CN101222939A - 眼科用防腐组合物 - Google Patents
眼科用防腐组合物 Download PDFInfo
- Publication number
- CN101222939A CN101222939A CNA2006800254213A CN200680025421A CN101222939A CN 101222939 A CN101222939 A CN 101222939A CN A2006800254213 A CNA2006800254213 A CN A2006800254213A CN 200680025421 A CN200680025421 A CN 200680025421A CN 101222939 A CN101222939 A CN 101222939A
- Authority
- CN
- China
- Prior art keywords
- hypochlorite
- testing liquid
- sodium
- ophthalmic
- ophthalmic use
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 32
- 239000003755 preservative agent Substances 0.000 title claims abstract description 21
- 230000002335 preservative effect Effects 0.000 title claims abstract description 21
- 239000007788 liquid Substances 0.000 claims abstract description 71
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 claims abstract description 56
- GLZPCOQZEFWAFX-UHFFFAOYSA-N Geraniol Chemical compound CC(C)=CCCC(C)=CCO GLZPCOQZEFWAFX-UHFFFAOYSA-N 0.000 claims abstract description 46
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000005792 Geraniol Substances 0.000 claims abstract description 23
- GLZPCOQZEFWAFX-YFHOEESVSA-N Geraniol Natural products CC(C)=CCC\C(C)=C/CO GLZPCOQZEFWAFX-YFHOEESVSA-N 0.000 claims abstract description 23
- 229940113087 geraniol Drugs 0.000 claims abstract description 23
- 238000002360 preparation method Methods 0.000 claims abstract description 21
- 239000003381 stabilizer Substances 0.000 claims abstract description 19
- -1 fatty acid ester Chemical class 0.000 claims abstract description 17
- 229920001214 Polysorbate 60 Polymers 0.000 claims abstract description 15
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims abstract description 13
- 239000008103 glucose Substances 0.000 claims abstract description 13
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 12
- 239000000194 fatty acid Substances 0.000 claims abstract description 12
- 229930195729 fatty acid Natural products 0.000 claims abstract description 12
- 150000005846 sugar alcohols Chemical class 0.000 claims abstract description 12
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 14
- 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 claims description 13
- 229930195725 Mannitol Natural products 0.000 claims description 13
- 239000000594 mannitol Substances 0.000 claims description 13
- 235000010355 mannitol Nutrition 0.000 claims description 13
- YYVFXSYQSOZCOQ-UHFFFAOYSA-N Oxyquinoline sulfate Chemical compound [O-]S([O-])(=O)=O.C1=C[NH+]=C2C(O)=CC=CC2=C1.C1=C[NH+]=C2C(O)=CC=CC2=C1 YYVFXSYQSOZCOQ-UHFFFAOYSA-N 0.000 claims description 12
- 229960001257 oxyquinoline sulfate Drugs 0.000 claims description 12
