％以下)与纤维素产物(微晶纤维素或微细纤维素或两者的混合物)一起，而不用加大量的湿粘合剂，制得良好质量的颗粒。本发明的制粒是通过不宽于12mm或者更小的连续流动的杯孔进行的。
为了得到新型颗粒，应用本领域众所周知的湿制粒法。多种治疗上有效的物质可用本发明，如β-内酰胺抗菌素类、四环素类、甾类化合物等等，但这些化合物在水中的溶解度必须在10wt％以下，最好在5wt％以下。例如根据本发明以下治疗上有效的物质可成功地用于制粒：
乙胺碘呋酮、阿莫西林、甲腈咪胍、氯霉素，增效黄胺甲基异噁唑、强力霉素一水合物、红霉素琥珀酸乙酯、氟甲喹、呋喃唑酮、水化碳酸氢氧化铝镁、布洛芬、消炎痛、L-多巴、萘普生、醋氨酚、青霉素-V酸、吡啶酸吡咯昔康、黄体酮、普罗孕酮、土霉素二水合物、黄胺甲基异噁唑、舒林酸、安体舒痛(螺内酯)、萘碱和甲氧苄啶。
最好首先将有效成分与微晶纤维素或微细纤维素或两者的混合物制成颗粒混合物。微晶纤维素对纯品是通用名，是部分解聚的纤维素产生的晶粉(由多孔颗粒组成)。已知商业名为AVICEL(微晶纤维素)，广泛用于辅助剂。某些级别的微晶纤维素，特别是AVICEL RC581，含有大约11wt％羧甲基纤维素钠湿粘合剂，而根据本发明，应用湿粘合剂(最好用微晶纤维素PH-102)也仅在10wt％以下。微细纤维素(ELCEMATM)也为粉末状纤维素，是由植物纤维材料经机械加工产生的α-纤维素。是一个普通的药物粘合剂和崩解剂。
在本说明书和权利要求书中“纤维素产物”特指微晶纤维素和微细纤维素及二者的混合物。纤维素产物的用量可为有效成分重量的20-100％，最好用量是35-45％。
可使用的已知各种成粒液体为二氯甲烷和异丙醇，但最好用水。根据有效物质的重量，成粒液体的用量可为40-135wt％，最好用量是60-90wt％
在颗粒混合物中，上述那些湿粘合剂的使用，根据有效物质的重量，应当避免或至少限制在不大于0.5wt％，最好在0.1wt％以下。否则，由这种颗粒制备的片剂的崩解性能受到不利影响。
许多上述有效物没有满意的流动性，导致压片混合物难以加工，而新颗粒及新颗粒制成的混合物，流动模式有大大改善。根据所说的标准试验，粉末可以不停流过的最窄流杯孔不宽于12mm，并且往往更窄。
本发明的颗粒照这样在水中迅速分散。任意选择一种或多种辅助剂由制成的颗粒所压的药片，进入大约20℃水中时，崩解性能非常好，一般在60秒内形成没有粗块的极好的悬浮液。
按照本发明制成的颗粒和包含这些颗粒的压片混合物的流动性能，可通过类杯样漏斗孔直径作为参数来定量，通过这种漏斗孔粉末可不停地流动。如果粉末可通过2.5mm的孔不停地流动，那么其流动性能就被定为“极好”。园筒形玻璃流动杯，长大约65mm，直径大约39mm。低呈园锥形，中间有孔。衬有氧化硅烷的杯，装上大约半杯的粉末。试验步骤开始，打开流动杯孔使粉末流动，只要流动以后，就应当不停地流出杯子直至流完为止。所使用的额定值为：
杯号 孔径 性能
1 2.5mm 优
2 5.0mm 良
3 8.0mm 中
4 12.0mm 合格
5 18.0mm 差
6 - 极差
通过以下实例对本发明做进一步阐述，然而本发明的解释并不限于此。
除非另有说明，本发明的百分数都是以有效物的重量为依据的。
所示分散时间系指用按实例28的配方所得颗粒制成的片剂，在大约20℃的水中的崩解度。CPS代表“厘泊”(粘度单位)低取代的羟丙基纤维素，是用LH11或者是用1-HPC表示。
实例1-27
按照下表所列的药物与40wt％(表1)，或100wt％(表2)微晶纤维素(AVICEL PH-102)和表1及表2中所述的水量混合。所得湿团物过2mm目筛，然后在大约60℃的流化床干燥器内干燥大约1小时。所得干颗粒过0.8mm目的筛并收集起来。
表1实例 含有40wt微晶纤维素 成粒 压片 颗粒 片剂崩解
AVICEL PH-102 液体 混合物 流孔 时间*(秒)
的有疗效化合物 wt％ 流孔 (mm)
(mm)1 乙胺碘呋酮 64 5 5 452 阿莫西林 64 5 5 503 甲腈咪胍 70 5 5 254 氯霉素 77 5 5 255 增效磺胺甲基异噁唑 64 8 12 256 强力霉素一水合物 64 2 2 207 氟甲喹 75 2 2 258 痢特灵 64 5 5 309 水化碳酸氢氧化铝镁 118 5 5 1010 布洛芬 84 5 12 4011 消炎痛 81 5 5 2512 L-多巴 84 5 5 2013 醋氨酚 91 5 5 2514 青霉青-V酸 64 2 2 2015 吡哌酸 77 5 5 2016 吡咯昔康 84 5 8 2017 黄体酮 65 5 5 4018 普罗孕酮 71 2 2 2519 土霉素二水合物 64 2 2 3520 磺胺甲基异噁唑 71 5 12 2021 舒林酸 94 5 5 2022 安体舒痛 70 2 2 2023 萘碱 64 2 2 20*在20℃左右的水中。
表2实例 含有100wt ％ 成粒 压片 颗粒 片剂崩解
AVICEL PH-102 液体 混合物 流孔 时间(秒)
的有疗效化合物 wt％ 流孔 (mm)
(mm)24 红霉素琥珀酸乙酯 133 8 12 5025 萘普生 133 5 5 2526 吡罗昔康 110 5 5 2027 甲氧苄啶 133 8 12 30*在20℃左右的水中
实例28
根据前面实例所得颗粒，与下面配方制成混合物以通常方法压片
90.25g 颗粒
