CN87103409A - 固体药物剂型的制备 - Google Patents
固体药物剂型的制备Info
- Publication number
- CN87103409A CN87103409A CN87103409.3A CN87103409A CN87103409A CN 87103409 A CN87103409 A CN 87103409A CN 87103409 A CN87103409 A CN 87103409A CN 87103409 A CN87103409 A CN 87103409A
- Authority
- CN
- China
- Prior art keywords
- polymer
- nvp
- acid
- reactive compound
- weight
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000007787 solid Substances 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 239000002552 dosage form Substances 0.000 title abstract description 6
- 229920000642 polymer Polymers 0.000 claims abstract description 43
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- 238000000034 method Methods 0.000 claims abstract description 36
- 239000000203 mixture Substances 0.000 claims abstract description 29
- 239000011230 binding agent Substances 0.000 claims abstract description 17
- 238000001125 extrusion Methods 0.000 claims abstract description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 10
- 230000008569 process Effects 0.000 claims abstract description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000001301 oxygen Substances 0.000 claims abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 44
- -1 hydroxyl ethyl Chemical group 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 239000006104 solid solution Substances 0.000 claims description 13
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 claims description 11
- 238000007334 copolymerization reaction Methods 0.000 claims description 10
- 238000009472 formulation Methods 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims description 6
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 claims description 6
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 claims description 6
- 239000003999 initiator Substances 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 6
- 239000007924 injection Substances 0.000 claims description 6
- 238000006116 polymerization reaction Methods 0.000 claims description 6
- 210000004051 gastric juice Anatomy 0.000 claims description 5
- 230000009477 glass transition Effects 0.000 claims description 5
- 150000002576 ketones Chemical class 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 claims description 4
- 150000001451 organic peroxides Chemical class 0.000 claims description 4
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 claims description 4
- CPJSUEIXXCENMM-UHFFFAOYSA-N phenacetin Chemical compound CCOC1=CC=C(NC(C)=O)C=C1 CPJSUEIXXCENMM-UHFFFAOYSA-N 0.000 claims description 4
- 239000004014 plasticizer Substances 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 claims description 4
- 229960000277 sulfaperin Drugs 0.000 claims description 4
- DZQVFHSCSRACSX-UHFFFAOYSA-N sulfaperin Chemical compound N1=CC(C)=CN=C1NS(=O)(=O)C1=CC=C(N)C=C1 DZQVFHSCSRACSX-UHFFFAOYSA-N 0.000 claims description 4
