CN1989966B - Pharmaceutical composition comprising rifamoin and isoniazid - Google Patents
Pharmaceutical composition comprising rifamoin and isoniazid Download PDFInfo
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- CN1989966B CN1989966B CN2005101307893A CN200510130789A CN1989966B CN 1989966 B CN1989966 B CN 1989966B CN 2005101307893 A CN2005101307893 A CN 2005101307893A CN 200510130789 A CN200510130789 A CN 200510130789A CN 1989966 B CN1989966 B CN 1989966B
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- Prior art keywords
- isoniazid
- rifampicin
- magnesium stearate
- weighing
- polyvidone
- Prior art date
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Links
- 229960003350 isoniazid Drugs 0.000 title claims description 21
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 title claims description 20
- 239000008194 pharmaceutical composition Substances 0.000 title description 12
- 238000000034 method Methods 0.000 claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 15
- 229940079593 drug Drugs 0.000 claims abstract description 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 46
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 claims description 40
- 229960001225 rifampicin Drugs 0.000 claims description 32
- 235000019359 magnesium stearate Nutrition 0.000 claims description 23
- 238000002360 preparation method Methods 0.000 claims description 22
- 239000003826 tablet Substances 0.000 claims description 18
- 229940049413 rifampicin and isoniazid Drugs 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 16
- 238000005303 weighing Methods 0.000 claims description 16
- 238000002156 mixing Methods 0.000 claims description 15
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 15
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 15
- 239000000463 material Substances 0.000 claims description 14
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 13
- 239000002671 adjuvant Substances 0.000 claims description 13
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 13
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 13
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 13
- 229960005206 pyrazinamide Drugs 0.000 claims description 12
- 239000008187 granular material Substances 0.000 claims description 11
- 239000011230 binding agent Substances 0.000 claims description 10
- 239000011248 coating agent Substances 0.000 claims description 10
- 238000000576 coating method Methods 0.000 claims description 10
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 claims description 10
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 10
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 10
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 claims description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- 239000007888 film coating Substances 0.000 claims description 8
- 238000009501 film coating Methods 0.000 claims description 8
- 238000005550 wet granulation Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 238000007908 dry granulation Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 239000007941 film coated tablet Substances 0.000 claims description 5
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 235000019270 ammonium chloride Nutrition 0.000 claims description 4
- 229910021538 borax Inorganic materials 0.000 claims description 4
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 4
- 239000004327 boric acid Substances 0.000 claims description 4
- UQGFMSUEHSUPRD-UHFFFAOYSA-N disodium;3,7-dioxido-2,4,6,8,9-pentaoxa-1,3,5,7-tetraborabicyclo[3.3.1]nonane Chemical compound [Na+].[Na+].O1B([O-])OB2OB([O-])OB1O2 UQGFMSUEHSUPRD-UHFFFAOYSA-N 0.000 claims description 4
- 239000004328 sodium tetraborate Substances 0.000 claims description 4
- 235000010339 sodium tetraborate Nutrition 0.000 claims description 4
- QZITYZUBVXLRPA-UHFFFAOYSA-N phthalic acid;potassium;sodium Chemical compound [Na].[K].OC(=O)C1=CC=CC=C1C(O)=O QZITYZUBVXLRPA-UHFFFAOYSA-N 0.000 claims description 2
