JP2022179821A - ophthalmic composition - Google Patents
ophthalmic composition Download PDFInfo
- Publication number
- JP2022179821A JP2022179821A JP2021185055A JP2021185055A JP2022179821A JP 2022179821 A JP2022179821 A JP 2022179821A JP 2021185055 A JP2021185055 A JP 2021185055A JP 2021185055 A JP2021185055 A JP 2021185055A JP 2022179821 A JP2022179821 A JP 2022179821A
- Authority
- JP
- Japan
- Prior art keywords
- salts
- ophthalmic composition
- salt
- component
- content
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 186
- 150000003839 salts Chemical class 0.000 claims abstract description 205
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 57
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 36
- 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 30
- 229960002362 neostigmine Drugs 0.000 claims abstract description 27
- LULNWZDBKTWDGK-UHFFFAOYSA-M neostigmine bromide Chemical compound [Br-].CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 LULNWZDBKTWDGK-UHFFFAOYSA-M 0.000 claims abstract description 27
- 229920001287 Chondroitin sulfate Polymers 0.000 claims abstract description 25
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 claims abstract description 23
- 229940059329 chondroitin sulfate Drugs 0.000 claims abstract description 23
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000004327 boric acid Substances 0.000 claims abstract description 22
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 18
- 239000000739 antihistaminic agent Substances 0.000 claims abstract description 18
- 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 claims description 66
- 229960002104 cyanocobalamin Drugs 0.000 claims description 33
- 235000000639 cyanocobalamin Nutrition 0.000 claims description 33
- 239000011666 cyanocobalamin Substances 0.000 claims description 33
- BYJAVTDNIXVSPW-UHFFFAOYSA-N tetryzoline Chemical compound N1CCN=C1C1C2=CC=CC=C2CCC1 BYJAVTDNIXVSPW-UHFFFAOYSA-N 0.000 claims description 26
- 229960003291 chlorphenamine Drugs 0.000 claims description 14
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 claims description 14
- 229960000337 tetryzoline Drugs 0.000 claims description 14
- CNIIGCLFLJGOGP-UHFFFAOYSA-N 2-(1-naphthalenylmethyl)-4,5-dihydro-1H-imidazole Chemical compound C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 CNIIGCLFLJGOGP-UHFFFAOYSA-N 0.000 claims description 13
- 229960005016 naphazoline Drugs 0.000 claims description 12
- 229940125715 antihistaminic agent Drugs 0.000 claims description 8
- 150000002462 imidazolines Chemical class 0.000 claims description 4
- -1 imidazoline compound Chemical class 0.000 abstract description 58
- 229960001484 edetic acid Drugs 0.000 abstract description 15
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 abstract description 10
- 230000001387 anti-histamine Effects 0.000 abstract description 10
- 235000002639 sodium chloride Nutrition 0.000 description 191
- 239000012085 test solution Substances 0.000 description 55
- 238000009472 formulation Methods 0.000 description 34
- 230000000694 effects Effects 0.000 description 32
- KXKPYJOVDUMHGS-OSRGNVMNSA-N chondroitin sulfate Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](OS(O)(=O)=O)[C@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](C(O)=O)O1 KXKPYJOVDUMHGS-OSRGNVMNSA-N 0.000 description 30
- DJDFFEBSKJCGHC-UHFFFAOYSA-N Naphazoline Chemical compound Cl.C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 DJDFFEBSKJCGHC-UHFFFAOYSA-N 0.000 description 18
- 239000004615 ingredient Substances 0.000 description 17
- OSZNNLWOYWAHSS-UHFFFAOYSA-M neostigmine methyl sulfate Chemical compound COS([O-])(=O)=O.CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 OSZNNLWOYWAHSS-UHFFFAOYSA-M 0.000 description 17
- 229960002253 neostigmine methylsulfate Drugs 0.000 description 17
- 238000012360 testing method Methods 0.000 description 17
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 14
- 229940046978 chlorpheniramine maleate Drugs 0.000 description 14
- 239000006196 drop Substances 0.000 description 14
- BJORNXNYWNIWEY-UHFFFAOYSA-N tetrahydrozoline hydrochloride Chemical compound Cl.N1CCN=C1C1C2=CC=CC=C2CCC1 BJORNXNYWNIWEY-UHFFFAOYSA-N 0.000 description 13
- 229940021790 tetrahydrozoline hydrochloride Drugs 0.000 description 13
- 239000007788 liquid Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 230000002708 enhancing effect Effects 0.000 description 11
- 239000003889 eye drop Substances 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 238000013329 compounding Methods 0.000 description 10
- 230000001747 exhibiting effect Effects 0.000 description 10
- 230000003204 osmotic effect Effects 0.000 description 10
- 229920000139 polyethylene terephthalate Polymers 0.000 description 9
- 239000005020 polyethylene terephthalate Substances 0.000 description 9
- 238000007796 conventional method Methods 0.000 description 8
- 229940012356 eye drops Drugs 0.000 description 7
- 229960004760 naphazoline hydrochloride Drugs 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000004698 Polyethylene Substances 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 6
- 239000011521 glass Substances 0.000 description 6
- 229920003023 plastic Polymers 0.000 description 6
- 239000004033 plastic Substances 0.000 description 6
- 229920000573 polyethylene Polymers 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000000654 additive Substances 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 229910021538 borax Inorganic materials 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 235000010339 sodium tetraborate Nutrition 0.000 description 5
- GLZPCOQZEFWAFX-UHFFFAOYSA-N Geraniol Chemical compound CC(C)=CCCC(C)=CCO GLZPCOQZEFWAFX-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 238000004040 coloring Methods 0.000 description 4
- 229920003207 poly(ethylene-2,6-naphthalate) Polymers 0.000 description 4
- 239000011112 polyethylene naphthalate Substances 0.000 description 4
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 4
- 239000004328 sodium tetraborate Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000004743 Polypropylene Substances 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
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 3
- 239000004359 castor oil Substances 0.000 description 3
- 235000019438 castor oil Nutrition 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 3
- NKGYBXHAQAKSSG-UHFFFAOYSA-N iproheptine Chemical compound CC(C)CCCC(C)NC(C)C NKGYBXHAQAKSSG-UHFFFAOYSA-N 0.000 description 3
- 229950000120 iproheptine Drugs 0.000 description 3
- UWKAYLJWKGQEPM-UHFFFAOYSA-N linalool acetate Natural products CC(C)=CCCC(C)(C=C)OC(C)=O UWKAYLJWKGQEPM-UHFFFAOYSA-N 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000000569 multi-angle light scattering Methods 0.000 description 3
- 229920001707 polybutylene terephthalate Polymers 0.000 description 3
- 229920001155 polypropylene Polymers 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 229910052724 xenon Inorganic materials 0.000 description 3
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 3
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 2
- 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 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
- VAZJLPXFVQHDFB-UHFFFAOYSA-N 1-(diaminomethylidene)-2-hexylguanidine Polymers CCCCCCN=C(N)N=C(N)N VAZJLPXFVQHDFB-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- URDCARMUOSMFFI-UHFFFAOYSA-N 2-[2-[bis(carboxymethyl)amino]ethyl-(2-hydroxyethyl)amino]acetic acid Chemical compound OCCN(CC(O)=O)CCN(CC(O)=O)CC(O)=O URDCARMUOSMFFI-UHFFFAOYSA-N 0.000 description 2
- LVYLCBNXHHHPSB-UHFFFAOYSA-N 2-hydroxyethyl salicylate Chemical compound OCCOC(=O)C1=CC=CC=C1O LVYLCBNXHHHPSB-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 2
- XLRHXNIVIZZOON-WFUPGROFSA-L Flavin adenine dinucleotide disodium Chemical compound [Na+].[Na+].C1=NC2=C(N)N=CN=C2N1[C@@H]([C@H](O)[C@@H]1O)O[C@@H]1COP([O-])(=O)OP([O-])(=O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C2=NC(=O)NC(=O)C2=NC2=C1C=C(C)C(C)=C2 XLRHXNIVIZZOON-WFUPGROFSA-L 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 229920002683 Glycosaminoglycan Polymers 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
- ZCVMWBYGMWKGHF-UHFFFAOYSA-N Ketotifene Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 ZCVMWBYGMWKGHF-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 102000016943 Muramidase Human genes 0.000 description 2
- 108010014251 Muramidase Proteins 0.000 description 2
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 2
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 2
- 239000004264 Petrolatum Substances 0.000 description 2
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- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- HUCJFAOMUPXHDK-UHFFFAOYSA-N Xylometazoline Chemical compound CC1=CC(C(C)(C)C)=CC(C)=C1CC1=NCCN1 HUCJFAOMUPXHDK-UHFFFAOYSA-N 0.000 description 2
- LFVVNPBBFUSSHL-UHFFFAOYSA-N alexidine Chemical compound CCCCC(CC)CNC(=N)NC(=N)NCCCCCCNC(=N)NC(=N)NCC(CC)CCCC LFVVNPBBFUSSHL-UHFFFAOYSA-N 0.000 description 2
- 229950010221 alexidine Drugs 0.000 description 2
- POJWUDADGALRAB-UHFFFAOYSA-N allantoin Chemical compound NC(=O)NC1NC(=O)NC1=O POJWUDADGALRAB-UHFFFAOYSA-N 0.000 description 2
- 229960002684 aminocaproic acid Drugs 0.000 description 2
- 208000003464 asthenopia Diseases 0.000 description 2
- UAHWPYUMFXYFJY-UHFFFAOYSA-N beta-myrcene Chemical compound CC(C)=CCCC(=C)C=C UAHWPYUMFXYFJY-UHFFFAOYSA-N 0.000 description 2
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- 239000003795 chemical substances by application Substances 0.000 description 2
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- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
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- UWKAYLJWKGQEPM-LBPRGKRZSA-N linalyl acetate Chemical compound CC(C)=CCC[C@](C)(C=C)OC(C)=O UWKAYLJWKGQEPM-LBPRGKRZSA-N 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
- 239000000463 material Substances 0.000 description 2
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 2
- 229940041616 menthol Drugs 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 229960004114 olopatadine Drugs 0.000 description 2
- JBIMVDZLSHOPLA-LSCVHKIXSA-N olopatadine Chemical compound C1OC2=CC=C(CC(O)=O)C=C2C(=C/CCN(C)C)\C2=CC=CC=C21 JBIMVDZLSHOPLA-LSCVHKIXSA-N 0.000 description 2
- 229940023490 ophthalmic product Drugs 0.000 description 2
- WYWIFABBXFUGLM-UHFFFAOYSA-N oxymetazoline Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C)=C1CC1=NCCN1 WYWIFABBXFUGLM-UHFFFAOYSA-N 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
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- 235000019271 petrolatum Nutrition 0.000 description 2
- 229940066842 petrolatum Drugs 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
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Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
本発明は、眼科組成物に関する。 The present invention relates to ophthalmic compositions.
