CN104203224A - Aqueous composition containing 2-amino-3-(4-bromobenzoyl)- phenylacetic acid - Google Patents
Aqueous composition containing 2-amino-3-(4-bromobenzoyl)- phenylacetic acid Download PDFInfo
- Publication number
- CN104203224A CN104203224A CN201380014630.8A CN201380014630A CN104203224A CN 104203224 A CN104203224 A CN 104203224A CN 201380014630 A CN201380014630 A CN 201380014630A CN 104203224 A CN104203224 A CN 104203224A
- Authority
- CN
- China
- Prior art keywords
- waterborne compositions
- amino
- polyoxyethylene sorbitan
- benzalkonium chloride
- salt
- 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.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 118
- ZBPLOVFIXSTCRZ-UHFFFAOYSA-N bromfenac Chemical compound NC1=C(CC(O)=O)C=CC=C1C(=O)C1=CC=C(Br)C=C1 ZBPLOVFIXSTCRZ-UHFFFAOYSA-N 0.000 title abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 54
- 229920001214 Polysorbate 60 Polymers 0.000 claims abstract description 49
- 229960000686 benzalkonium chloride Drugs 0.000 claims abstract description 48
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims abstract description 48
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims description 119
- 229960003424 phenylacetic acid Drugs 0.000 claims description 60
- 239000003279 phenylacetic acid Substances 0.000 claims description 60
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 45
- 238000004519 manufacturing process Methods 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 239000003889 eye drop Substances 0.000 claims description 11
- 239000003125 aqueous solvent Substances 0.000 claims description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 238000002347 injection Methods 0.000 claims description 6
- 239000007924 injection Substances 0.000 claims description 6
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 5
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 5
- 229920000053 polysorbate 80 Polymers 0.000 claims description 5
- 229940068968 polysorbate 80 Drugs 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 4
- 239000003221 ear drop Substances 0.000 claims description 3
- 239000003978 infusion fluid Substances 0.000 claims description 3
- 239000007923 nasal drop Substances 0.000 claims description 3
- -1 fatty acid ester Chemical class 0.000 abstract description 17
- 235000014113 dietary fatty acids Nutrition 0.000 abstract description 3
- 239000000194 fatty acid Substances 0.000 abstract description 3
- 229930195729 fatty acid Natural products 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 description 34
- 238000012360 testing method Methods 0.000 description 17
- 239000003814 drug Substances 0.000 description 12
- 239000000654 additive Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 230000000996 additive effect Effects 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- 239000002537 cosmetic Substances 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 239000007951 isotonicity adjuster Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 230000014759 maintenance of location Effects 0.000 description 6
- ITIONVBQFUNVJV-UHFFFAOYSA-N Etomidoline Chemical compound C12=CC=CC=C2C(=O)N(CC)C1NC(C=C1)=CC=C1OCCN1CCCCC1 ITIONVBQFUNVJV-UHFFFAOYSA-N 0.000 description 5
- 230000002421 anti-septic effect Effects 0.000 description 5
- 239000004327 boric acid Substances 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 229940006198 sodium phenylacetate Drugs 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229910021538 borax Inorganic materials 0.000 description 4
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 4
- 229960003655 bromfenac Drugs 0.000 description 4
- 238000011835 investigation Methods 0.000 description 4
- 239000003002 pH adjusting agent Substances 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 235000010339 sodium tetraborate Nutrition 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 230000006641 stabilisation Effects 0.000 description 4
- 238000013112 stability test Methods 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 238000010998 test method Methods 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 235000015165 citric acid Nutrition 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000003204 osmotic effect Effects 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- 239000004328 sodium tetraborate Substances 0.000 description 3
- 229960002920 sorbitol Drugs 0.000 description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 3
- 238000012800 visualization Methods 0.000 description 3
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 2
- 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 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
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- 229910052736 halogen Inorganic materials 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
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- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
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- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
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- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
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- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 1
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- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000005619 boric acid group Chemical group 0.000 description 1
- 229940006460 bromide ion Drugs 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- GBAOBIBJACZTNA-UHFFFAOYSA-L calcium sulfite Chemical compound [Ca+2].[O-]S([O-])=O GBAOBIBJACZTNA-UHFFFAOYSA-L 0.000 description 1
- 235000010261 calcium sulphite Nutrition 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 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
- 239000002526 disodium citrate Substances 0.000 description 1
- 235000019262 disodium citrate Nutrition 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
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- CEYULKASIQJZGP-UHFFFAOYSA-L disodium;2-(carboxymethyl)-2-hydroxybutanedioate Chemical compound [Na+].[Na+].[O-]C(=O)CC(O)(C(=O)O)CC([O-])=O CEYULKASIQJZGP-UHFFFAOYSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- LRBQNJMCXXYXIU-QWKBTXIPSA-N gallotannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@H]2[C@@H]([C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-QWKBTXIPSA-N 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 229940006461 iodide ion Drugs 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- JESHZQPNPCJVNG-UHFFFAOYSA-L magnesium;sulfite Chemical compound [Mg+2].[O-]S([O-])=O JESHZQPNPCJVNG-UHFFFAOYSA-L 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229960002969 oleic acid Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229950009379 palmoxiric acid Drugs 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229920001495 poly(sodium acrylate) polymer Polymers 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 1
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 239000001816 polyoxyethylene sorbitan tristearate Substances 0.000 description 1
- 235000010988 polyoxyethylene sorbitan tristearate Nutrition 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229940101027 polysorbate 40 Drugs 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229940099511 polysorbate 65 Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- AVTYONGGKAJVTE-OLXYHTOASA-L potassium L-tartrate Chemical compound [K+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O AVTYONGGKAJVTE-OLXYHTOASA-L 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- BHZRJJOHZFYXTO-UHFFFAOYSA-L potassium sulfite Chemical compound [K+].[K+].[O-]S([O-])=O BHZRJJOHZFYXTO-UHFFFAOYSA-L 0.000 description 1
- 235000019252 potassium sulphite Nutrition 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 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
- 235000011083 sodium citrates Nutrition 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- NNMHYFLPFNGQFZ-UHFFFAOYSA-M sodium polyacrylate Chemical compound [Na+].[O-]C(=O)C=C NNMHYFLPFNGQFZ-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- WUUHFRRPHJEEKV-UHFFFAOYSA-N tripotassium borate Chemical compound [K+].[K+].[K+].[O-]B([O-])[O-] WUUHFRRPHJEEKV-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000003021 water soluble solvent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Health & Medical Sciences (AREA)
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- Proteomics, Peptides & Aminoacids (AREA)
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- Medicinal Preparation (AREA)
Abstract
The present invention pertains to an aqueous composition which contains 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof and which may contain, if necessary, a benzalkonium chloride and/or a polyoxyethylene sorbitan fatty acid ester. The stability of 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a salt thereof can be kept by restricting the contents of a benzalkonium chloride and a polyoxyethylene sorbitan fatty acid ester respectively within specific ranges, whereby a composition which does not suffer any appearance change can be obtained.
