JP5478680B2 - Stabilizer for composition containing water-soluble polymer thickener - Google Patents
Stabilizer for composition containing water-soluble polymer thickener Download PDFInfo
- Publication number
- JP5478680B2 JP5478680B2 JP2012184559A JP2012184559A JP5478680B2 JP 5478680 B2 JP5478680 B2 JP 5478680B2 JP 2012184559 A JP2012184559 A JP 2012184559A JP 2012184559 A JP2012184559 A JP 2012184559A JP 5478680 B2 JP5478680 B2 JP 5478680B2
- Authority
- JP
- Japan
- Prior art keywords
- soluble polymer
- acid
- water
- stabilizer
- composition containing
- 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.)
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- 239000002562 thickening agent Substances 0.000 title claims description 64
- 239000000203 mixture Substances 0.000 title claims description 58
- 229920003169 water-soluble polymer Polymers 0.000 title claims description 44
- 239000003381 stabilizer Substances 0.000 title claims description 34
- 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 description 34
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 22
- 239000004327 boric acid Substances 0.000 claims description 22
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 claims description 21
- 229960001484 edetic acid Drugs 0.000 claims description 15
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 13
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 13
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 12
- 229940009662 edetate Drugs 0.000 claims description 12
- 229920001282 polysaccharide Polymers 0.000 claims description 11
- 239000005017 polysaccharide Substances 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 230000006641 stabilisation Effects 0.000 claims description 9
- 238000011105 stabilization Methods 0.000 claims description 9
- 229920002678 cellulose Polymers 0.000 claims description 8
- 239000001913 cellulose Substances 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 7
- 229920002472 Starch Polymers 0.000 claims description 6
- 235000019698 starch Nutrition 0.000 claims description 6
- 229920005613 synthetic organic polymer Polymers 0.000 claims description 6
- 229960002645 boric acid Drugs 0.000 claims description 4
- 150000004676 glycans Chemical class 0.000 claims 2
- 235000010338 boric acid Nutrition 0.000 description 18
- 235000002639 sodium chloride Nutrition 0.000 description 18
- 150000003839 salts Chemical class 0.000 description 16
- 239000004480 active ingredient Substances 0.000 description 11
- 239000007788 liquid Substances 0.000 description 9
- 238000002156 mixing Methods 0.000 description 9
- 150000004804 polysaccharides Chemical class 0.000 description 9
- 229920002451 polyvinyl alcohol Polymers 0.000 description 8
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 7
- -1 and for example Chemical class 0.000 description 7
- 239000003889 eye drop Substances 0.000 description 7
- 230000000087 stabilizing effect Effects 0.000 description 7
- 239000012085 test solution Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000004372 Polyvinyl alcohol Substances 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 229910021538 borax Inorganic materials 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 6
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 6
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 6
- 235000010339 sodium tetraborate Nutrition 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-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
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 4
- 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 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 229920003091 Methocel™ Polymers 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
- 239000000654 additive Substances 0.000 description 3
- 229920000615 alginic acid Polymers 0.000 description 3
- 235000010443 alginic acid Nutrition 0.000 description 3
- 239000000783 alginic acid Substances 0.000 description 3
- 229960001126 alginic acid Drugs 0.000 description 3
- 150000004781 alginic acids Chemical class 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 230000007423 decrease Effects 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
- 239000003814 drug Substances 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 229920002674 hyaluronan Polymers 0.000 description 3
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 229960003511 macrogol Drugs 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 235000017550 sodium carbonate Nutrition 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 3
- 229940042585 tocopherol acetate Drugs 0.000 description 3
- 229910001868 water Inorganic materials 0.000 description 3
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (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-carboxylic acid Chemical compound 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 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 2
- 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
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-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
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 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
- IMROMDMJAWUWLK-UHFFFAOYSA-N Ethenol Chemical compound OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- GLZPCOQZEFWAFX-UHFFFAOYSA-N Geraniol Chemical compound CC(C)=CCCC(C)=CCO GLZPCOQZEFWAFX-UHFFFAOYSA-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
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-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
- 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
- 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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229920002385 Sodium hyaluronate Polymers 0.000 description 2
- 229920002125 Sokalan® Polymers 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
- 235000011054 acetic acid Nutrition 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- POJWUDADGALRAB-UHFFFAOYSA-N allantoin Chemical compound NC(=O)NC1NC(=O)NC1=O POJWUDADGALRAB-UHFFFAOYSA-N 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 230000003078 antioxidant effect Effects 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
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 2
- 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
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 235000011148 calcium chloride Nutrition 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 229960004926 chlorobutanol Drugs 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 239000002826 coolant Substances 0.000 description 2
- 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
- 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 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 235000019800 disodium phosphate Nutrition 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- IFQUWYZCAGRUJN-UHFFFAOYSA-N ethylenediaminediacetic acid Chemical compound OC(=O)CNCCNCC(O)=O IFQUWYZCAGRUJN-UHFFFAOYSA-N 0.000 description 2
- 229940012356 eye drops Drugs 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 229960003160 hyaluronic acid Drugs 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000003589 local anesthetic agent Substances 0.000 description 2
- 239000004325 lysozyme Substances 0.000 description 2
- 235000010335 lysozyme Nutrition 0.000 description 2
- 229960000274 lysozyme Drugs 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- 229920000137 polyphosphoric acid Polymers 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229940010747 sodium hyaluronate Drugs 0.000 description 2
- 239000004328 sodium tetraborate Substances 0.000 description 2
- 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 2
- 239000005720 sucrose Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- BJORNXNYWNIWEY-UHFFFAOYSA-N tetrahydrozoline hydrochloride Chemical compound Cl.N1CCN=C1C1C2=CC=CC=C2CCC1 BJORNXNYWNIWEY-UHFFFAOYSA-N 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 1
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
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- 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
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Landscapes
- Compositions Of Macromolecular Compounds (AREA)
Description
本発明は、水溶性高分子増粘剤を含有する組成物を安定に保つことができる安定化剤に関する。 The present invention relates to a stabilizer capable of stably maintaining a composition containing a water-soluble polymer thickener.