- 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 12
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 10
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 10
- 229920000053 polysorbate 80 Polymers 0.000 claims description 10
- 229940068968 polysorbate 80 Drugs 0.000 claims description 10
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 9
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 9
- 239000011732 tocopherol Substances 0.000 claims description 8
- 235000010384 tocopherol Nutrition 0.000 claims description 8
- 229930003799 tocopherol Natural products 0.000 claims description 8
- 229960001295 tocopherol Drugs 0.000 claims description 8
- 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 claims description 3
- 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 claims description 3
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 3
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 3
- 235000010356 sorbitol Nutrition 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims description 3
- 235000010447 xylitol Nutrition 0.000 claims description 3
- 239000000811 xylitol Substances 0.000 claims description 3
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 3
- 229960002675 xylitol Drugs 0.000 claims description 3
- OSVXSBDYLRYLIG-UHFFFAOYSA-N dioxidochlorine(.) Chemical compound O=Cl=O OSVXSBDYLRYLIG-UHFFFAOYSA-N 0.000 abstract description 50
- 239000004155 Chlorine dioxide Substances 0.000 abstract description 25
- 235000019398 chlorine dioxide Nutrition 0.000 abstract description 25
- 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 abstract 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 abstract 1
- 229940109239 creatinine Drugs 0.000 abstract 1
- 230000002035 prolonged effect Effects 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- 230000002459 sustained effect Effects 0.000 abstract 1
- 229940042585 tocopherol acetate Drugs 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 70
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- 241000222122 Candida albicans Species 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 241000228245 Aspergillus niger Species 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 239000012085 test solution Substances 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 239000008213 purified water Substances 0.000 description 12
- 241000894006 Bacteria Species 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 9
- 238000004321 preservation Methods 0.000 description 9
- 238000010998 test method Methods 0.000 description 9
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 8
- 241000588724 Escherichia coli Species 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- 230000002421 anti-septic effect Effects 0.000 description 6