Description
Technical field
The present invention relates to contain 2-amino-3-(4-benzoyl bromide) phenylacetic acid or the waterborne compositions of its salt and the manufacture method of described waterborne compositions.
Background technology
2-amino-3-(4-benzoyl bromide) phenylacetic acid is the compound being shown below:
The bromfenac general by name (Bromfenac) of 2-amino-3-(4-benzoyl bromide) phenylacetic acid, is known as NSAID (non-steroidal anti-inflammatory drug), and it is used for the inflammation treatment of outer eye and front eye in field of ophthalmology as eye drop.
Known 2-amino-3-(4-benzoyl bromide) phenylacetic acid lacks the stability in aqueous solution, occurs red insoluble foreign body in preservation process.Therefore; in patent documentation 1; by hydrous water soluble macromolecular (polyvinylpyrrolidone etc.) and sulphite (sodium sulfite etc.) in the eye drop that contains 2-amino-3-(4-benzoyl bromide) phenylacetic acid, to seek the stabilisation of 2-amino-3-(4-benzoyl bromide) phenylacetic acid.
In patent documentation 2, report the compositions that a kind of stable storage can be provided be used in combination anti-bacterial high-molecule quaternary ammonium compound and boric acid in the ophthalmic composition of acidic drug time, and enumerated bromfenac as the example of acidic drug.
In patent documentation 3; report in the aqueous liquor that contains 2-amino-3-(4-benzoyl bromide) phenylacetic acid; by adding alkyl aryl polyether alcohol type polymer or cithrol, to seek the stabilisation of 2-amino-3-(4-benzoyl bromide) phenylacetic acid.
In patent documentation 4, disclose a kind of benzalkonium chloride that contains low concentration, there is the effect of preservation and stable bromfenac aqueous liquid preparation composition.
But; for in the waterborne compositions that contains 2-amino-3-(4-benzoyl bromide) phenylacetic acid or its salt by the content restriction of benzalkonium chloride and polyoxyethylene sorbitan carboxylic ester being studied within the specific limits to the stabilisation of 2-amino-3-(4-benzoyl bromide) phenylacetic acid or its salt, do not report completely.
On the other hand, also point out before this: in the manufacturing process of eye drop, ferrum divides likely and can sneak in the eye drop of manufacturing from manufacturing still.
Patent documentation 1: No. 4910225 description of United States Patent (USP)
Patent documentation 2: International Publication WO96/14829 pamphlet
Patent documentation 3: No. 2005/0239895 description of U.S. Patent Application Publication
Patent documentation 4: International Publication WO2012/99142 pamphlet
Summary of the invention
As mentioned above; in the waterborne compositions that contains 2-amino-3-(4-benzoyl bromide) phenylacetic acid in the past; up to now, still nobody by the content restriction of benzalkonium chloride and polyoxyethylene sorbitan carboxylic ester can be reached to the stabilisation of 2-amino-3-(4-benzoyl bromide) phenylacetic acid in aqueous solution within the specific limits.
Problem of the present invention is that the stability by making 2-amino-3-(4-benzoyl bromide) phenylacetic acid in waterborne compositions improves; following waterborne compositions is provided, though described waterborne compositions contain also can be fully stable in preserving for a long time 2-amino-3-(4-benzoyl bromide) phenylacetic acid.In addition, though have may be in manufacturing process from manufacturing ferrum that still sneak into divides, also fully keep the stability of 2-amino-3-(4-benzoyl bromide) phenylacetic acid in waterborne compositions.
In order to improve 2-amino-3-(4-benzoyl bromide) phenylacetic acid in the waterborne compositions that contains 2-amino-3-(4-benzoyl bromide) phenylacetic acid or its salt or the stability of its salt; the inventor etc. concentrate on studies; found that, if the content A (mass parts) of benzalkonium chloride for 2-amino-3-(4-benzoyl bromide) phenylacetic acid of 100 mass parts and the content B (mass parts) of polyoxyethylene sorbitan carboxylic ester are in following scope:
When 0≤A<1,0≤B<96A+5;
When A=1,1<B≤100;
When 1<A<3,5<B≤100;
3≤A≤10 o'clock, 20<B≤100;
The improved stability of 2-amino-3-(4-benzoyl bromide) phenylacetic acid or its salt still maintains high retention rate, and does not occur red insoluble foreign body, thereby completed the present invention in the situation that of long-term preservation.
Waterborne compositions of the present invention is also excellent aspect antiseptic effect.
, the present invention relates to following content:
(1) a kind of waterborne compositions; it contains 2-amino-3-(4-benzoyl bromide) phenylacetic acid or its salt; and according to circumstances contain benzalkonium chloride and/or polyoxyethylene sorbitan carboxylic ester; wherein, the content A (mass parts) of benzalkonium chloride for 2-amino-3-(4-benzoyl bromide) phenylacetic acid of 100 mass parts and the content B (mass parts) of polyoxyethylene sorbitan carboxylic ester are in following scope:
When 0≤A<1,0≤B<96A+5;
When A=1,1<B≤100;
When 1<A<3,5<B≤100;
3≤A≤10 o'clock, 20<B≤100.
(2) waterborne compositions as described in above-mentioned (1), wherein, the content A of benzalkonium chloride and the content B of polyoxyethylene sorbitan carboxylic ester are in following scope:
When 0≤A<1,0≤B<26A+5;
When A=1,2≤B≤30;
When 1<A<3,5<B≤30;
3≤A≤5 o'clock, 20<B≤30.