コンドロイチン硫酸又はその塩は酸性ムコ多糖の一種で、エネルギー代謝を促進させること、新陳代謝や細胞呼吸を促進して目の疲れを解消させること、涙液成分を補給すること等を目的として眼科製剤に配合されている(例えば、特許文献1)。 Chondroitin sulfate or its salt is a type of acidic mucopolysaccharide, and is used in ophthalmic preparations for the purpose of promoting energy metabolism, promoting metabolism and cell respiration to relieve eye fatigue, and replenishing tear components. are blended (for example, Patent Literature 1).
また、ネオスチグミン又はその塩は、ピントの調節機能を改善して目の疲れを解消させること等を目的として眼科製剤に配合されている。 In addition, neostigmine or a salt thereof is blended in ophthalmic preparations for the purpose of improving focus adjusting function and relieving eye fatigue.
本発明の目的は、新規な眼科組成物を提供することにある。 An object of the present invention is to provide novel ophthalmic compositions.
高濃度(例えば、0.7w/v%以上、好ましくは1.0w/v%以上)のコンドロイチン硫酸又はその塩と、ネオスチグミン若しくはその塩又はシアノコバラミン若しくはその塩とを含有する眼科組成物では、点眼容器からの滴下量のばらつきが大きいことが確認された。本発明者らは、高濃度のコンドロイチン硫酸又はその塩とネオスチグミン若しくはその塩及び/又はシアノコバラミン若しくはその塩に加えて、特定の成分を更に含有した眼科組成物が、意外にも滴下量のばらつきを抑制することを見出した。 An ophthalmic composition containing chondroitin sulfate or a salt thereof and neostigmine or a salt thereof or cyanocobalamin or a salt thereof at a high concentration (for example, 0.7 w/v% or more, preferably 1.0 w/v% or more) is It was confirmed that there was a large variation in the amount of dripping from the container. The present inventors have found that an ophthalmic composition further containing specific ingredients in addition to high-concentration chondroitin sulfate or a salt thereof and neostigmine or a salt thereof and/or cyanocobalamin or a salt thereof unexpectedly causes variation in the amount of drops. found to suppress
本発明は、例えば、以下の各発明を提供する。
[1]
(A)コンドロイチン硫酸及びその塩からなる群より選択される少なくとも1種と、(B)ネオスチグミン及びその塩、並びにシアノコバラミン及びその塩からなる群より選択される少なくとも1種と、(C)イミダゾリン化合物及び抗ヒスタミン剤からなる群より選択される少なくとも1種と、(D)ホウ酸及びその塩、リン酸及びその塩、クエン酸及びその塩、並びにエチレンジアミン四酢酸及びその塩からなる群より選択される少なくとも1種と、を含有する眼科組成物であって、(A)成分の含有量が該眼科組成物の総量を基準として0.7~1.2w/v%である、眼科組成物。
[2](C)成分が、テトラヒドロゾリン及びその塩、ナファゾリン及びその塩、並びにクロルフェニラミン及びその塩からなる群より選択される少なくとも1種である、[1]に記載の眼科組成物。
[3]
(C)成分として、テトラヒドロゾリン及びその塩から群より選択される少なくとも1種と、クロルフェニラミン及びその塩からなる群より選択される少なくとも1種とを含有する、[1]又は[2]に記載の眼科組成物。
[4]
(A)コンドロイチン硫酸及びその塩からなる群より選択される少なくとも1種と、(B1)ネオスチグミン及びその塩からなる群より選択される少なくとも1種と、(B2)シアノコバラミン及びその塩からなる群より選択される少なくとも1種と、(D)ホウ酸及びその塩、リン酸及びその塩、クエン酸及びその塩、並びにエチレンジアミン四酢酸及びその塩からなる群より選択される少なくとも1種と、を含有する眼科組成物であって、(A)成分の含有量が該眼科組成物の総量を基準として0.7~1.2w/v%である、眼科組成物。
The present invention provides, for example, the following inventions.
[1]
(A) at least one selected from the group consisting of chondroitin sulfate and its salts, (B) at least one selected from the group consisting of neostigmine and its salts, and cyanocobalamin and its salts, and (C) an imidazoline compound. and at least one selected from the group consisting of antihistamines, and (D) at least selected from the group consisting of boric acid and its salts, phosphoric acid and its salts, citric acid and its salts, and ethylenediaminetetraacetic acid and its salts 1, wherein the content of component (A) is 0.7 to 1.2 w/v% based on the total amount of the ophthalmic composition.
[2] The ophthalmic composition according to [1], wherein the component (C) is at least one selected from the group consisting of tetrahydrozoline and its salts, naphazoline and its salts, and chlorpheniramine and its salts.
[3]
(C) containing at least one selected from the group consisting of tetrahydrozoline and its salts and at least one selected from the group consisting of chlorpheniramine and its salts as the component [1] or [2] An ophthalmic composition as described.
[4]
(A) at least one selected from the group consisting of chondroitin sulfate and salts thereof, (B1) at least one selected from the group consisting of neostigmine and salts thereof, and (B2) from the group consisting of cyanocobalamin and salts thereof and (D) at least one selected from the group consisting of boric acid and its salts, phosphoric acid and its salts, citric acid and its salts, and ethylenediaminetetraacetic acid and its salts. wherein the content of component (A) is 0.7 to 1.2 w/v% based on the total amount of the ophthalmic composition.
本発明によれば、高濃度のコンドロイチン硫酸又はその塩とネオスチグミン若しくはその塩及び/又はシアノコバラミン若しくはその塩とを含有しながら、滴下量のばらつきが抑制された眼科組成物を提供することができる。 According to the present invention, it is possible to provide an ophthalmic composition containing chondroitin sulfate or a salt thereof and neostigmine or a salt thereof and/or cyanocobalamin or a salt thereof at a high concentration while suppressing variation in the amount of drops.
以下、本発明を実施するための形態について詳細に説明する。ただし、本発明は以下の実施形態に限定されるものではない。 DETAILED DESCRIPTION OF THE INVENTION Embodiments for carrying out the present invention will be described in detail below. However, the present invention is not limited to the following embodiments.
〔(A)成分〕
本実施形態に係る眼科組成物は、(A)コンドロイチン硫酸及びその塩からなる群より選択される少なくとも1種(単に「(A)成分」とも表記する。)を含有する。
[(A) component]
The ophthalmic composition according to the present embodiment contains (A) at least one selected from the group consisting of chondroitin sulfate and salts thereof (also referred to simply as "(A) component").
コンドロイチン硫酸及びその塩は、医薬上、薬理学的に(製薬上)又は生理学的に許容されるものであれば、特に制限されない。コンドロイチン硫酸及びその塩の分子量は、医薬上、薬理学的に(製薬上)又は生理学的に許容されることを限度として、特に制限されないが、通常、重量平均分子量で0.1万~10万程度、好ましくは0.5万~7万程度、より好ましくは1万~5万程度、更に好ましくは2万~4.5万程度、特に好ましくは2万~3万程度のものを使用できる。 Chondroitin sulfate and salts thereof are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. The molecular weight of chondroitin sulfate and its salts is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable, but usually the weight average molecular weight is 01,000 to 100,000. about 50,000 to 70,000, more preferably about 10,000 to 50,000, still more preferably about 20,000 to 45,000, particularly preferably about 20,000 to 30,000.
コンドロイチン硫酸の塩としては、例えば、アルカリ金属塩、アルカリ土類金属塩が挙げられる。アルカリ金属塩としては、例えば、ナトリウム塩、カリウム塩が挙げられる。アルカリ土類金属塩としては、例えば、マグネシウム塩、カルシウム塩が挙げられる。 Salts of chondroitin sulfate include, for example, alkali metal salts and alkaline earth metal salts. Examples of alkali metal salts include sodium salts and potassium salts. Examples of alkaline earth metal salts include magnesium salts and calcium salts.
コンドロイチン硫酸及びその塩としては、コンドロイチン硫酸及びコンドロイチン硫酸のアルカリ金属塩が好ましく、コンドロイチン硫酸及びコンドロイチン硫酸ナトリウムがより好ましく、コンドロイチン硫酸ナトリウムが更に好ましい。 Chondroitin sulfate and salts thereof are preferably chondroitin sulfate and alkali metal salts of chondroitin sulfate, more preferably chondroitin sulfate and sodium chondroitin sulfate, and still more preferably sodium chondroitin sulfate.
コンドロイチン硫酸及びその塩は、市販のものを用いることもできる。コンドロイチン硫酸及びその塩は、1種を単独で使用してもよく、又は2種以上を組み合わせて使用してもよい。コンドロイチン硫酸及びその塩は、様々な重量平均分子量のコンドロイチン硫酸及びその塩を組み合わせて使用することができる。例えば、重量平均分子量56000のコンドロイチン硫酸ナトリウムと重量平均分子量25000のコンドロイチン硫酸ナトリウムとを組み合わせて使用することができる。そのように組み合わせて使用する場合には、重量平均分子量が1万~5万、好ましくは2万~4.5万、より好ましくは2万~3万のコンドロイチン硫酸及びその塩を原料として含有することが好ましい。 Commercially available chondroitin sulfate and salts thereof can also be used. Chondroitin sulfate and its salt may be used alone or in combination of two or more. Chondroitin sulfates and salts thereof can be used in combination with various weight average molecular weights of chondroitin sulfates and salts thereof. For example, sodium chondroitin sulfate with a weight average molecular weight of 56,000 and sodium chondroitin sulfate with a weight average molecular weight of 25,000 can be used in combination. When used in combination, chondroitin sulfate having a weight average molecular weight of 10,000 to 50,000, preferably 20,000 to 45,000, more preferably 20,000 to 30,000 and a salt thereof are used as starting materials. is preferred.
