WO2007114300A1 - 保存剤 - Google Patents
保存剤 Download PDFInfo
- Publication number
- WO2007114300A1 WO2007114300A1 PCT/JP2007/056978 JP2007056978W WO2007114300A1 WO 2007114300 A1 WO2007114300 A1 WO 2007114300A1 JP 2007056978 W JP2007056978 W JP 2007056978W WO 2007114300 A1 WO2007114300 A1 WO 2007114300A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- salt
- acid
- preservative
- sodium
- present
- Prior art date
Links
- 239000003755 preservative agent Substances 0.000 title claims abstract description 65
- 230000002335 preservative effect Effects 0.000 claims abstract description 51
- 239000000203 mixture Substances 0.000 claims abstract description 47
- 150000003839 salts Chemical class 0.000 claims abstract description 37
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims abstract description 35
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000004327 boric acid Substances 0.000 claims abstract description 21
- 229960001484 edetic acid Drugs 0.000 claims abstract description 19
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical class OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 claims abstract description 12
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical group [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 13
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 13
- 230000001580 bacterial effect Effects 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 9
- 159000000000 sodium salts Chemical class 0.000 claims description 8
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 7
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 7
- 159000000007 calcium salts Chemical class 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- 159000000003 magnesium salts Chemical class 0.000 claims description 3
- 150000003751 zinc Chemical class 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 abstract description 10
- 230000002411 adverse Effects 0.000 abstract description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 239000003889 eye drop Substances 0.000 description 13
- 229940012356 eye drops Drugs 0.000 description 13
- -1 sodium dinucleotide Natural products 0.000 description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 241000894006 Bacteria Species 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 238000011109 contamination Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 230000000813 microbial effect Effects 0.000 description 6
- 239000012085 test solution Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 235000011054 acetic acid Nutrition 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 229940009662 edetate Drugs 0.000 description 5
- 241000588724 Escherichia coli Species 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 230000002421 anti-septic effect Effects 0.000 description 4
- 229910021538 borax Inorganic materials 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 229960004926 chlorobutanol Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 235000017550 sodium carbonate Nutrition 0.000 description 4
- 235000010339 sodium tetraborate Nutrition 0.000 description 4
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical group [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-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
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 229960003260 chlorhexidine Drugs 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- ACYGYJFTZSAZKR-UHFFFAOYSA-J dicalcium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Ca+2].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O ACYGYJFTZSAZKR-UHFFFAOYSA-J 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 230000009422 growth inhibiting effect Effects 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 2
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 description 2
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-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
- 229920002971 Heparan sulfate Polymers 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 102000016943 Muramidase Human genes 0.000 description 2
- 108010014251 Muramidase Proteins 0.000 description 2
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 2
- DJDFFEBSKJCGHC-UHFFFAOYSA-N Naphazoline Chemical compound Cl.C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 DJDFFEBSKJCGHC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 2
- VYGQUTWHTHXGQB-FFHKNEKCSA-N Retinol Palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-FFHKNEKCSA-N 0.000 description 2
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 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
- 239000008272 agar Substances 0.000 description 2
- POJWUDADGALRAB-UHFFFAOYSA-N allantoin Chemical compound NC(=O)NC1NC(=O)NC1=O POJWUDADGALRAB-UHFFFAOYSA-N 0.000 description 2
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 229960002684 aminocaproic acid Drugs 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 2
- 229960003872 benzethonium 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
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- FUWUEFKEXZQKKA-UHFFFAOYSA-N beta-thujaplicin Chemical compound CC(C)C=1C=CC=C(O)C(=O)C=1 FUWUEFKEXZQKKA-UHFFFAOYSA-N 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
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- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 description 2
- SIYLLGKDQZGJHK-UHFFFAOYSA-N dimethyl-(phenylmethyl)-[2-[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethoxy]ethyl]ammonium Chemical compound C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 SIYLLGKDQZGJHK-UHFFFAOYSA-N 0.000 description 2
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- 239000003205 fragrance Substances 0.000 description 2
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- 150000004677 hydrates Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
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- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
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- 239000002562 thickening agent Substances 0.000 description 2
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- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 239000002554 heparinoid Substances 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 229960002163 hydrogen peroxide Drugs 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229960004592 isopropanol Drugs 0.000 description 1
- NFIDBGJMFKNGGQ-UHFFFAOYSA-N isopropylmethylphenol Natural products CC(C)CC1=CC=CC=C1O NFIDBGJMFKNGGQ-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
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- JCQLYHFGKNRPGE-FCVZTGTOSA-N lactulose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 JCQLYHFGKNRPGE-FCVZTGTOSA-N 0.000 description 1
- 229960000511 lactulose Drugs 0.000 description 1
- PFCRQPBOOFTZGQ-UHFFFAOYSA-N lactulose keto form Natural products OCC(=O)C(O)C(C(O)CO)OC1OC(CO)C(O)C(O)C1O PFCRQPBOOFTZGQ-UHFFFAOYSA-N 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 229940074358 magnesium ascorbate Drugs 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- AIOKQVJVNPDJKA-ZZMNMWMASA-L magnesium;(2r)-2-[(1s)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2h-furan-3-olate Chemical compound [Mg+2].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] AIOKQVJVNPDJKA-ZZMNMWMASA-L 0.000 description 1
- RXMQCXCANMAVIO-CEOVSRFSSA-L magnesium;(2s)-2-amino-4-hydroxy-4-oxobutanoate Chemical compound [H+].[H+].[Mg+2].[O-]C(=O)[C@@H](N)CC([O-])=O.[O-]C(=O)[C@@H](N)CC([O-])=O RXMQCXCANMAVIO-CEOVSRFSSA-L 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
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- 229920000609 methyl cellulose Polymers 0.000 description 1
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- 239000001923 methylcellulose Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
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- 150000007522 mineralic acids Chemical class 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
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- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
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- 229960004760 naphazoline hydrochloride Drugs 0.000 description 1
- 229960004186 naphazoline nitrate Drugs 0.000 description 1
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- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
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- 235000005985 organic acids Nutrition 0.000 description 1
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- 239000006072 paste Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 150000004686 pentahydrates Chemical class 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride 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
- 235000019260 propionic acid Nutrition 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 1
- 229960004172 pyridoxine hydrochloride Drugs 0.000 description 1
