CN1237958C - 一种非缓释的、非咀嚼的药物片剂组合物 - Google Patents
一种非缓释的、非咀嚼的药物片剂组合物 Download PDFInfo
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- CN1237958C CN1237958C CNB998062316A CN99806231A CN1237958C CN 1237958 C CN1237958 C CN 1237958C CN B998062316 A CNB998062316 A CN B998062316A CN 99806231 A CN99806231 A CN 99806231A CN 1237958 C CN1237958 C CN 1237958C
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- chewing
- slow release
- pharmaceutical tablet
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- 239000007916 tablet composition Substances 0.000 title claims abstract description 39
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 title description 6
- 229960005319 delavirdine Drugs 0.000 title description 3
- 239000003814 drug Substances 0.000 claims abstract description 38
- 229940079593 drug Drugs 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 10
- 238000010438 heat treatment Methods 0.000 claims abstract description 9
- 238000000227 grinding Methods 0.000 claims abstract description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 42
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 38
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 38
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 38
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 37
- 230000001055 chewing effect Effects 0.000 claims description 32
- 238000001556 precipitation Methods 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 24
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 22
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 21
- 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 claims description 19
- XNZFUKOVJVOLPE-UHFFFAOYSA-N furan;pyridine Chemical compound C=1C=COC=1.C1=CC=NC=C1 XNZFUKOVJVOLPE-UHFFFAOYSA-N 0.000 claims description 19
- 229960001375 lactose Drugs 0.000 claims description 19
- 239000008101 lactose Substances 0.000 claims description 19
- -1 Hydroxypropyl Chemical group 0.000 claims description 16
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 15
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 15
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 15
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 15
- 239000000314 lubricant Substances 0.000 claims description 12
- 238000004132 cross linking Methods 0.000 claims description 11
- 235000019359 magnesium stearate Nutrition 0.000 claims description 11