- 210000001550 testis Anatomy 0.000 claims description 4
- 229920001169 thermoplastic Polymers 0.000 claims description 4
- 239000004416 thermosoftening plastic Substances 0.000 claims description 4
- JAHNSTQSQJOJLO-UHFFFAOYSA-N 2-(3-fluorophenyl)-1h-imidazole Chemical compound FC1=CC=CC(C=2NC=CN=2)=C1 JAHNSTQSQJOJLO-UHFFFAOYSA-N 0.000 claims description 3
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims description 3
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 claims description 3
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 3
- 229960003304 acetyldigoxin Drugs 0.000 claims description 3
- 229960001138 acetylsalicylic acid Drugs 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 239000002249 anxiolytic agent Substances 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 229960005274 benzocaine Drugs 0.000 claims description 3
- DERZBLKQOCDDDZ-JLHYYAGUSA-N cinnarizine Chemical compound C1CN(C(C=2C=CC=CC=2)C=2C=CC=CC=2)CCN1C\C=C\C1=CC=CC=C1 DERZBLKQOCDDDZ-JLHYYAGUSA-N 0.000 claims description 3
- 229960000876 cinnarizine Drugs 0.000 claims description 3
- 229960005156 digoxin Drugs 0.000 claims description 3
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 claims description 3
- 229960004704 dihydroergotamine Drugs 0.000 claims description 3
- HESHRHUZIWVEAJ-JGRZULCMSA-N dihydroergotamine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2[C@@H](C3=CC=CC4=NC=C([C]34)C2)C1)C)C1=CC=CC=C1 HESHRHUZIWVEAJ-JGRZULCMSA-N 0.000 claims description 3
- 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 claims description 3
- 229960003883 furosemide Drugs 0.000 claims description 3
- 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 claims description 3
- 229960000905 indomethacin Drugs 0.000 claims description 3
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 claims description 3
- 229960000991 ketoprofen Drugs 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- 239000011976 maleic acid Substances 0.000 claims description 3
- LVHBHZANLOWSRM-UHFFFAOYSA-N methylenebutanedioic acid Natural products OC(=O)CC(=C)C(O)=O LVHBHZANLOWSRM-UHFFFAOYSA-N 0.000 claims description 3
- 229960005489 paracetamol Drugs 0.000 claims description 3
- 229960005205 prednisolone Drugs 0.000 claims description 3
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 3
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 claims description 2
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 claims description 2
- ADVGKWPZRIDURE-UHFFFAOYSA-N 2'-Hydroxyacetanilide Chemical compound CC(=O)NC1=CC=CC=C1O ADVGKWPZRIDURE-UHFFFAOYSA-N 0.000 claims description 2
- JKWBQCHTVBSJDC-UHFFFAOYSA-N 3-(4-ethoxyphenyl)-2-methylquinazolin-4-one Chemical compound C1=CC(OCC)=CC=C1N1C(=O)C2=CC=CC=C2N=C1C JKWBQCHTVBSJDC-UHFFFAOYSA-N 0.000 claims description 2