- 238000005260 corrosion Methods 0.000 description 6
- 210000000695 crystalline len Anatomy 0.000 description 6
- 239000003889 eye drop Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- 239000001488 sodium phosphate Substances 0.000 description 5
- 229910000162 sodium phosphate Inorganic materials 0.000 description 5
- 235000011008 sodium phosphates Nutrition 0.000 description 5
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 5
- 241000233866 Fungi Species 0.000 description 4
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 4
- 235000019799 monosodium phosphate Nutrition 0.000 description 4
- 239000001103 potassium chloride Substances 0.000 description 4
- 235000011164 potassium chloride Nutrition 0.000 description 4
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 4
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 4
- 229960000984 tocofersolan Drugs 0.000 description 4
- 239000002076 α-tocopherol Substances 0.000 description 4
- 235000004835 α-tocopherol Nutrition 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-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
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 3
- 239000004327 boric acid Substances 0.000 description 3
- 229940095731 candida albicans Drugs 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
- 238000000151 deposition Methods 0.000 description 3
- 229960001031 glucose Drugs 0.000 description 3
- VAZJLPXFVQHDFB-UHFFFAOYSA-N 1-(diaminomethylidene)-2-hexylguanidine Polymers CCCCCCN=C(N)N=C(N)N VAZJLPXFVQHDFB-UHFFFAOYSA-N 0.000 description 2
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920002413 Polyhexanide Polymers 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 229960002684 aminocaproic acid Drugs 0.000 description 2
- 229960000686 benzalkonium chloride Drugs 0.000 description 2
- 229960001950 benzethonium chloride Drugs 0.000 description 2
- 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 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 2
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 2
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 2
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 2
- 239000001816 polyoxyethylene sorbitan tristearate Substances 0.000 description 2
- 235000010988 polyoxyethylene sorbitan tristearate Nutrition 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 239000004334 sorbic acid Substances 0.000 description 2
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- 229940075582 sorbic acid Drugs 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- ZKQDCIXGCQPQNV-UHFFFAOYSA-N Calcium hypochlorite Chemical compound [Ca+2].Cl[O-].Cl[O-] ZKQDCIXGCQPQNV-UHFFFAOYSA-N 0.000 description 1