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000000853 adhesive Substances 0.000 claims description 10
- 230000001070 adhesive effect Effects 0.000 claims description 10
- 239000008119 colloidal silica Substances 0.000 claims description 10
- 239000000843 powder Substances 0.000 claims description 10
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 9
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 8
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 8
- 229960001021 lactose monohydrate Drugs 0.000 claims description 8
- 229920000642 polymer Polymers 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 6
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 6
- 239000007921 spray Substances 0.000 claims description 6
- 229920002125 Sokalan® Polymers 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 150000003839 salts Chemical group 0.000 claims description 4
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 3
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 230000036760 body temperature Effects 0.000 claims description 3
- 239000012530 fluid Substances 0.000 claims description 3
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 3
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 3
- 229920000609 methyl cellulose Polymers 0.000 claims description 3
- 239000001923 methylcellulose Substances 0.000 claims description 3
- 235000010981 methylcellulose Nutrition 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 238000004088 simulation Methods 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- DVWJFTGEISXVSH-CWVFEVJCSA-N (1R,3S,5S,7Z,11R,12S,13Z,15Z,17Z,19Z,21R,23S,24R,25S)-21-[(2R,3S,4S,5S,6R)-4-amino-3,5-dihydroxy-6-methyloxan-2-yl]oxy-12-ethyl-1,3,5,25-tetrahydroxy-11-methyl-9-oxo-10,27-dioxabicyclo[21.3.1]heptacosa-7,13,15,17,19-pentaene-24-carboxylic acid Chemical compound CC[C@H]1\C=C/C=C\C=C/C=C\[C@@H](C[C@@H]2O[C@@](O)(C[C@H](O)[C@H]2C(O)=O)C[C@@H](O)C[C@@H](O)C\C=C/C(=O)O[C@@H]1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](N)[C@@H]1O DVWJFTGEISXVSH-CWVFEVJCSA-N 0.000 claims description 2
- ZERWDZDNDJBYKA-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O ZERWDZDNDJBYKA-UHFFFAOYSA-N 0.000 claims description 2
- LFKMOLWAKAJMHB-LFPSBFENSA-N (2R,3R,4S,5R,6S)-2-(hydroxymethyl)-6-[(2R,3S,4R,5R,6R)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol dihydrate Chemical compound O.O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O LFKMOLWAKAJMHB-LFPSBFENSA-N 0.000 claims description 2