- IWZKICVEHNUQTL-UHFFFAOYSA-M potassium hydrogen phthalate Chemical compound [K+].OC(=O)C1=CC=CC=C1C([O-])=O IWZKICVEHNUQTL-UHFFFAOYSA-M 0.000 claims description 2
- 239000007853 buffer solution Substances 0.000 abstract description 9
- 150000003839 salts Chemical class 0.000 abstract description 6
- 239000002253 acid Substances 0.000 abstract description 5
- 238000006731 degradation reaction Methods 0.000 abstract description 4
- 230000008901 benefit Effects 0.000 abstract description 3
- 230000015556 catabolic process Effects 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- KGTSLTYUUFWZNW-PPJQWWMSSA-N [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,27,29-pentahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-26-[(E)-(4-methylpiperazin-1-yl)iminomethyl]-6,23-dioxo-8,30-dioxa-24-azatetracyclo[23.3.1.14,7.05,28]triaconta-1(29),2,4,9,19,21,25,27-octaen-13-yl] acetate pyridine-4-carbohydrazide Chemical compound NNC(=O)c1ccncc1.CO[C@H]1\C=C\O[C@@]2(C)Oc3c(C2=O)c2c(O)c(\C=N\N4CCN(C)CC4)c(NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)c(O)c2c(O)c3C KGTSLTYUUFWZNW-PPJQWWMSSA-N 0.000 abstract 2
- 150000001447 alkali salts Chemical class 0.000 abstract 2
- 239000000890 drug combination Substances 0.000 abstract 2
- 239000003002 pH adjusting agent Substances 0.000 abstract 1
- 239000002775 capsule Substances 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 11
- 238000012360 testing method Methods 0.000 description 8
- -1 isoniazid compound Chemical class 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 238000011049 filling Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 239000012071 phase Substances 0.000 description 4
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 4
- YVOFSHPIJOYKSH-NLYBMVFSSA-M sodium rifomycin sv Chemical compound [Na+].OC1=C(C(O)=C2C)C3=C([O-])C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O YVOFSHPIJOYKSH-NLYBMVFSSA-M 0.000 description 4
- 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 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- PSWOBQSIXLVPDV-CXUHLZMHSA-N chembl2105120 Chemical compound C1=C(O)C(OC)=CC(\C=N\NC(=O)C=2C=CN=CC=2)=C1 PSWOBQSIXLVPDV-CXUHLZMHSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000013068 control sample Substances 0.000 description 3
- 238000004132 cross linking Methods 0.000 description 3
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229950006548 ftivazide Drugs 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229930189077 Rifamycin Natural products 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- HDFXRQJQZBPDLF-UHFFFAOYSA-L disodium hydrogen carbonate Chemical compound [Na+].[Na+].OC([O-])=O.OC([O-])=O HDFXRQJQZBPDLF-UHFFFAOYSA-L 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- AEUTYOVWOVBAKS-UWVGGRQHSA-N ethambutol Chemical compound CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 description 2
- AUAHHJJRFHRVPV-BZDVOYDHSA-N ethambutol dihydrochloride Chemical compound [Cl-].[Cl-].CC[C@@H](CO)[NH2+]CC[NH2+][C@@H](CC)CO AUAHHJJRFHRVPV-BZDVOYDHSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229960003292 rifamycin Drugs 0.000 description 2
- 229940062280 rifamycin sodium Drugs 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- FCRMJSYZVAIBRC-UHFFFAOYSA-N 1,2,4,5-tetraoxane-3,6-dione Chemical compound O=C1OOC(=O)OO1 FCRMJSYZVAIBRC-UHFFFAOYSA-N 0.000 description 1
- GHCZTIFQWKKGSB-UHFFFAOYSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid;phosphoric acid Chemical compound OP(O)(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O GHCZTIFQWKKGSB-UHFFFAOYSA-N 0.000 description 1
- FZIPCQLKPTZZIM-UHFFFAOYSA-N 2-oxidanylpropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O FZIPCQLKPTZZIM-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010015856 Extrasystoles Diseases 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- NGNYWBDWUIQPGS-UHFFFAOYSA-K [Na+].[K+].C(C=1C(C(=O)O)=CC=CC1)(=O)O.C(C=1C(C(=O)[O-])=CC=CC1)(=O)O.[K+].C(C=1C(C(=O)[O-])=CC=CC1)(=O)O.C(C=1C(C(=O)[O-])=CC=CC1)(=O)O Chemical compound [Na+].[K+].C(C=1C(C(=O)O)=CC=CC1)(=O)O.C(C=1C(C(=O)[O-])=CC=CC1)(=O)O.[K+].C(C=1C(C(=O)[O-])=CC=CC1)(=O)O.C(C=1C(C(=O)[O-])=CC=CC1)(=O)O NGNYWBDWUIQPGS-UHFFFAOYSA-K 0.000 description 1