- 206010007134 Candida infections Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229940122072 Carbonic anhydrase inhibitor Drugs 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- SNPLKNRPJHDVJA-ZETCQYMHSA-N D-panthenol Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCCO SNPLKNRPJHDVJA-ZETCQYMHSA-N 0.000 description 1
- 206010015946 Eye irritation Diseases 0.000 description 1
- BIVBRWYINDPWKA-VLQRKCJKSA-L Glycyrrhizinate dipotassium Chemical compound [K+].[K+].O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C([O-])=O)[C@@H]1O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@H]1O BIVBRWYINDPWKA-VLQRKCJKSA-L 0.000 description 1
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- 241000219739 Lens Species 0.000 description 1
- DJDFFEBSKJCGHC-UHFFFAOYSA-N Naphazoline Chemical compound Cl.C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 DJDFFEBSKJCGHC-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
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- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- TVQZAMVBTVNYLA-UHFFFAOYSA-N Pranoprofen Chemical compound C1=CC=C2CC3=CC(C(C(O)=O)C)=CC=C3OC2=N1 TVQZAMVBTVNYLA-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
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- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-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
- 229930003779 Vitamin B12 Natural products 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 239000000030 antiglaucoma agent Substances 0.000 description 1
- KBKZYWOOZPIUJT-UHFFFAOYSA-N azane;hypochlorous acid Chemical compound N.ClO KBKZYWOOZPIUJT-UHFFFAOYSA-N 0.000 description 1
- HPEWZLCIOKVLBZ-UHFFFAOYSA-N barium hypochlorite Chemical compound [Ba+2].Cl[O-].Cl[O-] HPEWZLCIOKVLBZ-UHFFFAOYSA-N 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 201000003984 candidiasis Diseases 0.000 description 1
- 239000003489 carbonate dehydratase inhibitor Chemical class 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
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Abstract
本发明的课题在于抑制含有次氯酸盐的眼科用液体制剂中二氧化氯的生成。含有眼科用防腐组合物的眼科用液体制剂可以抑制二氧化氯的生成,因此安全性优异,可长期维持防腐效果,其中,所述眼科用防腐组合物由次氯酸盐和选自下述1)~7)中的至少一种稳定剂构成。1)肌酸酐、2)香叶醇、3)葡萄糖、4)生育酚乙酸酯、5)羟喹啉硫酸盐、6)糖醇、7)聚氧乙烯失水山梨糖醇脂肪酸酯。
Description
技术领域
本发明涉及一种由次氯酸盐和其稳定剂构成的眼科用防腐组合物、及含有该组合物的眼科用液体制剂。
背景技术
滴眼液被直接施用到眼睛这样的人体敏感器官,另外,隐形眼镜也在与眼直接接触的环境中被使用。所以,从安全性方面考虑,需要注意滴眼液或隐形眼镜保存液的配合成分,特别是必须考虑眼刺激性、副作用等。
作为滴眼液的防腐成分,正在使用例如苯扎氯铵、苯索氯铵、山梨酸等,另外作为隐形眼镜保存液的防腐成分,正在使用例如聚六亚甲基双胍(PHMB)、POLYQUAD、过氧化氢、PURITE(稳定化二氧化氯)等。
但是,苯扎氯铵或苯索氯铵虽然防腐效果优异,但由于浓度升高时引发角膜病变,所以对其使用浓度有一定限制。另外,上述防腐剂与酸性添加物有时会发生配合变化(化学反应),具有易被吸附在滴眼容器或过滤器上的性质。山梨酸虽然对滴眼容器的吸附少,但防腐效果不充分,另外,随着pH变化稳定性降低,所以滴眼液中的配合存在一定的限制。另一方面,过氧化氢等过氧化类防腐剂配合于隐形眼镜保存液中时发挥优异的杀菌·洗涤作用,但由于具有刺激性,所以必须进行中和。
