DE102004007854A1 - Aqueous composition containing a benzimidazole derivative, particularly omeprazole, useful for treating ulcers, is adjusted to weakly basic pH and contains no organic solvent - Google Patents
Aqueous composition containing a benzimidazole derivative, particularly omeprazole, useful for treating ulcers, is adjusted to weakly basic pH and contains no organic solvent Download PDFInfo
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- DE102004007854A1 DE102004007854A1 DE102004007854A DE102004007854A DE102004007854A1 DE 102004007854 A1 DE102004007854 A1 DE 102004007854A1 DE 102004007854 A DE102004007854 A DE 102004007854A DE 102004007854 A DE102004007854 A DE 102004007854A DE 102004007854 A1 DE102004007854 A1 DE 102004007854A1
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- Germany
- Prior art keywords
- acid
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- tris
- salts
- hydroxymethyl
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- 239000000203 mixture Substances 0.000 title claims abstract description 30
- 239000003960 organic solvent Substances 0.000 title claims abstract description 10
- -1 omeprazole Chemical class 0.000 title claims description 4
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 title description 9
- 229960000381 omeprazole Drugs 0.000 title description 8
- 208000025865 Ulcer Diseases 0.000 title description 2
- 231100000397 ulcer Toxicity 0.000 title description 2
- 150000001556 benzimidazoles Chemical class 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- HBDKFZNDMVLSHM-UHFFFAOYSA-N 2-(pyridin-2-ylmethylsulfinyl)-1h-benzimidazole Chemical compound N=1C2=CC=CC=C2NC=1S(=O)CC1=CC=CC=N1 HBDKFZNDMVLSHM-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000012928 buffer substance Substances 0.000 claims abstract description 10
- 238000009472 formulation Methods 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract 3
- 239000000872 buffer Substances 0.000 claims description 21
- 239000000843 powder Substances 0.000 claims description 14
- 229940063517 omeprazole sodium Drugs 0.000 claims description 12
- KNVABRFVZVESIL-UHFFFAOYSA-N sodium;6-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1h-benzimidazole Chemical compound [Na+].N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C KNVABRFVZVESIL-UHFFFAOYSA-N 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 11
- 239000003381 stabilizer Substances 0.000 claims description 8
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 8
- DVLFYONBTKHTER-UHFFFAOYSA-N 3-(N-morpholino)propanesulfonic acid Chemical compound OS(=O)(=O)CCCN1CCOCC1 DVLFYONBTKHTER-UHFFFAOYSA-N 0.000 claims description 6
- JOCBASBOOFNAJA-UHFFFAOYSA-N N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid Chemical compound OCC(CO)(CO)NCCS(O)(=O)=O JOCBASBOOFNAJA-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- YNLCVAQJIKOXER-UHFFFAOYSA-N N-[tris(hydroxymethyl)methyl]-3-aminopropanesulfonic acid Chemical compound OCC(CO)(CO)NCCCS(O)(=O)=O YNLCVAQJIKOXER-UHFFFAOYSA-N 0.000 claims description 5
- 239000003963 antioxidant agent Substances 0.000 claims description 5
- 235000006708 antioxidants Nutrition 0.000 claims description 5
- 239000008139 complexing agent Substances 0.000 claims description 5
- 238000002347 injection Methods 0.000 claims description 5
- 239000007924 injection Substances 0.000 claims description 5
- 239000004475 Arginine Substances 0.000 claims description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 claims description 3
- AJTVSSFTXWNIRG-UHFFFAOYSA-N 2-[bis(2-hydroxyethyl)amino]ethanesulfonic acid Chemical compound OCC[NH+](CCO)CCS([O-])(=O)=O AJTVSSFTXWNIRG-UHFFFAOYSA-N 0.000 claims description 3
- 239000007995 HEPES buffer Substances 0.000 claims description 3
- OWXMKDGYPWMGEB-UHFFFAOYSA-N HEPPS Chemical compound OCCN1CCN(CCCS(O)(=O)=O)CC1 OWXMKDGYPWMGEB-UHFFFAOYSA-N 0.000 claims description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 3
- 239000007993 MOPS buffer Substances 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 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
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 239000011976 maleic acid Substances 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 229960003080 taurine Drugs 0.000 claims description 3
- MOMKYJPSVWEWPM-UHFFFAOYSA-N 4-(chloromethyl)-2-(4-methylphenyl)-1,3-thiazole Chemical compound C1=CC(C)=CC=C1C1=NC(CCl)=CS1 MOMKYJPSVWEWPM-UHFFFAOYSA-N 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 claims description 2