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 description 1
- 239000011764 pyridoxine hydrochloride Substances 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose 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[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 1
- 229960000342 retinol acetate Drugs 0.000 description 1
- 235000019173 retinyl acetate Nutrition 0.000 description 1
- 239000011770 retinyl acetate Substances 0.000 description 1
- QGNJRVVDBSJHIZ-QHLGVNSISA-N retinyl acetate Chemical compound CC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C QGNJRVVDBSJHIZ-QHLGVNSISA-N 0.000 description 1
- 229940108325 retinyl palmitate Drugs 0.000 description 1
- 235000019172 retinyl palmitate Nutrition 0.000 description 1
- 239000011769 retinyl palmitate Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- GQTHJBOWLPZUOI-FJXQXJEOSA-M sodium D-pantothenate Chemical compound [Na+].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O GQTHJBOWLPZUOI-FJXQXJEOSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate 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
- 229940037001 sodium edetate Drugs 0.000 description 1
- 229940068459 sodium pantothenate Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000004328 sodium tetraborate Substances 0.000 description 1
- XTXYCJOBMKKQOW-UHFFFAOYSA-N sodium;(4-aminophenyl)sulfonyl-(2,6-dimethylpyrimidin-4-yl)azanide Chemical compound [Na+].CC1=NC(C)=CC([N-]S(=O)(=O)C=2C=CC(N)=CC=2)=N1 XTXYCJOBMKKQOW-UHFFFAOYSA-N 0.000 description 1
- GEYJUFBPCGDENK-UHFFFAOYSA-M sodium;3,8-dimethyl-5-propan-2-ylazulene-1-sulfonate Chemical compound [Na+].CC(C)C1=CC=C(C)C2=C(S([O-])(=O)=O)C=C(C)C2=C1 GEYJUFBPCGDENK-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 150000003398 sorbic acids Chemical class 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 229960000654 sulfafurazole Drugs 0.000 description 1
- 229960005404 sulfamethoxazole Drugs 0.000 description 1
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229940021790 tetrahydrozoline hydrochloride Drugs 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 229960000337 tetryzoline Drugs 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 229940042585 tocopherol acetate Drugs 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 1
- 229960000401 tranexamic acid Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- VLCLHFYFMCKBRP-UHFFFAOYSA-N tricalcium;diborate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]B([O-])[O-].[O-]B([O-])[O-] VLCLHFYFMCKBRP-UHFFFAOYSA-N 0.000 description 1
- NFMWFGXCDDYTEG-UHFFFAOYSA-N trimagnesium;diborate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]B([O-])[O-].[O-]B([O-])[O-] NFMWFGXCDDYTEG-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960005066 trisodium edetate Drugs 0.000 description 1
- BIKXLKXABVUSMH-UHFFFAOYSA-N trizinc;diborate Chemical compound [Zn+2].[Zn+2].[Zn+2].[O-]B([O-])[O-].[O-]B([O-])[O-] BIKXLKXABVUSMH-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 239000011576 zinc lactate Substances 0.000 description 1
- 235000000193 zinc lactate Nutrition 0.000 description 1
- 229940050168 zinc lactate Drugs 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
- 229930007845 β-thujaplicin Natural products 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
- A61L2/18—Liquid substances or solutions comprising solids or dissolved gases
- A61L2/186—Peroxide solutions
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N59/00—Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
- A01N59/14—Boron; Compounds thereof
-
- 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
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K31/69—Boron compounds
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- 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
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L12/00—Methods or apparatus for disinfecting or sterilising contact lenses; Accessories therefor
- A61L12/08—Methods or apparatus for disinfecting or sterilising contact lenses; Accessories therefor using chemical substances
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
- C11D3/0005—Other compounding ingredients characterised by their effect
- C11D3/0078—Compositions for cleaning contact lenses, spectacles or lenses
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D7/00—Compositions of detergents based essentially on non-surface-active compounds
- C11D7/02—Inorganic compounds
- C11D7/04—Water-soluble compounds
- C11D7/08—Acids
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D7/00—Compositions of detergents based essentially on non-surface-active compounds
- C11D7/02—Inorganic compounds
- C11D7/04—Water-soluble compounds
- C11D7/10—Salts
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D7/00—Compositions of detergents based essentially on non-surface-active compounds
- C11D7/22—Organic compounds
- C11D7/32—Organic compounds containing nitrogen
- C11D7/3245—Aminoacids
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D7/00—Compositions of detergents based essentially on non-surface-active compounds
- C11D7/22—Organic compounds
- C11D7/34—Organic compounds containing sulfur
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to a preservative that is safe for the human body, which can suppress the growth of bacteria in an aqueous composition and maintain the quality of the aqueous composition.
- Aqueous compositions of pharmaceuticals and the like usually contain a preservative for the purpose of preventing the product from decaying due to microbial contamination.
- a preservative for the purpose of preventing the product from decaying due to microbial contamination.
- many ophthalmic compositions such as eye drops are presumed to be used many times after opening, and once opened, eye drops have microbial contamination in the air or in contact with skin. It is easy to happen. Therefore, preservatives are generally added to eye drops.
- trometamol for example, see Patent Document 1
- ketophetine for example, see Patent Document 2
- alcohol derivatives for example, Patent Document 3
- a method using hydrogen peroxide for example, see Patent Document 4
- basic amino acid polymer for example, see Patent Document 5
- a composition having a sufficient antiseptic effect and safe for the human body and the outer contour lens has not yet been obtained.
- Patent Document 1 JP-A-2004-43516
- Patent Document 2 JP 2004-203867
- Patent Document 3 JP 2005-187354
- Patent Document 4 JP-A-2-96531
- Patent Document 5 JP 2002-20320
- the main object of the present invention is to provide a safe preservative capable of preventing microbial contamination and the like in an aqueous composition such as a pharmaceutical product.
- the present inventor has (A) thiosulfate, (B) edetic acid and Z or a salt thereof, and (C) boric acid and Z or a salt thereof. It has been found that, by blending, the water-based composition exhibits excellent storage stability. Thiosulfate is widely used as an antioxidant for the purpose of improving the stability of unstable components, and is one of the highly safe ingredients used for decolorization of iodine. The use of acid salts for the purpose of antiseptic action has not been known until now. The present invention has been completed by further research based on such knowledge.
- the present invention provides the following preservative, ophthalmic composition and method for inhibiting bacterial growth.
- Item 1 A preservative containing (A) thiosulfate, (B) edetic acid and Z or a salt thereof, and (C) boric acid and Z or a salt thereof.
- Item 2 The preservative according to Item 1, wherein the thiosulfate is sodium thiosulfate.
- Item 3 The preservative according to Item 1, wherein the edetic acid salt is at least one selected from the group consisting of sodium salt, potassium salt and calcium salt of edetic acid.
- Item 4 The preservative according to Item 1, wherein the edetate is disodium edetate or calcium edetate.
- Item 5 The preservative according to Item 1, wherein the borate is at least one selected from the group consisting of sodium salt, potassium salt, calcium salt, magnesium salt, and zinc salt of boric acid.
- Item 6. The preservative according to Item 1, wherein the borate is sodium borate.
- Item 7 Preservative containing sodium thiosulfate, disodium edetate and boric acid.
- Item 8 An aqueous composition comprising the preservative according to any one of Items 1 to 7.
- Item 9 An ophthalmic composition comprising the preservative according to any one of Items 1 to 7.
- Item 10 A method for inhibiting bacterial growth, comprising (A) sodium thiosulfate, (B) edetic acid and Z or a salt thereof, and (C) boric acid and Z or a salt thereof in an aqueous composition.
- the invention's effect comprising (A) sodium thiosulfate, (B) edetic acid and Z or a salt thereof, and (C) boric acid and Z or a salt thereof in an aqueous composition.