- SZHJTBRHSAKQIF-UHFFFAOYSA-N [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].OB(O)O.[O-]B([O-])[O-].[O-]B([O-])[O-].[O-]B([O-])[O-].[O-]B([O-])[O-] Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].OB(O)O.[O-]B([O-])[O-].[O-]B([O-])[O-].[O-]B([O-])[O-].[O-]B([O-])[O-] SZHJTBRHSAKQIF-UHFFFAOYSA-N 0.000 description 1
- 230000009102 absorption Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- YBCVMFKXIKNREZ-UHFFFAOYSA-N acoh acetic acid Chemical group CC(O)=O.CC(O)=O YBCVMFKXIKNREZ-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- ALSPKRWQCLSJLV-UHFFFAOYSA-N azanium;acetic acid;acetate Chemical compound [NH4+].CC(O)=O.CC([O-])=O ALSPKRWQCLSJLV-UHFFFAOYSA-N 0.000 description 1
- ZRBROGSAUIUIJE-UHFFFAOYSA-N azanium;azane;chloride Chemical group N.[NH4+].[Cl-] ZRBROGSAUIUIJE-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GHXRKGHKMRZBJH-UHFFFAOYSA-N boric acid Chemical compound OB(O)O.OB(O)O GHXRKGHKMRZBJH-UHFFFAOYSA-N 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- CSVGEMRSDNSWRF-UHFFFAOYSA-L disodium;dihydrogen phosphate Chemical compound [Na+].[Na+].OP(O)([O-])=O.OP(O)([O-])=O CSVGEMRSDNSWRF-UHFFFAOYSA-L 0.000 description 1
- CBMPTFJVXNIWHP-UHFFFAOYSA-L disodium;hydrogen phosphate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].OP([O-])([O-])=O.OC(=O)CC(O)(C(O)=O)CC(O)=O CBMPTFJVXNIWHP-UHFFFAOYSA-L 0.000 description 1
- 229940072185 drug for treatment of tuberculosis Drugs 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 229960000285 ethambutol Drugs 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- GVBFBKODLPVQOA-UHFFFAOYSA-N heptane-1-sulfonic acid;sodium Chemical compound [Na].CCCCCCCS(O)(=O)=O GVBFBKODLPVQOA-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 229940080507 isoniazid 150 mg Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 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
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229940049552 rifinah Drugs 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical group 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- SPOMEWBVWWDQBC-UHFFFAOYSA-K tripotassium;dihydrogen phosphate;hydrogen phosphate Chemical compound [K+].[K+].[K+].OP(O)([O-])=O.OP([O-])([O-])=O SPOMEWBVWWDQBC-UHFFFAOYSA-K 0.000 description 1
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention involves a drug combinations including rifampin and isoniazid, the combination contains pH modifier of 0.1% ~ 10% (w/w). Said pH regulator is selected from weak acid- weak acid salt buffer system, weak alkali- weak alkali salt buffer system or weak acid salt- weak alkali salt buffer system. The drug combination in the invention can effectively reduce the product of polymer-3-formyl rifamycin SV isoniazone caused by rifampin and isoniazid degradation, and increased drug stability. The method of the invention has advantages as: operation is convenient, process is simple, equipment needs not improvment and the cost is low.
Description
Technical field:
The present invention relates to a kind of pharmaceutical composition that contains rifampicin and isoniazid, be specifically related to a kind of rifampicin of pH regulator agent and pharmaceutical composition of isoniazid of containing.
Background technology:
The compound preparation that contains rifampicin and isoniazid is that WHO (World Health Organization (WHO)) worldwide recommends as treatment choice drug lungy, through for many years clinical research confirmation its curative effect and safety.Compare with using single preparations of ephedrine respectively, have taking convenience, untoward reaction is few, drug resistance is low, the patient dependence advantages of higher.