(3) waterborne compositions as described in above-mentioned (1), wherein, the content A of benzalkonium chloride and the content B of polyoxyethylene sorbitan carboxylic ester are in following scope:
1<A<3, and 5<B≤30.
(4) waterborne compositions as described in above-mentioned (1), wherein, the content A of benzalkonium chloride and the content B of polyoxyethylene sorbitan carboxylic ester are in following scope:
1.2≤A≤2.5, and 7≤B≤20.
(5) a kind of waterborne compositions; it contains 2-amino-3-(4-benzoyl bromide) phenylacetic acid or its salt; and according to circumstances contain benzalkonium chloride and/or polyoxyethylene sorbitan carboxylic ester, the concentration X (w/v%) of benzalkonium chloride and the concentration Y (w/v%) of polyoxyethylene sorbitan carboxylic ester are in following scope:
When 0≤X<0.001,0≤Y<96X+0.005;
When X=0.001,0.001<Y≤0.1;
When 0.001<X<0.003,0.005<Y≤0.1;
0.003≤X≤0.01 o'clock, 0.02<Y≤0.1.
(6) waterborne compositions as described in above-mentioned (5), wherein, the concentration X of benzalkonium chloride and the concentration Y of polyoxyethylene sorbitan carboxylic ester are in following scope:
When 0≤X<0.001,0≤Y<26X+0.005;
When X=0.001,0.002≤Y≤0.03;
When 0.001<X<0.003,0.005<Y≤0.03;
0.003≤X≤0.005 o'clock, 0.02<Y≤0.03.
(7) waterborne compositions as described in above-mentioned (5), wherein, the concentration X of benzalkonium chloride and the concentration Y of polyoxyethylene sorbitan carboxylic ester are in following scope:
0.001<X<0.003, and 0.005<Y≤0.03.
(8) waterborne compositions as described in above-mentioned (5), wherein, the concentration X of benzalkonium chloride and the concentration Y of polyoxyethylene sorbitan carboxylic ester are in following scope:
0.0012≤X≤0.0025, and 0.008≤Y≤0.02.
(9) waterborne compositions as described in any one in above-mentioned (1)～(8), wherein, polyoxyethylene sorbitan carboxylic ester is polysorbate80.
(10) waterborne compositions as described in any one in above-mentioned (1)～(9), wherein, the concentration of 2-amino-3-(4-benzoyl bromide) phenylacetic acid in waterborne compositions is 0.01～1.0% (w/v).
(11) waterborne compositions as described in any one in above-mentioned (1)～(10), wherein further contains the sodium chloride of 0.01～3.0% (w/v).
(12) waterborne compositions as described in any one in above-mentioned (1)～(8), wherein, the pH of waterborne compositions is greater than 7.0 and be below 9.5.
(13) waterborne compositions as described in any one in above-mentioned (1)～(12), wherein, waterborne compositions is injection, infusion solution, nasal drop, ear drop or eye drop.
(14) waterborne compositions as described in above-mentioned (13), it is eye injection.
(15) waterborne compositions as described in above-mentioned (13), it is eye drop.
(16) manufacture method of the waterborne compositions described in any one in above-mentioned (1)～(15); it is characterized in that; by 2-amino-3-(4-benzoyl bromide) phenylacetic acid or its salt or their hydrate, and according to circumstances benzalkonium chloride and/or polyoxyethylene sorbitan carboxylic ester are dissolved in aqueous solvent.
It should be noted that, above-mentioned (1)～(16) every can select arbitrarily 2 and combine above.
The present invention also further relates to following content:
(17) a kind of by (4-benzoyl bromide) phenylacetic acid of the 2-amino-3-in waterborne compositions or its salt-stabilized method; with respect to 2-amino-3-(4-benzoyl bromide) phenylacetic acid 100 mass parts; polyoxyethylene sorbitan carboxylic ester shown in content B (mass parts) in the benzalkonium chloride of 0～10 mass parts (content A (mass parts)) and following ranges is added in above-mentioned aqueous solvent
When 0≤A<1,0≤B<96A+5;
When A=1,1<B≤100;
When 1<A<3,5<B≤100;
3≤A≤10 o'clock, 20<B≤100.
By the present invention; the waterborne compositions that can provide one to contain 2-amino-3-(4-benzoyl bromide) phenylacetic acid or its salt; described waterborne compositions is because (4-benzoyl bromide) phenylacetic acid of the 2-amino-3-in waterborne compositions or its salt are stablized in long-time, so can for example stably preserve more than 2 years under room temperature.In addition, though waterborne compositions of the present invention have may be in manufacturing process from manufacturing ferrum that still sneak into divides, also keep the sufficient stability of 2-amino-3-(4-benzoyl bromide) phenylacetic acid or its salt.
Detailed description of the invention
Below, the present invention is described in detail.
In this manual, the solvent (for example, mixture of the water-soluble solvent such as alcohol and water etc.) that " aqueous solvent " refers to water or contain water.Aqueous solvent, as long as water or the solvent that contains water, is not particularly limited, and is preferably purified water.
In a preferred embodiment; the waterborne compositions of waterborne compositions of the present invention for containing 2-amino-3-(4-benzoyl bromide) phenylacetic acid or its salt; for 2-amino-3-(4-benzoyl bromide) phenylacetic acid of 100 mass parts, the polyoxyethylene sorbitan carboxylic ester shown in the content B (mass parts) in benzalkonium chloride (content A (mass parts)) and following ranges that described waterborne compositions contains 0～10 mass parts:
When 0≤A<1,0≤B<96A+5;
When A=1,1<B≤100;
When 1<A<3,5<B≤100;
3≤A≤10 o'clock, 20<B≤100.
And in this waterborne compositions, 2-amino-3-(4-benzoyl bromide) phenylacetic acid or its salt exist with the state of uniform dissolution in aqueous solvent.
In waterborne compositions of the present invention; 2-amino-3-(4-benzoyl bromide) phenylacetic acid can-3-(4-benzoyl bromide) phenylacetic acid amino with the non-2-amino-3-dissociating (4-benzoyl bromide) phenylacetic acid itself, 2-salt, amphion body (carboxyl forms carboxylic acid ion, and the amino ammonium ion that forms), cation body (the only amino ammonium ion that forms), the form of anion body (only carboxyl formation carboxylic acid ion) exist with the form of dissolving.