- the preservative of the present invention can impart excellent preservation to an aqueous composition by preventing microbial contamination and the like, and is safe and has no damage to the human body (particularly the eyes). It is.
- the ophthalmic composition containing such a preservative of the present invention is capable of suppressing the decay of the composition due to microbial contamination and the like, and adsorbing to a contact lens that is highly safe for the human body (eye). Does not cause inconvenience.
- compositions can be enhanced by blending the active ingredients (A) to (C) in the present invention.
- the “preservative” of the present invention can suppress bacterial growth in the aqueous composition and maintain the quality of the aqueous composition.
- the aqueous composition is a composition containing water essential for the growth of microorganisms, and refers to solutions, suspensions, pastes, semi-pastes, pharmaceuticals, quasi drugs, foods, and the like. .
- it is a pharmaceutical, particularly an ophthalmic composition.
- the preservative of the present invention contains (A) thiosulfate, (B) edetic acid and Z or a salt thereof, and (C) boric acid and Z or a salt thereof as active ingredients.
- the thiosulfate used in the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include sodium thiosulfate, potassium thiosulfate, and ammonium thiosulfate.
- the thiosulfate used in the present invention is in the form of an anhydrous salt. Alternatively, it may be used in the form of a hydrate such as pentahydrate. These salts can be used alone or in combination of two or more. In the present invention, it is preferable to use sodium thiosulfate.
- the total amount of thiosulfate is about 0.4 to 98% by weight, preferably about 1.5 to 94% by weight, more preferably about 1.5 to 90% by weight. More preferably, it is desirable to add about 5 to 66% by weight.
- edetic acid ethylenediamine tetraacetic acid
- the edetic acid may be in the form of a salt or a mixture of edetic acid and edetate.
- the edetate may be in the form of an anhydride or a hydrate.
- the edetic acid salt is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, sodium salt, potassium salt, calcium salt and the like of edetic acid can be used.
- salts examples include disodium edetate, trisodium edetate, tetrasodium edetate, calcium edetate, calcium disodium edetate, dipotassium edetate, tripotassium edetate, and hydrates thereof. Etc. These salts can be used alone or in combination of two or more. In the present invention, sodium salt of edetic acid (more preferably disodium edetate) and calcium edetate are preferable.
- the total amount of the edetic acid and Z or a salt thereof is about 0.01 to 80% by weight, preferably about 0.08 to 55% by weight, more preferably 0.3 to It is desirable to add about 15% by weight.
- boric acid is used as one of the active ingredients.
- the boric acid may be in a salt state or a mixture of boric acid and borate.
- the borate may be in the form of an anhydride or a hydrate.
- the borate used in the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt.
- boric acid sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt and the like are used. be able to.
- Examples of such salts include sodium borate, calcium borate, magnesium borate, Examples thereof include potassium oxalate, zinc borate, and hydrates thereof. These salts can be used alone or in combination of two or more.
- boric acid or borax sodium borate
- the total amount of boric acid and Z or a salt thereof is about 1.8 to 99.5% by weight, preferably about 6 to 98% by weight, more preferably about 30 to 95% by weight. It is desirable to mix.
- Preferred combinations of the active ingredients (A) to (C) in the present invention include, for example, (A) sodium thiosulfate, (B) sodium salt of edetic acid (more preferably disodium edetate) and ( C) Boric acid.
- component (A) when the component (A) is 1 part by weight, the component (B) is about 0.0002 to 25 parts by weight, preferably about 0.0001 to 10 parts by weight, more preferably Is 0.005 to 200 parts by weight; component (C) is about 0.01 to 200 parts by weight, preferably about 0.05 to 60 parts by weight, more preferably 0.1 to 20 parts by weight, and still more preferably 0. It is desirable to blend the above components (A) to (C) so as to be 1 to 15 parts by weight.
- the preservative of the present invention can effectively act under a pH of about 5 to 8, preferably about 6 to 7.
- the preservative of the present invention By adding the preservative of the present invention to the aqueous composition in an amount of about 0.1% by weight or more, preferably about 0.2% by weight or more, the growth of bacteria in the aqueous composition is suppressed. Togashi.
- the preservative of the present invention includes conventionally known active ingredients, isotonic agents, inorganic salts, as long as the effects of the present invention are not impaired. , Buffers, thickeners, sugars, surfactants, solubilizers, cleaning ingredients, chelating agents, antioxidants, cooling agents, fragrances, local anesthetics, preservatives, pH adjusters, etc. Also good.
- Other active ingredients include, for example, decongestants such as epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, naphazoline hydrochloride, naphazoline nitrate, fe-rephrin hydrochloride, dl-methylephedrine hydrochloride; methyl sulfate Neostigmine, ⁇ -aminocaproic acid, allantoin, berberine chloride, berberine sulfate, zinc sulfate, zinc lactate, lysozyme chloride, dipotassium glycyrrhizinate, glycyrrhizic acid
- Anti-histamines such as humic, glycyrrhetinic acid, methyl salicylate, tranexamic acid, sodium azulene
- Water soluble vitamins such as sodium dinucleotide, pyridoxine hydrochloride, cyanocobalamin, panthenol, calcium pantothenate, sodium pantothenate; vitamins A (eg retinol acetate, retinol palmitate), vitamins E (tocolol acetate (
- fat-soluble vitamins such as acetic acid (da-tocofurol); potassium L-aspartate, magnesium L-aspartate, aminoethyl sulfonate, chondroit Amino acids such as sodium sulfate; sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sulfisomidine sodium, isopropylmethylphenol, hinokitiol, and other sulfa drugs; potassium chloride, calcium chloride, sodium chloride sodium Inorganic salts such as sodium hydrogen carbonate, sodium carbonate, dry sodium carbonate, magnesium sul
- the above active ingredients may be used alone or in combination of two or more.
- Examples of the tonicity agent include polyhydric alcohols such as glycerin and propylene glycol, and sugars (such as butter sugar and sorbitol).
- inorganic salts include sodium salt, potassium salt, sodium carbonate, sodium hydrogen carbonate, sodium salt calcium salt, magnesium sulfate, sodium hydrogen phosphate, disodium hydrogen phosphate.
- buffer examples include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, and the like.
- gum arabic As thickeners, gum arabic, cara gum, xanthan gum, casein, agar, alginic acid, a-cyclodextrin, dextrin, dextran, carrageenan, gelatin, collagen, pectin, starch, chitin and derivatives thereof, chitosan And derivatives thereof, elastin, heparin, heparinoid, heparin sulfate, heparan sulfate, hyaluronic acid, methylcellulose, hydroxyethylcellulose and other polysaccharides or derivatives thereof, ceramide, macro Examples thereof include gall, glycerin, popidone, polybula metatalylate, polybulu alcohol, polyacrylic acid, carboxybule polymer, and polyethyleneimine.
- saccharide examples include glucose, fructose, galactose, mannose, ribose, ribose, arabinose, xylose, lyxose, dexyloxyribose, maltose, trehalose, sucrose, cellobiose, latatoose, punoreran, lactulose, raffinose, manoleitol and the like.