ヒドロキシプロピルメチルセルロースやヒドロキシエチルセルロース、ポリビニルアルコール、ヒアルロン酸ナトリウム、アルギン酸及びその塩類、マクロゴール等の水溶性高分子増粘剤は、医薬組成物、食品等の様々な分野において汎用されている。しかしながら、この様な水溶性高分子増粘剤を含有する組成物を長期に亘って保存すると、共に配合されているホウ酸やホウ酸塩、酸化剤等によって加水分解が促進される等して、製品の粘度が低下することが知られている。また、長期間保存することで水溶性高分子増粘剤の変質がおこることもある。そのため、水溶性高分子増粘剤を含有する組成物を長期間保存すると、所期の粘度が得られなかったり、組成物が濁ったり、ｐＨが低下するといった問題があった。さらに、セルロース系高分子は、配合成分の影響により、少しの温度変化でも熱ゲル化を生じて濁ってしまうことがある。そこで、アルコール類を配合することによって粘度を安定化させる等の方法がとられたが、充分な効果は得られていない（例えば、特許文献１〜３を参照）。このような背景から、長期に亘って保存しても所期の粘度が保持され、組成物の濁りやｐＨ変動を抑制し得る、水溶性高分子増粘剤を含有する組成物の安定化剤が求められている。 Water-soluble polymer thickeners such as hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, sodium hyaluronate, alginic acid and salts thereof, and macrogol are widely used in various fields such as pharmaceutical compositions and foods. However, when a composition containing such a water-soluble polymer thickener is stored for a long period of time, hydrolysis is promoted by boric acid, borate, oxidizing agent, etc. blended together. It is known that the viscosity of the product decreases. In addition, the water-soluble polymer thickener may be altered by long-term storage. For this reason, when a composition containing a water-soluble polymer thickener is stored for a long period of time, the desired viscosity cannot be obtained, the composition becomes cloudy, and the pH decreases. Furthermore, the cellulosic polymer may become turbid due to thermal gelation even by a slight temperature change due to the influence of the blending components. Then, although the method of stabilizing a viscosity by mix | blending alcohol, etc. was taken, sufficient effect is not acquired (for example, refer patent documents 1-3). From such a background, a stabilizer for a composition containing a water-soluble polymer thickener that retains the desired viscosity even when stored for a long period of time and can suppress turbidity and pH fluctuation of the composition. Is required.
本発明は、水溶性高分子増粘剤を含有する組成物に対して優れた安定化作用を有し、長期間保存後も所期の粘度を保持し得る安定化剤を提供することを主な目的とする。 The present invention mainly provides a stabilizer that has an excellent stabilizing action on a composition containing a water-soluble polymer thickener and can maintain a desired viscosity even after long-term storage. With a purpose.
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、チオ硫酸塩が、水溶性高分子増粘剤を含有する組成物の保存による粘度及びｐＨの変動、ならびに濁りに対して優れた抑制作用を発揮することを見出した。チオ硫酸塩は、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、コンタクトレンズケア用品の中和剤等にも使用される安全性の高い成分の１つであるが、チオ硫酸塩自身が水溶性高分子増粘剤を含有する組成物の安定化作用を示すことは今まで知られていなかった。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。 As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that thiosulfate is excellent in viscosity and pH fluctuations and turbidity due to storage of a composition containing a water-soluble polymer thickener. It has been found that it exhibits an inhibitory action. Thiosulfate is widely used as an antioxidant for the purpose of improving the stability of unstable components, and is also one of the highly safe components used as a neutralizer for contact lens care products. However, it has not been known so far that thiosulfate itself exhibits a stabilizing action of a composition containing a water-soluble polymer thickener. The present invention has been completed by further research based on such knowledge.
本発明は、以下の水溶性高分子増粘剤を含有する組成物の安定化剤及び水溶性高分子増粘剤を含有する組成物の安定化方法を提供する。
項１．チオ硫酸塩に、エデト酸、エデト酸塩、ホウ酸及びホウ酸塩からなる群より選択される少なくとも１種を含む、水溶性高分子増粘剤を含有する組成物の安定化剤。
項２．チオ硫酸塩がチオ硫酸ナトリウムである、項１に記載の安定化剤。
項３．チオ硫酸ナトリウム、エデト酸二ナトリウム及びホウ酸を含む、項１または２に記載の安定化剤。
項４．チオ硫酸ナトリウム、ホウ酸及びホウ酸ナトリウムを含む、項１または２に記載の安定化剤。
項５．水溶性高分子増粘剤がセルロース系増粘剤、合成有機高分子化合物、多糖類、スターチ類及びアルコール系増粘剤からなる群より選択される少なくとも１種である、項１〜４のいずれかに記載の安定化剤。
項６．水溶性高分子増粘剤がセルロース系増粘剤、多糖類及びアルコール系増粘剤からなる群より選択される少なくとも１種である、項１〜４のいずれかに記載の安定化剤。
項７．水溶性高分子増粘剤を含有する組成物が眼科用組成物である、項１〜６のいずれかに記載の安定化剤。
項８．チオ硫酸塩、並びにエデト酸、エデト酸塩、ホウ酸及びホウ酸塩からなる群より選択される少なくとも１種を配合することを特徴とする、水溶性高分子増粘剤を含有する組成物の安定化方法。
項９．チオ硫酸ナトリウム、エデト酸二ナトリウム及びホウ酸を配合する、項９に記載する安定化方法。
項１０．水溶性高分子増粘剤がセルロース系増粘剤、合成有機高分子化合物、多糖類、スターチ類及びアルコール系増粘剤からなる群より選択される少なくとも１種である、項８または９に記載する安定化方法。
The present invention provides a stabilizer for a composition containing the following water-soluble polymer thickener and a method for stabilizing a composition containing the water-soluble polymer thickener.
Item 1. A stabilizer for a composition containing a water-soluble polymer thickener, wherein the thiosulfate contains at least one selected from the group consisting of edetic acid, edetate, boric acid and borate.
Item 2. Item 2. The stabilizer according to Item 1, wherein the thiosulfate is sodium thiosulfate.
Item 3. Item 3. The stabilizer according to Item 1 or 2, comprising sodium thiosulfate, disodium edetate and boric acid.
Item 4. Item 3. The stabilizer according to Item 1 or 2, comprising sodium thiosulfate, boric acid and sodium borate.
Item 5. Any one of Items 1-4, wherein the water-soluble polymer thickener is at least one selected from the group consisting of a cellulose-based thickener, a synthetic organic polymer compound, a polysaccharide, starches, and an alcohol-based thickener. The stabilizer according to crab.
Item 6. Item 5. The stabilizer according to any one of Items 1 to 4, wherein the water-soluble polymer thickener is at least one selected from the group consisting of a cellulose thickener, a polysaccharide, and an alcohol thickener.