次氯酸盐是具有ClO2 -离子的化合物,特别是次氯酸钠可以用作自来水的杀菌剂等。但是,通常认为次氯酸盐分解时产生氧化作用强的二氧化氯,对眼、皮肤、气管等具有刺激性。针对该问题,专利文献1公开了关于二氧化氯的生成方法及杀菌用组合物的发明,该发明使用过渡金属使次氯酸盐等二氧化氯前体生成二氧化氯,由此利用二氧化氯的强杀菌作用,对隐形眼镜等进行杀菌·清洗等。
专利文献1:特开平3-164402号公报
发明内容
一般认为二氧化氯与过氧化氢同样是强氧化剂,对眼、皮肤等具有强刺激性,所以使用次氯酸盐作为眼科用防腐成分时,抑制二氧化氯的生成来提高安全性是一个重要的课题。
本发明人等研究各种抑制二氧化氯生成的稳定剂时,发现含有下述眼科用防腐组合物的眼科用液体制剂通过显著抑制二氧化氯的生成,安全性优异,并且长期维持防腐效果,所述眼科用防腐组合物由为防腐成分的次氯酸盐和选自肌酸酐、香叶醇、葡萄糖、生育酚乙酸酯、羟喹啉硫酸盐、糖醇及聚氧乙烯失水山梨糖醇脂肪酸酯中的至少一种稳定剂构成。
即,本发明为,
(1)一种眼科用防腐组合物,含有次氯酸盐和选自下述1)~7)中的至少一种稳定剂。
1)肌酸酐
2)香叶醇
3)葡萄糖
4)生育酚乙酸酯
5)羟喹啉硫酸盐
6)糖醇、及
7)聚氧乙烯失水山梨糖醇脂肪酸酯
(2)如上述(1)所述的眼科用防腐组合物,其中,次氯酸盐为次氯酸钠,
(3)如上述(1)所述的眼科用防腐组合物,其中,糖醇为甘露醇、山梨醇或木糖醇,
(4)如上述(1)所述的眼科用防腐组合物,其中,聚氧乙烯失水山梨糖醇脂肪酸酯为聚山梨酸酯80,及
(5)一种眼科用液体制剂,含有上述(1)~(4)中任一项所述的眼科用防腐组合物,
(6)一种眼科用液体制剂,含有0.0001~1%(W/V)次氯酸盐和选自下述1)~7)中的至少一种稳定剂。
1)0.0001~5%(W/V)肌酸酐
2)0.00001~0.05%(W/V)香叶醇
3)0.0001~5%(W/V)葡萄糖
4)0.0001~1%(W/V)生育酚乙酸酯
5)0.00001~1%(W/V)羟喹啉硫酸盐
6)0.001~10%(W/V)糖醇、及
7)0.0001~10%(W/V)聚氧乙烯失水山梨糖醇脂肪酸酯。
本发明中,作为防腐成分的次氯酸盐只要为次氯酸的盐即可,没有特殊的限制,例如可以举出次氯酸钠、次氯酸钾等次氯酸碱金属盐,次氯酸钙、次氯酸镁、次氯酸钡等次氯酸碱土类金属盐,次氯酸铜、次氯酸铅、次氯酸铵等,较优选次氯酸钠。
眼科用液体制剂中的次氯酸盐的浓度优选为0.00001~1%(W/V),较优选为0.0001%~0.1%(W/V)。
本发明中,作为能够使防腐成分次氯酸盐稳定化、抑制二氧化氯生成的稳定剂,可以举出以下7种。
1)肌酸酐
2)香叶醇
3)葡萄糖
4)生育酚乙酸酯
5)羟喹啉硫酸盐
6)糖醇
7)聚氧乙烯失水山梨糖醇脂肪酸酯
此处,作为糖醇,可以举出甘露醇、山梨醇、木糖醇、白糖等,较优选为甘露醇。另外,作为聚氧乙烯失水山梨糖醇脂肪酸酯,可以举出聚山梨酸酯80[聚氧乙烯失水山梨糖醇单油酸酯]、聚山梨酸酯60[聚氧乙烯失水山梨糖醇单硬脂酸酯]、聚山梨酸酯40[聚氧乙烯失水山梨糖醇单棕榈酸酯]、聚氧乙烯失水山梨糖醇单月桂酸酯、聚氧乙烯失水山梨糖醇三油酸酯、聚山梨酸酯65[聚氧乙烯失水山梨糖醇三硬脂酸酯]等,较优选为聚山梨酸酯80。
眼科用液体制剂中的稳定剂的浓度,优选肌酸酐为0.0001~5%(W/V)、香叶醇为0.00001~0.05%(W/V)、葡萄糖为0.0001~5%(W/V)、生育酚乙酸酯(α、β、γ、δ)为0.0001~1%(W/V)、羟喹啉硫酸盐为0.00001~1%(W/V)、糖醇为0.001~10%(W/V)、聚氧乙烯失水山梨糖醇脂肪酸酯为0.0001~10%(W/V)。
上述7种稳定剂可以分别单独使用,另外也可以将其组合使用。
本发明的眼科用液体制剂优选用作例如滴眼液或隐形眼镜保存液,可以根据常用方法进行配制。
另外,本发明的眼科用液体制剂中,可以根据需要适当配合药物、以及等渗剂、缓冲剂、pH调节剂、增稠剂等。
本发明的眼科用液体制剂中配合的药物,没有特殊的限制,例如可以举出抗青光眼剂(噻吗洛尔、前列腺素衍生物、碳酸脱氢酶抑制剂等)、各种维生素类(维生素B2、维生素B6、维生素B12、维生素E、泛酰醇等)、减充血剂(盐酸四氢唑啉、盐酸萘唑啉等)、抗炎剂(双氯芬酸、吲哚美辛、氟米龙、普拉洛芬、甘草酸二钾、ε-氨基己酸等)、抗组胺剂(马来酸氯苯那敏、盐酸苯海拉明等)、抗过敏剂(色甘酸钠等)、抗菌剂(喹诺酮类抗菌剂、头孢菌素类、磺胺乙酰钠、磺胺甲噁唑等)、氨基酸类(L-天冬氨酸钾、氨基乙磺酸、硫酸软骨素钠等)、诊断用试剂(荧光素钠等)、透明质酸钠、甲硫酸新斯的明等。
作为等渗剂,例如可以举出甘油、丙二醇、聚乙二醇、氯化钠、氯化钾、氯化钙、氯化镁等。
作为缓冲剂,例如可以举出磷酸钠、磷酸二氢钠、磷酸氢二钠、磷酸钾、磷酸二氢钾、磷酸氢二钾等磷酸盐;硼酸钠、硼酸钾等硼酸盐;柠檬酸钠、柠檬酸二钠等柠檬酸盐;乙酸钠、乙酸钾等乙酸盐、碳酸钠、碳酸氢钠、氨丁三醇、ε-氨基己酸等碳酸盐等。
作为pH调节剂,例如可以举出盐酸、柠檬酸、磷酸、乙酸、氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠等。
作为增稠剂,例如可以举出羟丙基甲基纤维素、羟丙基纤维素、聚乙烯醇、羧基乙烯基聚合物、聚乙烯吡咯烷酮等。
本发明的眼科用液体制剂的pH为3~9,特别优选为5~8。
含有下述眼科用防腐组合物的眼科用液体制剂由于抑制二氧化氯的生成,所以安全性优异,可长期维持防腐效果,所述眼科用防腐组合物由次氯酸盐、和选自肌酸酐、香叶醇、葡萄糖、生育酚乙酸酯、羟喹啉硫酸盐、糖醇及聚氧乙烯失水山梨糖醇脂肪酸酯中的至少一种稳定剂构成。
具体实施方式
1.抑制二氧化氯生成的试验
(1)配制试样
试验溶液1
将7mg次氯酸盐、500mg肌酸酐及20mg磷酸氢钠溶解于约80mL精制水中,用稀盐酸或氢氧化钠将pH调至7.0,用精制水使总量为100mL,得到试验溶液1。
试验溶液2~6