- higher fatty acid esters such as polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan higher fatty acid esters such as polysorbate 80 and polyoxyethylene sorbine monooleate, sucrose fatty acid esters, polyoxy Nonionic surfactants such as ethylene polyoxypropylene block copolymers are listed.
- chelating agents include edetic acid (ethylenediamine amine acetic acid, EDTA), ethylenediamine amine acetic acid (EDDA) tartaric acid, phosphoric acids (polyphosphoric acid, hexametaphosphoric acid, metaphosphoric acid), and succinic acid.
- antioxidants examples include dibutylhydroxytoluene (BHT), tocopherol acetate, and magnesium ascorbate phosphate.
- fragrance cooling agent
- examples of the fragrance include menthol, camphor, borneol, eucalyptus oil, peppermint oil, bergamot oil, gera-ol and the like.
- Examples of the local anesthetic include chlorobutanol.
- Preservatives include: nonoxybenzoic acid ester, atalinol, salt benzalkonium salt, benzethonium chloride, cetylpyridinum chloride, chlorhexidine, polyhexamethylene biguanide, alkylpolyaminoethylglycine, darcon Chlorhexidine acid, benzenorenoreconole, phenenoleanoreconole, chlorobutanol monore, isopropanol, ethanol, thimerosal, lysozyme, sorbic acid, potassium sorbate, hydrogen peroxide, salified polydrodor -Um, hexad hydrochloride and the like.
- pH adjusters include inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, boric acid, etc.), organic acids (lactic acid, acetic acid, tartaric acid, malic acid, succinic acid, oxalic acid, darconic acid, fumaric acid) , Propionic acid, acetic acid, aspartic acid, epsilon aminocaproic acid, glutamic acid, aminoethylsulfonic acid, etc.), darconola tatone, ammonium acetate, inorganic base (sodium hydrogen carbonate) And sodium carbonate, potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, etc.).
- the aqueous composition can be prevented from being spoiled without blending the preservative, but the preservative of the present invention is combined with a preservative that has been widely used conventionally. It does not preclude the mode of using.
- the amount of the preservative can be reduced, eliminating problems such as cornea damage and contact lens adsorption. Or it is expected to be easily reduced.
- preservatives examples include benzalkonium chloride, benzethonium chloride, chlorhexidine dalconate, polyhexamide hydrochloride, polydrome chloride, chlorobutanol, and parabens. .
- the amount of the preservative is about 0 to 0.05% by weight, preferably about 0 to 0.01% by weight, more preferably 0 to 0.005% by weight. Degree.
- the preservative of the present invention described in (1) above By adding the preservative of the present invention described in (1) above to the ophthalmic composition, it is possible to prevent spoilage due to microbial contamination or the like in the course of use of the ophthalmic composition. Furthermore, since the preservative of the present invention does not cause contact lens alteration that cannot be adsorbed to the contact lens, it can be applied to ophthalmic compositions for contact lenses.
- the ophthalmic composition for contact lenses includes eye drops used at the time of wearing contact lenses, and includes contact lens agents to be described later.
- the present invention also provides an ophthalmic composition containing the above-described preservative.
- the blending amount of the preservative in the ophthalmic composition of the present invention is a force that can be appropriately adjusted within the range where the effects of the present invention are exerted, for example, about 0.1 to 6 wt%, preferably 0.1 to 4 wt%.
- the degree is more preferably about 0.2 to 3% by weight.
- the storage stability is excellent, the osmotic pressure does not become too high, and even when applied to an ophthalmic composition or the like, eye irritation is not caused, which is preferable.
- the pH of the ophthalmic composition of the present invention is desirably set to about 5 to 8, preferably about 6 to 7, and the osmotic pressure ratio desired to be set to about 1 is desirable.
- the ophthalmic composition of the present invention includes aqueous eye drops, non-aqueous eye drops, suspension eye drops, milk. Eye drops such as eye drops that can be instilled even when wearing turbid eye drops, soft contact lenses, hard contact lenses, etc .; eye ointments; eye wash; contact lens mounting solution, cleaning solution, preservative solution, bactericidal solution, etc. Contact lens agents and the like.
- the storage stability of the aqueous composition can be enhanced.
- the blending amounts and blending ratios of components (A) to (C) can be appropriately adjusted according to the range described in (1) above.
- Test example 1 Preservative efficacy test
- each component was dissolved in purified water to prepare a test solution with a total volume of lOOmL, which was sterile filtered.
- the storage efficacy of these test solutions was evaluated with reference to the 14th revised Japanese Pharmacopoeia preservation efficacy test method. Specifically, Escherichia coli (EC in the table) and Pseudomonas aeruginosa (PA in the table) were prepared, respectively, and each bacterial solution was added to the test solution so as to be 10 5 to: L0 6 CFU / mL. Inoculated and stored at 25 ° C. Thereafter, the number of viable cells was measured by the agar plate pour method on days 7, 14, 21, and 28, and the presence or absence of a bacterial growth inhibitory effect was determined. The results are shown in the judgment column of Table 1.
- the number of viable bacteria up to 14 days is more than 0.1% of the number of inoculated bacteria
- Test Example 2 Verification of blending amount of sodium thiosulfate
- Test Example 3 Verification of pH The storage efficacy of the ophthalmic composition in the general pH range (pH 5-8) was evaluated. According to the formulation shown in Table 3 below, a test solution was prepared according to the same method as in Test Example 1, and then the storage effect was evaluated. However, only Escherichia coli was used as the bacterial solution. The results are shown in the judgment column of Table 3.
- the preservatives of the present invention and compounds known to be blended as preservatives were evaluated for preservative efficacy.
- Table 4 a test solution was prepared according to the same method as in Test Example 1, and then the storage efficacy was evaluated.
- Aspergillus niger (AN in the table) prepared by the method shown in Test Example 1 was used in addition to Escherichia coli (EC in the table) and Pseudomonas aeruginosa (PA in the table). The results are shown in the judgment column of Table 4.
- the preservative of the present invention showed excellent preservation efficacy against all three types of bacteria compared to compounds known to be formulated as preservatives.