Item 7. Item 7. The stabilizer according to any one of Items 1 to 6, wherein the composition containing the water-soluble polymer thickener is an ophthalmic composition.
Item 8. A composition containing a water-soluble polymer thickener, characterized in that it contains thiosulfate and at least one selected from the group consisting of edetic acid, edetate, boric acid and borate. Stabilization method.
Item 9. Item 10. The stabilization method according to Item 9, wherein sodium thiosulfate, disodium edetate and boric acid are blended.
Item 10. Item 10. The water-soluble polymer thickener is at least one selected from the group consisting of cellulose thickeners, synthetic organic polymer compounds, polysaccharides, starches, and alcohol thickeners. Stabilization method.
本発明の安定化剤は、水溶性高分子増粘剤を含有する組成物に対して優れた安定化作用を有し、従って、水溶性高分子増粘剤を含有する製品を長期に亘って保存した場合であっても、該増粘剤の変質等による製品の粘度の低下を抑制し、さらには製品のｐＨの変化や濁りを抑制することができる。また、本発明の安定化剤に含まれる有効成分は、いずれも人体（特に眼）に対する傷害性が低く、安全性の高いものである。 The stabilizer of the present invention has an excellent stabilizing action on a composition containing a water-soluble polymer thickener, and therefore a product containing a water-soluble polymer thickener can be used for a long time. Even when stored, it is possible to suppress a decrease in the viscosity of the product due to the alteration of the thickener, and further to suppress a change in the pH and turbidity of the product. In addition, any active ingredient contained in the stabilizer of the present invention has low safety against human body (particularly eyes) and high safety.
本発明の安定化剤及び水溶性高分子増粘剤を配合した眼科用組成物は、長期に亘って保存しても所期の粘度を保持することができ、さらに該組成物の濁りやｐＨの変化が抑制され、長期間品質が安定に保たれる。 The ophthalmic composition containing the stabilizer of the present invention and the water-soluble polymer thickener can maintain the desired viscosity even when stored for a long period of time, and further the turbidity and pH of the composition. Changes are suppressed, and the quality is kept stable for a long time.
さらに、本発明における水溶性高分子増粘剤を含有する組成物の安定化剤の有効成分であるチオ硫酸塩を配合することにより、水溶性高分子増粘剤を含有する様々な組成物の粘度安定性を高めることが可能である。 Furthermore, by blending thiosulfate which is an active ingredient of the stabilizer of the composition containing the water-soluble polymer thickener in the present invention, various compositions containing the water-soluble polymer thickener are added. It is possible to increase the viscosity stability.
本発明において水溶性高分子増粘剤を含有する組成物の安定化とは、長期間保存後であっても水溶性高分子増粘剤を含有する組成物の所期の粘度を保持し得ることを指す。 In the present invention, stabilization of a composition containing a water-soluble polymer thickener means that the intended viscosity of the composition containing the water-soluble polymer thickener can be maintained even after long-term storage. Refers to that.
具体的には、例えば、水溶性高分子増粘剤を０．３重量％配合した組成物を、５０℃にて１ヶ月保存した後の粘度を、Ｂ型粘度計であるデジタル粘度計（型名：ＤＶ−ＩＩ＋、ブルックフィールド社製）を用い、スピンドルはＵＬＡを用いて、回転数６〜３０ｒｐｍ、液温２５℃の条件で測定した結果を用いて下記の式に従って計算して得られた値が９０％程度以上、好ましくは９５％程度以上であることを指す。
[５０℃１ヶ月保存後の粘度]／[初期（保存前）の粘度]×１００％
Specifically, for example, a viscosity obtained by storing a composition containing 0.3% by weight of a water-soluble polymer thickener at 50 ° C. for 1 month is used as a digital viscometer (type (Name: DV-II +, manufactured by Brookfield), and the spindle was obtained by calculation according to the following formula using the results measured under the conditions of a rotation speed of 6 to 30 rpm and a liquid temperature of 25 ° C. using ULA. The value is about 90% or more, preferably about 95% or more.
[Viscosity after storage at 50 ° C for 1 month] / [Viscosity after initial storage (before storage)] x 100%
また、より好ましくは、常温（２５℃）での上記組成物のｐＨ変化が保存前の値の±１程度、好ましくは±０．５程度に抑えられることを指し、さらに好ましくは該組成物に濁りを生じないことを指す。 More preferably, it indicates that the pH change of the composition at room temperature (25 ° C.) can be suppressed to about ± 1, preferably about ± 0.5 of the value before storage, and more preferably to the composition. It refers to not producing turbidity.
以下、本発明に使用される各成分について説明する。 Hereinafter, each component used in the present invention will be described.
（１）水溶性高分子増粘剤を含有する組成物の安定化剤
本発明の水溶性高分子増粘剤を含有する組成物の安定化剤は、チオ硫酸塩を有効成分とする。本発明において使用されるチオ硫酸塩としては、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、チオ硫酸ナトリウム、チオ硫酸カリウム、チオ硫酸アンモニウム、等が挙げられる。本発明において使用されるチオ硫酸塩は、無水塩の形態であってもよく、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もよい。本発明においては、チオ硫酸ナトリウムであることが好ましい。
(1) Stabilizer of composition containing water-soluble polymer thickener The stabilizer of the composition containing the water-soluble polymer thickener of the present invention contains thiosulfate as an active ingredient. 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 may be in the form of an anhydrous salt, or 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, sodium thiosulfate is preferable.
本発明の安定化剤は、上記チオ硫酸塩からなるものであってもよく、さらにエデト酸及び／又はホウ酸を含んでいてもよい。 The stabilizer of the present invention may be composed of the above thiosulfate, and may further contain edetic acid and / or boric acid.