In waterborne compositions of the present invention; the salt of the salt of 2-amino-3-(4-benzoyl bromide) phenylacetic acid as long as allowing as medicine; be not particularly limited; as salt, can enumerate with the salt of mineral acid, with organic acid salt, quaternary ammonium salt, with the salt of halogen ion, with alkali-metal salt, salt with alkaline-earth metal, slaine, with the salt of organic amine etc.As with the salt of mineral acid, can enumerate the salt with hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, sulphuric acid, phosphoric acid etc.As with organic acid salt, can enumerate and acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptonic acid, glucuronic acid, p-phthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1, the salt of 2-ethane disulfonic acid (1,2-ethanedisulfonic acid), isethionic acid, lactobionic acid, oleic acid, palmoxiric acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, lauryl sulfate, Methylsulfate, LOMAR PWA EINECS 246-676-2, sulfosalicylic acid etc.As quaternary ammonium salt, can enumerate the salt with methyl bromide, methyl iodide etc.As with the salt of halogen ion, can enumerate the salt with chloride ion, bromide ion, iodide ion etc.; As with alkali-metal salt, can enumerate the salt with lithium, sodium, potassium etc.; As with the salt of alkaline-earth metal, can enumerate the salt with calcium, magnesium etc.; As slaine, can enumerate the salt with ferrum, zinc etc.As with the salt of organic amine, can enumerate with triethylenediamine, 2-ethylaminoethanol, 2,2-imino group di-methylcarbinol, 1-deoxidation-1-(methylamino)-2-D-Sorbitol, 2-amino-2-(methylol)-1, ammediol, procaine, N, the salt of N-bis-(benzyl)-1，2-diaminoethane etc.In waterborne compositions of the present invention, the preferred salt of 2-amino-3-(4-benzoyl bromide) phenylacetic acid is sodium salt.
In waterborne compositions of the present invention; the concentration of 2-amino-3-(4-benzoyl bromide) phenylacetic acid is as long as obtaining the required enough amounts of desirable drug effect; be not particularly limited; be preferably 0.01～1.0% (w/v); more preferably 0.03～0.5% (w/v); more preferably 0.05～0.2% (w/v), most preferably is 0.08～0.1% (w/v).It should be noted that, in the time using the salt of 2-amino-3-(4-benzoyl bromide) phenylacetic acid or their hydrate, these concentration adopt the quality that is scaled 2-amino-3-(4-benzoyl bromide) phenylacetic acid to calculate.
In waterborne compositions of the present invention, benzalkonium chloride (following, also referred to as BAK) has [C
6h
5cH
2n (CH
3)
2r] chemical constitution shown in Cl is that this R is C
8h
17～C
18h
37material or their mixture.Preferably can enumerate R is C
12h
25n-benzyl-N, N-dimethyl lauryl chlorination ammonium (following, also referred to as BAK C12), R are C
14h
29n-benzyl-N, N-dimethyl tetradecyl ammonium chloride (following, also referred to as BAK C14) or R are C
16h
33n-benzyl-N-hexadecyldimethyl benzyl ammonium ammonium chloride (following, also referred to as BAK C16) or these mixture.In the present invention, preferred benzalkonium chloride is BAK C12.
In waterborne compositions of the present invention, polyoxyethylene sorbitan carboxylic ester (polyoxyethylene sorbitan fatty acid ester) is not particularly limited, as polyoxyethylene sorbitan carboxylic ester, can enumerate polysorbate80 (polysorbitan 80), polysorbate65, polysorbate60, polysorbate40, Tween-20, polyoxyethylene sorbitol acid anhydride trioleate etc., preferably polysorbate80.
In waterborne compositions of the present invention; about the content of benzalkonium chloride and polyoxyethylene sorbitan carboxylic ester, the content A (mass parts) of benzalkonium chloride for 2-amino-3-(4-benzoyl bromide) phenylacetic acid of 100 mass parts and the content B (mass parts) of polyoxyethylene sorbitan carboxylic ester are in following scope:
When 0≤A<1,0≤B<96A+5;
When A=1,1<B≤100;
When 1<A<3,5<B≤100;
3≤A≤10 o'clock, 20<B≤100,
Preferably in following scope:
When 0≤A<1,0≤B<26A+5;
When A=1,2≤B≤30;
When 1<A<3,5<B≤30;
3≤A≤5 o'clock, 20<B≤30,
More preferably in following scope:
1<A<3, and 5<B≤30,
Most preferably in following scope:
1.2≤A≤2.5, and 7≤B≤20.
With respect to 2-amino-3-(4-benzoyl bromide) phenylacetic acid of 100 mass parts; the upper limit of the content of the benzalkonium chloride in waterborne compositions of the present invention is preferably 10 mass parts; more preferably 6 mass parts; more preferably 5 mass parts; also 4 mass parts more preferably; be particularly preferably 3 mass parts, be more particularly preferably 2.5 mass parts, most preferably be 2 mass parts.On the other hand, the lower limit of content is preferably 0 mass parts, more preferably 0.2 mass parts, and more preferably 0.5 mass parts, also 0.8 mass parts more preferably, is particularly preferably 1 mass parts, most preferably is 1.2 mass parts.As the scope of the content of benzalkonium chloride, be preferably 0～10 mass parts, more preferably 0.2～5 mass parts, more preferably 0.5～3 mass parts, is particularly preferably 1～2.5 mass parts, most preferably is 1.2～2 mass parts.
With respect to 2-amino-3-(4-benzoyl bromide) phenylacetic acid of 100 mass parts; the upper limit of the content of the polyoxyethylene sorbitan carboxylic ester in waterborne compositions of the present invention is preferably 100 mass parts; more preferably 50 mass parts; more preferably 40 mass parts; also 30 mass parts more preferably; be particularly preferably 25 mass parts, most preferably be 20 mass parts.On the other hand, the lower limit of content is preferably 0 mass parts, more preferably 2 mass parts, and more preferably 5 mass parts, more preferably 6 mass parts, are particularly preferably 7 mass parts, most preferably are 9 mass parts.As the scope of the content of polyoxyethylene sorbitan carboxylic ester, be preferably 0～100 mass parts, more preferably 0～50 mass parts, more preferably 2～40 mass parts, also 5～30 mass parts more preferably, are particularly preferably 7～25 mass parts, most preferably are 9～20 mass parts.