- NLJVXZFCYKWXLH-DXTIXLATSA-N 3-[(3r,6s,9s,12s,15s,17s,20s,22r,25s,28s)-20-(2-amino-2-oxoethyl)-9-(3-aminopropyl)-3,22,25-tribenzyl-15-[(4-hydroxyphenyl)methyl]-6-(2-methylpropyl)-2,5,8,11,14,18,21,24,27-nonaoxo-12-propan-2-yl-1,4,7,10,13,16,19,23,26-nonazabicyclo[26.3.0]hentriacontan Chemical compound C([C@H]1C(=O)N[C@H](C(=O)N[C@@H](CCCN)C(=O)N[C@H](C(N[C@H](CC=2C=CC=CC=2)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(O)=O)N1)=O)CC(C)C)C(C)C)C1=CC=C(O)C=C1 NLJVXZFCYKWXLH-DXTIXLATSA-N 0.000 claims description 2
- 229930008281 A03AD01 - Papaverine Natural products 0.000 claims description 2
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims description 2
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- 108010026389 Gramicidin Proteins 0.000 claims description 2
- 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 claims description 2
- SMNOERSLNYGGOU-UHFFFAOYSA-N Mefruside Chemical compound C=1C=C(Cl)C(S(N)(=O)=O)=CC=1S(=O)(=O)N(C)CC1(C)CCCO1 SMNOERSLNYGGOU-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- 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 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 claims description 2
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 claims description 2
- NHUHCSRWZMLRLA-UHFFFAOYSA-N Sulfisoxazole Chemical compound CC1=NOC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1C NHUHCSRWZMLRLA-UHFFFAOYSA-N 0.000 claims description 2
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 claims description 2
- 108010021006 Tyrothricin Proteins 0.000 claims description 2
- DGDPBPLJSALKAP-UHFFFAOYSA-N [N].[S].NC(=O)N Chemical compound [N].[S].NC(=O)N DGDPBPLJSALKAP-UHFFFAOYSA-N 0.000 claims description 2
- VGZSUPCWNCWDAN-UHFFFAOYSA-N acetohexamide Chemical compound C1=CC(C(=O)C)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 VGZSUPCWNCWDAN-UHFFFAOYSA-N 0.000 claims description 2
- 229960001466 acetohexamide Drugs 0.000 claims description 2
- PHFDAOXXIZOUIX-UHFFFAOYSA-N anipamil Chemical compound C=1C=CC(OC)=CC=1C(CCCCCCCCCCCC)(C#N)CCCN(C)CCC1=CC=CC(OC)=C1 PHFDAOXXIZOUIX-UHFFFAOYSA-N 0.000 claims description 2
- 229950011530 anipamil Drugs 0.000 claims 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 claims description 2
- ANTSCNMPPGJYLG-UHFFFAOYSA-N chlordiazepoxide Chemical compound O=N=1CC(NC)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 ANTSCNMPPGJYLG-UHFFFAOYSA-N 0.000 claims description 2
- 229960004782 chlordiazepoxide Drugs 0.000 claims description 2
- 238000005660 chlorination reaction Methods 0.000 claims description 2
- 229940097572 chloromycetin Drugs 0.000 claims description 2
- 229960002155 chlorothiazide Drugs 0.000 claims description 2
- DGBIGWXXNGSACT-UHFFFAOYSA-N clonazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1Cl DGBIGWXXNGSACT-UHFFFAOYSA-N 0.000 claims description 2
- 229960003120 clonazepam Drugs 0.000 claims description 2
- 229960004126 codeine Drugs 0.000 claims description 2
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 claims description 2