本発明において使用され得るエデト酸（エチレンジアミン四酢酸）は、エデト酸塩の形態であってもよく、エデト酸とエデト酸塩の混合物であってもよい。また、エデト酸塩は、無水物の形態でもよく、水和物の形態であってもよい。エデト酸塩としては、薬学的に許容される塩であれば特に限定されず、エ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。この様な塩としては、例えば、エデト酸二ナトリウム、エデト酸三ナトリウム、エデト酸四ナトリウム、エデト酸カルシウム、エデト酸カルシウム二ナトリウム、エデト酸二カリウム、エデト酸三カリウム、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、エデト酸のナトリウム塩（より好ましくはエデト酸二ナトリウム）、エデト酸カルシウムであることが好ましい。 The edetic acid (ethylenediaminetetraacetic acid) that can be used in the present invention may be in the form of an edetate or a mixture of edetic acid and edetate. The edetate may be in the form of an anhydride or a hydrate. The edetate is not particularly limited as long as it is a pharmaceutically acceptable salt, and sodium salt, potassium salt, calcium salt and the like of edetic acid can be used. Examples of such salts include disodium edetate, trisodium edetate, tetrasodium edetate, calcium edetate, disodium calcium edetate, dipotassium edetate, tripotassium edetate, and hydrates thereof. Is mentioned. 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.
本発明において使用され得るホウ酸は、ホウ酸塩の形態であってもよく、ホウ酸とホウ酸塩の混合物であってもよい。また、ホウ酸塩は、無水物の形態でもよく、水和物の形態であってもよい。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（ホウ砂）、ホウ酸カルシウム、ホウ酸マグネシウム、ホウ酸カリウム、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、ホウ酸ナトリウム（ホウ砂）であることが好ましい。 The boric acid that can be used in the present invention may be in the form of borate or a mixture of boric acid and borate. The borate may be in the form of an anhydride or a hydrate. The borate is not particularly limited as long as it is a pharmaceutically acceptable salt, and for example, sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt and the like of boric acid can be used. Examples of such salts include sodium borate (borax), calcium borate, magnesium borate, potassium borate, zinc borate, and hydrates thereof. These salts can be used alone or in combination of two or more. In the present invention, boric acid and sodium borate (borax) are preferable.
本発明における上記有効成分の好ましい組み合わせとしては、例えば、チオ硫酸ナトリウム、エデト酸のナトリウム塩（より好ましくはエデト酸二ナトリウム）及びホウ酸；チオ硫酸ナトリウム及びホウ酸（又はホウ酸とホウ酸ナトリウムの混合物）が挙げられる。 Preferred combinations of the above active ingredients in the present invention include, for example, sodium thiosulfate, sodium salt of edetic acid (more preferably disodium edetate) and boric acid; sodium thiosulfate and boric acid (or boric acid and sodium borate) For example).
また、本発明の安定化剤には、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調整剤等の添加剤を添加してもよい。以下、各添加剤の例を挙げるが、本発明において使用される各種添加剤は、これらに限定されない。 Further, the stabilizer of the present invention includes conventionally known active ingredients, isotonic agents, inorganic salts, buffers, thickeners, saccharides, in addition to the above active ingredients, as long as the effects of the present invention are not impaired. , Surfactants, solubilizers, cleaning ingredients, chelating agents, antioxidants, cooling agents, fragrances, local anesthetics, preservatives, pH adjusters, and the like may be added. Hereinafter, although the example of each additive is given, the various additives used in this invention are not limited to these.
他の活性成分としては、例えば、エピネフリン、塩酸エピネフリン、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、塩酸フェニレフリン、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、塩化ベルベリン、硫酸ベルベリン、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ニウム、グリチルレチン酸、サリチル酸メチル、トラネキサム酸、ア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；塩酸イプロヘプチン、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ェニラミン等の抗ヒスタミン剤；フラビンアデニンジヌクレオチドナトリウム、塩酸ピリドキシン、シアノコバラミン、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（酢酸トコフェロール（例えば、酢酸ｄ−α−トコフェロール）等の脂溶性ビタミン類；Ｌ−アスパラギン酸カリウム、Ｌ−ア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ェノール、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、塩化ナトリウム、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、硫酸マグネシウム、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。 Examples of other active ingredients include decongestants such as epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, nafazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine hydrochloride; Extinguishing and converging of acids, allantoin, berberine chloride, berberine sulfate, zinc sulfate, zinc lactate, lysozyme chloride, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, glycyrrhetinic acid, methyl salicylate, tranexamic acid, sodium azulenesulfonate, sodium cromoglycate Agents: antihistaminics such as iproheptin hydrochloride, diphenhydramine hydrochloride, diphenhydramine, isothipentyl hydrochloride, chlorpheniramine maleate Agents; water-soluble vitamins such as sodium flavin adenine dinucleotide, pyridoxine hydrochloride, cyanocobalamin, panthenol, calcium pantothenate, sodium pantothenate; vitamins A (for example, retinol acetate, retinol palmitate), vitamin E (tocopherol acetate ( For example, fat-soluble vitamins such as d-α-tocopherol acetate); amino acids such as potassium L-aspartate, magnesium L-aspartate, aminoethylsulfonic acid, sodium chondroitin sulfate; sulfamethoxazole, sulfamethoxy Sulfur agents such as sodium solazole, sulfisoxazole, sodium sulfisomidine, isopropylmethylphenol, hinokitiol; potassium chloride, calcium chloride, sodium chloride, carbonated water Sodium, sodium carbonate, dried sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, and inorganic salts such as potassium dihydrogen phosphate and the like.
上記の活性成分は、その１種を単独で併用してもよく、２種以上を組み合わせて併用してもよい。 One of these active ingredients may be used alone, or two or more thereof may be used in combination.
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（ブトウ糖，ソルビトールなど）等が挙げられる。 Examples of tonicity agents include polyhydric alcohols such as glycerin and propylene glycol, and sugars (such as butter sugar and sorbitol).
無機塩類としては、塩化ナトリウム、塩化カリウム、炭酸ナトリウム、炭酸水素ナトリウム、塩化カルシウム、硫酸マグネシウム、リン酸水素ナトリウム、リン酸水素二ナトリウム、リン酸水素二カリウム、チオ硫酸ナトリウム、酢酸ナトリウム等が挙げられる。 Examples of inorganic salts include sodium chloride, potassium chloride, sodium carbonate, sodium hydrogen carbonate, calcium chloride, magnesium sulfate, sodium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium thiosulfate, sodium acetate and the like. It is done.
緩衝剤として、ホウ酸緩衝剤、リン酸緩衝剤、炭酸緩衝剤、クエン酸緩衝剤、酢酸緩衝剤等が挙げられる。 Examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, and acetate buffer.