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 claims description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 2
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 claims description 2
- 235000000072 L-ascorbyl-6-palmitate Nutrition 0.000 claims description 2
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 claims description 2
- 229940087168 alpha tocopherol Drugs 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 229960005070 ascorbic acid Drugs 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 claims description 2
- ZAKOWWREFLAJOT-UHFFFAOYSA-N d-alpha-Tocopheryl acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-UHFFFAOYSA-N 0.000 claims description 2
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 claims description 2
- 239000003978 infusion fluid Substances 0.000 claims description 2
- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 claims description 2
- 235000019983 sodium metaphosphate Nutrition 0.000 claims description 2
- 229940048086 sodium pyrophosphate Drugs 0.000 claims description 2
- 235000000346 sugar Nutrition 0.000 claims description 2
- 150000005846 sugar alcohols Chemical class 0.000 claims description 2
- 235000019818 tetrasodium diphosphate Nutrition 0.000 claims description 2
- 239000001577 tetrasodium phosphonato phosphate Substances 0.000 claims description 2
- 229960000984 tocofersolan Drugs 0.000 claims description 2
- 229940042585 tocopherol acetate Drugs 0.000 claims description 2
- 239000002076 α-tocopherol Substances 0.000 claims description 2
- 235000004835 α-tocopherol Nutrition 0.000 claims description 2
- 230000003078 antioxidant effect Effects 0.000 claims 1
- 238000000034 method Methods 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 239000000243 solution Substances 0.000 description 9
- 239000002253 acid Substances 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 4
- 239000003125 aqueous solvent Substances 0.000 description 4
- 239000012669 liquid formulation Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002585 base Substances 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
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 3
- 235000019799 monosodium phosphate Nutrition 0.000 description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000013011 aqueous formulation Substances 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 2
- IHOWSFVYYZTGSY-FOIRCHMTSA-N (2s)-2-amino-5-(diaminomethylideneamino)pentanoic acid;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N.OC(=O)[C@@H](N)CCCN=C(N)N.OC(=O)[C@@H](N)CCCN=C(N)N.OC(=O)CC(O)(C(O)=O)CC(O)=O IHOWSFVYYZTGSY-FOIRCHMTSA-N 0.000 description 1
- LOFGQZYYARWABM-BYPYZUCNSA-N (2s)-2-amino-5-(diaminomethylideneamino)pentanoyl chloride Chemical compound ClC(=O)[C@@H](N)CCCNC(N)=N LOFGQZYYARWABM-BYPYZUCNSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical compound [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 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
- 239000012153 distilled water Substances 0.000 description 1
- 229940071106 ethylenediaminetetraacetate Drugs 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960003174 lansoprazole Drugs 0.000 description 1
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000008058 pain sensation Effects 0.000 description 1
- 229960005019 pantoprazole Drugs 0.000 description 1
- 239000008194 pharmaceutical composition 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
- 239000008363 phosphate buffer Substances 0.000 description 1
- CCTIOCVIZPCTGO-BYPYZUCNSA-N phosphoarginine Chemical compound OC(=O)[C@@H](N)CCCNC(=N)NP(O)(O)=O CCTIOCVIZPCTGO-BYPYZUCNSA-N 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Classifications
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Wässrige pharmazeutische Zubereitung umfassend ein 2-[(2-Pyridyl)methylsulfinyl]benzimidazol oder eines seiner Salze und mindestens eine Puffersubstanz, gekennzeichnet durch einen pH-Wert der Formulierung zwischen 7 und 9, wobei die Zubereitung frei von organischen Lösungsmitteln ist.Aqueous pharmaceutical Preparation comprising a 2 - [(2-pyridyl) methylsulfinyl] benzimidazole or one of its salts and at least one buffer substance by a pH of the formulation between 7 and 9, wherein the Preparation is free of organic solvents.