- YCIHPQHVWDULOY-FMZCEJRJSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide;hydrochloride Chemical compound Cl.C1=CC=C2[C@](O)(C)[C@H]3C[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 YCIHPQHVWDULOY-FMZCEJRJSA-N 0.000 claims description 2
- AKUVRZKNLXYTJX-UHFFFAOYSA-N 3-benzylazetidine Chemical compound C=1C=CC=CC=1CC1CNC1 AKUVRZKNLXYTJX-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- ZNIFSRGNXRYGHF-UHFFFAOYSA-N Clonidine hydrochloride Chemical compound Cl.ClC1=CC=CC(Cl)=C1NC1=NCCN1 ZNIFSRGNXRYGHF-UHFFFAOYSA-N 0.000 claims description 2
- IJHNSHDBIRRJRN-UHFFFAOYSA-N N,N-dimethyl-3-phenyl-3-(2-pyridinyl)-1-propanamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=CC=C1 IJHNSHDBIRRJRN-UHFFFAOYSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- DOQPXTMNIUCOSY-UHFFFAOYSA-N [4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]-[2-(3,4-dimethoxyphenyl)ethyl]-methylazanium;chloride Chemical compound [H+].[Cl-].C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 DOQPXTMNIUCOSY-UHFFFAOYSA-N 0.000 claims description 2
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 claims description 2
- BNPSSFBOAGDEEL-UHFFFAOYSA-N albuterol sulfate Chemical compound OS(O)(=O)=O.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 BNPSSFBOAGDEEL-UHFFFAOYSA-N 0.000 claims description 2
- KLOHDWPABZXLGI-YWUHCJSESA-M ampicillin sodium Chemical compound [Na+].C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C([O-])=O)(C)C)=CC=CC=C1 KLOHDWPABZXLGI-YWUHCJSESA-M 0.000 claims description 2
- ANFSNXAXVLRZCG-RSAXXLAASA-N benzphetamine hydrochloride Chemical compound [Cl-].C([C@H](C)[NH+](C)CC=1C=CC=CC=1)C1=CC=CC=C1 ANFSNXAXVLRZCG-RSAXXLAASA-N 0.000 claims description 2
- 229960003150 bupivacaine Drugs 0.000 claims description 2
- SIEYLFHKZGLBNX-UHFFFAOYSA-N bupivacaine hydrochloride (anhydrous) Chemical compound [Cl-].CCCC[NH+]1CCCCC1C(=O)NC1=C(C)C=CC=C1C SIEYLFHKZGLBNX-UHFFFAOYSA-N 0.000 claims description 2
- 229960003291 chlorphenamine Drugs 0.000 claims description 2
- 229960001657 chlorpromazine hydrochloride Drugs 0.000 claims description 2
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 claims description 2
- 229960001200 clindamycin hydrochloride Drugs 0.000 claims description 2
- 229960002925 clonidine hydrochloride Drugs 0.000 claims description 2
- 229960001258 fluphenazine hydrochloride Drugs 0.000 claims description 2
- 235000013305 food Nutrition 0.000 claims description 2