増粘剤として、アラビアゴム、カラヤガム、キサンタンガム、カゼイン、寒天、アルギン酸、α−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、コラーゲン、ペクチン、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、ヘパリン、ヘパリノイド、ヘパリン硫酸、ヘパラン硫酸、ヒアルロン酸、メチルセルロース、ヒドロキシエ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、ポリビニルメタアクリレート、ポリビニルアルコール、ポリアクリル酸、カルボキシビニルポリマー、ポリエチレンイミン等が挙げられる。 As thickeners, gum arabic, karaya gum, xanthan gum, casein, agar, alginic acid, α-cyclodextrin, dextrin, dextran, carrageenan, gelatin, collagen, pectin, starch, chitin and derivatives thereof, chitosan and derivatives thereof, elastin, heparin , Heparinoids, heparin sulfate, heparan sulfate, hyaluronic acid, methylcellulose, hydroxyethylcellulose and other polysaccharides or derivatives thereof, ceramide, macrogol, glycerin, popidone, polyvinyl methacrylate, polyvinyl alcohol, polyacrylic acid, carboxyvinyl polymer, polyethyleneimine Etc.
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、アラビノース、キシロース、リキソース、デオキシリボース、マルトース、トレハロース、スクロース、セロビオース、ラクトース、プルラン、ラクツロース、ラフィノース、マル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。 Glucose, fructose, galactose, mannose, ribose, ribulose, arabinose, xylose, lyxose, deoxyribose, maltose, trehalose, sucrose, cellobiose, lactose, pullulan, lactulose, raffinose, maltitol, etc. and their pharmaceutically acceptable Salts to be used.
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オ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。 As surfactant, higher fatty acid ester such as polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan higher fatty acid ester such as polysorbate 80 and polyoxyethylene sorbine monooleate, sucrose fatty acid ester, polyoxyethylene polyoxypropylene block copolymer And nonionic surfactants.
キレート剤として、エデト酸（エチレンジアミン四酢酸，ＥＤＴＡ）、エチレンジアミン二酢酸（ＥＤＤＡ）酒石酸、リン酸類（ポリリン酸、ヘキサメタリン酸、メタリン酸）、コハク酸などが挙げられる。 Examples of chelating agents include edetic acid (ethylenediaminetetraacetic acid, EDTA), ethylenediaminediacetic acid (EDDA) tartaric acid, phosphoric acids (polyphosphoric acid, hexametaphosphoric acid, metaphosphoric acid), and succinic acid.
抗酸化剤として、ジブチルヒドロキシトルエン（ＢＨＴ）、酢酸トコフェロール、ア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。 Examples of the antioxidant include dibutylhydroxytoluene (BHT), tocopherol acetate, magnesium ascorbate phosphate, and the like.
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、ペパーミント油、ベルガモット油、ゲラニオール等が挙げられる。 Examples of the fragrance (cooling agent) include menthol, camphor, borneol, eucalyptus oil, peppermint oil, bergamot oil, geraniol and the like.
局所麻酔剤としては、クロロブタノール等が挙げられる。 Examples of the local anesthetic include chlorobutanol.
防腐剤としては、パラオキシ安息香酸エステル、アクリノール、塩化ベンザルコニウム、塩化ベンゼトニウム、塩化セチルピリジニウム、クロルヘキシジン、ポリヘキサメチレンビグアニド、アルキルポリアミノエチルグリシン、グルコン酸クロルヘキシジン、ベンジルアルコール、フェネチルアルコール、クロロブタノール、イソプロパノール、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、塩化ポリドロニウム、塩酸ヘキサニド等が挙げられる。 Preservatives include paraoxybenzoate, acrinol, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, chlorhexidine, polyhexamethylene biguanide, alkylpolyaminoethylglycine, chlorhexidine gluconate, benzyl alcohol, phenethyl alcohol, chlorobutanol, isopropanol Ethanol, thimerosal, lysozyme, sorbic acid, potassium sorbate, hydrogen peroxide, polydronium chloride, hexanide hydrochloride and the like.
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、シュウ酸、グルコン酸、フマル酸、プロピオン酸、酢酸、アスパラギン酸、イプシロン−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）、グルコノラクトン、酢酸アンモニウム、無機塩基（炭酸水素ナトリウム、炭酸ナトリウム、水酸化カリウム、水酸化ナトリウム、水酸化カルシウム、水酸化マグネシウムなど）等が挙げられる。 As pH adjusters, 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, gluconic acid, fumaric acid, propionic acid) , Acetic acid, aspartic acid, epsilon-aminocaproic acid, glutamic acid, aminoethylsulfonic acid, etc.), gluconolactone, ammonium acetate, inorganic base (sodium bicarbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, calcium hydroxide, water) Magnesium oxide, etc.).
本発明の安定化剤の有効成分としてチオ硫酸塩を単独で使用する場合は、水溶性高分子増粘剤を含有する組成物の１００重量部に対してチオ硫酸塩を０．００１〜１０重量部程度、好ましくは０．００５〜５重量部程度、より好ましくは０．０１〜３重量部程度、さらに好ましくは０．１〜１重量部程度含有する。あるいは、水溶性高分子増粘剤を含有する組成物の１００重量部に対してチオ硫酸塩を０．１５〜１０重量部程度、好ましくは０．１５〜５重量部程度、より好ましくは０．１５〜３重量部程度、さらに好ましくは０．１５〜１重量部程度含有する。 When thiosulfate is used alone as an active ingredient of the stabilizer of the present invention, 0.001 to 10 weight of thiosulfate is added to 100 weight parts of the composition containing a water-soluble polymer thickener. About 0.15 parts by weight, preferably about 0.005 to 5 parts by weight, more preferably about 0.01 to 3 parts by weight, and still more preferably about 0.1 to 1 part by weight. Alternatively, the thiosulfate is about 0.15 to 10 parts by weight, preferably about 0.15 to 5 parts by weight, and more preferably about 0.1 to 5 parts by weight with respect to 100 parts by weight of the composition containing the water-soluble polymer thickener. About 15 to 3 parts by weight, more preferably about 0.15 to 1 part by weight is contained.
本発明の安定化剤の有効成分としてチオ硫酸塩とエデト酸を併用する場合は、上記エデト酸及び／又はエデト酸塩を、チオ硫酸塩１重量に対して、０．０００１〜１０００重量部、好ましくは０．００１〜１００重量部、より好ましくは０．００１〜１０重量部配合することが望ましい。 When thiosulfate and edetic acid are used in combination as an active ingredient of the stabilizer of the present invention, the above edetic acid and / or edetate is 0.0001 to 1000 parts by weight with respect to 1 weight of thiosulfate, Preferably 0.001 to 100 parts by weight, more preferably 0.001 to 10 parts by weight is blended.