除分别使用5mg香叶醇、200mg葡萄糖、2g甘露醇、100mg聚山梨酸酯80、10mg羟喹啉硫酸盐代替试验溶液1的500mg肌酸酐以外,进行与试验溶液1相同的操作,得到试验溶液2~6。
试验溶液7
混合140mg乙酸d-α-生育酚和100mg聚山梨酸酯80,然后,加入7mg次氯酸盐、20mg磷酸氢钠及约80mL精制水,溶解,用稀盐酸或氢氧化钠将pH调至7.0,用精制水使总量为100mL,得到试验溶液7。
比较试验溶液1
将7mg次氯酸盐及20mg磷酸氢钠溶解于约80mL精制水中,用稀盐酸或氢氧化钠将pH调至7.0,用精制水使总量为100mL,得到比较试
验溶液1。
(2)试验方法及结果
1)采用DPD法进行二氧化氯的定量(14天)
使用试验溶液1~5及比较试验溶液1,根据上述试验方法记载的DPD法,测定生成二氧化氯的浓度(ppm)。上述试验结果如表1所示。
[表1]
稳定剂 | 二氧化氯浓度(ppm) | ||
7天后 | 14天后 | ||
试验溶液1 | 肌酸酐 | N.D.*1 | N.D. |
试验溶液2 | 香叶醇 | N.D. | N.D. |
试验溶液3 | 葡萄糖 | N.D. | N.D. |
试验溶液4 | 甘露醇 | N.D. | N.D. |
试验溶液5 | 聚山梨酸酯80 | N.D. | N.D. |
比较试验溶液1 | 0.087 | 0.15 |
注)*1:N.D.表示浓度为0.02ppm以下(DPD法的测定范围:0.02-5ppm)。
2)通过检测管确认二氧化氯的存在(14天)
对于试验溶液6及7,由于试验溶液着色,所以不能采用DPD法进行定量,因此使用通过检测管进行的简易试验方法,确认二氧化氯的存在。即,在减压条件下使试验溶液6、7及比较试验溶液1中的二氧化氯气化后,使用检测管,确认二氧化氯的存在。上述试验结果如表2所示。
[表2]
稳定剂 | 14天后的二氧化氯浓度(ppm) | |
试验溶液6 | 羟喹啉硫酸盐 | N.D.*2 |
试验溶液7 | 乙酸d-α-生育酚聚山梨酸酯80 | N.D. |
比较试验溶液1 | 0.2 |
注)*2:N.D.表示没有发现二氧化氯的存在(检测管的测定范围:0.05-0.6ppm)。
(3)讨论
从表1及表2可知,含有由次氯酸盐和各稳定剂(肌酸酐、香叶醇、葡萄糖、甘露醇、聚山梨酸酯80、羟喹啉硫酸盐、乙酸d-α-生育酚)构成的眼科用防腐组合物的眼科用液体制剂,能够显著地抑制二氧化氯的生成,因此安全性优异、对眼的刺激也少。
2.保存效力试验
(1)使用P.aeruginosa及C.albicans的保存效力试验
1)试样
使用上述试验溶液1~7。
2)试验方法及结果
以日本药典第十四版的保存效力试验法为基准进行保存效力试验,作为试验菌,使用绿脓杆菌(Pseudomonas aeruginosa)(P.aeruginosa)和白色念珠菌(Candida albicans)(C.albicans),测定7天后及14天后的存活菌数。根据下述计算式,计算菌的存活率(%)。
存活率(%)=取样时的存活菌数/初期菌数×100
上述试验结果如表3所示。
[表3]
稳定剂 | 试验菌 | 存活率(%) | ||
7天后 | 14天后 | |||
试验溶液1 | 肌酸酐 | P.aeruginosa | N.D.*3 | N.D. |
C.albicans | 20.7 | 10.0 | ||
试验溶液2 | 香叶醇 | P.aeruginosa | N.D. | N.D. |
C.albicans | 3.3 | 0.5 | ||
试验溶液3 | 葡萄糖 | P.aeruginosa | N.D. | N.D. |
C.albicans | N.D. | N.D. | ||
试验溶液4 | 甘露醇 | P.aeruginosa | N.D. | N.D. |
C.albicans | 65.3 | 54.0 | ||
试验溶液5 | 聚山梨酸酯80 | P.aeruginosa | N.D. | N.D. |
C.albicans | 66.7 | 66.7 | ||
试验溶液6 | 羟喹啉硫酸盐 | P.aeruginosa | N.D. | N.D. |
C.albicans | 5.1 | 0.1 | ||
试验溶液7 | 乙酸d-α-生育酚聚山梨酸酯80 | P.aeruginosa | N.D. | N.D. |
C.albicans | 58.7 | 17.3 |
注)*3:N.D.表示未检测到菌。
(2)使用A.niger的保存效力试验
1)试样配制
试验溶液8
将20mg次氯酸盐、5mg香叶醇及200mg磷酸氢钠溶解于精制水中,用稀盐酸或氢氧化钠将pH调至6.5,用精制水使总量为100mL,得到试验溶液8。
试验溶液9及10
除分别使用50mg肌酸酐、2g甘露醇代替试验溶液8的5mg香叶醇以外,进行与试验溶液8相同的操作,得到试验溶液9及10。
试验溶液11及12
除将试验溶液8的20mg次氯酸盐分别改为50mg、7mg以外,进行与试验溶液8相同的操作,得到试验溶液11及12。
2)试验方法及结果
使用试验溶液8~12,进行保存效力试验。以日本药典第十四版的保存效力试验法为基准进行保存效力试验,作为试验菌,使用黑曲霉(Aspergillus niger)(A.niger),测定7天后、14天后及28天后的存活菌数。以下给出以滴眼剂分类的类型IA的日本药典(JP)及美国药典(USP)的判定标准。
JP的判定标准(真菌):14天后及28天后的存活菌数与接种菌数程度相同或在其以下
USP的判定标准(真菌):7天后、14天后及28天后的存活菌数不多于接种菌数
上述试验结果如表4所示。
[表4]
稳定剂 | 次氯酸盐(mg) | 试验菌 | 判定结果(JP) | 判定结果(USP) | |
试验溶液8 | 香叶醇 | 20 | A.niger | 适合 | 适合 |
试验溶液9 | 肌酸酐 | 20 | A.niger | 适合 | 适合 |
试验溶液10 | 甘露醇 | 20 | A.niger | 适合 | 适合 |
试验溶液11 | 香叶醇 | 50 | A.niger | 适合 | 适合 |
试验溶液12 | 香叶醇 | 7 | A.niger | 适合 | 适合 |
(3)使用5个菌种的保存效力试验
1)配制试样
试验溶液13