本明細書において「重量平均分子量」は、多角度光散乱検出器(MALS検出器)と示差屈折率検出器(RI検出器)をオンライン接続したゲル浸透クロマトグラフィーを使用することによって求めることができる。具体的には、下記の条件が提示される。
<標準試料調製>
コンドロイチン硫酸又はその塩5mgに、0.1M硝酸ナトリウム水溶液10mLを加え、室温で緩やかに攪拌し、完全に溶解させたもの。
<重量平均分子量の測定条件>
装置 :ゲル浸透クロマトグラフ-多角度光散乱計
検出器 :示差屈折率検出器(Wyatt Technology製 Optilab rEX)
多角度光散乱検出器(Wyatt Technology製 DAWN HELEOS)
カラム :Shodex OHpak SB-806M HQ 2本(φ7.8mm×30cm、昭和電工製)
溶媒 :0.1M硝酸ナトリウム水溶液
流速 :0.7mL/min
カラム温度 :23℃
検出器温度 :23℃
注入量 :0.2mL
データ処理 :Wyatt Technology製データ処理システム(ASTRA)
上記の方法で算出されたコンドロイチン硫酸及びその塩の重量平均分子量は、特に制限されないが、重量平均分子量の下限値としては、10000以上、15000以上、及び20000以上が例示される。重量平均分子量の上限値としては、50000以下、45000以下、40000以下、35000以下、及び30000以下が例示される。好ましい重量平均分子量の範囲としては、10000~50000、20000~45000、及び20000~30000が例示される。
As used herein, the "weight average molecular weight" can be determined by using gel permeation chromatography in which a multi-angle light scattering detector (MALS detector) and a differential refractive index detector (RI detector) are connected online. . Specifically, the following conditions are presented.
<Standard sample preparation>
10 mL of 0.1 M sodium nitrate aqueous solution was added to 5 mg of chondroitin sulfate or its salt, and the mixture was gently stirred at room temperature to dissolve completely.
<Conditions for measuring weight average molecular weight>
Apparatus: Gel permeation chromatograph - multi-angle light scatterometer Detector: Differential refractive index detector (Optilab rEX manufactured by Wyatt Technology)
Multi-angle light scattering detector (DAWN HELEOS manufactured by Wyatt Technology)
Column: 2 Shodex OHpak SB-806M HQ (φ7.8 mm × 30 cm, manufactured by Showa Denko)
Solvent: 0.1 M sodium nitrate aqueous solution Flow rate: 0.7 mL/min
Column temperature: 23°C
Detector temperature: 23°C
Injection volume: 0.2 mL
Data processing: Wyatt Technology data processing system (ASTRA)
Although the weight-average molecular weight of chondroitin sulfate and its salt calculated by the above method is not particularly limited, the lower limit of the weight-average molecular weight is exemplified by 10,000 or more, 15,000 or more, and 20,000 or more. Examples of the upper limit of the weight average molecular weight include 50,000 or less, 45,000 or less, 40,000 or less, 35,000 or less, and 30,000 or less. Preferred weight average molecular weight ranges are 10,000 to 50,000, 20,000 to 45,000, and 20,000 to 30,000.
本実施形態に係る眼科組成物における(A)成分の含有量は、眼科組成物の総量を基準として、0.7w/v%以上1.2w/v%以下である。(A)成分の含有量の下限値は0.7w/v%以上であれば特に限定されないが、本発明による効果をより顕著に奏する観点から、例えば、0.8w/v%以上であることが好ましく、0.9w/v%以上であることがより好ましい。(A)成分の含有量の上限値は1.2w/v%以下であれば特に限定されないが、本発明による効果をより顕著に奏する観点から、例えば、1.1w/v%以下であることが好ましい。また、本実施形態に係る眼科組成物における(A)成分の含有量は、眼科組成物の総量を基準として、1.0w/v%であってもよい。 The content of component (A) in the ophthalmic composition according to this embodiment is 0.7 w/v% or more and 1.2 w/v% or less based on the total amount of the ophthalmic composition. Although the lower limit of the content of component (A) is not particularly limited as long as it is 0.7 w/v% or more, it is, for example, 0.8 w/v% or more from the viewpoint of exhibiting the effects of the present invention more remarkably. is preferred, and 0.9 w/v% or more is more preferred. The upper limit of the content of component (A) is not particularly limited as long as it is 1.2 w/v% or less. is preferred. Moreover, the content of the component (A) in the ophthalmic composition according to this embodiment may be 1.0 w/v% based on the total amount of the ophthalmic composition.
〔(B)成分〕
本実施形態に係る眼科組成物は、(A)成分に加えて、(B)ネオスチグミン及びその塩(「(B1)成分」とも表記する。)、並びにシアノコバラミン及びその塩からなる群より選択される少なくとも1種(「(B2)成分」とも表記する。)(これらをまとめて単に「(B)成分」とも表記する。)を含有する。
[(B) component]
In addition to the component (A), the ophthalmic composition according to the present embodiment is selected from the group consisting of (B) neostigmine and salts thereof (also referred to as "component (B1)"), and cyanocobalamin and salts thereof. It contains at least one type (also referred to as "(B2) component") (these are collectively referred to simply as "(B) component").
〔ネオスチグミン及びその塩〕
ネオスチグミン及びその塩は、医薬上、薬理学的に(製薬上)又は生理学的に許容されるものであれば、特に制限されない。ネオスチグミンの塩としては、例えば、メチル硫酸ネオスチグミンが挙げられる。ネオスチグミン及びその塩としては、メチル硫酸ネオスチグミンが好ましい。
[Neostigmine and its salt]
Neostigmine and its salts are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Salts of neostigmine include, for example, neostigmine methyl sulfate. As neostigmine and its salt, neostigmine methyl sulfate is preferred.
ネオスチグミン及びその塩は、市販されているものを使用することもできる。ネオスチグミン及びその塩は、1種を単独で使用してもよく、又は2種以上を組み合わせて使用してもよい。 Commercially available neostigmine and salts thereof can also be used. Neostigmine and salts thereof may be used singly or in combination of two or more.
(B)成分としてネオスチグミン及びその塩を用いる場合、本実施形態に係る眼科組成物におけるネオスチグミン及びその塩の含有量は特に限定されず、ネオスチグミン及びその塩の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。ネオスチグミン及びその塩の含有量は、眼科組成物の総量を基準として、ネオスチグミン及びその塩の総含有量が、0.0001~0.05w/v%であることが好ましく、0.0005~0.01w/v%であることがより好ましく、0.0008~0.008w/v%であることが更に好ましく、0.001~0.005w/v%であることが更に好ましい。 When neostigmine and its salt are used as the component (B), the content of neostigmine and its salt in the ophthalmic composition according to the present embodiment is not particularly limited. It is appropriately set according to the amount, the use of the ophthalmic composition, the formulation form, and the like. The total content of neostigmine and its salts is preferably 0.0001 to 0.05 w/v%, preferably 0.0005 to 0.05 w/v%, based on the total amount of the ophthalmic composition. 01 w/v%, more preferably 0.0008 to 0.008 w/v%, even more preferably 0.001 to 0.005 w/v%.
(B)成分としてネオスチグミン及びその塩を用いる場合、本実施形態に係る眼科組成物における、(A)成分に対するネオスチグミン及びその塩の含有比率は特に限定されず、(A)成分及びネオスチグミン及びその塩の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。(A)成分に対するネオスチグミン及びその塩の含有比率は、本発明による効果をより一層高める観点から、例えば、本実施形態に係る眼科組成物に含まれる(A)成分の総含有量1質量部に対して、ネオスチグミン及びその塩の総含有量が、0.0001~0.05質量部であることが好ましく、0.0005~0.01質量部であることがより好ましく、0.0008~0.008質量部であることが更に好ましく、0.001~0.005質量部であることが更に好ましい。 When neostigmine and its salt are used as the component (B), the content ratio of the neostigmine and its salt to the component (A) in the ophthalmic composition according to the present embodiment is not particularly limited. type, type and content of other compounding ingredients, application and formulation form of the ophthalmic composition, and the like. From the viewpoint of further enhancing the effects of the present invention, the content ratio of neostigmine and its salt to component (A) is, for example, 1 part by mass of the total content of component (A) contained in the ophthalmic composition according to the present embodiment. On the other hand, the total content of neostigmine and salts thereof is preferably 0.0001 to 0.05 parts by mass, more preferably 0.0005 to 0.01 parts by mass, and more preferably 0.0008 to 0.01 part by mass. 008 parts by mass, more preferably 0.001 to 0.005 parts by mass.
〔シアノコバラミン及びその塩〕
シアノコバラミン及びその塩は、医薬上、薬理学的に(製薬上)又は生理学的に許容されるものであれば、特に制限されない。シアノコバラミン及びその塩としては、シアノコバラミンが好ましい。
[Cyanocobalamin and its salt]
Cyanocobalamin and its salts are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Cyanocobalamin and its salts are preferably cyanocobalamin.
シアノコバラミン及びその塩は、市販されているものを使用することもできる。シアノコバラミン及びその塩は、1種を単独で使用してもよく、又は2種以上を組み合わせて使用してもよい。 Cyanocobalamin and its salt can also use what is marketed. Cyanocobalamin and its salt may be used alone or in combination of two or more.
(B)成分としてシアノコバラミン及びその塩を用いる場合、本実施形態に係る眼科組成物におけるシアノコバラミン及びその塩の含有量は特に限定されず、シアノコバラミン及びその塩の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。シアノコバラミン及びその塩の含有量は、本発明による効果をより顕著に奏する観点から、眼科組成物の総量を基準として、シアノコバラミン及びその塩の総含有量が、0.0001~5w/v%であることが好ましく、0.0005~1w/v%であることがより好ましく、0.001~1w/v%であることが更に好ましく、0.002~0.1w/v%であることが更により好ましく、0.004~0.02w/v%であることが特に好ましい。 When cyanocobalamin and its salt are used as the component (B), the content of cyanocobalamin and its salt in the ophthalmic composition according to the present embodiment is not particularly limited, and the type of cyanocobalamin and its salt, and the type and content of other compounding ingredients. It is appropriately set according to the amount, the use of the ophthalmic composition, the formulation form, and the like. The total content of cyanocobalamin and its salts is 0.0001 to 5 w/v% based on the total amount of the ophthalmic composition, from the viewpoint of exhibiting the effects of the present invention more remarkably. is preferably 0.0005 to 1 w/v%, more preferably 0.001 to 1 w/v%, even more preferably 0.002 to 0.1 w/v% Preferably, 0.004 to 0.02 w/v% is particularly preferred.