1.45g 微晶纤维素
5.34g 低取代的羟丙基纤维素
2.00g 调味剂
0.16g 胶体硅胶
0.80g 硬脂酸镁
使每种压片混合物通过流杯，以测定最小流孔，经过该孔每种混合物能一直不停地流动，这种结果列于上面的表1和表2。
得到的15mm片剂的硬度为100-150N，崩解时间列于表1和表2。该崩解时间是应用通常的USP崩解试验仪(ERWEKA)进行测定的。
实例29
200g阿莫西林(羟氨苄青霉素(三水合物与80g微细纤维素(ELCEMA G400)及150ml水混合。产生的湿团物捏合20分钟，过2mm目的筛，在流化床干燥器内，60℃左右大约干燥1小时，直至颗粒含水在10.5wt％以下。产生的干燥颗粒过0.8mm目筛并收集。
实例30
50g 实例29制备的干颗粒
3.09g 微细纤维素(ELCEMA G400)
3.09g 1-HPC
0.1g 胶体硅胶
0.56g 糖精
0.62g 调味剂
0.47g 硬脂酸镁
本颗粒与其他赋形剂混合10分钟以后所得混合物，在旋转压片机上压成片。制备的960mg片剂的硬度为106N，在20℃水中的崩解度为40秒以内。
实例31
100g 按实例2制成的含阿莫西林的颗粒
6.18g 微晶纤维素(AVICEL PH-102)
6.18g 交联聚乙烯吡咯烷酮(KOLLIDON CL)
0.19g 胶体硅胶
0.93g 硬脂酸镁
按实例30的方法制得的955mg片剂的硬度为107N，在20℃水中的崩解度为26秒。
实例32
单水合强力霉素(105.8g)和微晶纤维素(AVICEL PH-102)(45g)以行量式混合器混合15分钟。混合物以60mL水制粒。捏合10分钟后得到的湿团物过2mm目筛，湿颗粒在40℃左右干燥直至所含水分在2％以下。所得颗粒过0.71mm目筛，与下列物质混合20分钟：18g低取代羟丙基纤维素LH11，4g羟丙基甲基纤维素5CPS，10g糖精，0.6g胶体硅胶，再加乳糖至总量为248g。加2g硬脂酸镁继续混合2分钟。所得混合物压成约250mg的片剂，直径约9mm、硬度68-97N，或者压成约125mg的片子，硬度为58-87N，这两种片剂在20℃水中30-45秒内完全崩解。
实例33-36
根据表3所到的药物与40wt％微晶纤维素(AVICEL PH-102)和0.1wt％聚乙烯吡咯烷酮(PVPK30，平均分子量49000)混合。所得混合物与表3所述的水量混合制粒。所得团状物过2mm目筛，然后在60℃干燥过夜，干燥物过0.8mm目筛并收集起来。
表3实例 有疗效化合物 水 制片 颗粒 片分散度*
混合物 流孔 (秒)
wt％ 流孔 (mm)
(mm)33 磺胺甲基异噁唑 77 8 12 4334 甲基苄啶 84 5 8 4035 增效磺胺甲基异噁唑 77 5 5 3036 布洛芬 98 5 5 30*在大约20℃水中
实例37
根据实例33-36所得的颗粒用于下列混合物压片：
45.13g 颗粒
0.63g 微晶纤维素
2.67g 低取代羟丙基纤维素
1.00g 调味剂
0.08g 胶体硅胶
0.40g 硬脂酸镁
以流杯测定压片混合物的流动性。使每种混合物可不断地流动所穿过的最小孔可在表3中找到。所压的1130mg片剂，直径15mm，硬度100-150N。用USP崩解试验仪(ERWEKA)测定了在20℃水中的崩解时间。结果列于表3。
实例38
7.145g红霉素琥珀酸乙酯与0.0071g PVP K30和2.86g微晶纤维素混合。混合物用5mL异丙醇制成湿颗粒。产生的颗粒过2mm目筛，然后在60℃干燥过夜。干燥的颗粒过0.8mm目筛后，经过8mm孔的流杯不间断地流动。9g的颗粒与下列配料混合：
145mg 微晶纤维素
530mg 低取代羟丙基纤维素
200mg 调味剂
16mg 胶体硅胶
80mg 硬脂酸镁
所得压片混合物能不停地流过5mm的孔。所压的1130mg片剂(直径15mm)硬度100-150N。压制的片剂在20℃水中的崩解时间是40-50秒。
Claims (19)
1.通过湿法制粒制备可不间断地流过不宽于12mm流动杯孔的药物颗粒的方法，该方法包括下列步骤：
a.将水中溶解度小于10wt％的有效成分，20-100wt％纤维素产物，即微晶纤维素或微细纤维素或二者的混合物，和0-0.5wt％湿法制粒粘合剂与制粒水溶液混合成湿团块，所说的赋形剂的百分比以有效成分为基准，
b.将湿团块加工成颗粒，其特征在于该方法进一步包括下列步骤：
c.使所说的湿团块通过第一个筛，
d.使筛分的颗粒干燥，
e.使干燥的颗粒通过第二个筛，
f.收集所得颗粒。
2.根据权利要求1的方法，其特征在于颗粒包含至少50wt％的有效成分。
3.根据权利要求1的方法，其特征在于颗粒含有为有效成分的0-0.1wt％的湿法制粒粘合剂。
4.根据权利要求2的方法，其特征在于颗粒含有为有效成分的0-0.1wt％的湿法制粒粘合剂。
5.根据权利要求1的方法，其特征在于有效成分在水中的溶解度小于5wt％。
6.根据权利要求2的方法，其特征在于有效成分在水中的溶解度小于5wt％。
7.根据权利要求3的方法，其特征在于有效成分在水中的溶解度小于5wt％。
8根据权利要求4的方法，其特征在于有效成分在水中的溶解度小于5wt％。
9.根据权利要求1的方法，其特征在于颗粒含有为有效成分的35-45wt％的纤维素产物。
10.根据权利要求2的方法，其特征在于颗粒含有为有效成分的35-45wt％的纤维素产物。