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Abstract
【課題】水系組成物に優れた保存性を付与することができ、人体(眼)に対する傷害性が極めて低く、コンタクトレンズに悪影響を及ぼすことのない保存剤を提供する。
【解決手段】(A)チオ硫酸塩、(B)エデト酸及び/又はその塩及び(C)ホウ酸及び/又はその塩を有効成分とする、保存剤。
Description
明 細 書
保存剤
技術分野
[0001] 本発明は、水系組成物における細菌の増殖を抑制し、該水系組成物の品質を保 持し得る、人体にも安全な保存剤に関する。
背景技術
[0002] 医薬品の水性組成物等には、微生物汚染等による製品の腐敗を防止する目的で、 通常、防腐剤が配合されている。特に点眼薬等の眼科用組成物は、その多くが開封 後に何度も使用されることが前提とされており、一旦開封した点眼薬は、空気中や接 触した皮膚等力もの微生物汚染が起こりやすい。従って、点眼薬には防腐剤が配合 されるのが一般的である。例外的に、防腐剤が配合されてない点眼薬も存在するが、 それらは、開封後一回で使い切るタイプ (ユニットドーズ)の点眼薬に限られている。
[0003] 防腐剤として汎用されている塩ィ匕ベンザルコ-ゥム、塩ィ匕べンゼトニゥム、クロロブタ ノール、パラベン類等は、角膜細胞等に対する傷害性が指摘されているほか、コンタ クトレンズ装用中に点眼すると、コンタクトレンズに吸着してコンタクトレンズを変質さ せる恐れがある。また、変質したコンタクトレンズを装着することによる眼への悪影響も 指摘されている。従って、コンタクトレンズ装用中は、塩ィ匕ベンザルコ -ゥム等の防腐 剤を含む点眼薬を使用することは、通常禁止されている。
[0004] コンタクトレンズに吸着せず、安定性も高!、防腐剤としては、ソルビン酸類が汎用さ れているが、防腐効果が弱ぐ分解しやすいといった難点がある。
[0005] また、上述の毒性の高 ヽ防腐剤の代替成分として、トロメタモール (例えば、特許文 献 1を参照)、ケトフエチン (例えば、特許文献 2を参照)、アルコール誘導体 (例えば 、特許文献 3を参照)、過酸化水素 (例えば、特許文献 4を参照)、塩基性アミノ酸ポリ マー (例えば、特許文献 5を参照)等を用いる方法が報告されている。しかしながら、 充分な防腐効力を有し、人体とコンタ外レンズに対して安全な組成物は、まだ得られ ていなかった。
特許文献 1 :特開 2004— 43516
特許文献 2:特開 2004 - 203867
特許文献 3 :特開 2005— 187354
特許文献 4:特開平 2— 96531
特許文献 5:特開 2002— 20320
発明の開示
発明が解決しょうとする課題
[0006] 本発明は、医薬品等の水系組成物における微生物汚染等を防止し得る、安全な保 存剤を提供することを主な目的とする。
課題を解決するための手段
[0007] 本発明者は、上記課題を解決すべく鋭意検討を重ねた結果、(A)チォ硫酸塩、 (B )ェデト酸及び Z又はその塩、ならびに (C)ホウ酸及び Z又はその塩を配合すること によって、水系組成物において優れた保存安定性を発揮することを見出した。チォ 硫酸塩は、不安定な成分の安定性を向上させる目的で抗酸化剤等として広く使用さ れるほか、ヨウ素の脱色等にも使用される安全性の高い成分の 1つである力 チォ硫 酸塩を防腐作用を目的として用いることは今まで知られていな力つた。本発明は、こ のような知見に基づき、さらに研究を重ねることによって完成されたものである。
[0008] 本発明は、以下の保存剤、眼科用組成物及び細菌増殖抑制方法を提供する。
項 1. (A)チォ硫酸塩、(B)ェデト酸及び Z又はその塩、ならびに(C)ホウ酸及び Z 又はその塩を含有する、保存剤。
項 2.チォ硫酸塩が、チォ硫酸ナトリウムである、項 1に記載の保存剤。
項 3.ェデト酸塩が、ェデト酸のナトリウム塩、カリウム塩及びカルシウム塩力 なる群 より選択される少なくとも 1種である、項 1に記載の保存剤。
項 4.ェデト酸塩が、ェデト酸ニナトリウム又はェデト酸カルシウムである、項 1に記載 の保存剤。
項 5.ホウ酸塩が、ホウ酸のナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩及 び亜鉛塩力もなる群より選択される少なくとも 1種である、項 1に記載の保存剤。 項 6.ホウ酸塩が、ホウ酸ナトリウムである項 1に記載の保存剤。
項 7.チォ硫酸ナトリウム、ェデト酸ニナトリウム及びホウ酸を含有する保存剤。
項 8.項 1〜7のいずれかに記載の保存剤を含有する、水系組成物。
項 9.項 1〜7のいずれかに記載の保存剤を含有する、眼科用組成物。
項 10. (A)チォ硫酸ナトリウム、(B)ェデト酸及び Z又はその塩、ならびに(C)ホウ酸 及び Z又はその塩を水系組成物に配合することを特徴とする、細菌増殖抑制方法。 発明の効果
[0009] 本発明の保存剤は、微生物汚染等を防止することによって水系組成物に優れた保 存性を付与し得るものであり、且つ、人体 (特に眼)に対する傷害性がない、安全なも のである。
[0010] また、本発明の保存剤によれば、防腐効果は高くても種々の問題があった塩ィ匕べ ンザルコ-ゥム、塩ィ匕べンゼトニゥム等の従来の化合物を配合することなぐ組成物 の品質を保つことが可能である。従って、この様な本発明の保存剤を配合した眼科 用組成物は、微生物汚染等による組成物の腐敗が抑制され、且つ、人体 (眼)に対し て安全性が高ぐコンタクトレンズに対する吸着といった不都合を生じさせない。
[0011] さらに、本発明における有効成分 (A)〜(C)を配合することにより、様々な組成物 の保存安定性を高めることが可能である。
発明を実施するための最良の形態
[0012] 本発明の『保存剤』は、水系組成物における細菌の増殖を抑制し、該水系組成物 の品質を保持することができる。本発明において水系組成物とは、微生物の増殖に 必須である水を含む組成物であって、溶液、懸濁液、ペースト状、半ペースト状の医 薬品、医薬部外品、食品等を指す。好ましくは、医薬品であり、特に眼科用組成物を 指す。以下、本発明において使用される各成分について説明する。
[0013] (1)保存剤
本発明の保存剤は、(A)チォ硫酸塩、(B)ェデト酸及び Z又はその塩、ならびに( C)ホウ酸及び Z又はその塩を有効成分とする。
(A)チォ硫酸塩
本発明において使用されるチォ硫酸塩としては、薬学的に許容される塩であれば 特に限定されないが、例えば、チォ硫酸ナトリウム、チォ硫酸カリウム、チォ硫酸アン モ -ゥム等が挙げられる。本発明において使用されるチォ硫酸塩は、無水塩の形態
であってもよぐまた、例えば五水和物といった水和物の形態で用いてもよい。これら の塩を 1種単独で使用することもでき、 2種以上を組み合わせて用いてもよい。本発 明にお 、ては、チォ硫酸ナトリウムを用いることが好まし 、。