Description
Gegenstand der Erfindung sind stabile, wässrige Formulierungen mit hydrolyse- und säureempfindlichen 2-[(2-Pyridyl)methylsulfinyl]benzimidazolen oder deren Salzen, insbesondere Omeprazol-Natrium, Lyophilisate oder Pulver mit 2-[(2-Pyridyl)methylsulfinyl]benzimidazolen oder deren Salzen, sowie Arzneimittel-Kits, die diese Lyophilisate oder Pulver enthalten.object The invention is stable, aqueous Formulations with hydrolysis- and acid-sensitive 2 - [(2-pyridyl) methylsulfinyl] benzimidazoles or their salts, in particular omeprazole sodium, lyophilisates or powder with 2 - [(2-pyridyl) methylsulfinyl] benzimidazoles or their salts, as well as drug kits containing these lyophilisates or powder.
Zu den 2-[(2-Pyridyl)methylsulfinyl]benzimidazolen zählen beispielsweise Omeprazol, Lansoprazol oder Pantoprazol. Omeprazol (5-Methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridylmethyl-sulfinyl)-1H-benzimidazol) gehört zu den Protonenpumpeninhibitoren und wird zur Ulcustherapie eingesetzt. Bekanntermaßen zersetzt sich Omeprazol sehr rasch im sauren Milieu. Auch Feuchtigkeit, organische Lösungsmittel oder UV-Licht beschleunigen die Zersetzung von Omeprazol, wobei sich die Verbindung nicht nur in Lösung sondern auch in fester Form verfärbt. Gemäß M. Mathew (Drug Dev. Ind. Pharm., 21, 965–971, 1995) ist eine Omeprazol-Lösung mit einem pH = 5.9–7.0 einen Tag stabil, eine Lösung mit pH = 2.2–4.7 zersetzt sich innerhalb weniger Stunden. Laut A. Brändström (Acta Chem. Scand. 43, 536, 1989) stellt der säure-katalysierte Abbau von Omeprazol einen sehr komplexen Reaktionsablauf dar.To For example, the 2 - [(2-pyridyl) methylsulfinyl] benzimidazoles include Omeprazole, lansoprazole or pantoprazole. Omeprazole (5-methoxy-2- (4-methoxy-3,5-dimethyl-2-pyridylmethylsulfinyl) -1H-benzimidazole) belongs to the proton pump inhibitors and is used for ulcer therapy. As is known, Omeprazole decomposes very rapidly in an acidic environment. Also moisture, organic solvents or UV light accelerate the decomposition of omeprazole, wherein the connection not only in solution but also in solid Discolored shape. According to M. Mathew (Drug Dev. Ind. Pharm., 21, 965-971, 1995) is an omeprazole solution with a pH = 5.9-7.0 stable one day, a solution with pH = 2.2-4.7 decomposes within a few hours. According to A. Brändström (Acta Chem. Scand. 43, 536, 1989) represents the acid-catalyzed degradation of Omeprazole is a very complex reaction process.
Für Omeprazol wurden verschiedene Formen zur oralen Verabreichung entwickelt. Auch parenterale Formulierungen wurden beschrieben.For omeprazole Various forms have been developed for oral administration. Parenteral formulations have also been described.