But, contain the compound preparation poor stability of rifampicin and isoniazid, produce, in the storage, rifampicin and isoniazid are easily degraded, thereby influence the quality of product.Reason is as follows:
1. the rifampicin aqueous solution is very unstable, easily degraded
Through experiment confirm, the degraded of rifampicin mainly is the hydrolysis that carries out under solvent participates in rifampicin and the isoniazid compound solid preparation.Although the stability of rifampicin in solid preparation is higher in semi-solid preparation and solution, but still easily degrades.Because synthesis result of residual moisture, medicine isoniazid and some adjuvant moisture absorptions etc. etc. in a spot of water that solid preparation Chinese medicine and adjuvant contain, the wet granulation.
2. quicken the degraded of rifampicin when isoniazid exists
Document shows; at the flat 3-formoxyl Rifamycin Sodium that is decomposed into of acid condition diarrhea good fortune; when having isoniazid; 3-formoxyl Rifamycin Sodium and isoniazid reaction; become a kind of polymer: 3-formoxyl rifamycin ftivazide; the latter can quicken again rifampicin degraded (S.Singh et al.Pharm Pharmacol Commun, 2000.No6:405-410).
For solving the problem of residual moisture in the wet granulation, there is bibliographical information in the production of solid preparation, to adopt dry granulation, though this can be avoided the moisture brought in the wet-granulation process, but still can't avoid rifampicin degraded because of quickening with contacting of isoniazid in solid preparation.Can not solve root problem.
For avoid rifampicin in preparation with the contacting of isoniazid, the method that Chinese patent CN 02136930.5 takes is that rifampicin and isoniazid are made double-deck clad sheet, and its label is carried out Cotton seeds.Though the mode of double-deck clad sheet can be kept apart rifampicin and isoniazid, this method has increased operation, has prolonged the process time, has also needed to add new equipment, and cost is higher.
The method that Chinese patent CN 94214080.X keeps apart rifampicin and isoniazid is that rifampicin is made medicated powder, and isoniazid, pyrazinamide, ebutol are made in flakes coating more respectively, then last four kinds of materials is incapsulated.The method has following shortcoming: 1) more XXL troublesome poeration, three kinds of tablets need be distinguished tabletting, coating, need to increase workman's number, activity time is long, and is very uneconomical.2) leave big space in the capsule.Because of isoniazid, pyrazinamide, ebutol all are tablets, after incapsulating, several tablets in the capsule make and leave big space in the capsule, fill the gap though can utilize the rifampicin powder in theory, but because the filling of capsule 's content substep on capsule filling machine is finished one by one, actual rifampicin powder does not have the effect of filling the tablet gap; 3) practical operation is infeasible.The capsule filling machine that cause is used at present has only four stations at most, and one of them station is used to hold capsule, so can only fill three kinds of materials at most in a capsule, fills the in fact very difficult realization of material more than three kinds if desired in capsule.4) be difficult to realize the accurate of rifampicin powder filling dose.
It is more that last two kinds of methods increase the medicine cost, concerning vast tuberculosis patient, increased the weight of financial burden.
Though have report to point out that the degradation reaction of rifampicin is subjected to the influence of pH,, still do not have final conclusion at present about to the stable p H environment of rifampicin.The most stable pH value of rifampicin of different bibliographical informations is had nothing in common with each other, 6.2～7.2 (Wang Mingyuan etc., pharmacy circular, 1980 are arranged, Vol 15 (3): 6), 6.08 (Gao Hongke, Chinese Hospitals pharmaceutical journal, 1988 are arranged, Vol 8 (12): 564), also have 6.0～7.0 (Zhou Jingyun etc., Chinese Pharmaceutical Journal, 1996.7 Vol, 31 (7) 406-409).