将7mg次氯酸盐、5mg香叶醇、400mg氯化钾、100mg氯化钠及1g硼酸溶解于精制水中,用稀盐酸或氢氧化钠将pH调至7.5,用精制水使总量为100mL,得到试验溶液13。
试验溶液14
除使用2g甘露醇代替试验溶液13的5mg香叶醇以外,进行与试验溶液13相同的操作,得到试验溶液14。
比较试验溶液2
将400mg氯化钾、100mg氯化钠及1g硼酸溶解于精制水中,用稀盐酸或氢氧化钠将pH调至7.5,用精制水使总量为100mL,得到比较试验溶液2。
2)试验方法及结果
使用试验溶液13~14及比较试验溶液2,进行保存效力试验。以日本药典第十四版的保存效力试验法为基准进行保存效力试验,作为试验菌,使用大肠杆菌(Escherichia coli)(E.coli)、绿脓杆菌(P.aeruginosa)、金黄色葡萄球菌(Staphylococcus aureus)(S.aureus)、白色念珠菌(C.albicans)及黑曲霉(A.niger),测定14天后及28天后的存活菌数。根据下述计算式,算出菌的存活率(%)。
存活率(%)=取样时的存活菌数/初期菌数×100
上述试验结果如表5所示。
[表5]
稳定剂 | 试验菌 | 存活率(%) | ||
14天后 | 28天后 | |||
试验溶液13 | 香叶醇 | E.coli | 0.0 | 0.0 |
P.aeruginosa | 0.0 | 0.0 | ||
S.aureus | 0.0 | 0.0 | ||
C.albicans | 0.9 | 0.0 | ||
A.niger | 0.6 | 0.5 | ||
试验溶液14 | 甘露醇 | E.coli | 0.0 | 0.0 |
P.aeruginosa | 0.0 | 0.0 | ||
S.aureus | 0.0 | 0.0 | ||
C.albicans | 0.0 | 0.0 | ||
A.niger | 0.1 | 0.1 | ||
比较试验溶液2 | E.coli | 123.1 | 92.3 | |
P.aeruginosa | 0.4 | 0.1 | ||
S.aureus | 0.8 | 0.0 | ||
C.albicans | 47.4 | 0.0 | ||
A.niger | 0.7 | 2.6 |
(3)讨论
从表3~5可知,含有由次氯酸盐和上述各稳定剂构成的眼科用防腐组合物的眼科用液体制剂对绿脓杆菌(革兰氏阴性菌)、念珠菌(真菌)、黑曲霉菌(真菌)等各种菌发挥优异的防腐效果。
3.制剂例
以下给出代表性的制剂例。
处方例1(pH7)
100ml中
透明质酸钠 100mg
次氯酸钠 7mg
肌酸酐 50mg
氯化钠 850mg
磷酸二氢钠 200mg
氢氧化钠 适量
稀盐酸 适量
灭菌精制水 适量
处方例2(pH7)
100ml中
透明质酸钠 100mg
次氯酸钠 7mg
香叶醇 5mg
氯化钠 900mg
磷酸二氢钠 200mg
氢氧化钠 适量
稀盐酸 适量
灭菌精制水 适量
处方例3(pH7)
100ml中
透明质酸钠 100mg
次氯酸钠 7mg
甘露醇 2g
磷酸二氢钠 200mg
氢氧化钠 适量
稀盐酸 适量
灭菌精制水 适量
处方例4(pH7)
100ml中
氯化钾 100mg
氯化钠 400mg
次氯酸钠 7mg
香叶醇 5mg
硼酸 1g
氢氧化钠 适量
稀盐酸 适量
灭菌精制水 适量
Claims (6)
1.一种眼科用防腐组合物,由次氯酸盐和选自下述1)~7)中的至少一种稳定剂构成,
1)肌酸酐、
2)香叶醇、
3)葡萄糖、
4)生育酚乙酸酯、
5)羟喹啉硫酸盐、
6)糖醇、及
7)聚氧乙烯失水山梨糖醇脂肪酸酯。
2.如权利要求1所述的眼科用防腐组合物,其中,次氯酸盐为次氯酸钠。
3.如权利要求1所述的眼科用防腐组合物,其中,糖醇为甘露醇、山梨醇或木糖醇。
4.如权利要求1所述的眼科用防腐组合物,其中,聚氧乙烯失水山梨糖醇脂肪酸酯为聚山梨酸酯80。
5.一种眼科用液体制剂,含有权利要求1~4中任一项所述的眼科用防腐组合物。
6.一种眼科用液体制剂,含有0.00001~1%(W/V)的次氯酸盐和选自下述1)~7)中的至少一种稳定剂,
1)0.0001~5%(W/V)肌酸酐、
2)0.00001~0.05%(W/V)香叶醇、
3)0.0001~5%(W/V)葡萄糖、
4)0.0001~1%(W/V)生育酚乙酸酯、
5)0.00001~1%(W/V)羟喹啉硫酸盐、
6)0.001~10%(W/V)糖醇、及
7)0.0001~10%(W/V)聚氧乙烯失水山梨糖醇脂肪酸酯。
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RU2528912C1 (ru) * | 2013-10-09 | 2014-09-20 | Станислав Анатольевич Кедик | Глазные капли на основе композиции фармацевтически приемлемой аддитивной соли кислоты и метилэтилпиридинола, содержащие композицию витаминов группы в |
CA3020197A1 (en) | 2017-09-01 | 2019-03-01 | Micropure, Inc. | Aliphatic anionic compounds and oxidative compounds with improved stability and efficacy for use in pharmaceutical compositions |
WO2019210041A1 (en) * | 2018-04-27 | 2019-10-31 | Allergan, Inc. | Sodium chlorite compositions with enhanced anti-microbial efficacy and reduced toxicity |
AU2021318237A1 (en) * | 2020-07-30 | 2023-03-09 | Rohto Pharmaceutical Co., Ltd. | Aqueous composition |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