また、本発明の安定化剤の有効成分としてチオ硫酸塩とホウ酸を併用する場合は、上記ホウ酸及び／又はホウ酸塩を、チオ硫酸塩１重量に対して、０．００１〜５０００重量部、好ましくは０．０２〜６００重量部、より好ましくは０．１〜２００重量部配合することが望ましい。 Moreover, when using together thiosulfate and boric acid as an active ingredient of the stabilizer of this invention, the said boric acid and / or borate are 0.001-5000 weight with respect to 1 weight of thiosulfate. Parts, preferably 0.02 to 600 parts by weight, more preferably 0.1 to 200 parts by weight.
上記範囲内であれば、ホウ酸やホウ酸塩を配合した系においても水溶性高分子増粘剤を含有する組成物の安定化作用に優れ、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いため好ましい。 Within the above range, even in a system containing boric acid or borate, the composition containing the water-soluble polymer thickener is excellent in stabilizing action, and the osmotic pressure does not become too high. Even when applied to an object or the like, it is preferable because it does not cause eye irritation.
本発明の安定化剤は、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。 The stabilizer of the present invention can act effectively under a pH of about 5 to 8, preferably about 6 to 7.
本発明の安定化剤は、水溶性高分子増粘剤を含有する組成物に対して優れた粘度安定化作用を発揮することができる。本発明における水溶性高分子増粘剤としては、例えば、セルロース系増粘剤、合成有機高分子化合物、多糖類、スターチ類、アルコール系増粘剤等が挙げられ、好ましくはセルロース系増粘剤、多糖類、アルコール系増粘剤である。 The stabilizer of this invention can exhibit the outstanding viscosity stabilization effect | action with respect to the composition containing a water-soluble polymer thickener. Examples of the water-soluble polymer thickener in the present invention include cellulose thickeners, synthetic organic polymer compounds, polysaccharides, starches, alcohol thickeners, and the like, preferably cellulose thickeners. , Polysaccharides, alcohol thickeners.
セルロース系増粘剤としては、例えば、ヒドロキシプロピルメチルセルロース、ヒドロキシメチルセルロース、ヒドロキシプロピルセルロース、メチルセルロース、ヒドロキシエチルセルロース、カルボキシメチルセルロース、またはこれらの塩等が挙げられる。また、商業的に入手できる増粘剤を用いてもよい。商業的に入手できるものとして、例えば、ＨＰＭＣ２９１０、ＨＰＭＣ２９０６及びＨＰＭＣ２２０８（信越化学工業（株）製のメトローズ６０ＳＨ−１５、６０ＳＨ−５０、６０ＳＨ−４０００、６０ＳＨ−１００００、メトローズ６５ＳＨ−５０、６５ＳＨ−４００、６５ＳＨ−１５００、６５ＳＨ−４０００、メトローズ９０ＳＨ−１００、９０ＳＨ−４００，９０ＳＨ−４０００、ＴＣ−５等）；メトセルシリーズ（ダウ・ケミカル日本株式会社製のメトセルＥ、メトセルＦ、メトセルＫ等）；マーポローズ（松本油脂製薬株式会社製のマーポローズ６０ＭＰ、マーポローズ６５ＭＰ、マーポローズ９０ＭＰ等；ＨＥＣ（ダイセル化学工業（株）製のダイセルＨＥＣ８５０ＳＥ、９００ＳＥ等）；ＰＶＡ（日本合成化学（株）製のゴーセノールＥＧ−４０、ＥＧ−０５等）が挙げられる。 Examples of the cellulose-based thickener include hydroxypropylmethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, or salts thereof. Commercially available thickeners may also be used. As commercially available products, for example, HPMC2910, HPMC2906, and HPMC2208 (Metroze 60SH-15, 60SH-50, 60SH-4000, 60SH-10000, Metrows 65SH-50, 65SH-400, manufactured by Shin-Etsu Chemical Co., Ltd.) 65SH-1500, 65SH-4000, Metroles 90SH-100, 90SH-400, 90SH-4000, TC-5, etc.); Methocel series (Metcell E, Methocel F, Methocel K, etc. manufactured by Dow Chemical Japan Co., Ltd.); Marporose (Matsumoto Yushi Seiyaku Co., Ltd. Marporose 60MP, Marporose 65MP, Marporose 90MP, etc.); HEC (Daicel Chemical Industries, Ltd. Daicel HEC850SE, 900SE, etc.); PVA (Nippon Synthetic Chemical Co., Ltd.) Senoru EG-40, EG-05, etc.).
合成有機高分子化合物やアルコール系増粘剤としては、ポリビニルアルコール、ポリ−Ｎ−ビニルピロリドン、ポリエチレングリコール、マクロゴール、ポリプロピレングリコール、ポリアクリルアミド等が挙げられる。多糖類としては、ヒアルロン酸やコンドロイチン硫酸、アルギン酸またはこれらの塩等が挙げられる。 Examples of the synthetic organic polymer compound and alcohol thickener include polyvinyl alcohol, poly-N-vinyl pyrrolidone, polyethylene glycol, macrogol, polypropylene glycol, polyacrylamide and the like. Examples of the polysaccharide include hyaluronic acid, chondroitin sulfate, alginic acid, and salts thereof.
本発明では水溶性高分子増粘剤として、上記化合物を１種単独で、又は２種以上を組み合わせて使用することができる。 In this invention, the said compound can be used individually by 1 type or in combination of 2 or more types as a water-soluble polymer thickener.
本発明における水溶性高分子増粘剤を含有する組成物中には、上記の水溶性高分子増粘剤が０．００１〜２０重量％程度、好ましくは０．００５〜１８重量％程度、より好ましくは０．０１〜１５重量％程度、さらに好ましくは０．１〜５重量％程度含まれる。このような組成物としては、水系組成物が挙げられ、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、食品等が挙げられる。なかでも好ましくは、医薬品であり、特に眼科用組成物である。 In the composition containing the water-soluble polymer thickener in the present invention, the above-mentioned water-soluble polymer thickener is about 0.001 to 20 wt%, preferably about 0.005 to 18 wt%. Preferably about 0.01 to 15% by weight, more preferably about 0.1 to 5% by weight. Examples of such a composition include an aqueous composition, which is a composition containing water, and includes solutions, suspensions, pasty and semi-paste pharmaceuticals, quasi drugs, foods, and the like. Of these, pharmaceuticals are preferable, and ophthalmic compositions are particularly preferable.