Summary of the invention:
The technical problem to be solved in the present invention provides a kind of pharmaceutical composition that contains rifampicin and isoniazid of good stability, and overcomes complicated operation, defect of high cost that prior art exists.
The present inventor is through experiment confirm, and the degraded of rifampicin is that pH is dependent, and pH is the degraded minimum of 5.5～7.5 o'clock rifampicin.The inventor proposes following technical scheme through intensive big quantity research:
In the preparation that contains rifampicin and isoniazid, add the pH regulator agent, the pH of the liquid phase environment of rifampicin degradation reaction in the control preparation, the degraded that slows down rifampicin, thereby the stability of assurance compound preparation.
Described pH regulator agent is selected from weak acid-salt of weak acid buffer system, weak base-weak base salt buffer system, or the acid salt buffer system, and described salt is sodium salt, potassium salt or ammonium salt;
Described weak acid-salt of weak acid buffer system is selected from acetic acid-acetate, citric acid-phosphate, citric acid-citrate, boric acid-borate, carbonic acid-carbonate; Preferred acetic acid-sodium acetate, acetic acid-ammonium acetate, citric acid-sodium hydrogen phosphate, citric acid-sodium citrate, carbonic acid-sodium carbonate or boric acid-sodium tetraborate;
Described weak base-weak base salt buffer system is ammonia-ammonium chloride;
Described acid salt buffer system is selected from one or both the mixture in phosphate, phthalate, acetate, citrate, the carbonate.Preferably phosphoric acid potassium dihydrogen-sodium hydrogen phosphate, sodium hydrogen phosphate-sodium dihydrogen phosphate, potassium dihydrogen phosphate-dipotassium hydrogen phosphate, Potassium Hydrogen Phthalate-phthalic acid potassium sodium, or sodium carbonate-sodium bicarbonate.
The content of above-mentioned pH regulator agent in pharmaceutical composition should be controlled at 0.1%～10% (w/w), is preferably 0.5%～5% (w/w).
Pharmaceutical composition of the present invention can also contain one or more other anti-tuberculosis drugs, example hydrochloric acid ethambutol, pyrazinamide etc. except that containing Rimactazid and pH regulator agent.
Can also contain conventional adjuvant, batching of other pharmaceutical preparation well known to those skilled in the art etc. in the pharmaceutical composition of the present invention.
Pharmaceutical composition of the present invention can adopt the preparation of conventional formulation technology.
The dosage form of pharmaceutical composition of the present invention can be dosage forms such as tablet, capsule or injectable powder.
Through adopting high performance liquid chromatography that pharmaceutical composition of the present invention and the Rimactazid compound preparation that does not add the pH regulator agent are tested, the pharmaceutical composition of the present invention that confirms to have added the pH regulator agent can effectively reduce the generation of the polymer (the mould SV ftivazide of the sharp good fortune of 3-formoxyl) that rifampicin and isoniazid degraded produced.By the different good fortune sheet (Rimactazid bigeminy compound recipe sheet) of the present invention preparation through national drug clinical research base Medical University Of Chongqing clinical pharmacology research department clinical research confirmation: contain rifampicin 300mg with every of Milan, ITA Gruppo Lepetit SPA pharmaceutical factory production import, the different good fortune sheet (trade name Rifinah) of isoniazid 150mg has bioequivalence.
Advantage of the present invention is:
1. the increase medicine stability reduces the degraded of production, storage and transportation Chinese medicine;
2. easy to operate, technology is simple;
3. do not need scrap build, with low cost.
Provide some specific embodiments below, be used to describe in detail this method, but do not limit the present invention with this.