About the concentration of the benzalkonium chloride in waterborne compositions of the present invention and polyoxyethylene sorbitan carboxylic ester, the concentration Y (w/v%) of the concentration X of benzalkonium chloride (w/v%) and polyoxyethylene sorbitan carboxylic ester is preferably in following scope:
When 0≤X<0.001,0≤Y<96X+0.005;
When X=0.001,0.001<Y≤0.1;
When 0.001<X<0.003,0.005<Y≤0.1;
0.003≤X≤0.01 o'clock, 0.02<Y≤0.1,
More preferably in following scope:
When 0≤X<0.001,0≤Y<26X+0.005;
When X=0.001,0.002≤Y≤0.03;
When 0.001<X<0.003,0.005<Y≤0.03;
0.003≤X≤0.005 o'clock, 0.02<Y≤0.03,
Further preferably in following scope:
0.001<X<0.003, and 0.005<Y≤0.03,
Most preferably in following scope:
0.0012≤X≤0.0025, and 0.008≤Y≤0.02.
The upper limit of the concentration of the benzalkonium chloride in waterborne compositions of the present invention is preferably 0.01% (w/v), more preferably 0.006% (w/v), more preferably 0.005% (w/v), also 0.004% (w/v) more preferably, be particularly preferably 0.003% (w/v), more be particularly preferably 0.0025% (w/v), most preferably be 0.002% (w/v).On the other hand, the lower limit of concentration is preferably 0% (w/v), more preferably 0.0002% (w/v), more preferably 0.0005% (w/v), also 0.0008% (w/v) more preferably, be particularly preferably 0.001% (w/v), most preferably be 0.0012% (w/v).As the scope of concentration, be preferably 0～0.01% (w/v), more preferably 0.0002～0.005% (w/v), more preferably 0.0005～0.003% (w/v), be particularly preferably 0.001～0.0025% (w/v), most preferably be 0.0012～0.002% (w/v).
The upper limit of the concentration of the polyoxyethylene sorbitan carboxylic ester in waterborne compositions of the present invention is preferably 0.1% (w/v), more preferably 0.05% (w/v), more preferably 0.04% (w/v), also 0.03% (w/v) more preferably, be particularly preferably 0.025% (w/v), most preferably be 0.02% (w/v).On the other hand, the lower limit of concentration is preferably 0% (w/v), more preferably 0.002% (w/v), more preferably 0.005% (w/v), also 0.008% (w/v) more preferably, be particularly preferably 0.009% (w/v), most preferably be 0.01% (w/v).As the scope of concentration, be preferably 0～0.1% (w/v), more preferably 0～0.05% (w/v), more preferably 0.002～0.04% (w/v), also 0.005～0.03% (w/v) more preferably, be particularly preferably 0.008～0.025% (w/v), most preferably be 0.01～0.02% (w/v).
In scope of the present invention, also comprise following waterborne compositions, this waterborne compositions contains 2-amino-3-(4-benzoyl bromide) phenylacetic acid or its salt, does not contain any one in benzalkonium chloride and polyoxyethylene sorbitan carboxylic ester.
In addition, in waterborne compositions of the present invention, can add as required the additives such as buffer agent, isotonic agent, pH adjusting agent, stabilizing agent, antiseptic, solubilizing agent, thickening agent.
In waterborne compositions of the present invention, the buffer agent that can coordinate the additive that can serve as medicine to use.As the example of buffer agent, can enumerate phosphoric acid or its salt, boric acid or its salt, citric acid or its salt, acetic acid or its salt, carbonic acid or its salt, tartaric acid or its salt, episilon amino caproic acid, tromethane etc.As phosphate, can enumerate sodium phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate etc.; As borate, can enumerate Borax, sodium borate, potassium borate etc.; As citrate, can enumerate sodium citrate, disodium citrate etc.; As acetate, can enumerate sodium acetate, potassium acetate etc.; As carbonate, can enumerate sodium carbonate, sodium bicarbonate etc.; As tartrate, can enumerate sodium tartrate, Soluble tartar. etc.In the present invention, preferred buffer agent is boric acid or its salt, for example, and boric acid, Borax.
About the concentration of the buffer agent in waterborne compositions of the present invention, can consider medicine, other additive and/or the impact of osmotic pressure ratio and suitably regulating, as its total amount, be preferably 0.01～15% (w/v), more preferably 0.05～10% (w/v), more preferably 0.1～5% (w/v), is particularly preferably 0.25～4% (w/v), most preferably is 0.5～3% (w/v).
In waterborne compositions of the present invention, the isotonic agent that can suitably coordinate the additive that can serve as medicine to use.As the example of isotonic agent, can enumerate ion-type isotonic agent and nonionic isotonic agent etc.As ion-type isotonic agent, can enumerate sodium chloride, potassium chloride, calcium chloride, magnesium chloride etc.; As nonionic isotonic agent, can enumerate glycerol, propylene glycol, Sorbitol, mannitol etc.Preferred isotonic agent is sodium chloride, can obtain keeping the stability of 2-amino-3-(4-benzoyl bromide) phenylacetic acid or its salt and the compositions without cosmetic variation.
In waterborne compositions of the present invention, the pH adjusting agent that can coordinate in right amount the additive that can serve as medicine to use.As the example of pH adjusting agent, can enumerate hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate etc.In the present invention, preferred pH adjusting agent is hydrochloric acid, sodium hydroxide.
The pH of waterborne compositions of the present invention is preferably 7.0～9.5, and more preferably 7.5～9.0, more preferably 8.0～8.6, most preferably be 8.2～8.4.
In waterborne compositions of the present invention, the stabilizing agent that can suitably coordinate the additive that can serve as medicine to use.As the example of stabilizing agent, can enumerate ethylenediaminetetraacetic acid, sodium ethylene diamine tetracetate, sulphite, water soluble polymer etc.As sulphite, can enumerate sodium sulfite, potassium sulfite, magnesium sulfite, calcium sulfite etc.As water soluble polymer, can enumerate polyvinylpyrrolidone, polyvinyl alcohol, carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, sodium polyacrylate etc.