- XHILEZUETWRSHC-NRGUFEMZSA-N hydromorphone hydrochloride Chemical compound [H+].[Cl-].O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O XHILEZUETWRSHC-NRGUFEMZSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- RGPDIGOSVORSAK-STHHAXOLSA-N naloxone hydrochloride Chemical compound Cl.O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C RGPDIGOSVORSAK-STHHAXOLSA-N 0.000 claims description 2
- 229960005250 naloxone hydrochloride Drugs 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 229960001190 pheniramine Drugs 0.000 claims description 2
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 claims description 2
- 229960001802 phenylephrine Drugs 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 239000000454 talc Substances 0.000 claims description 2
- 235000012222 talc Nutrition 0.000 claims description 2
- 229910052623 talc Inorganic materials 0.000 claims description 2
- 229930183279 tetramycin Natural products 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 229960000881 verapamil hydrochloride Drugs 0.000 claims description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000000835 fiber Substances 0.000 claims 1
- 229940031705 hydroxypropyl methylcellulose 2910 Drugs 0.000 claims 1
- 239000011230 binding agent Substances 0.000 abstract description 18
- 230000001376 precipitating effect Effects 0.000 abstract 2
- 238000013268 sustained release Methods 0.000 abstract 1
- 239000012730 sustained-release form Substances 0.000 abstract 1
- 239000003826 tablet Substances 0.000 description 22
- 239000000463 material Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000000975 co-precipitation Methods 0.000 description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 description 3
- 238000007906 compression Methods 0.000 description 3
- 230000006835 compression Effects 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 2
- 239000007910 chewable tablet Substances 0.000 description 2
- 229940068682 chewable tablet Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000007891 compressed tablet Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 239000007888 film coating Substances 0.000 description 2
- 238000009501 film coating Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 238000005498 polishing Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000007962 solid dispersion Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- IIUZTXTZRGLYTI-UHFFFAOYSA-N Dihydrogriseofulvin Natural products COC1CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 IIUZTXTZRGLYTI-UHFFFAOYSA-N 0.000 description 1
- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 description 1
- 229920003114 HPC-L Polymers 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- DDUHZTYCFQRHIY-UHFFFAOYSA-N Negwer: 6874 Natural products COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- XLMALTXPSGQGBX-GCJKJVERSA-N dextropropoxyphene Chemical compound C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 XLMALTXPSGQGBX-GCJKJVERSA-N 0.000 description 1
- 229960004193 dextropropoxyphene Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- DDUHZTYCFQRHIY-RBHXEPJQSA-N griseofulvin Chemical compound COC1=CC(=O)C[C@@H](C)[C@@]11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-RBHXEPJQSA-N 0.000 description 1
- 229960002867 griseofulvin Drugs 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- ZKJKXGCLZUMGNT-UHFFFAOYSA-N methanesulfonic acid;piperazine Chemical compound CS(O)(=O)=O.C1CNCCN1 ZKJKXGCLZUMGNT-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 229960002036 phenytoin Drugs 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 239000002491 polymer binding agent Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 238000005550 wet granulation Methods 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
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (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)
- Cephalosporin Compounds (AREA)
Abstract
本发明公开了一种非缓释的药物片剂组合物,它包含约5-60%的快速沉淀的药物和至少一种选自约2-25%的粘合剂和约6-40%的超崩解剂的物质,其中将快速沉淀的药物、“粘合剂”和超崩解剂混合并压缩成片剂,而无需加热、溶剂或研磨。
Description
本发明是一种降低快速沉淀药物的沉淀速率并改善溶解性的片剂。
美国专利5563142(实施例105)公开了代呋啶(delavirdine)。
基于PCT专利申请PCT/US 95/02166的国际公开号WO 95/28398公开了“S”和“T”两种结晶形式的甲磺酸代呋啶。
美国专利5358941公开了一种压缩片,该片含约0.5-40%活性成分、约10-80%无水乳糖、约5-50%(重量)微晶纤维素、约0.5-10%(重量)交联羧甲基纤维素钠和约0.1-5%硬脂酸镁。本发明的药物片剂不需要乳糖。
专利EP 283925公开了在高剪切力作用下使用基于溶剂的聚合物将沉淀切分为最小的颗粒以纯化可吸收聚酯产物的方法。在本发明中,在与其它成分配制之前,聚合物与快速沉淀的药物在任何溶剂系统中都不会产生共沉淀,但在常规的压制片剂中是依赖于干粘合剂或超崩解剂与快速沉淀的药物的紧密接近性。
International Journal of Pharmaceutics,154,59-66(1997)公开了在液体系统中使用各种聚合物比例的HPMC、HPC和PVP从而延迟沉淀的方法。所述方法包括通过共沉淀方法或研磨方法制备固体分散体以提高溶解度特性。本发明使用常规的直接压片方法而不使用任何固体分散体技术,例如通过使用溶剂的共沉淀方法或实现共沉淀的研磨方法。
A.Wade和P.J.Weller编辑的Handbook of Drug Excipients,2nd,Ed.,1994年第141页和许多其它药学参考文献描述了使用含量占制剂1-2%但不高于5%的超崩解剂,例如交联羧甲基纤维素钠帮助片剂崩解的常规用途。由于交联羧甲基纤维素钠胶凝形成松散的基质,而这种基质公知会阻碍许多药物化合物的溶解,因此不使用或不建议使用更高含量。本发明使用了高于6%的交联羧甲基纤维素钠。
A.Wade和P.J.Weller编辑的Handbook of Drug Excipients,2nd,Ed.,1994年第223、229和392页及许多其它药学参考文献描述了水溶性聚合物,例如HPMC、HPC-L和PVP在速释或缓释片剂中作为粘合剂(湿粘合剂或干粘合剂)的常规用途。对于非缓释应用,这些粘合剂的用量不高于5%。由于会阻碍许多药物的溶解速率,不建议使用更高的含量。高于5%的这些粘合剂,尤其是HPMC通常仅用于缓释剂型,并且这些粘合剂通常是高分子量的。在本发明中,粘合剂的用量高于5%。