[0014] 本発明の保存剤には、上記チォ硫酸塩を、総量として 0. 4〜98重量%程度、好ま しくは 1. 5〜94重量%、より好ましくは 1. 5〜90重量%程度、さらに好ましくは 5〜6 6重量%程度配合することが望ま 、。
[0015] (B)ェデト酸及び Z又はその塩
本発明にお 、ては、ェデト酸 (エチレンジァミン四酢酸)を有効成分の 1つとして使 用する。ェデト酸は、塩の状態であってもよぐェデト酸とェデト酸塩の混合物であつ てもよい。また、ェデト酸塩は、無水物の形態でもよぐ水和物の形態であってもよい 。ェデト酸塩としては、薬学的に許容される塩であれば特に限定されず、例えば、ェ デト酸のナトリウム塩、カリウム塩、カルシウム塩等を使用することができる。このような 塩としては、例えば、ェデト酸ニナトリウム、ェデト酸三ナトリウム、ェデト酸四ナトリウ ム、ェデト酸カルシウム、ェデト酸カルシウムニナトリウム、ェデト酸二カリウム、ェデト 酸三カリウム、これらの水和物等が挙げられる。これらの塩を 1種単独で使用すること もでき、 2種以上を組み合わせて用いてもよい。本発明においては、ェデト酸のナトリ ゥム塩 (より好ましくはェデト酸ニナトリウム)、ェデト酸カルシウムであることが好ましい
[0016] 本発明の保存剤には、上記ェデト酸及び Z又はその塩を、総量として 0. 01〜80 重量%程度、好ましくは 0. 08〜55重量%程度、より好ましくは 0. 3〜15重量%程 度配合することが望ましい。
[0017] (C)ホウ酸及び Z又はその塩
本発明においては、ホウ酸を有効成分の 1つとして使用する。ホウ酸は、塩の状態 であってもよぐホウ酸とホウ酸塩の混合物でもよい。また、ホウ酸塩は、無水物の形 態でもよぐ水和物の形態であってもよい。本発明において使用されるホウ酸塩として は、薬学的に許容される塩であれば特に限定されず、例えば、ホウ酸のナトリウム塩、 カリウム塩、カルシウム塩、マグネシウム塩、亜鉛塩等を使用することができる。このよ うな塩としては、例えば、ホウ酸ナトリウム、ホウ酸カルシウム、ホウ酸マグネシウム、ホ
ゥ酸カリウム、ホウ酸亜鉛、これらの水和物等が挙げられる。これらの塩を 1種単独で 使用することもでき、 2種以上を組み合わせてもよい。本発明においては、ホウ酸、ホ ゥ砂 (ホウ酸ナトリウム)であることが好ま 、。
[0018] 本発明には、上記ホウ酸及び Z又はその塩を、総量として 1. 8〜99. 5重量%程 度、好ましくは 6〜98重量%程度、より好ましくは 30〜95重量%程度配合することが 望ましい。
[0019] 上記有効成分 (A)〜(C)の本発明における好ま 、組み合わせは、例えば、(A) チォ硫酸ナトリウム、(B)ェデト酸のナトリウム塩 (より好ましくはェデト酸ニナトリウム) 及び (C)ホウ酸である。
[0020] 本発明の保存剤において、(A)成分を 1重量部とした場合に、(B)成分を 0. 0002 〜25重量部程度、好ましくは 0. 0017〜10重量部程度、より好ましくは 0. 005-2 重量部;(C)成分を 0. 01〜200重量部程度、好ましくは 0. 05〜60重量部程度、よ り好ましくは 0. 1〜20重量部、さらに好ましくは 0. 1〜15重量部になるように上記成 分 (A)〜 (C)を配合することが望ま 、。
[0021] 本発明の保存剤は、 pH5〜8程度、好ましくは 6〜7程度のもとで有効に作用し得る ものである。
[0022] 本発明の保存剤を、水系組成物に対して、 0. 1重量%程度以上、好ましくは 0. 2 重量%程度以上配合することにより、水系組成物における細菌の増殖を抑制するこ とがでさる。
[0023] また、本発明の保存剤には、本発明の効果を損なわない限りにおいて、上記有効 成分 (A)〜(C)の他に、従来公知の活性成分、等張化剤、無機塩類、緩衝剤、増粘 剤、糖類、界面活性剤、可溶化剤、洗浄成分、キレート剤、抗酸化剤、清涼化剤、香 料、局所麻酔剤、防腐剤、 pH調整剤等を添加してもよい。
[0024] 他の活性成分としては、例えば、ェピネフリン、塩酸ェピネフリン、塩酸エフェドリン 、塩酸テトラヒドロゾリン、硝酸テトラヒドロゾリン、塩酸ナファゾリン、硝酸ナファゾリン、 塩酸フエ-レフリン、 dl—塩酸メチルエフェドリン等の充血除去剤;メチル硫酸ネオス チグミン、 ε —アミノカプロン酸、アラントイン、塩化ベルべリン、硫酸ベルべリン、硫酸 亜鉛、乳酸亜鉛、塩化リゾチーム、グリチルリチン酸二カリウム、グリチルリチン酸アン
モ-ゥム、グリチルレチン酸、サリチル酸メチル、トラネキサム酸、ァズレンスルホン酸 ナトリウム、クロモグリク酸ナトリウム等の消炎 '収斂剤;塩酸ィプロヘプチン、塩酸ジフ ェンヒドラミン、ジフェンヒドラミン、塩酸イソチペンジル、マレイン酸クロルフエ-ラミン 等の抗ヒスタミン剤;フラビンアデ-ンジヌクレオチドナトリウム、塩酸ピリドキシン、シァ ノコバラミン、パンテノール、パントテン酸カルシウム、パントテン酸ナトリウム等の水溶 性ビタミン類;ビタミン A類(例えば酢酸レチノール、パルミチン酸レチノール)、ビタミ ン E類(酢酸トコフ ロール(例えば、酢酸 d— a トコフ ロール)等の脂溶性ビタミン 類; Lーァスパラギン酸カリウム、 Lーァスパラギン酸マグネシウム、アミノエチルスルホ ン酸、コンドロイチン硫酸ナトリウム等のアミノ酸類;スルファメトキサゾール、スルファメ トキサゾールナトリウム、スルフイソキサゾール、スルフイソミジンナトリウム、イソプロピ ルメチルフエノール、ヒノキチオール等のサルファ剤;塩化カリウム、塩化カルシウム、 塩ィ匕ナトリウム、炭酸水素ナトリウム、炭酸ナトリウム、乾燥炭酸ナトリウム、硫酸マグネ シゥム、リン酸水素ナトリウム、リン酸二水素ナトリウム、リン酸二水素カリウム等の無機 塩類等が挙げられる。
[0025] 上記の活性成分は、その 1種を単独で併用してもよぐ 2種以上を組み合わせて併 用してちょい。
[0026] 等張化剤として、グリセリン、プロピレングリコールなどの多価アルコール、糖類 (ブト ゥ糖,ソルビトールなど)等が挙げられる。
[0027] 無機塩類としては、塩ィ匕ナトリウム、塩ィ匕カリウム、炭酸ナトリウム、炭酸水素ナトリウ ム、塩ィ匕カルシウム、硫酸マグネシウム、リン酸水素ナトリウム、リン酸水素ニナトリウム
、リン酸水素二カリウム、チォ硫酸ナトリウム、酢酸ナトリウム等が挙げられる。
[0028] 緩衝剤として、ホウ酸緩衝剤、リン酸緩衝剤、炭酸緩衝剤、クェン酸緩衝剤、酢酸 緩衝剤等が挙げられる。
[0029] 増粘剤として、アラビアゴム、カラャガム、キサンタンガム、カゼイン、寒天、アルギン 酸、 a—シクロデキストリン、デキストリン、デキストラン、カラギーナン、ゼラチン、コラ 一ゲン、ぺクチン、デンプン、キチン及びその誘導体、キトサン及びその誘導体、エラ スチン、へパリン、へパリノイド、へパリン硫酸、へパラン硫酸、ヒアルロン酸、メチルセ ルロース、ヒドロキシェチルセルロース等の多糖類又はその誘導体、セラミド、マクロ