In
Der
pH-Wert der Körperflüssigkeiten
liegt im schwach alkalischen Bereich bei pH = 7.4. Bei Injektionslösungen machen
sich geringe Abweichungen vom pH-Wert und dem osmotischen Druck
des Blutes nur wenig hinsichtlich des Schmerzempfindens bei der
Injektion bemerkbar. Dagegen sollten Infusionslösungen isohydrisch und isotonisch
sein, da die Gefahr einer Hämolyse
besteht. Eine stark alkalische Formulierung mit einem pH-Wert größer 9.5
wie in
Aufgabe der Erfindung ist die Bereitstellung einer parenteralen Formulierung mit 2-[(2-Pyridyl)methylsulfinyl]benzimidazolen oder deren Salzen, deren pH-Wert im Bereich von 7–9 liegt. Die Formulierung soll frei von organischen Lösungsmittel sein.task The invention is to provide a parenteral formulation with 2 - [(2-pyridyl) methylsulfinyl] benzimidazoles or salts thereof whose pH is in the range of 7-9. The formulation should be free of organic solvents.
Überraschenderweise wurde nun gefunden, daß eine stabile parenterale Formulierung mit 2-[(2-Pyridyl)methylsulfinyl]benzimidazolen oder deren Salzen, insbesondere mit Omeprazol-Natrium unter Verwendung einer schwach basischen Puffersubstanz erreicht werden kann. Als Puffer eignen sich Maleinsäure, Phosphorsäure und Arginin oder deren physiologisch verträglichen Salze. Zur Herstellung der Puffersubstanzen können sowohl die freien Säuren als auch die entsprechenden Alkali-, Erdalkali- oder Ammoniumsalze eingesetzt werden. Es können auch organische Puffersubstanzen wie N,N-Bis(2-hydroxyethyl)-2-aminoethansulfonsäure (BES), 3-(N-Morpholino)propansulfonsäure (MOPS), Tris(hydroxymethyl)aminomethan (TRIS), N-Tris-(hydroxymethyl)methyl-2-aminoethansulfonsäure (TES), N-2-Hydroxyethylpiperazin-N'-2-aminoethansulfonsäure (HEPES), N-2-Hydroxyethylpiperazin-N'-2-aminopropansulfonsäure (EPPS) oder N-Tris(hydroxymethyl)methyl-3-aminopropansulfonsäure verwendet werden. Es können auch Mischungen verschiedener Puffersubstanzen und/oder deren Salze vorliegen. Die Konzentrationen der Puffersubstanzen werden vorteilhaft so gewählt, daß sowohl der gewünschte pH-Wert als auch eine ausreichende Pufferkapazität erzielt werden. In der Regel liegen die Konzentrationen, in der die Puffersubstanzen in der wässrigen Zusammensetzung eingesetzt werden, zwischen 0.5 und 300 mMol/l, vorzugsweise zwischen 2 und 150 mMol/l.Surprisingly has now been found that one stable parenteral formulation with 2 - [(2-pyridyl) methylsulfinyl] benzimidazoles or their salts, especially with omeprazole sodium using a weak basic buffer substance can be achieved. Suitable as a buffer maleic acid, phosphoric acid and Arginine or its physiologically acceptable salts. For the production the buffer substances can both the free acids as well as the corresponding alkali, alkaline earth or ammonium salts be used. It can also organic buffer substances, such as N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid (BES), 3- (N-morpholino) propanesulfonic acid (MOPS), tris (hydroxymethyl) aminomethane (TRIS), N-tris (hydroxymethyl) methyl-2-aminoethanesulfonic acid (TES), N-2-hydroxyethylpiperazine-N'-2-aminoethanesulfonic acid (HEPES), N-2-Hydroxyethylpiperazine-N'-2-aminopropanesulphonic acid (EPPS) or N-tris (hydroxymethyl) methyl-3-aminopropanesulfonic acid become. It can also mixtures of different buffer substances and / or salts thereof available. The concentrations of the buffer substances will be advantageous chosen so that both the desired one pH as well as a sufficient buffer capacity can be achieved. Usually are the concentrations in which the buffer substances in the aqueous Composition can be used, between 0.5 and 300 mmol / l, preferably between 2 and 150 mmol / l.