The specific embodiment:
Embodiment 1 rifampicin and isoniazid compound recipe Film coated tablets
1000 tablet recipes:
Rifampicin 300g
Isoniazid 150g
Potassium dihydrogen phosphate 6g
Dipotassium hydrogen phosphate 12g
Microcrystalline Cellulose 40g
Polyvidone 10g
Cross-linking sodium carboxymethyl cellulose 7.5g
Magnesium stearate 6g
Method for making: Rimactazid, microcrystalline Cellulose, polyvidone, cross-linking sodium carboxymethyl cellulose, potassium dihydrogen phosphate, dipotassium hydrogen phosphate are crossed 80 eye mesh screens respectively; take by weighing above-mentioned powder and 4g magnesium stearate and mix homogeneously by recipe quantity; get dried granule with dry granulation mechanism; get tabletting behind dried granule and the 2g magnesium stearate mix homogeneously, control strip focuses on 520mg～540mg.Plain sheet carries out film coating with the Opadry coating material.
Embodiment 2 Rimactazids and pyrazinamide compound recipe Film coated tablets
1000 tablet recipes:
Rifampicin 120g
Isoniazid 80g
Pyrazinamide 250g
Citric acid 2g
Sodium hydrogen phosphate 9g
Microcrystalline Cellulose 45g
Polyvidone 10g
Cross-linking sodium carboxymethyl cellulose 8g
Magnesium stearate 5g
Method for making: former, adjuvant are crossed 80 eye mesh screens respectively, taken by weighing the 3g magnesium stearate and take by weighing other former, adjuvants by recipe quantity; mixing; get dried granule with dry granulation mechanism, get tabletting behind dried granule and the 2g magnesium stearate mix homogeneously, control strip focuses on 520mg～540mg.Plain sheet carries out film coating with the Opadry coating material.
Embodiment 3 Rimactazids and pyrazinamide compound capsule
1000 prescriptions:
Rifampicin 60g
Isoniazid 40g
Pyrazinamide 125g
Polyvidone 5g
Acetic acid 0.1g
Ammonium acetate 5g
Pregelatinized Starch 15g
Magnesium stearate 5g
Method for making: the polyvidone, acetic acid, the sodium acetate that take by weighing recipe quantity are dissolved in the 50ml water, make binding agent.Solid is former, adjuvant is crossed 80 eye mesh screens respectively, is taken by weighing former, adjuvant except that magnesium stearate by recipe quantity, mixing, and the binding agent wet granulation that usefulness prepares is got dried granule and 5g magnesium stearate mixing after the drying, fill No. 2 capsule.
Embodiment 4 Rimactazid compound recipe thin membrane coated tablets
1000 tablet recipes:
Rifampicin 300g
Isoniazid 150g
Polyvidone 10g
Weak ammonia is an amount of
Ammonium chloride 15g
Microcrystalline Cellulose 50g
Polyvinylpolypyrrolidone 8g
Magnesium stearate 6g
Method for making: the polyvidone, the ammonium chloride that take by weighing recipe quantity are dissolved in the 90ml water, make binder solution, and weak ammonia adjusting PH to 7.0, and is standby.Solid is former, adjuvant is crossed 80 eye mesh screens respectively, is taken by weighing Rimactazid, microcrystalline Cellulose, polyvinylpolypyrrolidone mixing by recipe quantity, with the binder solution wet granulation for preparing, get dried granule and 6g magnesium stearate mixing after the drying, tabletting, control strip focuses between 530～550mg, and plain sheet carries out film coating with the Opadry coating material.
Embodiment 5 Rimactazids, pyrazinamide compound recipe thin membrane coated tablet
1000 tablet recipes:
Rifampicin 120g
Isoniazid 80g
Pyrazinamide 250g
Polyvidone 10g
Boric acid is an amount of
Sodium tetraborate 10g
Microcrystalline Cellulose 45g
Polyvinylpolypyrrolidone 8g
Magnesium stearate 5g
Method for making: the polyvidone, sodium tetraborate that take by weighing recipe quantity are made binder solution in 50ml water, and regulate PH to 6.5 with boric acid, and be standby.Solid is former, adjuvant is crossed 80 eye mesh screens respectively, is taken by weighing Rimactazid, pyrazinamide, microcrystalline Cellulose, polyvinylpolypyrrolidone mixing by recipe quantity, with the binding agent wet granulation for preparing, get dried granule and 5g magnesium stearate mixing after the drying, tabletting, control strip focuses between 520～540mg, and plain sheet carries out film coating with the Opadry coating material.