ゴール、グリセリン、ポピドン、ポリビュルメタアタリレート、ポリビュルアルコール、ポリ アクリル酸、カルボキシビュルポリマー、ポリエチレンィミン等が挙げられる。
[0030] 糖類として、グルコース、フルクトース、ガラクトース、マンノース、リボース、リブロー ス、ァラビノース、キシロース、リキソース、デ才キシリボース、マルトース、トレハロース 、スクロース、セロビオース、ラタトース、プノレラン、ラクッロース、ラフイノース、マノレチト ール等及びこれらの薬学的に許容される塩類が挙げられる。
[0031] 界面活性剤として、ポリオキシエチレン硬化ヒマシ油等の高級脂肪酸エステル、ポリ ソルベート 80やポリオキシエチレンソルビンモノォレエート等のポリオキシエチレンソ ルビタン高級脂肪酸エステル、ショ糖脂肪酸エステル、ポリオキシエチレンポリオキシ プロピレンブロックコポリマーなどの非イオン性界面活性剤などが挙げられる。
[0032] キレート剤として、ェデト酸(エチレンジァミン四酢酸, EDTA)、エチレンジァミン二 酢酸 (EDDA)酒石酸、リン酸類 (ポリリン酸、へキサメタリン酸、メタリン酸)、コハク酸 などが挙げられる。
[0033] 抗酸化剤として、ジブチルヒドロキシトルエン(BHT)、酢酸トコフエロール、ァスコル ビン酸リン酸エステルマグネシウム塩等が挙げられる。
[0034] 香料 (清涼化剤)としては、メントール、カンフル、ボルネオール、ユーカリ油、ぺパ 一ミント油、ベルガモット油、ゲラ-オール等が挙げられる。
[0035] 局所麻酔剤としては、クロロブタノール等が挙げられる。
[0036] 防腐剤としては、ノ ラオキシ安息香酸エステル、アタリノール、塩ィ匕ベンザルコユウ ム、塩化べンゼトニゥム、塩化セチルピリジ-ゥム、クロルへキシジン、ポリへキサメチ レンビグアニド、アルキルポリアミノェチルグリシン、ダルコン酸クロルへキシジン、ベ ンジノレアノレコーノレ、フエネチノレアノレコーノレ、クロロブタノ一ノレ、イソプロパノーノレ、エタ ノール、チメロサール、リゾチーム、ソルビン酸、ソルビン酸カリウム、過酸化水素、塩 化ポリドロ-ゥム、塩酸へキサ-ド等が挙げられる。
[0037] pH調整剤としては、無機酸 (塩酸、硫酸、リン酸、ポリリン酸、ホウ酸など)、有機酸( 乳酸、酢酸、酒石酸、リンゴ酸、コハク酸、シユウ酸、ダルコン酸、フマル酸、プロピオ ン酸、酢酸、ァスパラギン酸、ィプシロン アミノカプロン酸、グルタミン酸、アミノエチ ルスルホン酸など)、ダルコノラタトン、酢酸アンモ-ゥム、無機塩基 (炭酸水素ナトリウ
ム、炭酸ナトリウム、水酸ィ匕カリウム、水酸化ナトリウム、水酸ィ匕カルシウム、水酸化マ グネシゥムなど)等が挙げられる。
[0038] 本発明の保存剤によれば、前記防腐剤を配合しなくても水系組成物の腐敗を防止 することができるが、従来力 汎用されている防腐剤と組み合わせて本発明の保存剤 を使用する態様を妨げるものではない。本発明の保存剤を従来汎用されてきた防腐 剤と組み合わせて使用することにより、防腐剤の配合量を減少させることができ、角 膜への傷害性、コンタクトレンズへの吸着といった問題点が解消又は低減されやすく なると期待される。従来汎用されてきた防腐剤としては、例えば、塩化べンザルコニゥ ム、塩化べンゼトニゥム、ダルコン酸クロルへキシジン、塩酸ポリへキサ -ド、塩化ポリ ドロ-ゥム、クロロブタノール、パラベン類等が挙げられる。本発明の保存剤に防腐剤 を配合する場合の防腐剤の配合量は、 0〜0. 05重量%程度、好ましくは 0〜0. 01 重量%程度、より好ましくは 0〜0. 005重量%程度である。
[0039] (2)眼科用組成物
上記(1)に記載する本発明の保存剤を眼科用組成物に配合することにより、該眼 科用組成物の使用過程における微生物汚染等による腐敗を防止することができる。 さらに、本発明の保存剤は、コンタクトレンズに吸着することがなぐコンタクトレンズの 変質を引き起こすこともな 、ため、コンタクトレンズ用の眼科用組成物にも適用するこ とができる。ここで、コンタクトレンズ用の眼科用組成物とは、コンタクトレンズ装着時に 使用される点眼剤を含み、後述のコンタクトレンズ用剤等も含むものである。
[0040] 従って、本発明は、前述の保存剤を含む眼科用組成物をも提供するものである。本 発明の眼科用組成物における保存剤の配合量は、本発明の効果を奏する範囲にお いて適宜調整され得る力 例えば、 0. 1〜6重量%程度、好ましくは 0. 1〜4重量% 程度、より好ましくは 0. 2〜3重量%程度以である。前記範囲内であれば、保存安定 性に優れ、且つ浸透圧が高くなりすぎず、眼科用組成物等に適用した場合でも眼刺 激を引き起こすことがな 、ため好ま 、。
[0041] 本発明の眼科用組成物の pHは、 5〜8程度、好ましくは 6〜7程度に設定すること が望ましぐ浸透圧比は、 1付近に設定することが望ましい。
[0042] 本発明の眼科用組成物としては、水性点眼剤、非水性点眼剤、懸濁性点眼剤、乳
濁性点眼剤、ソフトコンタクトレンズ、ハードコンタクトレンズ等を装用した状態でも点 眼が可能な点眼剤等の点眼剤;眼軟膏剤;洗眼剤;コンタクトレンズ装着液、洗浄液 、保存液、殺菌液等のコンタクトレンズ用剤等が挙げられる。
[0043] (3)細菌増殖抑制方法
上記成分 (A)、(B)及び (C)を前述の水系組成物に配合することによって、該水系 組成物の保存性を高めることができる。成分 (A)〜(C)の配合量及び配合比率は、 上記(1)に記載される範囲に従って、適宜調整され得る。
実施例
[0044] 以下、実施例及び比較例を挙げてより詳細に本発明を説明するが、本発明はこれ らに限定されない。
(1)試験例 1 :保存効力試験
下記表 1の処方に従い、各成分を精製水に溶解させて全量を lOOmLとして試験液 を調製し、これを滅菌濾過した。これらの試験液について、第 14改正日本薬局方の 保存効力試験方法を参考に、保存効力を評価した。具体的には、 Escherichia col i (表中 E.C.)及び Pseudomonas aeruginosa (表中 P.A.)の菌液をそれぞれ調製し 、各菌液を、 105〜: L06CFU/mLになるように試験液に接種し、 25°Cで保管した。 その後、 7、 14、 21及び 28日目に寒天平板混釈法によって生菌数を測定し、細菌増 殖抑制効果の有無を判定した。結果を表 1の判定の欄に示す。
判定基準は以下の通りである。
<判定基準 >
〇: 14日までに生菌数が接種した菌数の 0. 1%以下になった
X: 14日までの生菌数が接種した菌数の 0. 1%より多い
[0045] [表 1]
表 1 .