11.根据权利要求3的方法，其特征在于颗粒含有为有效成分的35-45wt％的纤维素产物。
12.根据权利要求4的方法，其特征在于颗粒含有为有效成分的35-45wt％的纤维素产物。
13.根据权利要求5的方法，其特征在于颗粒含有为有效成分的35-45wt％的纤维素产物。
14.根据权利要求6的方法，其特征在于颗粒含有为有效成分的35-45wt％的纤维素产物。
15.根据权利要求7的方法，其特征在于颗粒含有为有效成分的35-45wt％的纤维素产物。
16.根据权利要求8的方法，其特征在于颗粒含有为有效成分的35-45wt％的纤维素产物。
17.根据权利要求1，2，3，4，5，6，7，8，9，10，11，12，13，14，15或16的方法，其特征在于有效成分是两性β内酰胺抗菌素。
18.根据权利要求1，2，3，4，5，6，7，8，9，10，11，12，13，14，15或16的方法，其特征在于有效成分是四环素抗菌素。
19.根据权利要求1，2，3，4，5，6，7，8，9，10，11，12，13，14，15或16的方法，其特征在于有效成分是水化碳酸氢氧化铝镁
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| IT1246188B (it) * | 1990-07-27 | 1994-11-16 | Resa Farma | Procedimento per la preparazione di composizioni farmaceutiche aventi aumentata velocita' di dissoluzione della sostanza attiva e composizioni ottenute. |
| IE77165B1 (en) * | 1991-01-30 | 1997-12-03 | Wellcome Found | Water-dispersible tablet containing acyclovir |
| US5629016A (en) * | 1991-01-30 | 1997-05-13 | Glaxo Wellcome Inc. | Water-dispersible tablets |
| DE69331839T2 (de) * | 1992-01-29 | 2002-12-12 | Takeda Chemical Industries, Ltd. | Schnellösliche Tablette und ihre Herstellung |
| DE9321574U1 (de) * | 1992-03-11 | 2000-06-29 | Asta Medica Ag, 01277 Dresden | Tabletten, Granulate und Pellets mit hohem Gehalt an Wirkstoffen für hochkonzentrierte, feste Darreichungsformen |
| JP2964195B2 (ja) * | 1992-04-28 | 1999-10-18 | エスエス製薬株式会社 | ピロキシカム錠及びその製造法 |
| GB9215908D0 (en) * | 1992-07-27 | 1992-09-09 | Wellcome Found | Water dispersible tablets |
| US5698226A (en) * | 1993-07-13 | 1997-12-16 | Glaxo Wellcome Inc. | Water-dispersible tablets |
| CA2159419C (en) * | 1994-10-17 | 2006-07-04 | Pieter De Haan | Solid pharmaceutical composition comprising an excipient capable of binding water |
| SE504902C2 (sv) * | 1994-11-02 | 1997-05-26 | Diabact Ab | Beredning för påvisande av Helicobacter pylori i magsäcken |
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| SK3999A3 (en) * | 1996-07-16 | 1999-07-12 | Gist Brocades Nv | 'beta'-lactam granules free of organic solvents |
| DE69728290T2 (de) * | 1996-08-14 | 2004-08-05 | Yamanouchi Europe B.V. | Eine wasserlösliche verbindung und cellulose enhaltende granulate |
| AU1970797A (en) * | 1997-02-25 | 1998-09-09 | Procter & Gamble Company, The | Wet granulating method |