- WTYGAUXICFETTC-UHFFFAOYSA-N cyclobarbital Chemical compound C=1CCCCC=1C1(CC)C(=O)NC(=O)NC1=O WTYGAUXICFETTC-UHFFFAOYSA-N 0.000 claims description 2
- 229960004138 cyclobarbital Drugs 0.000 claims description 2
- 229960003957 dexamethasone Drugs 0.000 claims description 2
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 claims description 2
- DOBMPNYZJYQDGZ-UHFFFAOYSA-N dicoumarol Chemical compound C1=CC=CC2=C1OC(=O)C(CC=1C(OC3=CC=CC=C3C=1O)=O)=C2O DOBMPNYZJYQDGZ-UHFFFAOYSA-N 0.000 claims description 2
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- ZWCXYZRRTRDGQE-SORVKSEFSA-N gramicidina Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CC=3C4=CC=CC=C4NC=3)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CC=3C4=CC=CC=C4NC=3)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CC=3C4=CC=CC=C4NC=3)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](C(C)C)NC(=O)[C@H](C)NC(=O)[C@H](NC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H](NC=O)C(C)C)CC(C)C)C(=O)NCCO)=CNC2=C1 ZWCXYZRRTRDGQE-SORVKSEFSA-N 0.000 claims description 2
- 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 claims description 2
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- 229960000890 hydrocortisone Drugs 0.000 claims description 2
- DMDGGSIALPNSEE-UHFFFAOYSA-N hydroflumethiazide Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O DMDGGSIALPNSEE-UHFFFAOYSA-N 0.000 claims description 2
- 229960003313 hydroflumethiazide Drugs 0.000 claims description 2
- ZTKMNYDOFAYRAK-UHFFFAOYSA-N isoacronycine Natural products CN1C2=CC=CC=C2C(=O)C2=C1C=C1OC(C)(C)C=CC1=C2OC ZTKMNYDOFAYRAK-UHFFFAOYSA-N 0.000 claims description 2
- FQPSGWSUVKBHSU-UHFFFAOYSA-N methacrylamide Chemical compound CC(=C)C(N)=O FQPSGWSUVKBHSU-UHFFFAOYSA-N 0.000 claims description 2
- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 claims description 2
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 claims description 2
- 229960001597 nifedipine Drugs 0.000 claims description 2
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- A61K9/00—Medicinal preparations characterised by special physical form
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- 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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- 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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
- B29K2105/00—Condition, form or state of moulded material or of the material to be shaped
- B29K2105/0005—Condition, form or state of moulded material or of the material to be shaped containing compounding ingredients
- B29K2105/0035—Medical or pharmaceutical agents
Abstract
一种制备固体药物剂型的方法,它通过将一种或多种药物活性化合物与一种或多种易熔的、药理学上可耐受的粘结剂,必要时与其它一些常规药物辅助剂在50—180℃下混合,再使混合物注塑或挤塑成型。其中所用的易熔粘结剂为一种NVP聚合物,它含NVP共聚单元不低于20(重量)%,而且在共聚单元存在时,其全部共聚单体均含氮和(或)氧。
Description
本发明涉及利用注塑或挤塑成形法制备固体药物剂型的方法,该剂型以N-乙烯基吡咯烷-2-酮(NVP)聚合物作为粘结剂。