Der pH-Wert der erfindungsgemäßen Zusammensetzung liegt im Bereich von 7 bis 9. Falls erforderlich kann der pH-Wert auch noch mit Hilfe anderer Säuren oder Basen auf den gewünschten pH-Wert eingestellt werden. Geeignete Säuren sind beispielsweise Salzsäure, Essigsäure oder Citronensäure. Geeignete Basen sind beispielsweise Alkali- und/oder Erdalkalihydroxide, Alkalicarbonate, Alkaliacetate, Alkalicitrate, z. B. Natriumhydroxid, Natriumcarbonat, Natriumcitrat oder Ammoniak.The pH of the composition according to the invention is in the range from 7 to 9. If necessary, the pH can also be adjusted to the desired pH with the aid of other acids or bases. Suitable acids are, for example, hydrochloric acid, acetic acid or citric acid. Suitable bases are, for example, alkali metal and / or alkaline earth metal hydroxides, alkali metal carbonates, alkali metal acetates, alkali citrates, z. For example, sodium hydroxide, sodium carbonate, sodium citrate or ammonia.
In den erfindungsgemäßen pharmazeutischen Zusammensetzungen liegt das 2-[(2-Pyridyl)methylsulfinyl]benzimidazol oder dessen Salz in einer Konzentration zwischen 0.01 und 50 mg/ml, vorzugsweise zwischen 0.1 und 0.8 mg/ml vor.
- – Der pH-Wert der flüssigen Formulierung mit einem Maleat-Puffer liegt bevorzugt im Bereich von 7–8.
- – Der pH-Wert der flüssigen Formulierung mit einem Phosphat-Puffer liegt im Bereich von 7-9, insbesondere zwischen pH = 7 und pH = 8. Bevorzugt werden Puffer mit Natriumdihydrogenphosphat und Dinatriumhydrogenphosphat bzw. Kaliumdihydrogenphosphat und Dikaliumhydrogenphosphat eingesetzt.
- – Der pH-Wert der flüssigen Formulierung mit einem Arginin-Puffer liegt im Bereich von 7–9, insbesondere 8–9. Bevorzugt wird Argininphosphat, Arginincitrat oder Argininchlorid als Puffer eingesetzt.
- – Der pH-Wert der flüssigen Formulierung mit einem TRIS-Puffer liegt bevorzugt im Bereich von 7–9.
- The pH of the liquid formulation with a maleate buffer is preferably in the range of 7-8.
- The pH of the liquid formulation with a phosphate buffer is in the range of 7-9, in particular between pH = 7 and pH = 8. Preference is given to using buffers with sodium dihydrogen phosphate and disodium hydrogen phosphate or potassium dihydrogen phosphate and dipotassium hydrogen phosphate.
- The pH of the liquid formulation with an arginine buffer is in the range of 7-9, especially 8-9. Arginine phosphate, arginine citrate or arginine chloride is preferably used as the buffer.
- The pH of the liquid formulation with a TRIS buffer is preferably in the range of 7-9.
Die erfindungsgemäßen Zusammensetzungen können weitere Stabilisierungsmittel und/oder Hilfsstoffe wie isotonisierende Mittel, Antioxidantien und/oder Komplexbildner enthalten.The Compositions of the invention can further stabilizers and / or auxiliaries such as isotonizing Contains agents, antioxidants and / or complexing agents.
Als isotonisierende Mittel eignen sich Zucker oder Zuckeralkohole wie Saccharose, Maltose, Fructose, Lactose, Mannit, Sorbit und/oder Glycerin.When isotonizing agents are sugars or sugar alcohols such as Sucrose, maltose, fructose, lactose, mannitol, sorbitol and / or Glycerol.
Als Antioxidantien können beispielsweise Ascorbinsäure oder ihre Salze, Ascorbinsäurepalmitat, Ascorbinsäurestearat, Triamylgallat, alpha-Tocopherol, Tocopherolacetat und/oder Butylhydroxyanisol verwendet werden.When Antioxidants can for example, ascorbic acid or their salts, ascorbic acid palmitate, Ascorbinsäurestearat, Triamyl gallate, alpha-tocopherol, tocopherol acetate and / or butylhydroxyanisole be used.