美国专利5225197公开了一种咀嚼片。但本发明不是咀嚼片。
JP 84-185584公开了通过加热将HPC、PVP和其它粘合剂与难溶性药物一起使用。而本发明不使用加热方法。
本发明公开了一种非缓释的药物片剂组合物,包含:约5-60%的快速沉淀的药物;微晶纤维素和至少一种选自约2-25%的粘合剂和约6-40%的超崩解剂的物质,其中将快速沉淀的药物、微晶纤维素、粘合剂和超崩解剂混合并压缩成片剂,而无需加热、溶剂或研磨。
还公开了一种非缓释的药物片剂组合物,组成是:
含量(大约范围)
成分
%
甲磺酸代呋啶 10-40
羟丙基甲基纤维素 5-20
交联羧甲基纤维素钠 6-35
微晶纤维素 10-50
乳糖 0-15
胶态二氧化硅 0-5
硬脂酸镁 0-5
其中将甲磺酸代呋啶、微晶纤维素、羟丙基甲基纤维素和交联羧甲基纤维素钠混合并压缩成片,而无需加热、溶剂或研磨。
本发明的片剂需快速沉淀的药物(5-60%)、微晶纤维素(10-50%)、粘合剂(2-25%)和超崩解剂(6-40%)。虽然不是所必需,但理想地是它通常使用一种或多种下列药学成分:微晶纤维素(0-50%)、乳糖(0-80%)、助流剂(0-5%)和润滑剂(0-5%)。
快速沉淀的药物是药物化合物或其盐形式,在体温下,当将其引入水中或模拟生理体液时,在60分钟内,药物开始相当快的溶解,然后开始从溶液中快速沉淀出来成为微溶的形式,提供低于治疗浓度的浓度。这种沉淀导致缓慢的和不完全性溶解。在多数情况下,沉淀的量可高达90%或高于90%,使药物水平达到治疗活性的约10%或10%以下。快速沉淀的药物优选是溶解性较差的游离碱或游离酸药物的相当易溶或易溶的盐形式或者溶解性较差的游离碱或游离酸药物的无水形式。本领域技术人员公知,快速沉淀的药物易于过饱和。快速沉淀的药物优选选自甲磺酸代呋啶、苯妥英、呋塞米、假麻黄碱、盐酸氯洁霉素、盐酸可乐定(cloridine)、盐酸苯海拉明、盐酸氟奋乃静、灰黄霉素、盐酸氢吗啡酮、盐酸纳洛酮、盐酸土霉素、盐酸苯福林、马来酸苯吡胺、盐酸四环素、盐酸维拉帕米、盐酸丙氧芬、萘磺酸丙氧酚、重酒石酸二氢可待因(hydrocodine)、阿昔洛韦钠、硫酸沙丁胺醇、氨苄青霉素钠、甲磺酸苯托品、盐酸苄非他明、盐酸丁哌卡因、盐酸安非他酮(bupropin)、马来那敏、盐酸氯丙嗪。快速沉淀的药物最优选是甲磺酸代呋啶。快速沉淀的药物的含量应为约5-60%,优选约10-40%。
代呋啶,1-[5-甲磺酰氨基吲哚基-2-羰基]-4-[3-(1-甲基乙基-氨基)-2-吡啶基]哌嗪是已知的,参见美国专利5563142(实施例105)。“S”和“T”两种不同结晶形式的甲磺酸代呋啶也是公知的,参见基于PCT专利申请PCT/US 95/02166的国际公告WO 95/28398。
本发明的片剂形式是非缓释的药物片剂组合物,它含有约5-60%的快速沉淀的药物;微晶纤维素(10-50%)和至少一种选自约2-25%的粘合剂和约6-40%的超崩解剂的物质,其中将快速沉淀的药物、微晶纤维素、粘合剂和超崩解剂混合并压缩成片剂,而无需加热、溶剂或研磨。优选粘合剂、微晶纤维素和超崩解剂三者都存在。
本发明的片剂可使用粘合剂。粘合剂优选选自羟丙基甲基纤维素、PVP、羟丙基纤维素、微晶纤维素、羟甲基纤维素、卡波普和羧甲基纤维素钠;粘合剂更优选选自羟丙基甲基纤维素,尤其是2910(U.S.P.,3cps)。还优选是PVP。粘合剂优选为约5-20%的羟丙基甲基纤维素,约2-15%的PVP,约5-20%的羟丙基纤维素或羟乙基纤维素,约3-20%的卡波普、甲基纤维素和羧甲基纤维素钠。对于本领域技术人员来说显而易见,本发明的粘合剂是完全不同于非聚合物粘合剂的聚合物粘合剂。
超崩解剂选自交联羧甲基纤维素钠、淀粉乙醇酸钠、L-羟丙基纤维素;超崩解剂更优选是交联羧甲基纤维素。超崩解剂的含量应为约6-40%。超崩解剂的含量优选为约6-35%;更优选为约10-30%。超崩解剂是对快速沉淀的药物起延迟沉淀作用的物质之一。
制备本发明的片剂不是绝对需要微晶纤维素。但在大多数情况下,理想地是含有微晶纤维素。片剂可用微晶纤维素作为稀释剂。当含有微晶纤维素时,微晶纤维素优选选自微晶纤维素粗粉、微晶纤维素中等细度的粉和微晶纤维素200;微晶纤维素更优选是微晶纤维素N.F.粗粉。微晶纤维素的含量应为约5-50%。微晶纤维素的含量优选为约10-50%。
制备本发明的片剂不是绝对需要乳糖。但在大多数情况下,理想地是可含有高达约80%的乳糖。当含有乳糖时,乳糖优选选自喷雾方法标准的乳糖一水合物、乳糖一水合物、无水乳糖、乳糖二水合物、DMV乳糖;乳糖更优选是喷雾方法标准的乳糖一水合物N.F.。乳糖的含量应为约0-80%。乳糖的含量优选为约5-20%。
制备本发明的片剂不是绝对需要助流剂。但在大多数情况下,理想地是含有助流剂。当含有助流剂时,它优选选自胶态二氧化硅和滑石;助流剂更优选选自胶态二氧化硅N.F.。当存在助流剂时,其含量至多为约5%。助流剂的含量优选为约0.25-2%。
制备本发明的片剂不绝对需要润滑剂。但在大多数情况下,理想地是含有润滑剂。当含有润滑剂时,它优选选自硬脂酸镁和硬脂酸;润滑剂更优选是硬脂酸镁。当含有润滑剂时,其含量至多为约5%。润滑剂的含量优选为约0.25-2%。
本领域技术人员公知,可按照本领域公知的技术,对片剂进行着色、调味和/或膜包衣。