传统的制片机用阳模和阴模以循环加工方法操作。此方法需要充分预混合及专门制备的压片物料,因此全过程是多步的和昂贵的。生产活性化合物的控释固体药物剂型极为昂贵。一方面,这需要一些阻滞措施,另一方面需要一些改善活性化合物吸收的措施。
改善微溶活性化合物吸收的一个可能方法是使用活性化合物在水溶性聚合物中的固体溶液。在NVP聚合物中的这类已知的固体溶液,是通过将活性化合物和聚合物一起溶于某种有机溶剂中然后除去溶剂的方法制备的。为了同时溶解疏水化合物和亲水聚合物,通常需要氯代烃类。完全除去这些溶解剂极为昂贵。为了避免环境污染,必须尽可能完全地从废空气中除去这些溶剂,这本身就极为昂贵。例如在美国专利3089818中;在T.Tachibana和A.Nakamura,“Kolloid Zeitschrift和Zeitschrift für Polymere”203(1965),130页中;在日本专利24379中;在M.Mayersohn等人,“J.Pharm,Sci.”55(1966),1323页中;在西德专利-B-1137009中;以及在W.Scholten,“Arzn.Forschung”14(1964),469页中均对这种类型的方法已有介绍。
活性化合物-聚合物混合物的挤塑已经有人介绍过(参见例如西德专利-A-1229248和P.Speiser“PharmaceuticaActa Helv.”41(1966),340页以及同一杂志46(1971),31页)。但是,没有一个方法不是将无溶剂的NVP聚合物与其它聚合物或水混合的条件下熔化的,暂不说挤塑过程,而且也没有文献描述过一种将微溶的活性化合物在水溶性聚合物中形成某种固体溶液。
在R.Voigt著“Lehrbuch der Pharmazeutischen Technologie,”第五版,Verlag Chemie,Weinheim,1984,221-222页中,一般性地描述了利用使活性化合物-热塑性混合物注塑或挤塑成形法制备固体药物制剂,但是没有提供任何具体的资料,尤其是关于适用于这个目的的聚合物类型的资料。这里所说的聚合物无疑并不是高度亲水的聚合物,如NVP聚合物,因为在迄今为止的药物部门中,这些聚合物并不是经由干熔体加工的,而总是以带有溶剂(通常是水)的基质而加工的(参见例如英国专利1388786)。
本发明的一个目的是提供一种制备固体药物剂型,特别是可控释活性化合物的固体药物剂型的简便方法。
我们发现,本发明目的可由这样一种制备固体药物剂型的方法所达到,即在50-180℃下,最好在60-160℃下,将一种或多种药物活性化合物与一种或多种易熔的药理学上允许的粘结剂以及(必要时的)其它常规的药物辅助剂混合,然后使所说的混合物经过注塑或挤塑成形,其中所用的易熔粘结剂是无溶剂的NVP聚合物,此聚合物含水量不高于3.5(重量)%,而且作为共聚单元含NVP不少于20(重量)%,最好不少于60%,尤其是100%,而且在共聚单元存在时,其全部共聚单体均含有氮和/或氧,以及至少当所说混合物的玻璃化转变温度高于120℃时,所使用的NVP聚合物是在有机溶剂中聚合得到的或者使用有机过氧化物作为引发剂在水溶液中聚合得到的,而且该混合物不含有任何在胃液中微溶的(6小时内溶解量低于10%)热塑性物质。
作为共聚单元,所说的NVP聚合物应含不低于20(重量)%的NVP,最好不少于60%,尤其是100%,而且FikentscherK值(“Cellulose-chemie”,13(1932),58-64和71-74页)为10-70,较好为10-50,更好是12-40,尤其是12-35,使用NVP均聚物时最好为12-35,尤其是12-17。
聚合粘结剂在全部成份的整个混合物中必须在50-180℃,最好在60-130℃下软化或熔化,以便可以挤塑此熔体。因此,所说混合物的玻璃化转变温度无论如何都应当低于180℃,最好低于130℃。必要时,利用常规的药理上适用的增塑剂降低此玻璃化转变温度,所说的增塑剂例如:长链醇类、1,2-亚乙基二醇、丙二醇、三羟甲基丙烷、二缩三乙二醇、丁二醇、戊醇类、己醇类、聚乙二醇类、芳族羧酸酯类(如苯二甲酸二烷基酯类、偏苯三酸酯类、苯甲酸酯类或对苯二甲酸酯类)、脂族二羧酸酯类(如己二酸二烷基酯类、癸二酸酯类、壬二酸酯类、柠檬酸酯类或酒石酸酯类)或脂肪酸酯类。按照聚合物重量计,所说的增塑剂最好总共不多于20%。特别好的NVP聚合物应该是不需要这类添加剂的,也就是说它们与活性成份及(必要时的)常规的药物助剂的混合物,即使在没有那些具有特定增塑作用的添加剂存在下也会在所需的温度范围内软化或熔化。在低于某温度下熔化或软化可能是必须的,因为否则不仅活性成份,而且NVP聚合物也可能出现热损坏和/或氧化损坏。挤塑时NVP聚合物可能变黄,正是因为这个原因,迄今才通常不挤塑NVP聚合物。然而,该聚合物如果不是用过氧化氢作引发剂于水溶液中得到的,而是按照例如德国专利申请P3642633.4中的方法或按照美国专利4520179和4520180中所述的方法,即在有机溶剂中或使用有机过氧化物作为引发剂在水中制得的,则在低于180℃,特别是低于130℃挤塑温度下几乎不会变黄。
如果所说的K值大于17,尤其是大于30或甚至于大于40(直至最大值70),而且不存在高度增塑的成份,则唯一适用的共聚物类是玻璃化转变温度Tg低于120℃,最好低于100℃的共聚物,或者该NVP聚合物(包括均聚物)一定不是在含有H2O2作为引发剂的水中制备的,否则会使聚合物端基在提高的温度下变黄。
适用的共聚单体,是不饱和羧酸类,例如甲基丙烯酸、丁烯酸、马来酸和衣康酸及其与1-12个碳原子,特别是1-8个碳原子的醇类的酯,以及羟乙基或羟丙基的丙烯酸酯和甲基丙烯酸酯,甲基丙烯酰胺和丙烯酰胺,马来酸和衣康酸的酐或半酯类(所说的半酯类最好在聚合之后才形成),N-乙烯基己内酰胺和丙酸乙烯基酯。
优选的共聚单体是丙烯酸,尤其是乙酸乙烯酯。因此,优选的NVP聚合物是这样一些物质,它们只包含NVP或乙酸乙烯酯作为唯一的共聚单体,或者作为共聚单元,含量不少于聚合物重量的10%,最好不少于30%。聚合之后,部分或全部乙酸乙烯酯和丙酸乙烯酯可以水解。
无溶剂意指不加入有机溶剂,尤其是不加入氯代烃。而且不应当掺入在胃液中难溶的热塑性物质,NVP聚合物的水含量不应超过3.5(重量)%,(这种水量是自空气中自然吸附的水份,而不是有意加入的水)。较高的水含量有害,因为聚合物-活性化合物的挤塑物自阴模中出来后,水的蒸发导致模制品多孔或者可能使模制品表面具有裂缝。