About the concentration of the whole stabilizing agents in waterborne compositions of the present invention, can consider that it is on medicine, other additive and/or the affecting situation of osmotic pressure ratio and suitably regulating.
In waterborne compositions of the present invention, the antiseptic that can suitably coordinate the additive that can serve as medicine to use.As the example of antiseptic, can enumerate benzethonium chloride, sorbic acid, potassium sorbate, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, methaform etc.
About the concentration of the antiseptic in waterborne compositions of the present invention, can consider medicine, other additive and/or the affecting situation of osmotic pressure ratio and suitably regulating, as its total amount, be preferably 0.00005～0.01% (w/v), more preferably 0.0001～0.005% (w/v), more preferably 0.0002～0.004% (w/v), be particularly preferably 0.0005～0.003% (w/v), most preferably be 0.001～0.002% (w/v).
The dosage form of waterborne compositions of the present invention is as long as can, as the dosage form of medicine, being not particularly limited.As dosage form, for example, can enumerate injection, infusion solution, nasal drop, ear drop, eye drop etc.Preferably can enumerate eye injection, eye drop, particularly preferably can enumerate eye drop.
Waterborne compositions of the present invention can be by being dissolved in 2-amino-3-(4-benzoyl bromide) phenylacetic acid or its salt or their hydrate and benzalkonium chloride and polyoxyethylene sorbitan carboxylic ester in aqueous solvent and manufacturing.
In the time of preparation waterborne compositions of the present invention, except 2-amino-3-(4-benzoyl bromide) phenylacetic acid or its salt, can also use their hydrate.As such hydrate; specifically can enumerate 2-amino-3-(4-benzoyl bromide) sodium phenylacetate 1/2 hydrate, 2-amino-3-(4-benzoyl bromide) sodium phenylacetate 1 hydrate, 2-amino-3-(4-benzoyl bromide) sodium phenylacetate 3/2 hydrate etc., can preferably enumerate 2-amino-3-(4-benzoyl bromide) sodium phenylacetate 3/2 hydrate.
As aqueous solvent, can use the solvent of recording above.
Therefore; the invention still further relates to the manufacture method of waterborne compositions; described waterborne compositions contains 2-amino-3-(4-benzoyl bromide) phenylacetic acid or its salt and according to circumstances contains benzalkonium chloride and/or polyoxyethylene sorbitan carboxylic ester, and the content A (mass parts) of benzalkonium chloride for 2-amino-3-(4-benzoyl bromide) phenylacetic acid of 100 mass parts and the content B (mass parts) of polyoxyethylene sorbitan carboxylic ester are in following scope:
When 0≤A<1,0≤B<96A+5;
When A=1,1<B≤100;
When 1<A<3,5<B≤100;
3≤A≤10 o'clock, 20<B≤100,
The manufacture method of described waterborne compositions is characterised in that, by 2-amino-3-(4-benzoyl bromide) phenylacetic acid or its salt or their hydrate and according to circumstances benzalkonium chloride and/or polyoxyethylene sorbitan carboxylic ester are dissolved in aqueous solvent.
The present invention further also relates to (4-benzoyl bromide) phenylacetic acid of the 2-amino-3-in waterborne compositions or its salt-stabilized method; described method is in the waterborne compositions that contains 2-amino-3-(4-benzoyl bromide) phenylacetic acid or its salt; with respect to 2-amino-3-(4-benzoyl bromide) phenylacetic acid of 100 mass parts, the polyoxyethylene sorbitan carboxylic ester shown in the content B (mass parts) in the benzalkonium chloride of 0～10 mass parts (content A (mass parts)) and following scope is added in described aqueous solvent:
When 0≤A<1,0≤B<96A+5;
When A=1,1<B≤100;
When 1<A<3,5<B≤100;
3≤A≤10 o'clock, 20<B≤100.
Below, provide result of the test and formulation example, these are for understanding better the present invention, noting delimit the scope of the invention.
1. estimation of stability test (1)
Study the stability of waterborne compositions of the present invention.
1-1. is subject to the preparation of test preparation
Embodiment 1
2-amino-3-of 0.1g (4-benzoyl bromide) sodium phenylacetate 3/2 hydrate is (following; also referred to as this compound), 1.25g boric acid, 1.0g Borax, 0.02g sodium ethylene diamine tetracetate hydrate, 0.005g polysorbate80,0.001g benzalkonium chloride adds in 90mL purified water, fully stir.Add 1N sodium hydrate aqueous solution and dilute hydrochloric acid (10%), regulate pH to 8.3 left and right, then add appropriate purified water, total amount is settled to 100mL.
Adopt the method same with the preparation method of embodiment 1, the preparation of the comparative example 1 shown in preparation table 1.
1-2. test method
Adopt high performance liquid chromatography (HPLC), the content of 2-amino-3-(4-benzoyl bromide) phenylacetic acid when being subject to test preparation to be saved to 6 months at 25 DEG C and 40 DEG C has carried out quantitatively, and has calculated its retention rate (%).In addition, also by visualization the variation of outward appearance.
1-3. result of the test and investigation
Result of the test is shown in Table 1.
[table 1]
PE: polyethylene, PP: polypropylene
Cosmetic variation is not found in-expression.
As shown in Table 1, compared with the preparation of comparative example 1, the preparation of embodiment 1 has maintained higher retention rate at 25 DEG C and 40 DEG C in 6 months, and be always clear and bright, yellow, containing the state of precipitation.According to above result, confirm to there is excellent stability as the preparation of the embodiment 1 of waterborne compositions of the present invention.
2. estimation of stability test (2)
The stability of the waterborne compositions of the present invention while having studied the content that changes benzalkonium chloride and polyoxyethylene sorbitan carboxylic ester.
2-1. is subject to the preparation of test preparation
Adopt the method same with the preparation method of embodiment 1, prepared the preparation of the embodiment 2～15 shown in table 2～4 and comparative example 2～8.