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| GB9720061D0 (en) | 1997-09-19 | 1997-11-19 | Crosfield Joseph & Sons | Metal compounds as phosphate binders |
| WO1999018965A1 (en) * | 1997-10-10 | 1999-04-22 | Yamanouchi Europe B.V. | Oral compositions containing a cephalosporin antibiotic |
| FR2772617B1 (fr) * | 1997-12-19 | 2001-03-09 | Besins Iscovesco Lab | Comprime de progesterone et son procede de preparation |
| EP2298298A3 (en) * | 1998-12-23 | 2011-05-11 | Novartis AG | Use of AT-1 receptor antagonist or AT-2 receptor modulator for treating diseases associated with an increase of AT-1 or AT-2 receptors |
| EA003052B1 (ru) | 1999-07-27 | 2002-12-26 | Балканфарма Холдинг АД | Антиаритмическое лекарственное средство |
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| RU2181290C1 (ru) * | 2001-04-26 | 2002-04-20 | Открытое акционерное общество "Химико-фармацевтический комбинат "Акрихин" | Фармацевтическая композиция, обладающая антимикробным действием |
| EP1469829B1 (en) * | 2002-02-01 | 2016-01-27 | Bend Research, Inc | Immediate release dosage forms containing solid drug dispersions |
| US6958161B2 (en) * | 2002-04-12 | 2005-10-25 | F H Faulding & Co Limited | Modified release coated drug preparation |
| RU2237478C2 (ru) * | 2002-12-25 | 2004-10-10 | Открытое акционерное общество "Химико-фармацевтический комбинат "Акрихин" | Антимикробная фармацевтическая композиция |
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| MY157620A (en) * | 2006-01-31 | 2016-06-30 | Cytochroma Dev Inc | A granular material of a solid water-soluble mixed metal compound capable of binding phosphate |
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| GB0714670D0 (en) * | 2007-07-27 | 2007-09-05 | Ineos Healthcare Ltd | Use |
| GB0720220D0 (en) * | 2007-10-16 | 2007-11-28 | Ineos Healthcare Ltd | Compound |
| GB0913525D0 (en) | 2009-08-03 | 2009-09-16 | Ineos Healthcare Ltd | Method |
| GB201001779D0 (en) | 2010-02-04 | 2010-03-24 | Ineos Healthcare Ltd | Composition |
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| JPS5438167B2 (zh) * | 1974-04-27 | 1979-11-19 | ||
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-
1989
- 1989-02-20 EP EP89200430A patent/EP0330284B1/en not_active Expired - Lifetime
- 1989-02-20 AT AT89200430T patent/ATE108996T1/de not_active IP Right Cessation