本発明の安定化剤は、例えばＨＰＭＣ２９１０（信越化学工業（株）製のメトローズ６０ＳＨ−４０００等）、ＨＰＭＣ２９０６（信越化学工業（株）製のメトローズ６５ＳＨ−１５００、６５ＳＨ−４０００等）、ＨＰＭＣ２２０８（信越化学工業（株）製のメトローズ９０ＳＨ−４０００等）、ＨＥＣ（ダイセル化学工業（株）製のダイセルＨＥＣ８５０ＳＥ、９００ＳＥ等）、ＰＶＡ（日本合成化学（株）製のゴーセノールＥＧ−４０、ＥＧ−０５等）、ヒアルロン酸ナトリウムを含有する組成物に対して極めて優れた安定化作用を発揮することができる。 Examples of the stabilizer of the present invention include HPMC 2910 (Metrozu 60SH-4000, manufactured by Shin-Etsu Chemical Co., Ltd.), HPMC 2906 (Metrozu 65SH-1500, 65SH-4000, etc., manufactured by Shin-Etsu Chemical Co., Ltd.), HPMC 2208 (Shin-Etsu). Chemicals Co., Ltd. Metroise 90SH-4000, etc.), HEC (Daicel Chemical Industries, Ltd. Daicel HEC850SE, 900SE, etc.), PVA (Nippon Synthetic Chemical Co., Ltd. Gohsenol EG-40, EG-05, etc.) ), An extremely excellent stabilizing action can be exerted on a composition containing sodium hyaluronate.
（２）眼科用組成物
上記（１）に記載する本発明の安定化剤を、水溶性高分子増粘剤を含有する眼科用組成物に配合させることにより、長期にわたる保存でも該眼科用組成物の所期の粘度を保持し、濁りの発生やｐＨの変動を抑制することができる。また、本発明の安定化剤は、コンタクトレンズに吸着することがなく、コンタクトレンズの変質を引き起こすこともないため、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。コンタクトレンズ用の眼科用組成物とは、コンタクトレンズを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まれる。
(2) Ophthalmic composition By blending the stabilizer of the present invention described in (1) above with an ophthalmic composition containing a water-soluble polymer thickener, the ophthalmic composition can be stored even for a long period of time. The desired viscosity of the object can be maintained, and the occurrence of turbidity and pH fluctuation can be suppressed. Moreover, since the stabilizer of the present invention does not adsorb to contact lenses and does not cause deterioration of contact lenses, it can also be applied to ophthalmic compositions for contact lenses. The ophthalmic composition for contact lenses includes eye drops used when wearing contact lenses, and includes contact lens agents described below.
従って、本発明は、前述の安定化剤を含有する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前記安定化剤の配合量は、本発明の効果を奏する範囲において適宜調整され得るが、例えば、チオ硫酸塩の配合量は０．００１〜１０重量％程度、好ましくは０．００５〜５重量％程度、より好ましくは０．０１〜３重量％程度である。あるいは、０．１５〜１０重量％程度、好ましくは０．１５〜５重量％程度、より好ましくは０．１５〜３重量％程度である。 Accordingly, the present invention also provides an ophthalmic composition containing the aforementioned stabilizer. The blending amount of the stabilizer in the ophthalmic composition of the present invention can be appropriately adjusted within the range where the effects of the present invention are exhibited. For example, the blending amount of thiosulfate is about 0.001 to 10% by weight, preferably Is about 0.005 to 5% by weight, more preferably about 0.01 to 3% by weight. Alternatively, it is about 0.15 to 10% by weight, preferably about 0.15 to 5% by weight, more preferably about 0.15 to 3% by weight.
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く、浸透圧比は、１付近に設定することが望ましい。 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 is desirably set to around 1.
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。 As the ophthalmic composition of the present invention, an eye drop that can be instilled even when it is worn with an aqueous eye drop, a non-aqueous eye drop, a suspension eye drop, an emulsion eye drop, a soft contact lens, a hard contact lens, etc. Eye drops; eye ointments; eye wash; contact lens preparations such as contact lens mounting liquid, cleaning liquid, preservative liquid, and bactericidal liquid.
（３）粘度安定化方法
上記（１）に記載される成分を配合することによって、水溶性高分子増粘剤を含有する組成物の粘度安定性を高めることができ、加えて、該組成物におけるｐＨの変動抑制及び濁りの発生を抑制することもできる。各成分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。
(3) Viscosity stabilization method By blending the components described in (1) above, the viscosity stability of the composition containing the water-soluble polymer thickener can be increased, and in addition, the composition It is also possible to suppress the fluctuation of pH and the occurrence of turbidity. The blending amount and blending ratio of each component can be appropriately adjusted according to the range described in (1) above.
以下、実施例及び比較例を挙げて本発明をさらに詳細に説明するが、本発明はこれらに限定されない。 EXAMPLES Hereinafter, although an Example and a comparative example are given and this invention is demonstrated further in detail, this invention is not limited to these.
（１）試験例１：安定性試験
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１００ｍＬとして試験液を調製し、これを滅菌濾過した。各試験液を５０℃にて１ヶ月保存し、以下の基準に従って、粘度安定性、ｐＨ変動及び濁りの発生を判断した。結果を下記表１に示す。
(1) Test Example 1: Stability test According to the formulation shown in Table 1 below, each component was dissolved in purified water to prepare a test solution with a total volume of 100 mL, and this was sterile filtered. Each test solution was stored at 50 ° C. for 1 month, and viscosity stability, pH fluctuation, and occurrence of turbidity were judged according to the following criteria. The results are shown in Table 1 below.
＜粘度安定性判定基準＞
粘度の測定は、Ｂ型粘度計であるデジタル粘度計（型名：ＤＶ−ＩＩ＋、ブルックフィールド社製）を用い、スピンドルはＵＬＡを用いて、回転数６〜３０ｒｐｍ、液温２５℃の条件で行った。粘度安定性は、下記式で求めた値を用いて判断した。
[５０℃１ヶ月保存後の粘度]／[初期（保存前）の粘度]×１００％
○：５０℃１ヶ月保存後の粘度が初期値（保存前粘度）の９０％以上
×：５０℃１ヶ月保存後の粘度が初期値（保存前粘度）の９０％未満
<Viscosity stability criteria>
The viscosity is measured using a digital viscometer (model name: DV-II +, manufactured by Brookfield), which is a B-type viscometer, the spindle is using ULA, the rotation speed is 6 to 30 rpm, and the liquid temperature is 25 ° C. went. Viscosity stability was judged using the value obtained by the following formula.