Als Komplexbildner geeignet sind beispielsweise Citrat, Dinatriumethylendiamintetraacetat (EDTA), Natriumpyrophosphat und/oder Natriummetaphosphat.When Suitable complexing agents are, for example, citrate, disodium ethylenediaminetetraacetate (EDTA), sodium pyrophosphate and / or sodium metaphosphate.
Zur Herstellung der erfindungsgemäßen Zusammensetzungen werden die Puffersubstanzen und gegebenenfalls weitere Stabilisierungsmittel und/oder Hilfsstoffe zunächst in sterilem Wasser gelöst. Falls erforderlich wird der pH-Wert der Pufferlösung mit anderen Säuren oder Basen, wie oben genannt, eingestellt. Nach einem Sterilisierungsschritt wird das 2-[(2-Pyridyl)methylsulfinyl]benzimidazol zugegeben.to Preparation of the compositions of the invention be the buffer substances and optionally further stabilizers and / or auxiliaries first dissolved in sterile water. If necessary, the pH of the buffer solution with other acids or Bases, as mentioned above, set. After a sterilization step becomes 2 - [(2-pyridyl) methylsulfinyl] benzimidazole added.
Die erfindungsgemäße Zusammensetzung kann als Infusions- oder Injektionslösung, insbesondere zur intravenösen, intramuskulären oder subkutanen Verabreichung vorliegen.The Composition according to the invention can be used as an infusion or injection solution, in particular for intravenous, intramuscular or subcutaneous administration.
Gegenstand der vorliegenden Erfindung sind ferner 2-[(2-Pyridyl)methylsulfinyl]benzimidazol-haltige Lyophilisate und Pulver, die eine Puffersubstanz umfassen. Solche Lyophilisate und Pulver lasssen sich beispielsweise durch Lyophilisieren oder Sprühtrocknen aus den zuvor beschriebenen wässrigen Zusammensetzungen erhalten. In diesen Lyophilisaten oder Pulvern liegt ein 2-[(2-Pyridyl)methylsulfinyl]benzimidazol oder dessen Salz, ein oder mehrere Puffersubstanzen sowie gegebenfalls Stabilisierungsmittel und/oder Hilfsstoffe in solchen Mengen vor, daß nach dem Auflösen in Wasser eine 2-[(2-Pyridyl)methylsulfinyl]benzimidazol-haltige Zusammensetzung mit einem pH-Wert zwischen 7 und 9 erhalten wird.object The present invention further includes 2 - [(2-pyridyl) methylsulfinyl] benzimidazole-containing lyophilisates and powders comprising a buffer substance. Such lyophilisates and powder can be, for example, by lyophilization or spray drying from the aqueous described above Get compositions. In these lyophilisates or powders is a 2 - [(2-pyridyl) methylsulfinyl] benzimidazole or its Salt, one or more buffer substances and optionally stabilizing agent and / or auxiliaries in such amounts that after dissolving in water a 2 - [(2-pyridyl) methylsulfinyl] benzimidazole-containing Composition having a pH between 7 and 9 is obtained.
Die erfindungsgemäßen Lyophilisate oder Pulver können beispielsweise in Form eines Arzneimittel-Kits bereitgestellt werden, in dem Lyophilisat oder Pulver räumlich getrennt von einer geeigneten Menge eines wässrigen Lösungsmittels vorliegen. Die gepufferte wässrige Zusammensetzung kann beispielsweise vom medizinischen Personal hergestellt werden.The Lyophilisates according to the invention or powder can for example, in the form of a drug kit, in the lyophilisate or powder spatially separated from a suitable amount of an aqueous solvent. The buffered aqueous Composition can be made, for example, by medical personnel become.