按照本领域技术人员公知的直接压制技术制备本发明的片剂组合物。优选首先将快速沉淀的药物与微晶纤维素通过本领域技术人员熟知的方法,优选使用高剪切混合机进行充分混合。将羟丙基甲基纤维素、交联羧甲基纤维素、乳糖和过筛的胶态二氧化硅单独混合,优选在高剪切混合机中混合,并将其加到药物-微晶纤维素混合物中,再将所有的成分充分混合,优选在高剪切混合机中混合。将硬脂酸镁过筛,加入药物混合物中并混合均匀。将所得的混合物通过本领域技术人员熟知的方法压缩制备为含有所需量的活性药物物质的片剂。可按照本领域技术人员公知的方法,对这些片剂进行包衣和抛光。这些片剂按照U.S.P.和/或F.D.A.的要求/法律进行制备,符合上市产品和使用的要求。或者,但次为优选地,使粘合剂成溶剂化物,并用于湿法制粒过程。
根据本发明的片剂能够降低快速沉淀药物的沉淀速率并改进了药物的溶解性。
下面对术语的定义和解释适用于整个中请文件,包括说明书和权利要求书。
代呋啶是指1-[5-甲磺酰氨基吲哚基-2-羰基]-4-[3-(1-甲基乙基-氨基)-2-吡啶基]哌嗪。
甲磺酸代呋啶是指1-[5-甲磺酰氨基吲哚基-2-羰基]-4-[3-(1-甲基乙基-氨基)-2-吡啶基]哌嗪甲磺酸盐。
在本发明特别优选的实施方式中,甲磺酸代呋啶的含量为50-300mg/片,更优选200mg或300mg/片。
“快速沉淀的药物”是药物化合物或其盐形式,在体温下,当将其引入水中或模拟生理体液时,在60分钟内,药物开始相当快的溶解,然后开始从溶液中快速沉淀出来成为微溶的形式,提供低于治疗浓度的浓度。
所有的温度均是以摄氏度表示。
可药用是指基于药理学/毒理学的观点,这些特性和/或物质对于患者是可接受的;基于有关组合物、制剂、稳定性、患者接受性和生物利用度的物理/化学观点,这些特性和/或物质对制药学家是可接受的。
当混合物中使用两种或多种固体时,所示wt/wt或wt.wt.表示它们的重量/重量。
PVP是指聚乙烯吡咯烷酮。
无需进一步说明,本领域技术人员可以看出利用前述说明,可最大限度地实践本发明。描述如何制备各种化合物和/或施行本发明的方法的下列具体实施例仅是说明性的,而不是对前面公开的内容加以任何方式的限制。本领域普通技术人员将十分容易认识到反应物及反应条件和技术方法的适宜变化。
实施例1 200mg甲磺酸代呋啶片剂
200mg片剂
成分(wt.wt)
量/片
%
甲磺酸代呋啶 200.00mg 30.2
微晶纤维素N.F.粗粉 198.76mg 30.0
乳糖一水合物NF 71.29mg 10.7
(喷雾方法标准的)
羟丙基甲基纤维素 75.00mg 11.3
2910(U.S.P.3cps)
交联羧甲基纤维素钠 110.00mg 16.6
N.F.(A型)
胶态二氧化硅N.F. 1.50mg 0.23
硬脂酸镁N.F.粉(食品级-V 5.00mg 0.76
过筛的)
上面的片剂通过在高剪切搅拌机中充分混合甲磺酸代呋啶和微晶纤维素而制备。然后在高剪切混合机中加入羟丙基甲基纤维素、交联羧甲基纤维素、乳糖和过筛的胶态二氧化硅并混合。最后将过筛的硬脂酸镁和润滑剂加到高剪切混合机中。按照本领域技术人员的常规知识,将所得混合物压缩、膜包衣并抛光,得到约200mg甲磺酸代呋啶/片的片剂,该片符合U.S.P.和/或F.D.A.的要求。
Claims (32)
1、一种非缓释的、非咀嚼的药物片剂组合物,其中含有:
含量为5-60%的快速沉淀的药物,含量为2-25%的聚合物粘合剂,含量为6-40%的超崩解剂,和含量至多为5%的润滑剂,其中所述%为重量百分数;
其中所述快速沉淀的药物是溶解性较差的游离碱或游离酸药物的相当易溶或易溶的盐形式,或者是溶解性较差的游离碱或游离酸药物的无水形式,并且在体温下在与水或模拟生理体液接触后60分钟内有90%以上的所述快速沉淀的药物沉淀出来;
其中上述组成被混合并压缩成片剂,而无需加热、溶剂或研磨。
2、权利要求1的非缓释的、非咀嚼的药物片剂组合物,其中的聚合物粘合剂是一种选自下列的成分:
羟丙基甲基纤维素、PVP、羟丙基纤维素、甲基纤维素、羟乙基纤维素、卡波普和羧甲基纤维素钠。
3、权利要求2的非缓释的、非咀嚼的药物片剂组合物,其中的聚合物粘合剂是羟丙基甲基纤维素。
4、权利要求2的非缓释的、非咀嚼的药物片剂组合物,其中的聚合物粘合剂是PVP。
5、权利要求2的非缓释的、非咀嚼的药物片剂组合物,其中的聚合物粘合剂含量如下:5-20%的羟丙基甲基纤维素,2-15%的PVP,5-20%的羟丙基纤维素,3-20%的甲基纤维素,5-20%的羟乙基纤维素,3-20%的卡波普,和3-20%的羧甲基纤维素钠。
6、权利要求1的非缓释的、非咀嚼的药物片剂组合物,其中的超崩解剂是交联羧甲基纤维素钠、淀粉乙醇酸钠或L-羟丙基纤维素。
7、权利要求1的非缓释的、非咀嚼的药物片剂组合物,其中超崩解剂的含量为6-35%。
8、权利要求7的非缓释的、非咀嚼的药物片剂组合物,其中超崩解剂的含量为10-30%。
9、权利要求1的非缓释的、非咀嚼的药物片剂组合物,其中含有含量至多为50%的微晶纤维素。
10、权利要求9的非缓释的、非咀嚼的药物片剂组合物,其中微晶纤维素选自微晶纤维素粗粉、微晶纤维素中等细度的粉和微晶纤维素200。
11、权利要求9的非缓释的、非咀嚼的药物片剂组合物,其中的微晶纤维素是微晶纤维素N.F.粗粉。
12、权利要求9的非缓释的、非咀嚼的药物片剂组合物,其中微晶纤维素的含量为10-50%。
13、权利要求1的非缓释的、非咀嚼的药物片剂组合物,它含有至多80%的乳糖。
14、权利要求13的非缓释的、非咀嚼的药物片剂组合物,其中的乳糖选自喷雾方法标准的乳糖一水合物、乳糖一水合物、无水乳糖、乳糖二水合物、DMV乳糖。
15、权利要求13的非缓释的、非咀嚼的药物片剂组合物,其中的乳糖是喷雾方法标准的乳糖一水合物N.F.。
16、权利要求13的非缓释的、非咀嚼的药物片剂组合物,其中乳糖的含量为5-20%。
17、权利要求1的非缓释的、非咀嚼的药物片剂组合物,它含有至多5%的助流剂。