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EP0196075B1 (en) * | 1985-03-26 | 1990-03-14 | Toray Industries, Inc. | Cleaning system for contact lenses and process for cleaning the same |
DE69333011T2 (de) * | 1992-12-17 | 2004-03-25 | Advanced Medical Optics, Inc., Santa Ana | Oxidationsmittel und polyvinylpyrrolidon enthaltende desinfektionslösung für kontaktlinsen |
US5648074A (en) * | 1993-05-25 | 1997-07-15 | Allergan | Compositions and methods for disinfecting contact lenses and reducing proteinaceous deposit formation |
US6251372B1 (en) * | 1998-02-27 | 2001-06-26 | The Procter & Gamble Company | Oral care compositions comprising chlorite and methods |
US6846478B1 (en) * | 1998-02-27 | 2005-01-25 | The Procter & Gamble Company | Promoting whole body health |
WO2000012137A1 (en) * | 1998-09-02 | 2000-03-09 | Allergan Sales, Inc. | Preserved cyclodextrin-containing compositions |
ATE355855T1 (de) * | 2001-12-21 | 2007-03-15 | Senju Pharma Co | Augentropfen |
US20050196370A1 (en) * | 2003-03-18 | 2005-09-08 | Zhi-Jian Yu | Stable ophthalmic oil-in-water emulsions with sodium hyaluronate for alleviating dry eye |
-
2006
- 2006-07-13 PL PL06781064T patent/PL1905453T3/pl unknown
- 2006-07-13 EP EP06781064A patent/EP1905453B1/en not_active Not-in-force
- 2006-07-13 CA CA002615108A patent/CA2615108A1/en not_active Abandoned
- 2006-07-13 US US11/988,613 patent/US20080269353A1/en not_active Abandoned
- 2006-07-13 RU RU2008105323/15A patent/RU2413534C2/ru not_active IP Right Cessation
- 2006-07-13 PT PT67810648T patent/PT1905453E/pt unknown
- 2006-07-13 ES ES06781064T patent/ES2393675T3/es active Active
- 2006-07-13 DK DK06781064.8T patent/DK1905453T3/da active
- 2006-07-13 WO PCT/JP2006/313944 patent/WO2007007832A1/ja active Application Filing
- 2006-07-13 KR KR1020077029711A patent/KR101354892B1/ko not_active IP Right Cessation
- 2006-07-13 CN CN2006800254213A patent/CN101222939B/zh not_active Expired - Fee Related
-
2008
- 2008-02-08 NO NO20080725A patent/NO339109B1/no not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
KR101354892B1 (ko) | 2014-01-22 |
RU2413534C2 (ru) | 2011-03-10 |
NO20080725L (no) | 2008-02-15 |
RU2008105323A (ru) | 2009-08-20 |
WO2007007832A1 (ja) | 2007-01-18 |
EP1905453B1 (en) | 2012-10-31 |
NO339109B1 (no) | 2016-11-14 |
EP1905453A1 (en) | 2008-04-02 |
CN101222939B (zh) | 2010-11-24 |
EP1905453A4 (en) | 2010-11-17 |
PT1905453E (pt) | 2012-12-04 |
DK1905453T3 (da) | 2012-11-26 |
CA2615108A1 (en) | 2007-01-18 |
KR20080039342A (ko) | 2008-05-07 |
US20080269353A1 (en) | 2008-10-30 |
ES2393675T3 (es) | 2012-12-27 |
PL1905453T3 (pl) | 2013-02-28 |
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