(B)成分としてシアノコバラミン及びその塩を用いる場合、本実施形態に係る眼科組成物における、(A)成分に対するシアノコバラミン及びその塩の含有比率は特に限定されず、(A)成分及びシアノコバラミン及びその塩の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。(A)成分に対するシアノコバラミン及びその塩の含有比率は、本発明による効果をより一層高める観点から、例えば、本実施形態に係る眼科組成物に含まれる(A)成分の総含有量1質量部に対して、シアノコバラミン及びその塩の総含有量が、0.0001~5質量部であることが好ましく、0.0005~1質量部であることがより好ましく、0.001~1質量部であることが更に好ましく、0.002~0.1質量部であることが更により好ましく、0.004~0.02質量部であることが特に好ましい。 When cyanocobalamin and its salt are used as the component (B), the content ratio of the cyanocobalamin and its salt to the component (A) in the ophthalmic composition according to the present embodiment is not particularly limited. type, type and content of other compounding ingredients, application and formulation form of the ophthalmic composition, and the like. From the viewpoint of further enhancing the effects of the present invention, the content ratio of cyanocobalamin and its salt to component (A) is, for example, 1 part by mass of the total content of component (A) contained in the ophthalmic composition according to the present embodiment. On the other hand, the total content of cyanocobalamin and its salts is preferably 0.0001 to 5 parts by mass, more preferably 0.0005 to 1 part by mass, and 0.001 to 1 part by mass. is more preferable, 0.002 to 0.1 parts by mass is even more preferable, and 0.004 to 0.02 parts by mass is particularly preferable.
〔(C)成分〕
本実施形態に係る眼科組成物は、(A)成分及び(B)成分に加えて、(C)イミダゾリン化合物及び抗ヒスタミン剤からなる群より選択される少なくとも1種(単に「(C)成分」とも表記する。)を含有する。
[(C) component]
In addition to components (A) and (B), the ophthalmic composition according to the present embodiment includes at least one selected from the group consisting of (C) imidazoline compounds and antihistamines (also referred to simply as "(C) component"). ).
〔イミダゾリン化合物及びその塩〕
イミダゾリン化合物及びその塩は、分子内にイミダゾリン環を有する化合物及びその塩である。イミダゾリン化合物及びその塩は、医薬上、薬理学的に(製薬上)又は生理学的に許容されるものであれば、特に制限されない。
[Imidazoline compound and its salt]
The imidazoline compound and its salt are compounds and its salt having an imidazoline ring in the molecule. The imidazoline compound and its salt are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable.
イミダゾリン化合物及びその塩の具体例としては、テトラヒドロゾリン、ナファゾリン、オキシメタゾリン、キシロメタゾリン、トラマゾリン、チマゾリン、メチゾリン及びそれらの塩が挙げられる。イミダゾリン化合物及びその塩としては、テトラヒドロゾリン塩酸塩(塩酸テトラヒドロゾリン)、テトラヒドロゾリン硝酸塩(硝酸テトラヒドロゾリン)、ナファゾリン塩酸塩(塩酸ナファゾリン)が好ましく、テトラヒドロゾリン塩酸塩(塩酸テトラヒドロゾリン)がより好ましい。 Specific examples of imidazoline compounds and salts thereof include tetrahydrozoline, naphazoline, oxymetazoline, xylometazoline, tramazoline, timazoline, methizoline and salts thereof. As the imidazoline compound and its salt, tetrahydrozoline hydrochloride (tetrahydrozoline hydrochloride), tetrahydrozoline nitrate (tetrahydrozoline nitrate), and naphazoline hydrochloride (naphazoline hydrochloride) are preferable, and tetrahydrozoline hydrochloride (tetrahydrozoline hydrochloride) is more preferable.
イミダゾリン化合物及びその塩は、市販されているものを使用することもできる。イミダゾリン化合物及びその塩は、1種を単独で使用してもよく、又は2種以上を組み合わせて使用してもよい。 Commercially available imidazoline compounds and salts thereof can also be used. An imidazoline compound and its salt may be used individually by 1 type, or may be used in combination of 2 or more type.
(C)成分としてイミダゾリン化合物及びその塩を用いる場合、本実施形態に係る眼科組成物におけるイミダゾリン化合物及びその塩の含有量は特に限定されず、イミダゾリン化合物及びその塩の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。イミダゾリン化合物及びその塩の含有量は、本発明による効果をより顕著に奏する観点から、眼科組成物の総量を基準として、イミダゾリン化合物及びその塩の総含有量が、0.00001~1w/v%であることが好ましく、0.00005~0.5w/v%であることがより好ましく、0.0001~0.1w/v%であることが更に好ましく、0.0002~0.1w/v%であることが更により好ましく、0.0006~0.05w/v%であることが特に好ましい。 When an imidazoline compound and its salt are used as the component (C), the content of the imidazoline compound and its salt in the ophthalmic composition according to the present embodiment is not particularly limited. It is appropriately set according to the type and content, the application and formulation form of the ophthalmic composition, and the like. The content of the imidazoline compound and its salt is 0.00001 to 1 w/v% based on the total amount of the ophthalmic composition, from the viewpoint of exhibiting the effects of the present invention more remarkably. is preferably 0.00005 to 0.5 w/v%, more preferably 0.0001 to 0.1 w/v%, even more preferably 0.0002 to 0.1 w/v% is even more preferable, and 0.0006 to 0.05 w/v% is particularly preferable.
(C)成分としてイミダゾリン化合物及びその塩を用いる場合、本実施形態に係る眼科組成物における、(A)成分に対するイミダゾリン化合物及びその塩の含有比率は特に限定されず、(A)成分及びイミダゾリン化合物及びその塩の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。(A)成分に対するイミダゾリン化合物及びその塩の含有比率は、本発明による効果をより一層高める観点から、例えば、本実施形態に係る眼科組成物に含まれる(A)成分の総含有量1質量部に対して、イミダゾリン化合物及びその塩の総含有量が、0.00001~1質量部であることが好ましく、0.00005~0.5質量部であることがより好ましく、0.0001~0.1質量部であることが更に好ましく、0.0002~0.1質量部であることが更により好ましく、0.0006~0.05質量部であることが特に好ましい。 When an imidazoline compound and its salt are used as the component (C), the content ratio of the imidazoline compound and its salt to the component (A) in the ophthalmic composition according to the present embodiment is not particularly limited. and the type of salt thereof, the type and content of other compounding ingredients, the application and formulation form of the ophthalmic composition, and the like. The content ratio of the imidazoline compound and its salt to the component (A) is, for example, 1 part by mass of the total content of the component (A) contained in the ophthalmic composition according to the present embodiment, from the viewpoint of further enhancing the effects of the present invention. The total content of the imidazoline compound and its salt is preferably 0.00001 to 1 part by mass, more preferably 0.00005 to 0.5 part by mass, more preferably 0.0001 to 0.5 part by mass. It is more preferably 1 part by mass, even more preferably 0.0002 to 0.1 part by mass, and particularly preferably 0.0006 to 0.05 part by mass.
(C)成分としてテトラヒドロゾリン及びその塩を用いる場合、本実施形態に係る眼科組成物におけるテトラヒドロゾリン及びその塩の含有量は特に限定されず、テトラヒドロゾリン及びその塩の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。テトラヒドロゾリン及びその塩の含有量は、本発明による効果をより顕著に奏する観点から、眼科組成物の総量を基準として、テトラヒドロゾリン及びその塩の総含有量が、0.0001~1w/v%であることが好ましく、0.0005~0.5w/v%であることがより好ましく、0.001~0.1w/v%であることが更に好ましく、0.002~0.1w/v%であることが更により好ましい。 When tetrahydrozoline and its salt are used as the component (C), the content of the tetrahydrozoline and its salt in the ophthalmic composition according to the present embodiment is not particularly limited. It is appropriately set according to the amount, the use of the ophthalmic composition, the formulation form, and the like. The total content of tetrahydrozoline and its salts is 0.0001 to 1 w/v% based on the total amount of the ophthalmic composition, from the viewpoint of exhibiting the effects of the present invention more remarkably. is preferably 0.0005 to 0.5 w/v%, more preferably 0.001 to 0.1 w/v%, and 0.002 to 0.1 w/v% is even more preferred.
(C)成分としてテトラヒドロゾリン及びその塩を用いる場合、本実施形態に係る眼科組成物における、(A)成分に対するテトラヒドロゾリン及びその塩の含有比率は特に限定されず、(A)成分及びテトラヒドロゾリン及びその塩の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。(A)成分に対するテトラヒドロゾリン及びその塩の含有比率は、本発明による効果をより一層高める観点から、例えば、本実施形態に係る眼科組成物に含まれる(A)成分の総含有量1質量部に対して、テトラヒドロゾリン及びその塩の総含有量が、0.0001~1質量部であることが好ましく、0.0005~0.5質量部であることがより好ましく、0.001~0.1質量部であることが更に好ましく、0.002~0.1質量部であることが更により好ましい。 When tetrahydrozoline and its salt are used as the component (C), the content ratio of the tetrahydrozoline and its salt to the component (A) in the ophthalmic composition according to the present embodiment is not particularly limited. type, type and content of other compounding ingredients, application and formulation form of the ophthalmic composition, and the like. From the viewpoint of further enhancing the effects of the present invention, the content ratio of tetrahydrozoline and its salt to component (A) is, for example, 1 part by mass of the total content of component (A) contained in the ophthalmic composition according to the present embodiment. On the other hand, the total content of tetrahydrozoline and its salt is preferably 0.0001 to 1 part by mass, more preferably 0.0005 to 0.5 part by mass, and 0.001 to 0.1 part by mass. parts, and even more preferably 0.002 to 0.1 parts by mass.