此新方法例如适于加工下列活性化合物:倍他米松、硫辛酸(thioctic acid)、心得怡、舒喘灵、去甲苯福林、水飞蓟素氢化麦角胺、丁咯地尔、依托贝特、消炎痛、去甲羟基安定、β-乙酰地高辛、炎痛喜康(Piroxicam)、氯哌丁苯、ISMN、盐酸阿米替林、二氯苯胺苯乙酸、硝基吡啶、戊脉安、脑复新、尼群地平、强力霉素、心消痰、甲强龙、氯压定、非诺贝特、别嘌吟醇、哌仑西平、左旋甲状腺素、他莫西芬、甲基地高辛、邻-(β-羟乙基)芦丁、苯丙西林、阿昔洛维单硝酸酯(aciclovir mononitrate)、扑热息痛、萘呋胺、己酮可可碱、普罗帕酮(抗心率失常药)、醋丁酰心安、左旋甲状腺素、曲马多(镇痛药)、溴隐亭(催乳激素抑制剂)、氯苯哌酰胺、酮替芬(ketotifen)、芬特醇、cadobelisate、丙醇心安(propanolol)、二甲胺四环素、麦角溴烟脂、氨溴醇、美多心安、β-谷甾醇、苯脂丙脯酸马来酸氢盐(enalapril-hydrogen maleate)、苯扎贝特、ISDN、胺棓戊腈(gallopamil)、烟胺羟丙碱、狄戈辛、氟硝基安定(flunitrazepam,弱安定药)、苄环庚烷、泛醇、心得乐、氯羟安定、硫氮
酮、吡咯烷醋胺、苯氧甲基青霉素、呋喃苯胺酸、溴安定、氟苯桂嗪(flunarizin,冠状血管扩张药)、红霉素、灭吐灵、阿西美辛、雷尼替丁(ranitidin)、安克痉、安乃近、多虑平、氯氮替哌二钾(dipotassium chloroazepate)、四氢安定、雌二醇氮芥磷酸盐、间羟舒喘灵、甲巯丙脯酸、麦普替林、哌唑嗪、氨酰心安、优降糖、氯头孢菌素、盐酸乙苯福林、甲腈咪胍、茶碱、氢化吗啡酮、布洛芬、扑癫酮、氧异安定、奥沙西罗、甲孕酮、氟苄胺、吡哆醛-5-磷酸谷氨酸镁(mgpyridoxal 5-phosphate glutaminate)、羟甲香豆素、羟乙茶碱祛脂乙酯(etofyllineclofibrate)、长春安、肉桂苯哌嗪、安定、酮洛芬、三氟噻吨、吗斯胺(molsimine)、甲磺冰片脲、二甲基吡茚、美哌隆、索奎心安(soquinolol)、双氢可待因、氯甲噻唑、克立马丁、唑磺
脲、舒管素、麻黄苯丙酮、氯苯氨丁酸、羧甲基半胱氨酸、甲硫达嗪、甲胺异吡啶、L-色氨酸、香桃木油、菠萝酶制剂、乳酸心可定、抑氮磺胺吡啶、阿司咪唑、止吐灵、benzerazide、二苯氮
、乙酰水杨酸、双氯苯咪唑、制霉菌剂、酮康唑(ketoconazole)、皮考磺酸钠(Na picosulfate)、消胆胺脂、二甲苯氧庚酸(gemfibrozil)、利福平、氟考龙、脉律定、羟氨苄青霉素、丁苯哌丁醇(terfenadrin)、粘多糖多硫酸酯、三唑苯二氮
、米安舍林(抗组胺药)、噻洛芬酸、甲硫酸氯苯哒嗪(交感神经兴奋药)、甲氟喹、丙丁酚、奎尼丁、氨甲酰苯
、L-天门冬胺酸镁、环戊丁心安、苯吡磺苯酸(piretanide)、阿米替林制剂、环孕酮(抗雄激素药)、丙戊酸钠、麦皮凡林、双醋苯啶、5-氨基水杨酸、双肼肽嗪、镁铝水合物、苯丙羟基香豆素、金刚胺、甲萘普生、卡得心安(carteolol)、法莫替丁(famotidine)α-甲基多巴、醋硫葡金、雌三醇、萘羟心安、左旋甲丙嗪、阿霉素、medofenoxate、硫唑嘌呤、氟硝丁酰胺、去氟氧辛(norfloxacin)、苯乙二苯丙胺、丙缓脉灵酸式酒石酸盐(prajmalium bitartrate)和七叶素。
特别优选下列活性化合物的固体溶液:乙酰氨基苯酚(扑热息痛)醋磺环己脲、乙酰地高辛、乙酰水杨酸、山油柑碱(acronycin)、anipamil、苯佐卡因、β-葫萝卜素、氯霉素、利眠宁、氯化孕酮醋酸酯、氯噻嗪、肉桂苯哌嗪、氯硝安定、可待因、地塞米松、安定、双香豆素、洋地黄毒甙、地高辛、氢化麦角胺、氢乙罂粟碱、弱安定药氟硝西泮、呋喃苯胺酸、短杆菌肽、灰黄霉素、环己巴比妥、双塞克尿塞制剂、氢化可的松、氢氟甲噻嗪、消炎痛、酮洛芬、lonetil、去氧安定、倍可降、去氢甲睪酮、甲强龙、磺胺甲基嘧啶(异磺胺甲基嘧啶)、萘啶酸、心痛定、硝基安定、呋喃坦啶、制霉菌素、雌二醇、罂粟碱、非那西丁、苯巴比妥、保泰松、苯妥英、强的松、利血平、安体舒通、链霉素、磺胺二甲嘧啶、磺胺甲噻二唑、磺胺甲基异噻唑、磺胺甲氧磺胺嘧啶(消炎磺)、异磺胺甲基嘧啶、磺胺噻唑、磺胺异噁唑、睪丸酮、甲磺氮
脲、甲磺丁脲、甲氧苄嘧啶和短杆菌素。
熟练的技术人员例如从本文起始部分引用的文献中会熟悉术语“固体溶液”。在药物活性化合物和聚合物形成的固体溶液中,活性化合物在聚合物中以分子分散形式存在。
所说活性化合物在NVP聚合物中形成固体溶液未曾被预见过,而且更令人惊奇的是,因为微溶于水的许多活性化合物在其它聚合物中并不形成(以分子分散的形式)固体溶液,而只是在一些特定的聚合物中以固体颗粒形式掺入,而这是可以用电子显微镜检测的。而在结晶形的活性化合物情况下,它们也显示出Debye-Scherrer图案,与固体溶液形成对照。
如果除了本发明所用的粘结剂之外还使用其它水溶性易熔粘结剂,则根据所用全部易熔粘结剂重量计,第一次提到的粘结剂量不应少于50%,最好不少于70%。
就本发明目的来说,固体药物剂型例如是片剂、片核、颗粒剂和栓剂。
就本发明目的来说,药物活性化合物是既具有药物作用又具有很低副作用的所有那些物质,条件是这些物质在加工条件下不分解。活性化合物在每个剂量单位中的量及浓度,可以根据活性及释放速度在很宽范围内变化,唯一的条件是它们应足以收到所需的效果。例如,活性化合物的浓度按重量计可以是0.1-95%,最好是从20-80%,尤其是从30-70%。也可以使用几种活性化合物的组合物。就本发明目的来说,维生素类也是活性化合物。微溶于水的活性化合物是那些在胃肠道内的吸收由于溶解度低通常不能令人满意的物质。
可以把一种或几种活性化合物与所说的粘结剂,而且必要时还与其它常规的药物添加剂在该聚合物粘结剂熔化之前或之后,用工业上常规使用的方法混合。混合最好是在具有混合区的挤压机中,特别是在双螺旋挤压机中进行,或者在注塑机的螺旋输送区中进行。
成形可在注塑或挤塑之后进行,例如通过将塑性挤出物热面裁切成粒或模塑成片,例如利用使挤出物从按相反方向驱动的两辊之间通过,在所说的辊壳上具有一些互相相对的凹陷处,这些凹陷处的形状决定着片剂的形状。也可以采用冷面切粒法,并随后把这些颗粒压成片。对于本发明目的来说,所说的挤塑包括注塑。
根据预期的用途,通过改变共聚单体的类型和数量,可以把NVP聚合物制成亲水性足够强或足够弱的片剂,使之迅速或延迟地在口中(口腔片)溶解,或在胃中溶解,或达到肠中才溶解,或者使之溶胀以便释放出活性化合物。在相对湿度为90%条件下贮存时,这些片剂吸收10(重量)%以上的水后可以充分溶胀。如果希望含羧基的粘结剂仅在抵达肠的碱性介质中之后才释放出所说的活性化合物,则上述的吸收水只适于中性形式(盐形)的聚合物(其中羧基的部分或全部质子被铵、钠或钾的离子所取代)。
按聚合物重量计,总量可以高达100%的常规药物辅助剂,例如是扩充剂(例如硅酸盐、二氧化硅、硬脂酸或其与例如镁或钙形成的盐,甲基纤维素、羧甲基纤维素钠、滑石、蔗糖、乳糖、谷物淀粉或玉米淀粉、马铃薯粉或聚乙烯醇)以及湿润剂、防腐剂、崩解剂、吸收剂、着色剂和调味剂(参见例如H.Sucker等,“Pharmazeutische Technologie”,Thieme-Verlag,Stuttgart,1978)。