Embodiment 6 Rimactazid compound recipe thin membrane coated tablets
1000 tablet recipes:
Rifampicin 300g
Isoniazid 150
Polyvidone 10g
Potassium Hydrogen Phthalate 12
Phthalic acid potassium sodium 13
Microcrystalline Cellulose 50g
Polyvinylpolypyrrolidone 8g
Magnesium stearate 6g
Method for making: solid is former, adjuvant is crossed 80 eye mesh screens respectively, is taken by weighing all former, auxiliary materials and mixing except that magnesium stearate by recipe quantity, dry granulation is got dried granule and 5g magnesium stearate mixing, tabletting, control strip focuses between 540～560mg, and plain sheet carries out film coating with the Opadry coating material.
Experimental example 1 adds and the medicine stability contrast test of not adding the pH regulator agent
1. test objective: investigate by accelerated test and to add the influence of pH regulator agent to drug quality stability.
2. trial drug
Test specimen: present embodiment 1 obtained tablet.
Control sample: after pH regulator agent potassium dihydrogen phosphate, dipotassium hydrogen phosphate in embodiment 1 prescription removed, make the contrast tablet by embodiment 1 method for making.
3. test method:
1) under 40 ℃, RH 75% condition, test specimen and control sample were placed 6 months,, measured the content of rifampicin and isoniazid respectively at sampling in 1,2,3,6 month, and catabolite 3-formoxyl rifamycin ftivazide content.
2) adopt high performance liquid chromatography detection of drugs and content of degradation products.Chromatographic condition is:
Chromatographic column is
250-4
PAH (Alltima Cyano100 250 * 4.6mm 5 μ m): diode array UV-detector (SPD-10A vp), detection wavelength are 254nm; 0.01mol/L (phosphoric acid,diluted is regulated pH value to 2.2)-acetonitrile (44: 56) is a mobile phase to the heptanesulfonic acid sodium solution, flow velocity 0.55ml/min.
Assay method: 10 of sample thiefs, remove film-coat, the accurate title, decide, porphyrize, precision takes by weighing fine powder an amount of (being equivalent to rifampicin 60mg approximately), puts in the 100ml measuring bottle, adds the mobile phase dissolving and is diluted to scale, shake up, filter, precision is measured subsequent filtrate 5ml, puts in the 50ml measuring bottle, be diluted to scale with mobile phase, shake up.Precision is measured 20 μ l and is injected chromatograph of liquid, the record chromatogram; Other gets rifampicin and the isoniazid reference substance is an amount of, and accurate the title decides, and dissolves also quantitatively dilution with mobile phase and makes the solution identical with need testing solution concentration, measures with method.Press external standard method with calculated by peak area main peak content, promptly.
3. experimental result
See the following form
40 ℃, RH 75% accelerated test result
4. experiment conclusion
Compare with the control sample that does not add the pH regulator agent, test specimen is at the equal good stability of each experimental stage, and the degradation material of generation is few.
Claims (3)
1. rifampicin and isoniazid compound solid preparation are Film coated tablets, and the prescription of 1000 tablets of medicines of preparation is as follows:
Rifampicin 300g
Isoniazid 150g
Polyvidone 10g
Weak ammonia is an amount of
Ammonium chloride 15g
Microcrystalline Cellulose 50g
Polyvinylpolypyrrolidone 8g
Magnesium stearate 6g
Method for making: take by weighing polyvidone, ammonium chloride is dissolved in the 90ml water, makes binder solution, and weak ammonia regulates pH to 7.0, standby; Solid is former, adjuvant is crossed 80 eye mesh screens respectively, is taken by weighing Rimactazid, microcrystalline Cellulose, polyvinylpolypyrrolidone mixing, with the binder solution wet granulation for preparing, get dried granule and 6g magnesium stearate mixing after the drying, tabletting, control strip focuses between 530～550mg, and plain sheet carries out film coating with the Opadry coating material.