(C)成分としてナファゾリン及びその塩を用いる場合、本実施形態に係る眼科組成物におけるナファゾリン及びその塩の含有量は特に限定されず、ナファゾリン及びその塩の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。ナファゾリン及びその塩の含有量は、本発明による効果をより顕著に奏する観点から、眼科組成物の総量を基準として、ナファゾリン及びその塩の総含有量が、0.00001~0.1w/v%であることが好ましく、0.00005~0.05w/v%であることがより好ましく、0.0001~0.01w/v%であることが更に好ましく、0.0002~0.005w/v%であることが更により好ましい。 (C) When using naphazoline and its salt as the component, the content of naphazoline and its salt in the ophthalmic composition according to the present embodiment is not particularly limited, the type of naphazoline and its salt, the type and content of other ingredients It is appropriately set according to the amount, the use of the ophthalmic composition, the formulation form, and the like. The total content of naphazoline and its salts is 0.00001 to 0.1 w/v%, based on the total amount of the ophthalmic composition, from the viewpoint of exhibiting the effects of the present invention more remarkably. is preferably 0.00005 to 0.05 w/v%, more preferably 0.0001 to 0.01 w/v%, even more preferably 0.0002 to 0.005 w/v% is even more preferred.
(C)成分としてナファゾリン及びその塩を用いる場合、本実施形態に係る眼科組成物における、(A)成分に対するナファゾリン及びその塩の含有比率は特に限定されず、(A)成分及びナファゾリン及びその塩の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。(A)成分に対するナファゾリン及びその塩の含有比率は、本発明による効果をより一層高める観点から、例えば、本実施形態に係る眼科組成物に含まれる(A)成分の総含有量1質量部に対して、ナファゾリン及びその塩の総含有量が、0.00001~0.1質量部であることが好ましく、0.00005~0.05質量部であることがより好ましく、0.0001~0.01質量部であることが更に好ましく、0.0002~0.005質量部であることが更により好ましい。 When naphazoline and its salt are used as the component (C), the content ratio of the naphazoline and its salt to the component (A) in the ophthalmic composition according to the present embodiment is not particularly limited, and the component (A) and the naphazoline and its salt type, type and content of other compounding ingredients, application and formulation form of the ophthalmic composition, and the like. From the viewpoint of further enhancing the effects of the present invention, the content ratio of naphazoline and its salt to component (A) is, for example, 1 part by mass of the total content of component (A) contained in the ophthalmic composition according to the present embodiment. On the other hand, the total content of naphazoline and its salts is preferably 0.00001 to 0.1 parts by mass, more preferably 0.00005 to 0.05 parts by mass, and more preferably 0.0001 to 0.05 parts by mass. 01 parts by mass, and even more preferably 0.0002 to 0.005 parts by mass.
〔抗ヒスタミン剤〕
抗ヒスタミン剤は、抗ヒスタミン作用を有する化合物、及びその塩である。抗ヒスタミン剤は、医薬上、薬理学的に(製薬上)又は生理学的に許容されるものであれば、特に制限されない。
[Antihistamine]
Antihistamines are compounds and salts thereof that have antihistamine action. Antihistamines are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable.
抗ヒスタミン剤の具体例としては、クロルフェニラミン、イプロヘプチン、ジフェンヒドラミン、ケトチフェン、オロパタジン、レボカバスチン、及びそれらの塩が挙げられる。抗ヒスタミン剤としては、クロルフェニラミン及びその塩が好ましく、クロルフェニラミンマレイン酸塩がより好ましい。 Specific examples of antihistamines include chlorpheniramine, iproheptine, diphenhydramine, ketotifen, olopatadine, levocabastine, and salts thereof. As the antihistamine, chlorpheniramine and its salts are preferred, and chlorpheniramine maleate is more preferred.
抗ヒスタミン剤は、市販されているものを使用することもできる。抗ヒスタミン剤は、1種を単独で使用してもよく、又は2種以上を組み合わせて使用してもよい。 A commercially available antihistamine can also be used. One type of antihistamine may be used alone, or two or more types may be used in combination.
本実施形態に係る眼科組成物における抗ヒスタミン剤の含有量は特に限定されず、抗ヒスタミン剤の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。抗ヒスタミン剤の含有量は、本発明による効果をより顕著に奏する観点から、眼科組成物の総量を基準として、抗ヒスタミン剤の総含有量が、0.001~1w/v%であることが好ましく、0.003~0.5w/v%であることがより好ましく、0.005~0.1w/v%であることが更に好ましく、0.01~0.05w/v%であることが更により好ましく、0.02~0.04w/v%(例えば0.03w/v%)であることが特に好ましい。 The content of the antihistamine in the ophthalmic composition according to the present embodiment is not particularly limited, and is appropriately set according to the type of antihistamine, the type and content of other ingredients, the application and formulation form of the ophthalmic composition, and the like. The content of the antihistamines is preferably 0.001 to 1 w/v% based on the total amount of the ophthalmic composition, from the viewpoint of exhibiting the effect of the present invention more remarkably. 003 to 0.5 w/v%, more preferably 0.005 to 0.1 w/v%, even more preferably 0.01 to 0.05 w/v%, Particularly preferred is 0.02 to 0.04 w/v% (eg 0.03 w/v%).
本実施形態に係る眼科組成物における、(A)成分に対する抗ヒスタミン剤の含有比率は特に限定されず、(A)成分及び抗ヒスタミン剤の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。(A)成分に対する抗ヒスタミン剤の含有比率は、本発明による効果をより一層高める観点から、例えば、本実施形態に係る眼科組成物に含まれる(A)成分の総含有量1質量部に対して、0.001~1質量部であることが好ましく、0.003~0.5質量部であることがより好ましく、0.005~0.1質量部であることが更に好ましく、0.01~0.05質量部であることが更により好ましく、0.02~0.04質量部(例えば0.03質量部)であることが特に好ましい。 The content ratio of the antihistamine to the component (A) in the ophthalmic composition according to the present embodiment is not particularly limited. It is appropriately set according to the formulation form and the like. From the viewpoint of further enhancing the effect of the present invention, the content ratio of the antihistamine to the component (A) is, for example, 1 part by mass of the total content of the component (A) contained in the ophthalmic composition according to the present embodiment. It is preferably 0.001 to 1 part by mass, more preferably 0.003 to 0.5 part by mass, even more preferably 0.005 to 0.1 part by mass, and 0.01 to 0 0.05 parts by weight is even more preferred, and 0.02 to 0.04 parts by weight (eg 0.03 parts by weight) is particularly preferred.
(C)成分としてクロルフェニラミン及びその塩を用いる場合、本実施形態に係る眼科組成物におけるクロルフェニラミン及びその塩の含有量は特に限定されず、クロルフェニラミン及びその塩の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。クロルフェニラミン及びその塩の含有量は、本発明による効果をより顕著に奏する観点から、眼科組成物の総量を基準として、クロルフェニラミン及びその塩の総含有量が、0.001~1w/v%であることが好ましく、0.003~0.5w/v%であることがより好ましく、0.005~0.1w/v%であることが更に好ましく、0.01~0.05w/v%であることが更により好ましく、0.02~0.04w/v%(例えば0.03w/v%)であることが特に好ましい。 (C) When chlorpheniramine and its salt are used as the component, the content of chlorpheniramine and its salt in the ophthalmic composition according to the present embodiment is not particularly limited. It is appropriately set according to the type and content of the compounding ingredients, the application and formulation form of the ophthalmic composition, and the like. From the viewpoint of exhibiting the effects of the present invention more remarkably, the content of chlorpheniramine and its salts is 0.001 to 1 w/w based on the total amount of the ophthalmic composition. v%, more preferably 0.003 to 0.5 w/v%, even more preferably 0.005 to 0.1 w/v%, and 0.01 to 0.05 w/v% v% is even more preferred, and 0.02 to 0.04 w/v% (eg 0.03 w/v%) is particularly preferred.
(C)成分としてクロルフェニラミン及びその塩を用いる場合、本実施形態に係る眼科組成物における、(A)成分に対するクロルフェニラミン及びその塩の含有比率は特に限定されず、(A)成分及びクロルフェニラミン及びその塩の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。(A)成分に対するクロルフェニラミン及びその塩の含有比率は、本発明による効果をより一層高める観点から、例えば、本実施形態に係る眼科組成物に含まれる(A)成分の総含有量1質量部に対して、クロルフェニラミン及びその塩の総含有量が、0.001~1質量部であることが好ましく、0.003~0.5質量部であることがより好ましく、0.005~0.1質量部であることが更に好ましく、0.01~0.05質量部であることが更により好ましく、0.02~0.04質量部(例えば0.03質量部)であることが特に好ましい。 When chlorpheniramine and its salt are used as the component (C), the content ratio of the chlorpheniramine and its salt to the component (A) in the ophthalmic composition according to the present embodiment is not particularly limited. It is appropriately set according to the type of chlorpheniramine and its salt, the type and content of other compounding ingredients, the application and formulation form of the ophthalmic composition, and the like. From the viewpoint of further enhancing the effects of the present invention, the content ratio of chlorpheniramine and its salt to component (A) is, for example, 1 mass of the total content of component (A) contained in the ophthalmic composition according to the present embodiment. part, the total content of chlorpheniramine and its salts is preferably 0.001 to 1 part by mass, more preferably 0.003 to 0.5 part by mass, and 0.005 to It is more preferably 0.1 parts by mass, even more preferably 0.01 to 0.05 parts by mass, and 0.02 to 0.04 parts by mass (for example, 0.03 parts by mass). Especially preferred.
本実施形態に係る眼科組成物は、(A)成分、(B)成分及び(C)成分に加えて、(D)ホウ酸及びその塩、リン酸及びその塩、クエン酸及びその塩、並びにエチレンジアミン四酢酸及びその塩からなる群より選択される少なくとも1種(「(D)成分」ともいう。)を含有する。 In addition to components (A), (B) and (C), the ophthalmic composition according to this embodiment includes (D) boric acid and its salts, phosphoric acid and its salts, citric acid and its salts, and It contains at least one selected from the group consisting of ethylenediaminetetraacetic acid and salts thereof (also referred to as "component (D)").