[0046] 表 1に示されるように、チォ硫酸ナトリウム、ェデト酸ニナトリウム及びホウ酸を組み 合わせることによって、優れた細菌増殖抑制効果が示された。
[0047] (2)試験例 2:チォ硫酸ナトリウムの配合量の検証
下記表 2の処方に従って、試験例 1と同様の方法により試験液を調製した後、保存 効力を評価した。ただし、菌液は Escherichia coliのみを用いた。結果を表 2の判 定の欄に示す。
[0048] [表 2]
表 2 .
[0049] 表 2より、チォ硫酸ナトリウムを 0. 05重量%以上配合し、ホウ酸、ェデト酸ナトリウム を組み合わせることによって、より高い細菌増殖抑制効果が得られることが示された。
[0050] (3)試験例 3 : pHの検証
眼科用組成物の一般的な pH範囲 (pH5〜8)における保存効力を評価した。下記 表 3の処方に従って、試験例 1と同様の方法に従って試験液を調製した後、保存効 力を評価した。ただし、菌液は Escherichia coliのみを用いた。結果を表 3の判定 の欄に示す。
[表 3]
表 3 .
[0052] 表 3に示されるように、眼科用組成物として一般的な pHの範囲において有効な保 存効力が確認された。
[0053] (4)試験例 4 :他の成分との効果の比較
本発明の保存剤と、防腐剤として配合されることが公知の化合物について保存効 力を評価した。下記表 4の処方に従って、試験例 1と同様の方法に従って試験液を 調製した後、保存効力を評価した。ただし、菌液として、 Escherichia coli (表中 EC )及び Pseudomonas aeruginosa (表中 PA)の他に、試験例 1に示される方法で調 製された Aspergillus niger (表中 AN)を用いた。結果を表 4の判定の欄に示す。
[0054] [表 4]
表 4 ·
表 4に示されるように、防腐剤として配合されることが公知の化合物に比べ、本発明 の保存剤は、 3種全ての菌に対して優れた保存効力を示した。
Claims
[1] (A)チォ硫酸塩、 (B)ェデト酸及び Z又はその塩、ならびに(C)ホウ酸及び Z又は その塩を含有する、保存剤。
[2] チォ硫酸塩が、チォ硫酸ナトリウムである、請求項 1に記載の保存剤。
[3] ェデト酸塩が、ェデト酸のナトリウム塩、カリウム塩及びカルシウム塩力 なる群より 選択される少なくとも 1種である、請求項 1に記載の保存剤。
[4] ホウ酸塩が、ホウ酸のナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩及び 亜鉛塩力もなる群より選択される少なくとも 1種である、請求項 1に記載の保存剤。
[5] チォ硫酸ナトリウム、ェデト酸ニナトリウム及びホウ酸を含有する保存剤。
[6] 請求項 1〜5のいずれかに記載の保存剤を含有する、眼科用組成物。
[7] (A)チォ硫酸ナトリウム、 (B)ェデト酸及び Z又はその塩、ならびに(C)ホウ酸及び
Z又はその塩を水系組成物に配合することを特徴とする、細菌増殖抑制方法。
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JP2006096132A JP2007269673A (ja) | 2006-03-30 | 2006-03-30 | 保存剤 |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010152088A (ja) * | 2008-12-25 | 2010-07-08 | Menicon Nect:Kk | コンタクトレンズ用組成物 |
JP2019059718A (ja) * | 2017-09-22 | 2019-04-18 | ロート製薬株式会社 | コンタクトレンズ用眼科組成物 |
Families Citing this family (1)
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FR2956671B1 (fr) | 2010-02-23 | 2012-03-30 | Ahlstroem Oy | Support a base de fibres cellulosiques contenant une couche de pva modifie - procede d'elaboration et utilisation |
Citations (4)
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---|---|---|---|---|
US4880601A (en) * | 1985-09-27 | 1989-11-14 | Laboratoires, P.O.S. | Hydrogen peroxide disinfecting system for contact lenses |
JPH04242649A (ja) * | 1990-12-28 | 1992-08-31 | Tome Sangyo Kk | 含水性カラーコンタクトレンズの消毒方法 |
JPH08133911A (ja) * | 1994-11-04 | 1996-05-28 | Senju Pharmaceut Co Ltd | 抗菌組成物 |
JP2001242427A (ja) * | 1999-12-21 | 2001-09-07 | Tanaka Kagaku Kenkyusho:Kk | コンタクトレンズ用洗浄剤 |
Family Cites Families (2)
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JP2004196671A (ja) * | 2002-12-16 | 2004-07-15 | Saga Seiyaku Kk | 水溶性アズレン含有点眼剤 |
JP2005002048A (ja) * | 2003-06-12 | 2005-01-06 | Saga Seiyaku Kk | 水溶性アズレン製剤 |
-
2006
- 2006-03-30 JP JP2006096132A patent/JP2007269673A/ja not_active Withdrawn
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2007
- 2007-03-29 WO PCT/JP2007/056978 patent/WO2007114300A1/ja active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4880601A (en) * | 1985-09-27 | 1989-11-14 | Laboratoires, P.O.S. | Hydrogen peroxide disinfecting system for contact lenses |
JPH04242649A (ja) * | 1990-12-28 | 1992-08-31 | Tome Sangyo Kk | 含水性カラーコンタクトレンズの消毒方法 |
JPH08133911A (ja) * | 1994-11-04 | 1996-05-28 | Senju Pharmaceut Co Ltd | 抗菌組成物 |
JP2001242427A (ja) * | 1999-12-21 | 2001-09-07 | Tanaka Kagaku Kenkyusho:Kk | コンタクトレンズ用洗浄剤 |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010152088A (ja) * | 2008-12-25 | 2010-07-08 | Menicon Nect:Kk | コンタクトレンズ用組成物 |
JP2019059718A (ja) * | 2017-09-22 | 2019-04-18 | ロート製薬株式会社 | コンタクトレンズ用眼科組成物 |
JP7195838B2 (ja) | 2017-09-22 | 2022-12-26 | ロート製薬株式会社 | コンタクトレンズ用眼科組成物 |
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