2-2. test method
Adopt high performance liquid chromatography (HPLC); to be saved to 6 months or the content of 2-amino-3-(4-benzoyl bromide) phenylacetic acid in the time being saved to 1 month for 60 DEG C has carried out quantitatively in 40 DEG C by test preparation, and calculate its retention rate (%).In addition, also by visualization the variation of outward appearance.
2-3. result of the test and investigation
Result of the test is shown in table 2～4.
[table 2]
Cosmetic variation is not found in-expression.
[table 3]
Cosmetic variation is not found in-expression.
[table 4]
Cosmetic variation is not found in-expression.
Cosmetic variation is found in+expression.
From table 2～4, the preparation of embodiment 2～15 has maintained high retention rate at 40 DEG C in 6 months or at 60 DEG C in 1 month, and the state that is always clear and bright, yellow, does not contain precipitation.According to above result, confirm to there is excellent stability as the preparation of the embodiment 2～15 of waterborne compositions of the present invention.
3. estimation of stability test (3)
Study the stability of the waterborne compositions of the present invention while changing pH.
3-1. is subject to the preparation of test preparation
Adopt the method same with the preparation method of embodiment 1, prepared the preparation of the embodiment 16～19 shown in table 5.
3-2. test method
By visual, to the variation of the outward appearance that is subject to test preparation in the time being saved to 1 month for 60 DEG C is observed.
3-3. result of the test and investigation
Result of the test is shown in Table 5.
[table 5]
Cosmetic variation is not found in-expression.
As shown in Table 5, the state that the preparation of embodiment 16～19 was always clear and bright, yellow, does not contain precipitation at 60 DEG C in 1 month.According to above result, confirm to there is excellent stability as the preparation of the embodiment 16～19 of waterborne compositions of the present invention.
4. estimation of stability test (4)
Study the stability of the waterborne compositions of the present invention in the situation that ferrum divides existence.
4-1. is subject to the preparation of test preparation
Adopt the method same with the preparation method of embodiment 1, prepared the preparation of the embodiment 20～23 shown in table 6 and comparative example 9.
4-2. test method
Preparation is subject to test preparation, then adds the each 5 μ g of iron chloride (III).Adopt high performance liquid chromatography (HPLC); the content of 2-amino-3-(4-benzoyl bromide) phenylacetic acid while being saved to 2 weeks for 60 DEG C has carried out quantitatively; amount to the moisture from container evaporation is revised, and has calculated the retention rate (%) of this compound.In addition, also by visualization the variation of outward appearance.
4-3. result of the test and investigation
Result of the test is shown in Table 6.
[table 6]
Cosmetic variation is not found in-expression.
As shown in Table 6, compared with the preparation of comparative example 9, the preparation of embodiment 20～23 is more stable in 2 weeks at 60 DEG C, and be always clear and bright, yellow, containing the state of precipitation.According to above results verification: still there is excellent stability even exist ferrum to divide in the preparation as the embodiment 20～23 of waterborne compositions of the present invention.
5. formulation example
Below, provide the representational formulation example that has used this compound.It should be noted that, in following formulation example, the use level of each composition is the content in 100mL.
Formulation example 1
Formulation example 2
Formulation example 3
It should be noted that, the each composition in previous formulations example 1～3, that is, use level and the match ratio of this compound, polysorbate80, benzalkonium chloride and other additive can be properly adjusted.
Claims (16)
1. a waterborne compositions; it contains 2-amino-3-(4-benzoyl bromide) phenylacetic acid or its salt; and according to circumstances contain benzalkonium chloride and/or polyoxyethylene sorbitan carboxylic ester, the content A (mass parts) of benzalkonium chloride for 2-amino-3-(4-benzoyl bromide) phenylacetic acid of 100 mass parts and the content B (mass parts) of polyoxyethylene sorbitan carboxylic ester are in following scope:
When 0≤A<1,0≤B<96A+5;
When A=1,1<B≤100;
When 1<A<3,5<B≤100;
3≤A≤10 o'clock, 20<B≤100.
2. waterborne compositions as claimed in claim 1, wherein, the content A of benzalkonium chloride and the content B of polyoxyethylene sorbitan carboxylic ester are in following scope:
When 0≤A<1,0≤B<26A+5;
When A=1,2≤B≤30;
When 1<A<3,5<B≤30;
3≤A≤5 o'clock, 20<B≤30.
3. waterborne compositions as claimed in claim 1, wherein, the content A of benzalkonium chloride and the content B of polyoxyethylene sorbitan carboxylic ester are in following scope:
1<A<3, and 5<B≤30.
4. waterborne compositions as claimed in claim 1, wherein, the content A of benzalkonium chloride and the content B of polyoxyethylene sorbitan carboxylic ester are in following scope:
1.2≤A≤2.5, and 7≤B≤20.
5. a waterborne compositions; it contains 2-amino-3-(4-benzoyl bromide) phenylacetic acid or its salt; and according to circumstances contain benzalkonium chloride and/or polyoxyethylene sorbitan carboxylic ester, the concentration X (w/v%) of benzalkonium chloride and the concentration Y (w/v%) of polyoxyethylene sorbitan carboxylic ester are in following scope:
When 0≤X<0.001,0≤Y<96X+0.005;
When X=0.001,0.001<Y≤0.1;
When 0.001<X<0.003,0.005<Y≤0.1;
0.003≤X≤0.01 o'clock, 0.02<Y≤0.1.
6. waterborne compositions as claimed in claim 5, wherein, the concentration X of benzalkonium chloride and the concentration Y of polyoxyethylene sorbitan carboxylic ester are in following scope:
When 0≤X<0.001,0≤Y<26X+0.005;
When X=0.001,0.002≤Y≤0.03;
When 0.001<X<0.003,0.005<Y≤0.03;
0.003≤X≤0.005 o'clock, 0.02<Y≤0.03.
7. waterborne compositions as claimed in claim 5, wherein, the concentration X of benzalkonium chloride and the concentration Y of polyoxyethylene sorbitan carboxylic ester are in following scope:
0.001<X<0.003, and 0.005<Y≤0.03.
8. waterborne compositions as claimed in claim 5, wherein, the concentration X of benzalkonium chloride and the concentration Y of polyoxyethylene sorbitan carboxylic ester are in following scope:
0.0012≤X≤0.0025, and 0.008≤Y≤0.02.