ホウ酸又はその塩としては、ホウ酸、ホウ酸アルカリ金属塩(ホウ酸ナトリウム、テトラホウ酸カリウム、メタホウ酸カリウム、ホウ酸アンモニウム、ホウ砂等)、ホウ酸アルカリ土類金属塩等が挙げられる。リン酸又はその塩としては、リン酸、リン酸アルカリ金属塩(リン酸水素二ナトリウム、リン酸二水素ナトリウム、リン酸二水素カリウム、リン酸三ナトリウム、リン酸三カリウム等)、リン酸アルカリ土類金属塩(リン酸一水素カルシウム、リン酸二水素カルシウム等)等が挙げられる。クエン酸又はその塩としては、クエン酸、クエン酸アルカリ金属塩(クエン酸ナトリウム、クエン酸カリウム、クエン酸カルシウム、クエン酸二水素ナトリウム、クエン酸二ナトリウム等)、クエン酸アルカリ土類金属塩等が挙げられる。エチレンジアミン四酢酸(EDTA)又はその塩としては、EDTA、EDTAアルカリ金属塩(EDTA二ナトリウム等)等が挙げられる。 Examples of boric acid or salts thereof include boric acid, alkali metal borates (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.), alkaline earth metal borates, and the like. Phosphoric acid or its salt includes phosphoric acid, alkali metal phosphate (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, etc.), alkali phosphate Examples include earth metal salts (calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.). Citric acid or salts thereof include citric acid, alkali metal citrate salts (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.), alkaline earth metal citrate salts, etc. is mentioned. Examples of ethylenediaminetetraacetic acid (EDTA) or salts thereof include EDTA, EDTA alkali metal salts (EDTA disodium, etc.), and the like.
(D)成分としては、ホウ酸又はその塩が好ましく、ホウ酸又はホウ砂がより好ましい。 Component (D) is preferably boric acid or a salt thereof, more preferably boric acid or borax.
(D)成分は、市販されているものを使用してもよい。(D)成分は、1種を単独で使用してもよく、又は2種以上を組み合わせて使用してもよい。 (D) Component may use what is marketed. (D) Component may be used individually by 1 type, or may be used in combination of 2 or more type.
本実施形態に係る眼科組成物における(D)成分の含有量は特に限定されず、(D)成分の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。(D)成分の含有量としては、本発明による効果をより顕著に奏する観点から、例えば、眼科組成物の総量を基準として、(D)成分の総含有量が、0.01~10w/v%であることが好ましく、0.05~5w/v%であることがより好ましく、0.1~3w/v%であることが更に好ましい。 The content of component (D) in the ophthalmic composition according to the present embodiment is not particularly limited, and depends on the type of component (D), the type and content of other ingredients, the application and formulation form of the ophthalmic composition, and the like. is set as appropriate. As for the content of the component (D), from the viewpoint of exhibiting the effects of the present invention more remarkably, for example, the total content of the component (D) is 0.01 to 10 w/v based on the total amount of the ophthalmic composition. %, more preferably 0.05 to 5 w/v %, even more preferably 0.1 to 3 w/v %.
本実施形態に係る眼科組成物における、(A)成分に対する(D)成分の含有比率は特に限定されず、(A)成分及び(D)成分の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。(A)成分に対する(D)成分の含有比率としては、本発明による効果をより一層高める観点から、例えば、本実施形態に係る眼科組成物に含まれる(A)成分の総含有量1質量部に対して、(D)成分の総含有量が、0.01~100質量部であることが好ましく、0.05~50質量部であることがより好ましく、0.1~30質量部であることが更に好ましい。 The content ratio of component (D) to component (A) in the ophthalmic composition according to the present embodiment is not particularly limited. It is appropriately set according to the use, formulation form, etc. of the ophthalmic composition. From the viewpoint of further enhancing the effect of the present invention, the content ratio of component (D) to component (A) is, for example, 1 part by mass of the total content of component (A) contained in the ophthalmic composition according to the present embodiment. The total content of component (D) is preferably 0.01 to 100 parts by mass, more preferably 0.05 to 50 parts by mass, and 0.1 to 30 parts by mass. is more preferred.
(D)成分としてホウ酸及びその塩、リン酸及びその塩、クエン酸及びその塩を用いる場合、本実施形態に係る眼科組成物におけるホウ酸及びその塩、リン酸及びその塩、クエン酸及びその塩の含有量は特に限定されず、ホウ酸及びその塩、リン酸及びその塩、クエン酸及びその塩の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。ホウ酸及びその塩、リン酸及びその塩、クエン酸及びその塩の含有量は、本発明による効果をより顕著に奏する観点から、眼科組成物の総量を基準として、ホウ酸及びその塩、リン酸及びその塩、クエン酸及びその塩の総含有量が、0.01~10w/v%であることが好ましく、0.05~5w/v%であることがより好ましく、0.1~3w/v%であることが更に好ましい。 (D) When using boric acid and its salts, phosphoric acid and its salts, citric acid and its salts as the component, boric acid and its salts, phosphoric acid and its salts, citric acid and The content of the salt is not particularly limited, boric acid and its salts, phosphoric acid and its salts, citric acid and its salts types, types and contents of other ingredients, use and formulation form of the ophthalmic composition, etc. is set as appropriate. The contents of boric acid and its salts, phosphoric acid and its salts, and citric acid and its salts are based on the total amount of the ophthalmic composition, from the viewpoint of exhibiting the effects of the present invention more remarkably. The total content of acid and its salts, citric acid and its salts is preferably 0.01 to 10 w/v%, more preferably 0.05 to 5 w/v%, 0.1 to 3 w /v% is more preferred.
(D)成分としてホウ酸及びその塩、リン酸及びその塩、クエン酸及びその塩を用いる場合、本実施形態に係る眼科組成物における、(A)成分に対するホウ酸及びその塩、リン酸及びその塩、クエン酸及びその塩の含有比率は特に限定されず、(A)成分及びホウ酸及びその塩、リン酸及びその塩、クエン酸及びその塩の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。(A)成分に対するホウ酸及びその塩、リン酸及びその塩、クエン酸及びその塩の含有比率は、本発明による効果をより一層高める観点から、例えば、本実施形態に係る眼科組成物に含まれる(A)成分の総含有量1質量部に対して、ホウ酸及びその塩、リン酸及びその塩、クエン酸及びその塩の総含有量が、0.01~10質量部であることが好ましく、0.05~5質量部であることがより好ましく、0.1~3質量部であることが更に好ましい。 (D) When using boric acid and its salts, phosphoric acid and its salts, and citric acid and its salts as the component, boric acid and its salts, phosphoric acid and The content ratio of its salt, citric acid and its salt is not particularly limited, type of component (A) and boric acid and its salt, phosphoric acid and its salt, citric acid and its salt, type and content of other ingredients It is appropriately set according to the amount, the use of the ophthalmic composition, the formulation form, and the like. The content ratio of boric acid and its salts, phosphoric acid and its salts, and citric acid and its salts to the component (A) is, for example, included in the ophthalmic composition according to the present embodiment, from the viewpoint of further enhancing the effects of the present invention. The total content of boric acid and its salts, phosphoric acid and its salts, citric acid and its salts is 0.01 to 10 parts by mass with respect to 1 part by mass of the total content of the component (A) It is preferably from 0.05 to 5 parts by mass, and even more preferably from 0.1 to 3 parts by mass.
(D)成分としてエチレンジアミン四酢酸(EDTA)又はその塩を用いる場合、本実施形態に係る眼科組成物におけるエチレンジアミン四酢酸(EDTA)又はその塩の含有量は特に限定されず、エチレンジアミン四酢酸(EDTA)又はその塩の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。エチレンジアミン四酢酸(EDTA)又はその塩の含有量は、本発明による効果をより顕著に奏する観点から、眼科組成物の総量を基準として、エチレンジアミン四酢酸(EDTA)又はその塩の総含有量が、0.001~0.5w/v%であることが好ましく、0.005~0.1w/v%であることがより好ましく、0.01~0.05w/v%であることが更に好ましい。 When ethylenediaminetetraacetic acid (EDTA) or a salt thereof is used as the component (D), the content of ethylenediaminetetraacetic acid (EDTA) or a salt thereof in the ophthalmic composition according to the present embodiment is not particularly limited. ) or its salt, the type and content of other compounding ingredients, the application and formulation form of the ophthalmic composition, and the like. The content of ethylenediaminetetraacetic acid (EDTA) or a salt thereof, based on the total amount of the ophthalmic composition, is such that the total content of ethylenediaminetetraacetic acid (EDTA) or a salt thereof is It is preferably 0.001 to 0.5 w/v%, more preferably 0.005 to 0.1 w/v%, even more preferably 0.01 to 0.05 w/v%.