2. rifampicin and isoniazid compound solid preparation are Film coated tablets, and the prescription of 1000 tablets of medicines of preparation is as follows:
Rifampicin 120g
Isoniazid 80g
Pyrazinamide 250g
Polyvidone 10g
Boric acid is an amount of
Sodium tetraborate 10g
Microcrystalline Cellulose 45g
Polyvinylpolypyrrolidone 8g
Magnesium stearate 5g
Method for making: take by weighing polyvidone, sodium tetraborate in 50ml water, make binder solution, and regulate pH to 6.5 with boric acid, standby; Solid is former, adjuvant is crossed 80 eye mesh screens respectively, is taken by weighing Rimactazid, pyrazinamide, microcrystalline Cellulose, polyvinylpolypyrrolidone mixing, with the binding agent wet granulation for preparing, get dried granule and 5g magnesium stearate mixing after the drying, tabletting, control strip focuses between 520～540mg, and plain sheet carries out film coating with the Opadry coating material.
3. rifampicin and isoniazid compound solid preparation are Film coated tablets, and the prescription of 1000 tablets of medicines of preparation is as follows:
Rifampicin 300g
Isoniazid 150
Polyvidone 10g
Potassium Hydrogen Phthalate 12g
Phthalic acid potassium sodium 13g
Microcrystalline Cellulose 50g
Polyvinylpolypyrrolidone 8g
Magnesium stearate 6g
Method for making: solid is former, adjuvant is crossed 80 eye mesh screens respectively, is taken by weighing all former, auxiliary materials and mixing except that magnesium stearate by recipe quantity, dry granulation is got dried granule and 5g magnesium stearate mixing, tabletting, control strip focuses between 540～560mg, and plain sheet carries out film coating with the Opadry coating material.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2005101307893A CN1989966B (en) | 2005-12-30 | 2005-12-30 | Pharmaceutical composition comprising rifamoin and isoniazid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2005101307893A CN1989966B (en) | 2005-12-30 | 2005-12-30 | Pharmaceutical composition comprising rifamoin and isoniazid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1989966A CN1989966A (en) | 2007-07-04 |
| CN1989966B true CN1989966B (en) | 2011-06-08 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2005101307893A Expired - Fee Related CN1989966B (en) | 2005-12-30 | 2005-12-30 | Pharmaceutical composition comprising rifamoin and isoniazid |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9814711B2 (en) | 2013-07-26 | 2017-11-14 | Sanofi | Antitubercular composition comprising rifampicin, isoniazid, ethambutol and pyrazinamide and its process of preparation |
| US9814680B2 (en) | 2013-07-26 | 2017-11-14 | Sanofi | Anti-tuberculosis stable pharmaceutical composition in a form of a dispersible tablet comprising granules of isoniazid and granules of rifapentine and its process of preparation |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1097986A (en) * | 1993-07-28 | 1995-02-01 | 高绪侠 | Complex rifampin injection |
| CN1190581A (en) * | 1998-02-25 | 1998-08-19 | 高绪侠 | Complex rifampin injection |
-
2005
- 2005-12-30 CN CN2005101307893A patent/CN1989966B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1097986A (en) * | 1993-07-28 | 1995-02-01 | 高绪侠 | Complex rifampin injection |
| CN1190581A (en) * | 1998-02-25 | 1998-08-19 | 高绪侠 | Complex rifampin injection |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9814711B2 (en) | 2013-07-26 | 2017-11-14 | Sanofi | Antitubercular composition comprising rifampicin, isoniazid, ethambutol and pyrazinamide and its process of preparation |
| US9814680B2 (en) | 2013-07-26 | 2017-11-14 | Sanofi | Anti-tuberculosis stable pharmaceutical composition in a form of a dispersible tablet comprising granules of isoniazid and granules of rifapentine and its process of preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1989966A (en) | 2007-07-04 |
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