- 1989-02-20 ES ES89200430T patent/ES2060737T3/es not_active Expired - Lifetime
- 1989-02-20 DE DE68916983T patent/DE68916983T2/de not_active Expired - Lifetime
- 1989-02-21 CA CA000591676A patent/CA1338553C/en not_active Expired - Lifetime
- 1989-02-21 IE IE54589A patent/IE69366B1/en not_active IP Right Cessation
- 1989-02-21 AU AU30158/89A patent/AU611999B2/en not_active Expired
- 1989-02-22 IL IL89378A patent/IL89378A/xx unknown
- 1989-02-24 NZ NZ228122A patent/NZ228122A/xx unknown
- 1989-02-24 PT PT89823A patent/PT89823B/pt not_active IP Right Cessation
- 1989-02-24 US US07/315,268 patent/US5085869A/en not_active Expired - Lifetime
- 1989-02-24 KR KR1019890002201A patent/KR0135289B1/ko not_active Expired - Lifetime
- 1989-02-24 FI FI890884A patent/FI100219B/fi not_active IP Right Cessation
- 1989-02-24 NO NO890789A patent/NO178485C/no not_active IP Right Cessation
- 1989-02-24 DK DK198900863A patent/DK175306B1/da not_active IP Right Cessation
- 1989-02-25 CN CN89101157A patent/CN1048395C/zh not_active Expired - Lifetime
- 1989-02-27 JP JP1046330A patent/JP2939262B2/ja not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| IL89378A (en) | 1993-01-31 |
| FI890884L (fi) | 1989-08-26 |
| DK86389A (da) | 1989-08-26 |
| KR0135289B1 (ko) | 1998-04-23 |
| ATE108996T1 (de) | 1994-08-15 |
| EP0330284A3 (en) | 1990-11-07 |
| EP0330284A2 (en) | 1989-08-30 |
| US5085869A (en) | 1992-02-04 |
| AU3015889A (en) | 1989-08-31 |
| CN1035433A (zh) | 1989-09-13 |
| KR900012603A (ko) | 1990-09-01 |
| DE68916983T2 (de) | 1995-01-19 |
| NZ228122A (en) | 1991-04-26 |
| AU611999B2 (en) | 1991-06-27 |
| DE68916983D1 (de) | 1994-09-01 |
| IE69366B1 (en) | 1996-09-04 |
| FI100219B (fi) | 1997-10-31 |
| EP0330284B1 (en) | 1994-07-27 |
| NO890789L (no) | 1989-08-28 |
| FI890884A0 (fi) | 1989-02-24 |
| JPH023606A (ja) | 1990-01-09 |
| PT89823A (pt) | 1989-10-04 |
| DK86389D0 (da) | 1989-02-24 |
| CA1338553C (en) | 1996-08-27 |
| PT89823B (pt) | 1994-04-29 |
| JP2939262B2 (ja) | 1999-08-25 |
| IL89378A0 (en) | 1989-09-10 |
| ES2060737T3 (es) | 1994-12-01 |
| DK175306B1 (da) | 2004-08-16 |
| NO178485C (no) | 1996-04-10 |
| NO178485B (no) | 1996-01-02 |
| IE890545L (en) | 1989-08-25 |
| NO890789D0 (no) | 1989-02-24 |
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