(D)成分としてエチレンジアミン四酢酸(EDTA)又はその塩を用いる場合、本実施形態に係る眼科組成物における、(A)成分に対するエチレンジアミン四酢酸(EDTA)又はその塩の含有比率は特に限定されず、(A)成分及びエチレンジアミン四酢酸(EDTA)又はその塩の種類、他の配合成分の種類及び含有量、眼科組成物の用途及び製剤形態等に応じて適宜設定される。(A)成分に対するエチレンジアミン四酢酸(EDTA)又はその塩の含有比率は、本発明による効果をより一層高める観点から、例えば、本実施形態に係る眼科組成物に含まれる(A)成分の総含有量1質量部に対して、エチレンジアミン四酢酸(EDTA)又はその塩の総含有量が、0.001~0.5質量部であることが好ましく、0.005~0.1質量部であることがより好ましく、0.01~0.05質量部であることが更に好ましい When ethylenediaminetetraacetic acid (EDTA) or a salt thereof is used as component (D), the content ratio of ethylenediaminetetraacetic acid (EDTA) or a salt thereof to component (A) in the ophthalmic composition according to the present embodiment is not particularly limited. , types of component (A) and ethylenediaminetetraacetic acid (EDTA) or salts thereof, types and contents of other compounding components, application and formulation form of the ophthalmic composition, and the like. The content ratio of ethylenediaminetetraacetic acid (EDTA) or a salt thereof to component (A) is, for example, the total content of component (A) contained in the ophthalmic composition according to the present embodiment, from the viewpoint of further enhancing the effects of the present invention. The total content of ethylenediaminetetraacetic acid (EDTA) or a salt thereof is preferably 0.001 to 0.5 parts by mass, more preferably 0.005 to 0.1 parts by mass, per 1 part by mass. is more preferable, and more preferably 0.01 to 0.05 parts by mass
本発明に係る眼科組成物の別の実施形態は、(A)コンドロイチン硫酸及びその塩からなる群より選択される少なくとも1種と、(B1)ネオスチグミン及びその塩からなる群より選択される少なくとも1種と、(B2)シアノコバラミン及びその塩からなる群より選択される少なくとも1種と、(D)ホウ酸及びその塩、リン酸及びその塩、クエン酸及びその塩、並びにエチレンジアミン四酢酸及びその塩からなる群より選択される少なくとも1種と、を含有する眼科組成物であって、(A)成分の含有量が該眼科組成物の総量を基準として0.7~1.2w/v%である。当該実施形態において、各成分の種類及び含有量等は上記で説明したとおりである。 Another embodiment of the ophthalmic composition according to the present invention comprises (A) at least one selected from the group consisting of chondroitin sulfate and salts thereof, and (B1) at least one selected from the group consisting of neostigmine and salts thereof. (B2) at least one selected from the group consisting of cyanocobalamin and its salts; and (D) boric acid and its salts, phosphoric acid and its salts, citric acid and its salts, and ethylenediaminetetraacetic acid and its salts. and at least one selected from the group consisting of, wherein the content of component (A) is 0.7 to 1.2 w/v% based on the total amount of the ophthalmic composition be. In the said embodiment, the kind, content, etc. of each component are as having demonstrated above.
本実施形態に係る眼科組成物のpHは、医薬上、薬理学的に(製薬上)又は生理学的に許容される範囲内であれば特に限定されるものではない。本実施形態に係る眼科組成物のpHとしては、例えば、4.0~9.5であってよく、4.0~9.0であることが好ましく、4.5~9.0であることがより好ましく、4.5~8.5であることが更に好ましく、5.0~8.5であることが更により好ましく、5.0~8.0であることが特に好ましく、5.3~7.5であることが更に特に好ましく、5.5~7.0であることが最も好ましい。 The pH of the ophthalmic composition according to this embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable range. The pH of the ophthalmic composition according to this embodiment may be, for example, 4.0 to 9.5, preferably 4.0 to 9.0, and more preferably 4.5 to 9.0. is more preferable, more preferably 4.5 to 8.5, even more preferably 5.0 to 8.5, particularly preferably 5.0 to 8.0, 5.3 ~7.5 is more particularly preferred, and 5.5 to 7.0 is most preferred.
本実施形態に係る眼科組成物は、必要に応じて、生体に許容される範囲内の浸透圧比に調節することができる。適切な浸透圧比は、眼科組成物の用途、製剤形態、使用方法等に応じて適宜設定され得るが、例えば、0.4~5.0とすることができ、0.6~3.0とすることが好ましく、0.8~2.2とすることがより好ましく、0.8~2.0とすることが更に好ましい。浸透圧比は、第十七改正日本薬局方に基づき、286mOsm(0.9w/v%塩化ナトリウム水溶液の浸透圧)に対する試料の浸透圧の比とし、浸透圧は日本薬局方記載の浸透圧測定法(凝固点降下法)を参考にして測定する。なお、浸透圧比測定用標準液(0.9w/v%塩化ナトリウム水溶液)は、塩化ナトリウム(日本薬局方標準試薬)を500~650℃で40~50分間乾燥した後、デシケーター(シリカゲル)中で放冷し、その0.900gを正確に量り、精製水に溶かし正確に100mLとして調製するか、市販の浸透圧比測定用標準液(0.9w/v%塩化ナトリウム水溶液)を用いることができる。 The ophthalmic composition according to the present embodiment can be adjusted to have an osmotic pressure ratio within a range acceptable to living organisms, if necessary. An appropriate osmotic pressure ratio can be appropriately set according to the application, formulation form, method of use, etc. of the ophthalmic composition, and can be, for example, 0.4 to 5.0, and 0.6 to 3.0. , more preferably 0.8 to 2.2, even more preferably 0.8 to 2.0. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (osmotic pressure of 0.9 w/v% sodium chloride aqueous solution) based on the 17th revision of the Japanese Pharmacopoeia, and the osmotic pressure is the osmotic pressure measurement method described in the Japanese Pharmacopoeia. (freezing point depression method). The standard solution for osmotic pressure ratio measurement (0.9 w/v% sodium chloride aqueous solution) was obtained by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500 to 650 ° C. for 40 to 50 minutes and then placing it in a desiccator (silica gel). After allowing to cool, 0.900 g thereof is accurately weighed and dissolved in purified water to prepare exactly 100 mL, or a commercially available standard solution for osmotic pressure ratio measurement (0.9 w/v % sodium chloride aqueous solution) can be used.
本実施形態に係る眼科組成物の粘度は、医薬上、薬理学的に(製薬上)又は生理学的に許容される範囲内であれば、特に限定されるものではない。本実施形態に係る眼科組成物の粘度としては、例えば、回転粘度計(TV-20型粘度計、東機産業社製、ローター;1°34’×R24)で測定した20℃における粘度が1~10000mPa・sであることが好ましく、1~8000mPa・sであることがより好ましく、1~1000mPa・sであることが更に好ましく、1~100mPa・sであることが更により好ましく、1~20mPa・sであることが特に好ましく、1.5~10mPa・sであることが最も好ましい。 The viscosity of the ophthalmic composition according to this embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable range. As the viscosity of the ophthalmic composition according to the present embodiment, for example, the viscosity at 20 ° C. measured with a rotational viscometer (TV-20 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor; 1 ° 34' × R24) is 1 It is preferably from 1 to 10,000 mPa s, more preferably from 1 to 8,000 mPa s, still more preferably from 1 to 1,000 mPa s, even more preferably from 1 to 100 mPa s, and from 1 to 20 mPa. · s is particularly preferred, and 1.5 to 10 mPa·s is most preferred.
本実施形態に係る眼科組成物は、本発明の効果を損なわない範囲であれば、上記成分の他に種々の薬理活性成分及び生理活性成分から選択される成分を組み合わせて適当量含有していてもよい。当該成分は特に制限されず、例えば、要指導・一般用医薬品製造販売承認基準2017年版(一般社団法人 レギュラトリーサイエンス学会 監修)に記載された眼科用薬における有効成分が例示できる。眼科用薬において用いられる成分として、具体的には、例えば、次のような成分が挙げられる。
抗アレルギー剤:例えば、クロモグリク酸ナトリウム、トラニラスト、ペミロラストカリウム、アシタザノラスト、アンレキサノクス、イブジラスト等。
抗ヒスタミン剤:例えば、ジフェンヒドラミン又はその塩(例えば、塩酸ジフェンヒドラミン)、イプロヘプチン又はその塩(例えば、塩酸イプロヘプチン)、レボカバスチン又はその塩(例えば、塩酸レボカバスチン)、ケトチフェン又はその塩(例えば、フマル酸ケトチフェン)、ペミロラストカリウム、オロパタジン又はその塩(例えば、塩酸オロパタジン)等。
ステロイド剤:例えば、プロピオン酸フルチカゾン、フランカルボン酸フルチカゾン、フランカルボン酸モメタゾン、プロピオン酸ベクロメタゾン、フルニソリド等。
充血除去剤: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、塩酸フェニレフリン、dl-塩酸メチルエフェドリン等。
眼筋調節薬剤:例えば、アセチルコリンと類似した活性中心を有するコリンエステラーゼ阻害剤、具体的にはトロピカミド、ヘレニエン、硫酸アトロピン、塩酸ピロカルピン等。
消炎剤:例えば、サリチル酸メチル、サリチル酸グリコール、アラントイン、トラネキサム酸、リゾチーム、塩化リゾチーム、インドメタシン、プラノプロフェン、イブプロフェン、イブプロフェンピコノール、ケトプロフェン、フェルビナク、ベンダザック、ピロキシカム、ブフェキサマク、フルフェナム酸ブチル、イプシロン-アミノカプロン酸、塩化ベルベリン、硫酸ベルベリン、アズレンスルホン酸ナトリウム、グリチルリチン酸又はその塩(例えば、グリチルリチン酸二カリウム、グリチルリチン酸モノアンモニウム)、硫酸亜鉛、乳酸亜鉛等。
ビタミン類:例えば、酢酸レチノール、パルミチン酸レチノール、酢酸トコフェロール、フラビンアデニンジヌクレオチドナトリウム、ピリドキシン塩酸塩、パンテノール、パントテン酸カルシウム、アスコルビン酸、アスコルビン酸ナトリウム等。
アミノ酸類:例えば、L-アルギニン、グルタミン酸、グリシン、アラニン、リジン、γ-アミノ酪酸、γ-アミノ吉草酸、トリメチルグリシン、タウリン、アスパラギン酸及びそれらの塩等。
収斂剤:例えば、亜鉛華等。
その他:例えば、スルファメトキサゾール、スルフイソキサゾール、スルフイソミジン及びそれらの塩等。
The ophthalmic composition according to the present embodiment contains, in addition to the above components, an appropriate amount of a combination of components selected from various pharmacologically active components and physiologically active components within a range that does not impair the effects of the present invention. good too. The ingredients are not particularly limited, and examples thereof include active ingredients in ophthalmic drugs described in the 2017 edition of the Standards for Manufacturing and Marketing Approval of Over-the-Counter Drugs (supervised by the Japanese Society of Regulatory Science). Specific examples of components used in ophthalmic drugs include the following components.
Antiallergic agents: for example, cromoglycate sodium, tranilast, pemirolast potassium, acitazanolast, amlexanox, ibudilast and the like.
Antihistamines: e.g. diphenhydramine or salts thereof (e.g. diphenhydramine hydrochloride), iproheptine or salts thereof (e.g. iproheptine hydrochloride), levocabastine or salts thereof (e.g. levocabastine hydrochloride), ketotifen or salts thereof (e.g. ketotifen fumarate), mirolast potassium, olopatadine or a salt thereof (eg, olopatadine hydrochloride), and the like.