9. the waterborne compositions as described in any one in claim 1～8, wherein, polyoxyethylene sorbitan carboxylic ester is polysorbate80.
10. the waterborne compositions as described in any one in claim 1～9, wherein, the concentration of 2-amino-3-(4-benzoyl bromide) phenylacetic acid in waterborne compositions is 0.01～1.0% (w/v).
11. waterborne compositions as described in any one in claim 1～10, wherein, further contain the sodium chloride of 0.01～3.0% (w/v).
12. waterborne compositions as described in any one in claim 1～11, wherein, the pH of waterborne compositions is greater than 7.0 and be below 9.5.
13. waterborne compositions as described in any one in claim 1～12, wherein, waterborne compositions is injection, infusion solution, nasal drop, ear drop or eye drop.
14. waterborne compositions as claimed in claim 13, it is eye injection.
15. waterborne compositions as claimed in claim 13, it is eye drop.
The manufacture method of the waterborne compositions in 16. claim 1～15 described in any one; described manufacture method is characterised in that, by 2-amino-3-(4-benzoyl bromide) phenylacetic acid or its salt or their hydrate and according to circumstances benzalkonium chloride and/or polyoxyethylene sorbitan carboxylic ester are dissolved in aqueous solvent.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2012073181 | 2012-03-28 | ||
| JP2012-073181 | 2012-03-28 | ||
| PCT/JP2013/059211 WO2013147000A1 (en) | 2012-03-28 | 2013-03-28 | Aqueous composition containing 2-amino-3-(4-bromobenzoyl)- phenylacetic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104203224A true CN104203224A (en) | 2014-12-10 |
Family
ID=49260248
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201380014630.8A Pending CN104203224A (en) | 2012-03-28 | 2013-03-28 | Aqueous composition containing 2-amino-3-(4-bromobenzoyl)- phenylacetic acid |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JP5922609B2 (en) |
| KR (1) | KR20140139501A (en) |
| CN (1) | CN104203224A (en) |
| IN (1) | IN2014DN07767A (en) |
| MY (1) | MY170840A (en) |
| PH (1) | PH12014502171A1 (en) |
| SG (1) | SG11201405837YA (en) |
| TW (1) | TWI604858B (en) |
| WO (1) | WO2013147000A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111712238A (en) * | 2017-12-14 | 2020-09-25 | 参天制药株式会社 | Eye drops containing 2-amino-3- (4-bromobenzoyl) phenylacetic acid or its salt |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20180016469A (en) * | 2015-06-10 | 2018-02-14 | 산텐 세이야꾸 가부시키가이샤 | Eye drops, and eye drops preservative efficacy methods |
| CN114224830A (en) * | 2021-12-24 | 2022-03-25 | 辰欣药业股份有限公司 | Single-dose bacteriostatic-free ophthalmic preparation and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1823754A (en) * | 2006-03-28 | 2006-08-30 | 卢秀莲 | Sodium bromophenolate eye drops and its preparation method |
| CN101965183A (en) * | 2008-02-21 | 2011-02-02 | 伊斯塔药品公司 | Eye NSAID as adjuvant |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002308764A (en) * | 2001-02-09 | 2002-10-23 | Taisho Pharmaceut Co Ltd | Pharmaceutical composition for ophthalmic use |
| EP1683526B1 (en) * | 2003-11-14 | 2012-04-11 | Senju Pharmaceutical Co., Ltd. | Aqueous solution preparation containing aminoglycoside antibiotic and bromfenac |
| CN101313899B (en) * | 2007-06-01 | 2012-02-29 | 北京德众万全药物技术开发有限公司 | Medicament composition for eyes containing sodium bromfenac |
| CN101322683B (en) * | 2008-07-30 | 2013-01-16 | 浙江三叶药业有限公司 | Gel for eye containing bromfenac sodium hydrate and preparation thereof |
| US9107888B2 (en) * | 2011-01-18 | 2015-08-18 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid bromfenac composition having preservative efficacy |
| JP6012231B2 (en) * | 2011-04-08 | 2016-10-25 | ロート製薬株式会社 | Bromfenac-containing composition |
-
2013
- 2013-03-27 TW TW102110918A patent/TWI604858B/en not_active IP Right Cessation
- 2013-03-28 MY MYPI2014702590A patent/MY170840A/en unknown
- 2013-03-28 WO PCT/JP2013/059211 patent/WO2013147000A1/en active Application Filing
- 2013-03-28 SG SG11201405837YA patent/SG11201405837YA/en unknown
- 2013-03-28 CN CN201380014630.8A patent/CN104203224A/en active Pending
- 2013-03-28 JP JP2013068407A patent/JP5922609B2/en not_active Expired - Fee Related
- 2013-03-28 IN IN7767DEN2014 patent/IN2014DN07767A/en unknown
- 2013-03-28 KR KR1020147025807A patent/KR20140139501A/en active IP Right Grant
-
2014
- 2014-09-26 PH PH12014502171A patent/PH12014502171A1/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1823754A (en) * | 2006-03-28 | 2006-08-30 | 卢秀莲 | Sodium bromophenolate eye drops and its preparation method |
| CN101965183A (en) * | 2008-02-21 | 2011-02-02 | 伊斯塔药品公司 | Eye NSAID as adjuvant |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111712238A (en) * | 2017-12-14 | 2020-09-25 | 参天制药株式会社 | Eye drops containing 2-amino-3- (4-bromobenzoyl) phenylacetic acid or its salt |
Also Published As
| Publication number | Publication date |
|---|---|
| JP5922609B2 (en) | 2016-05-24 |
| KR20140139501A (en) | 2014-12-05 |
| SG11201405837YA (en) | 2014-11-27 |
| TWI604858B (en) | 2017-11-11 |
| PH12014502171A1 (en) | 2014-12-10 |
| MY170840A (en) | 2019-09-10 |
| TW201343197A (en) | 2013-11-01 |
| WO2013147000A1 (en) | 2013-10-03 |
| IN2014DN07767A (en) | 2015-05-15 |
| JP2013227300A (en) | 2013-11-07 |
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Application publication date: 20141210 |