18、权利要求17的非缓释的、非咀嚼的药物片剂组合物,其中的助流剂选自胶态二氧化硅和滑石。
19、权利要求17的非缓释的、非咀嚼的药物片剂组合物,其中的助流剂是胶态二氧化硅N.F.。
20、权利要求17的非缓释的、非咀嚼的药物片剂组合物,其中助流剂的含量为0.25-2%。
21、权利要求1的非缓释的、非咀嚼的药物片剂组合物,其中的润滑剂选自硬脂酸镁和硬脂酸。
22、权利要求21的非缓释的、非咀嚼的药物片剂组合物,其中的润滑剂是硬脂酸镁。
23、权利要求1的非缓释的、非咀嚼的药物片剂组合物,其中润滑剂的含量为0.25-2%。
24、权利要求1的非缓释的、非咀嚼的药物片剂组合物,其中快速沉淀的药物选自甲磺酸代呋啶、盐酸氯洁霉素、盐酸可乐定、盐酸苯海拉明、盐酸氟奋乃静、盐酸氢吗啡酮、盐酸纳洛酮、盐酸土霉素、盐酸苯福林、马来酸苯吡胺、盐酸四环素、盐酸维拉帕米、盐酸丙氧芬、重酒石酸二氢可待因、阿昔洛韦钠、硫酸沙丁胺醇、氨苄青霉素钠、甲磺酸苯托品、盐酸苄非他明、盐酸丁哌卡因、盐酸安非他酮、马来那敏和盐酸氯丙嗪。
25、权利要求1的非缓释的、非咀嚼的药物片剂组合物,其中快速沉淀的药物的含量为10-40%。
26、权利要求1的非缓释的、非咀嚼的药物片剂组合物,其中快速沉淀的药物是甲磺酸代呋啶。
27、权利要求26的非缓释的、非咀嚼的药物片剂组合物,其中甲磺酸代呋啶的含量为50mg-300mg/片。
28、权利要求27的非缓释的、非咀嚼的药物片剂组合物,其中甲磺酸代呋啶的含量为200mg或300mg/片。
29、一种根据权利要求1的非缓释的、非咀嚼的药物片剂组合物,其组成为:
含量
成分
%
甲磺酸代呋啶 10-40
羟丙基甲基纤维素 5-20
交联羧甲基纤维素钠 6-35
微晶纤维素 10-50
乳糖 0-15
胶态二氧化硅 0-5
硬脂酸镁 0-5
其中所述片剂是通过将甲磺酸代呋啶、微晶纤维素、羟丙基甲基纤维素和交联羧甲基纤维钠混合并压缩而制成的,无需加热、溶剂或研磨,其中所述%为重量百分数。
30、权利要求29的非缓释的、非咀嚼的药物片剂组合物,其组成是:
成分
含量%
甲磺酸代呋啶 30.2
微晶纤维素N.F.粗粉 30.0
喷雾方法标准的乳糖一水合物NF 10.7
羟丙基甲基纤维素2910,U.S.P.3cps 11.3
A型交联羧甲基纤维素钠N.F. 16.6
胶态二氧化硅N.F. 0.23
食品级-V过筛的硬脂酸镁N.F.粉 0.76
31、一种制备权利要求1-30任一项所述的非缓释的、非咀嚼的药物片剂组合物的方法,该方法包括将各成分混合并压制,而无需加热、研磨或溶剂。
32、根据权利要求31的方法,其中所述混合是在高剪切混合器中进行的。
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US8896098P | 1998-06-11 | 1998-06-11 | |
US60/088,960 | 1998-06-11 |
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EA200100024A1 (ru) | 2001-06-25 |
CN1301149A (zh) | 2001-06-27 |
DK1083885T3 (da) | 2007-02-26 |
CA2328703C (en) | 2007-10-30 |
BR9910481A (pt) | 2001-01-09 |
CA2328703A1 (en) | 1999-12-16 |
AU753241C (en) | 2003-05-08 |
ATE349203T1 (de) | 2007-01-15 |
ZA200006090B (en) | 2001-10-29 |
EA004311B1 (ru) | 2004-02-26 |
HUP0102206A2 (hu) | 2002-03-28 |
JP4827296B2 (ja) | 2011-11-30 |
US6177101B1 (en) | 2001-01-23 |
NZ508762A (en) | 2003-07-25 |
US7108864B1 (en) | 2006-09-19 |
AU4213499A (en) | 1999-12-30 |
WO1999063970A1 (en) | 1999-12-16 |
DE69934582D1 (de) | 2007-02-08 |
HUP0102206A3 (en) | 2002-12-28 |
AU753241B2 (en) | 2002-10-10 |
EP1083885B1 (en) | 2006-12-27 |
US20060257476A1 (en) | 2006-11-16 |
DE69934582T2 (de) | 2007-10-04 |
KR20010052717A (ko) | 2001-06-25 |
PL200163B1 (pl) | 2008-12-31 |
KR20070040426A (ko) | 2007-04-16 |
EP1083885A1 (en) | 2001-03-21 |
CY1105924T1 (el) | 2011-04-06 |
ES2277682T3 (es) | 2007-07-16 |
PL344328A1 (en) | 2001-10-22 |
HK1036417A1 (en) | 2002-01-04 |
KR100724016B1 (ko) | 2007-05-31 |
PT1083885E (pt) | 2007-01-31 |
JP2002517430A (ja) | 2002-06-18 |
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