必要时,该固体药物剂型也可进行常规的包衣,以改进外观和(或)香味(包衣片剂)或者附带起到延迟释放活性成份的作用。对于活性化合物的缓释口服片剂来说,利用一种已知的技术制备成有封闭气囊的多孔形片剂可能是有利的,以便使这种片剂浮于胃中,因而使之在胃中停留得更长。
对于迅速释放活性化合物的固体药物剂型来说,本新方法要比传统的压片工艺可允许药物剂型的设计更自由和广泛。例如片剂上可以刻上标记或制成任何形状,即使由视力减弱的那些人也可以识别清楚。某些形状,例如半球形也可能适于达到活性化合物的某些特性释放。通过挤塑或将挤出物热或冷面切粒法,可以以简单方式生产出极小粒状和均一形状的颗粒剂,例如多剂量单位剂型的颗粒剂(for multiple-unit forms)。
在下列实施例中,份数和百分数均指重量而言。活性化合物的释放时间用半变化试验法(the half-change test method)加以测定。
实施例1
100℃下于注塑机中,将45份共聚物(由60%重量的N-乙烯基吡咯烷酮和40%重量的乙酸乙烯酯共聚而成,K值为30)、5份十八烷醇和50份茶碱加工成片核。所得到的这种片核对机械作用稳定而且在输送和包装期间不磨损。与按美国药典21版的桨式搅拌法(the paddle method)联用,在半变化试验(参见例如R.Voigt“Lehrbuch der Pharmazeut.Technologie”,第5版,Verl.Chemie.Weinheim;Deerfield Beach,Florida;Basel,1984,627页)中,活性化合物在6-8小时期间内完全释出。
实施例2
120℃下于注塑机中将50份实施例1中的共聚物和50份茶碱加工成长度为1cm的椭园形片剂。此例中如此得到的片剂对机械作用也稳定,而且在1-2小时期间内也完全释出活性成份。
实施例3
将47.5份共聚物(由按重量计60%的N-乙烯基吡咯烷酮和40%乙酸乙烯酯共聚而成,K值为30)、2.5份交联聚乙烯基吡咯烷酮(PVP,作为片剂的崩解剂)和50份茶碱在双螺旋挤塑机中混合并挤出。五个注塑区的温度均为120℃。模具为130℃。将此仍具有塑性的挤出物压成椭园形片剂,使用的设备如同时提交的德国专利申请P36 12 211.4中所述。此片剂对机械作用稳定,而且在30-45分钟期间内释放出活性化合物。
实施例4
在双螺旋挤塑机中,将50份(由按重量计30%N-乙烯基吡咯烷酮和70%乙酸乙烯酯聚合而成,K值为52)共聚物以及50份茶碱加以混合和挤压。五个注塑区的温度分别为30、60、100、100和120℃。模具同样被加热到120℃。按照实施例3所述的方法,将仍具有塑性的挤出物压成对机械作用稳定的椭园形片剂。在8小时之内活性化合物被完全释放出。
实施例5
使47.5份(由按重量计60%的N-乙烯基吡咯烷酮和40%的乙酸乙烯酯聚合而成,K值为30)共聚物和2.5份十八烷醇以及50份茶碱,在注塑机中于100℃熔化,然后压成片核。模具处于室温下。这样生产出的片核对机械作用稳定,而且在6小时内完全释放出活性化合物。
在实施例6-11中,在下列温度下于单螺旋挤塑机中分别将由按重量计50%NVP均聚物(PVP,Fikentscher K值为12-60)和50%的茶碱组成的混合物压制成形:
于模拟的胃液中完全溶解如此得到的片剂中的活性化合物所需的时间为:实施例6和7的小于30分钟,实施例8和9的为1-2小时,实施例10的大于2小时。在实施例11中,PVP含十八烷醇为10(重量)%,释放时间为8小时。
实施例12-14
将36份(由按重量计60%的N-乙烯基吡咯烷酮和40%的乙酸乙烯酯聚合而成,K值为30)共聚物、4份十八烷醇、40份茶碱和20份:
淀粉(实施例12)
乳糖(实施例13)和
蔗糖(实施例14)
在6-注塑区双螺旋挤塑机中混合成形为与实施例1相似的片剂,各注塑区温度分别为90、100、110、120、130和130℃,模具温度为135℃。在6小时期间内活性化合物从片剂中完全溶出。
实施例15
在与实施例12-14中所用的同样温度和同样设备等条件下,将50份实施例12-14的共聚物和50份碳酸锂压成片剂。这些片剂在15-20分钟期间内完全释放出(于模拟的胃液中)活性化合物。
实施例16
按照实施例12-14所述,将50份实施例12-14的共聚物与50份戊脉安压制成形为片剂。此例中于大约3小时之内释放出活性化合物。
制备固体溶液所用的共聚物具有以下组成(按重量计)和K值:
A)60%的NVP和40%乙酸乙烯酯,K值约33;
B)100%NVP,K值30;
C)100%NVP,K值12;
D)100%NVP,K值12。
聚合物B、C和D是按照德国专利申请P3642633.4所述于水中用有机过氧化物作引发剂加以制备的。
实施例17
将3份共聚物A和1.5份苯佐卡因于犁头混合机(plowsharemixer)中预混合,然后在一台简单的6-注塑区挤塑机中挤压,每个注塑区的温度按朝着模具方向的顺序为:30、30、40、50、60和70℃。模具温度约为70℃。挤出物由一种固体溶液所组成,如Debye-Scherrer照片所表明的那样,该照片未显出任何细微的结晶性标志。在其余的实施例中(见表)使用了类似的方法,而且获得了同样结果。
T1-T6是注塑区1-6的温度(℃)。
实施例50
在一台注塑机上于模温度为130℃下重复实施例18、19和20。制得由固体溶液构成的片剂。
实施例51
按照重量比为1∶1将活性成份维生素C和下列NVP聚合物(按重量计)于双螺旋挤塑机中混合,在下表所列注塑区1-6和模具温度下挤压此混合物,借助于压延机将此挤出物成形为片剂,成形法见同时提出的德国专利申请P3612211.4:
a)60%共聚物和40%乙酸乙烯酯,K值约为33;
b)90%共聚物(a)和10%十八烷醇;
c)NVP均聚物,K值为17。
T1 T2 T3 T4 T5 T6 模具
a) 60 80 100 110 120 120 120℃
b) 60 80 80 100 100 110 110℃
c) 60 80 100 110 120 120 125℃
在此三例中,维生素于1-2小时内释放在水中。在所述的加工期间内,维生素未遭受任何分解,而且在这种形式下长时间贮存时受到保护而不受光线和大气氧的影响。
Claims (9)
1、制备固体药物剂型的方法,它通过把一种或多种药物活性化合物与一种或多种易熔的药理学上可耐受的粘结剂以及(必要时)其它一些常规的药物辅助剂加以混合,并且将该混合物在50-180℃下注塑成形或挤塑成形,其中使用的易熔粘结剂是无溶剂的N-乙烯基吡咯烷酮聚合物,该聚合物按重量计含有不高于3.5%的水,而且含有不低于20%的N-乙烯基吡咯烷-2-酮(NVP)作为共聚的单元,可以存在的全部共聚的共聚单体均含有氮和(或)氧,而且至少当该混合物的玻璃化转变温度高于120℃时,使用在有机溶剂中聚合得到的或者在水溶液中使用有机过氧化物作引发剂聚合得到的NVP聚合物,并且该混合物不含有微溶在胃液中的任何热塑性物质。