[Viscosity after storage at 50 ° C for 1 month] / [Viscosity after initial storage (before storage)] x 100%
○: The viscosity after storage at 50 ° C. for 1 month is 90% or more of the initial value (viscosity before storage) ×: The viscosity after storage at 50 ° C. for 1 month is less than 90% of the initial value (viscosity before storage)
＜濁りの有無判定基準＞
目視にて濁りの有無を確認した。
○：５０℃１ヶ月保存後の試験液で濁りなし
×：５０℃１ヶ月保存後の試験液で濁りあり
<Judgment criteria for turbidity>
The presence or absence of turbidity was confirmed visually.
○: No turbidity in test solution after storage at 50 ° C for 1 month ×: Turbidity in test solution after storage at 50 ° C for 1 month
＜ｐＨ安定性判断基準＞
ｐＨ安定性は、下記式で求めた値を用いて判断した。
[５０℃１ヶ月保存後のpＨ]−[初期（保存前）のpＨ]
○：５０℃１ヶ月保存後のｐＨと初期値（保存前ｐＨ）の差が±１
×：５０℃１ヶ月保存後のｐＨと初期値（保存前ｐＨ）の差が１より大きいか−１未満
<Criteria for pH stability>
The pH stability was judged using the value obtained by the following formula.
[PH after storage at 50 ° C for one month]-[pH of initial (before storage)]
○: The difference between the pH after 1 month storage at 50 ° C. and the initial value (pH before storage) is ± 1
X: Difference between pH after storage at 50 ° C. for 1 month and initial value (pH before storage) is greater than 1 or less than −1
※表中ＨＰＭＣ２９１０は、信越化学工業株式会社製メトローズ６０ＳＨ−４０００である。
※表中の添加成分配合量の単位は、ｇ／１００ｍＬである。
* HPMC2910 in the table is Metroze 60SH-4000 manufactured by Shin-Etsu Chemical Co., Ltd.
* The unit of the additive component content in the table is g / 100 mL.
表１より、チオ硫酸ナトリウムを配合した試験液は、粘度安定性が高く、長期間保存しても濁りを生じることがなく、またｐＨの大幅な変動を引き起こすこともないことが示された。 From Table 1, it was shown that the test solution containing sodium thiosulfate had high viscosity stability, did not cause turbidity even when stored for a long time, and did not cause a significant change in pH.
（２）試験例２：水溶性高分子増粘剤の種類の検証
下記表２の処方に従い、各成分を精製水に溶解させて全量を１００ｍＬとして試験液を調製し、これを滅菌濾過した。各試験液を５０℃にて２週間保存し、以下の基準に従って、粘度安定性を判断した。結果を下記表２に示す。
(2) Test Example 2: Verification of Type of Water-Soluble Polymer Thickener According to the formulation in Table 2 below, each component was dissolved in purified water to prepare a test solution with a total volume of 100 mL, and this was sterile filtered. Each test solution was stored at 50 ° C. for 2 weeks, and the viscosity stability was judged according to the following criteria. The results are shown in Table 2 below.
＜粘度安定性判定基準＞
粘度安定性は、下記式で求めた値を用いて判断した。
<Viscosity stability criteria>
Viscosity stability was judged using the value obtained by the following formula.
[５０℃２週間保存後の粘度]／[初期（保存前）の粘度]×１００％
○：５０℃２週間保存後の粘度が初期値（保存前粘度）の９０％以上
×：５０℃２週間保存後の粘度が初期値（保存前粘度）の９０％未満
粘度の測定は、Ｂ型粘度計であるデジタル粘度計（型名：ＤＶ−ＩＩ＋、ブルックフィールド社製）を用い、スピンドルはＵＬＡを用いて、回転数６〜３０ｒｐｍ、液温２５℃の条件で行った。
[Viscosity after storage at 50 ° C for 2 weeks] / [Initial (before storage) viscosity] x 100%
○: The viscosity after storage at 50 ° C. for 2 weeks is 90% or more of the initial value (viscosity before storage) ×: The viscosity after storage at 50 ° C. for 2 weeks is less than 90% of the initial value (viscosity before storage). A digital viscometer (model name: DV-II +, manufactured by Brookfield Co., Ltd.), which is a type viscometer, was used, and the spindle was used under the conditions of a rotation speed of 6 to 30 rpm and a liquid temperature of 25 ° C. using ULA.
※表中ＨＰＭＣ２９１０は、信越化学工業株式会社製メトローズ６０ＳＨ−４０００、ＨＰＭＣ２２０８は、信越化学工業株式会社製メトローズ９０ＳＨ−４０００、ＨＥＣはダイセル化学工業（株）製のダイセルＨＥＣ８５０ＳＥ、ＰＶＡは日本合成化学（株）製のゴーセノールＥＧ−０５である。
※表中の各成分の配合量の単位は、ｇ／１００ｍＬである。
* In the table, HPMC2910 is Shin-Etsu Chemical Co., Ltd. Metroles 60SH-4000, HPMC2208 is Shin-Etsu Chemical Co., Ltd. Metroze 90SH-4000, HEC is Daicel Chemical Industries, Ltd. Daicel HEC850SE, PVA is Nippon Synthetic Chemical ( It is Gohsenol EG-05 made by Co., Ltd.
* The unit of the amount of each component in the table is g / 100 mL.
表２より、各種水溶性高分子増粘剤を配合した試験液において、チオ硫酸ナトリウムを配合した試験液は粘度安定性が高いことが示された。 From Table 2, it was shown that the test liquid containing sodium thiosulfate had high viscosity stability in the test liquid containing various water-soluble polymer thickeners.
上記表１及び表２に示される結果より、多糖類であるＨＰＭＣやＨＥＣに対する本発明の安定化剤の効果が確認されたことから、同じく多糖類であるヒアルロン酸類等のムコ多糖類に対しても同様の効果が得られると予想される。 From the results shown in Tables 1 and 2 above, the effect of the stabilizer of the present invention on HPMC and HEC, which are polysaccharides, was confirmed, and thus against mucopolysaccharides such as hyaluronic acids, which are also polysaccharides. Is expected to have the same effect.
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