Alternativ können die zur Herstellung der stabilen wässrigen Zusammensetzungen erforderlichen Puffersubstanzen und gegebenfalls die weiteren Stabilisierungsmittel und/oder Hilfsstoffe nur im wässrigen Lösungsmittel vorliegen, während Lyophilisat oder Pulver lediglich das 2-[(2-Pyridyl)methylsulfinyl]benzimidazol, insbesondere Omeprazol-Natrium enthalten. Puffersubstanzen, Stabilisierungsmittel und/oder Hilfsstoffe können sowohl im Lyophilisat oder Pulver als auch im wässrigen Lösungsmittel vorliegen.alternative can those required to prepare the stable aqueous compositions Buffer substances and optionally the other stabilizers and / or auxiliaries only in aqueous solvent present while Lyophilisate or powder only the 2 - [(2-pyridyl) methylsulfinyl] benzimidazole, in particular Contain omeprazole sodium. Buffer substances, stabilizers and / or auxiliaries both in the lyophilisate or powder and in the aqueous solvent.
Die erfindungsgemäßen Zusammensetzungen sind frei von organischen Lösungsmitteln wie Polyethylenglycol, Propylenglycol oder Ethanol.The Compositions of the invention are free of organic solvents such as polyethylene glycol, propylene glycol or ethanol.
Die Erfindung wird durch nachstehende Beispiele näher erläutert, ohne aber den Erfindungsumfang damit einzuschränken.The Invention will be explained in more detail by the following examples, but without the scope of the invention thus limit.
Beispiel 1example 1
Die folgenden Stoffe werden zur Herstellung einer wässrigen Omeprazol-Natrium Lösung verwendet.The The following substances are used to prepare an aqueous omeprazole sodium solution.
Dikaliumhydrogenphosphat wird in sterilem, destilliertem Wasser gelöst und mit Kaliumdihydrogenphophat auf pH = 8 eingestellt. Nach Zugabe von Omeprazol-Natrium wird die Lösung durch ein Sterilfilter filtriert.dipotassium is dissolved in sterile, distilled water and with potassium dihydrogen phosphate adjusted to pH = 8. After adding omeprazole sodium, the solution filtered through a sterile filter.
Zur Bestimmung der Stabilität wurde die Konzentration an Omeprazol-Natrium mittels HPLC gemessen.to Determination of stability the concentration of omeprazole sodium was measured by HPLC.
Wie aus der Tabelle hervorgeht, ist eine wässrige, phosphatgepufferte Lösung mit Omeprazol-Natrium über einen Zeitraum von 10 Stunden stabil.As from the table is an aqueous, phosphate buffered solution with omeprazole sodium over stable for a period of 10 hours.
Claims (17)
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| DE102004007854A DE102004007854A1 (en) | 2004-02-17 | 2004-02-17 | Aqueous composition containing a benzimidazole derivative, particularly omeprazole, useful for treating ulcers, is adjusted to weakly basic pH and contains no organic solvent |
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| EP1430895A1 (en) * | 2000-01-11 | 2004-06-23 | The Curators of the University of Missouri | Novel substituted benzimidazole dosage forms and method of using same |
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2004
- 2004-02-17 DE DE102004007854A patent/DE102004007854A1/en not_active Withdrawn
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| US6699885B2 (en) * | 1996-01-04 | 2004-03-02 | The Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and methods of using same |
| WO1999018959A1 (en) * | 1997-10-14 | 1999-04-22 | Eisai Co., Ltd. | Pharmaceutical formulation comprising glycine as a stabilizer |
| EP1430895A1 (en) * | 2000-01-11 | 2004-06-23 | The Curators of the University of Missouri | Novel substituted benzimidazole dosage forms and method of using same |
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| CASTRO,D.,et.al.: Comparison of derivative spectrophotometric and liquid chromatograpic methods for the determination of ome- prazole in aqueous solutions during stability studies. In: Jour- nal of Pharmaceutical and Biomedical Analysis 21,1999,S.291-S.298 * |
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