2、根据权利要求1的方法,其中所用的聚合物粘结剂含有不少于60(重量)%的NVP作为共聚单元。
3、根据权利要求1或2的方法,其中使用按聚合物重量计不高于20%的增塑剂。
4、根据权利要求1-3中任何一项的方法,其中所用的聚合物粘结剂由聚乙烯吡咯烷酮所组成,或者除N-乙烯吡咯烷酮之外仅含有乙酸乙烯酯作为共聚单元。
5、根据权利要求1-3中任何一项的方法,其中使用的聚合物粘结剂的共聚单体选自下列物质:丙烯酸、甲基丙烯酸、丁烯酸、马来酸、马来酸酐、衣康酸、衣康酸酐以及上述酸与1-12个碳原子醇类形成的酯或所说的二羧酸与1-12个碳原子醇类形成的半酯,以及丙烯酸和甲基丙烯酸的羟乙酯和羟丙酯,丙烯酰胺、甲基丙烯酰胺、N-乙烯基己内酰胺和丙酸乙烯酯。
6、根据权利要求1-5中任何一项的方法,其中所用的活性化合物是微溶于水的,在不加溶剂或水的条件下溶解在所说的聚合物熔体中生成分子分散溶液,而且在熔体固化后形成固体溶液。
7、根据权利要求6的方法,其中使用下列物质中的一种或多种活性化合物:乙酰氨基苯酚(扑热息痛)、醋磺环己脲、乙酰地高辛、乙酰水杨酸、山油柑碱(acronycin)、anipamil、苯佐卡因、β-葫萝卜素、氯霉素、利眠宁、氯化孕酮、氯噻嗪、肉桂苯哌嗪、氯硝安定、可待因、地塞米松、安定、双香豆素、洋地黄毒甙、地高辛、氢化麦角胺、氢乙罂粟碱、弱安定药氟硝西洋、呋喃苯胺酸、短杆菌肽、灰黄霉素、环己巴比妥、双塞克尿塞制剂、氢化可的松、氢氟甲噻嗪、消炎痛、酮洛芬、lonetil、去氧安定、倍可降、去氢甲睪酮、甲强龙、磺胺甲基嘧啶(异磺胺甲基嘧啶)、萘啶酸、心痛定、硝基安定、呋喃坦啶、制霉菌剂、雌二醇、罂粟碱、非那西丁、苯巴比妥、保泰松、苯妥英、强的松、利血平、安体舒通、链霉素、磺胺二甲嘧啶、磺胺甲噻二唑、磺胺甲基异噁唑、磺胺对甲氧嘧啶(消炎磺)、异磺胺甲基嘧啶、磺胺噻唑、磺胺异噁唑、睪丸酮、甲磺氮
脲、甲磺丁脲、甲氧苄氨嘧啶和短杆菌素。
8、根据权利要求1-7中任何一项的方法,其中使用Fikentscher K值为10-50的NVP聚合物。
9、根据权利要求1-7中任何一项的方法,其中使用Fikentscher K值为12-35的NVP聚合物。
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- 1987-03-31 EP EP87104724A patent/EP0240904B1/de not_active Expired - Lifetime
- 1987-03-31 ES ES198787104724T patent/ES2037020T3/es not_active Expired - Lifetime
- 1987-03-31 DE DE8787104724T patent/DE3780059D1/de not_active Expired - Lifetime
- 1987-04-03 YU YU59187A patent/YU46534B/sh unknown
- 1987-04-06 US US07/034,938 patent/US4801460A/en not_active Expired - Lifetime
- 1987-04-08 CS CS872532A patent/CS268177B2/cs not_active IP Right Cessation
- 1987-04-08 FI FI871539A patent/FI87887C/fi not_active IP Right Cessation
- 1987-04-09 JP JP62085889A patent/JPH089551B2/ja not_active Expired - Lifetime
- 1987-04-10 HU HU871617A patent/HU196132B/hu not_active IP Right Cessation
- 1987-04-10 SU SU874202334A patent/SU1731037A3/ru active
- 1987-04-10 UA UA4202334A patent/UA13038A1/uk unknown
- 1987-04-10 NO NO871513A patent/NO170570C/no not_active IP Right Cessation
- 1987-04-10 PT PT84661A patent/PT84661B/pt not_active IP Right Cessation
- 1987-04-10 CA CA000534435A patent/CA1308353C/en not_active Expired - Lifetime
- 1987-04-10 AU AU71413/87A patent/AU587897B2/en not_active Ceased
- 1987-04-11 CN CN87103409A patent/CN1022666C/zh not_active Expired - Lifetime
- 1987-04-11 KR KR1019870003527A patent/KR920003575B1/ko not_active IP Right Cessation
-
1992
- 1992-10-01 GR GR920402198T patent/GR3005866T3/el unknown
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1994
- 1994-12-29 MD MD95-0073A patent/MD374C2/ro unknown
Cited By (4)
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CN102176901B (zh) * | 2008-10-07 | 2014-10-08 | 巴斯夫欧洲公司 | 生产可控释放口服剂型的方法 |
CN102573755A (zh) * | 2009-09-18 | 2012-07-11 | 巴斯夫欧洲公司 | 制备具有低水溶性的物质的制剂的方法 |
CN104666084A (zh) * | 2014-11-27 | 2015-06-03 | 天津坤健生物制药有限公司 | 一种提高缓控释包衣片溶出度稳定性的方法 |
CN104666084B (zh) * | 2014-11-27 | 2018-07-13 | 天津坤健生物制药有限公司 | 一种提高缓控释包衣片溶出度稳定性的方法 |
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