Steroid agents: for example, fluticasone propionate, fluticasone furoate, mometasone furoate, beclomethasone propionate, flunisolide and the like.
Decongestants: For example, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, dl-methylephedrine hydrochloride and the like.
Ocular muscle modulating drug: For example, a cholinesterase inhibitor having an active center similar to that of acetylcholine, specifically tropicamide, helenien, atropine sulfate, pilocarpine hydrochloride and the like.
Anti-inflammatory agents: for example, methyl salicylate, glycol salicylate, allantoin, tranexamic acid, lysozyme, lysozyme chloride, indomethacin, pranoprofen, ibuprofen, ibuprofen piconol, ketoprofen, felbinac, bendazac, piroxicam, bufexamac, butyl flufenamate, epsilon- aminocaproic acid, berberine chloride, berberine sulfate, sodium azulene sulfonate, glycyrrhizic acid or its salts (eg, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate), zinc sulfate, zinc lactate and the like.
Vitamins: for example, retinol acetate, retinol palmitate, tocopherol acetate, flavin adenine dinucleotide sodium, pyridoxine hydrochloride, panthenol, calcium pantothenate, ascorbic acid, sodium ascorbate and the like.
Amino acids: for example, L-arginine, glutamic acid, glycine, alanine, lysine, γ-aminobutyric acid, γ-aminovaleric acid, trimethylglycine, taurine, aspartic acid and salts thereof.
Astringent: For example, zinc white and the like.
Others: For example, sulfamethoxazole, sulfisoxazole, sulfisomidine and salts thereof and the like.
本実施形態に係る眼科組成物には、本発明の効果を損なわない範囲であれば、その用途及び製剤形態に応じて、常法に従い、様々な添加物を適宜選択し、1種又はそれ以上を併用して適当量含有させてもよい。このような添加物として、例えば、医薬品添加物事典2016(日本医薬品添加剤協会編集)に記載された各種添加物が例示できる。代表的な成分として次の添加物が挙げられる。
担体:例えば、水、含水エタノール等の水性溶媒。
キレート剤:例えば、(EDDA)、エチレンジアミン三酢酸、N-(2-ヒドロキシエチル)エチレンジアミン三酢酸(HEDTA)、ジエチレントリアミン五酢酸(DTPA)等。
基剤:例えば、オクチルドデカノール、酸化チタン、臭化カリウム、プラスチベース等。
pH調節剤:例えば、塩酸、酢酸、水酸化ナトリウム、水酸化カリウム、水酸化カルシウム、水酸化マグネシウム、トリエタノールアミン、モノエタノールアミン、ジイソプロパノールアミン等。
界面活性剤:例えば、チロキサポール、ポリオキシエチレンソルビタン脂肪酸エステル類、ステアリン酸ポリオキシル、ポリオキシエチレンヒマシ油、ポリオキシエチレン硬化ヒマシ油、ポロクサマー類等の非イオン界面活性剤;ポリオキシエチレンアルキルエーテルリン酸塩、ポリオキシエチレンアルキルエーテル硫酸塩、アルキルベンゼンスルホン酸塩、アルキル硫酸塩、N-アシルタウリン塩等の陰イオン界面活性剤;ラウリルジメチルアミノ酢酸ベタイン等の両性イオン界面活性剤等。
香料又は清涼化剤:例えば、メントール、メントン、カンフル、ボルネオール、ゲラニオール、シネオール、シトロネロール、カルボン、アネトール、オイゲノール、リモネン、リナロール、酢酸リナリル、チモール、シメン、テルピネオール、ピネン、カンフェン、イソボルネオール、フェンチェン、ネロール、ミルセン、ミルセノール、酢酸リナロール、ラバンジュロール、ユーカリ油、ベルガモット油、ペパーミント油、クールミント油、スペアミント油、ハッカ油、ウイキョウ油、ケイヒ油、ローズ油、樟脳油等。これらは、d体、l体又はdl体のいずれでもよい。
増粘剤:例えば、メチルセルロース、エチルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロースナトリウム等のセルロース系高分子化合物;グアーガム;ヒドロキシプロピルグアーガム;アラビアゴム;カラヤガム;キサンタンガム;寒天;アルギン酸及びその塩(ナトリウム塩等);ヘパリン類似物質、ヘパリン、ヘパリン硫酸、ヘパラン硫酸、ヘパリノイド、ヒアルロン酸及びその塩(ナトリウム塩等)のムコ多糖類;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;カラギーナン;ブドウ糖等の単糖類等。
(D)成分以外の緩衝剤:例えば、炭酸緩衝剤、酢酸緩衝剤、乳酸緩衝剤、コハク酸緩衝剤、トリス緩衝剤、AMPD緩衝剤等。
安定化剤:例えば、ナトリウムホルムアルデヒドスルホキシレート(ロンガリット)、モノステアリン酸アルミニウム、モノステアリン酸グリセリン、シクロデキストリン、モノエタノールアミン、ジブチルヒドロキシトルエン、亜硫酸水素ナトリウム、ピロ亜硫酸ナトリウム等。
防腐剤:例えば、アルキルポリアミノエチルグリシン類第四級アンモニウム塩(例えば、塩化ベンザルコニウム、塩化ベンゼトニウム等)、グルコン酸クロルヘキシジン、塩化ポリドロニウム、安息香酸ナトリウム、エタノール、クロロブタノール、ソルビン酸、ソルビン酸カリウム、デヒドロ酢酸ナトリウム、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル、パラオキシ安息香酸ブチル、硫酸オキシキノリン、フェネチルアルコール、ベンジルアルコール、ビグアニド化合物(具体的には、塩酸ポリヘキサニド(ポリヘキサメチレンビグアニド)、アレキシジン等)、グローキル(ローディア社製 商品名)等。
等張化剤:例えば、塩化カリウム、塩化カルシウム、塩化ナトリウム、塩化マグネシウム、酢酸カリウム、酢酸ナトリウム、炭酸水素ナトリウム、炭酸ナトリウム、チオ硫酸ナトリウム、硫酸マグネシウム、グリセリン、プロピレングリコール、亜硫酸水素ナトリウム、亜硫酸ナトリウム等。
糖アルコール類:例えば、キシリトール、ソルビトール、マンニトール、グリセリン等。これらはd体、l体又はdl体のいずれでもよい。
油類:例えば、ゴマ油、ヒマシ油、ダイズ油、オリーブ油等の植物油;スクワラン等の動物油;流動パラフィン、ワセリン等の鉱物油等。
In the ophthalmic composition according to the present embodiment, various additives are appropriately selected in accordance with conventional methods according to the application and formulation form, as long as the effects of the present invention are not impaired, and one or more additives are added. may be used in combination and contained in an appropriate amount. Examples of such additives include various additives described in Pharmaceutical Excipient Encyclopedia 2016 (edited by Japan Pharmaceutical Excipients Association). Typical ingredients include the following additives.
Carrier: For example, an aqueous solvent such as water or hydrous ethanol.
Chelating agents: for example (EDDA), ethylenediaminetriacetic acid, N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA) and the like.
Base: For example, octyldodecanol, titanium oxide, potassium bromide, Plastibase and the like.
pH adjuster: for example, hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, diisopropanolamine and the like.
Surfactants: nonionic surfactants such as tyloxapol, polyoxyethylene sorbitan fatty acid esters, polyoxyl stearate, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamers; polyoxyethylene alkyl ether phosphate salt, anionic surfactants such as polyoxyethylene alkyl ether sulfates, alkylbenzenesulfonates, alkyl sulfates, N-acyl taurine salts; zwitterionic surfactants such as betaine lauryldimethylaminoacetate;
Perfumes or cooling agents: e.g. menthol, menthone, camphor, borneol, geraniol, cineol, citronellol, carvone, anethole, eugenol, limonene, linalool, linalyl acetate, thymol, cymene, terpineol, pinene, camphene, isoborneol, fenchen , nerol, myrcene, myrcenol, linalool acetate, lavandulol, eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, rose oil, camphor oil, etc. These may be d-, l- or dl-isomers.
Thickeners: cellulosic polymer compounds such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; guar gum; hydroxypropylguar gum; gum arabic; karaya gum; xanthan gum; Heparin-like substances, heparin, heparin sulfate, heparan sulfate, heparinoids, hyaluronic acid and mucopolysaccharides thereof (such as sodium salts); starch; chitin and its derivatives; chitosan and its derivatives; carrageenan;
(D) Buffers other than component: For example, carbonate buffer, acetate buffer, lactate buffer, succinate buffer, Tris buffer, AMPD buffer and the like.
Stabilizers: For example, sodium formaldehyde sulfoxylate (Rongalite), aluminum monostearate, glyceryl monostearate, cyclodextrin, monoethanolamine, dibutylhydroxytoluene, sodium bisulfite, sodium pyrosulfite and the like.
Preservatives: e.g. quaternary ammonium salts of alkylpolyaminoethylglycines (e.g. benzalkonium chloride, benzethonium chloride, etc.), chlorhexidine gluconate, polydronium chloride, sodium benzoate, ethanol, chlorobutanol, sorbic acid, potassium sorbate , sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexanide hydrochloride (polyhexamethylene biguanide ), Alexidine, etc.), Glokill (trade name of Rhodia), etc.
Tonicity agents: e.g. potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol, sodium bisulfite, sodium sulfite etc.
Sugar alcohols: For example, xylitol, sorbitol, mannitol, glycerin and the like. These may be d-, l- or dl-isomers.
Oils: For example, vegetable oils such as sesame oil, castor oil, soybean oil and olive oil; animal oils such as squalane; mineral oils such as liquid paraffin and petrolatum.
本実施形態に係る眼科組成物は、本発明の効果を顕著に奏することができる観点から、ワセリン、ポリビニルアルコール、フラビンアデニンジヌクレオチドナトリウム、イプシロン-アミノカプロン酸、アレキシジン、塩化亜鉛、メントール、アズレンスルホン酸及びその塩、並びにベルベリン及びその塩からなる群より選択される少なくとも1種を含有しないことが好ましい。 From the viewpoint that the effects of the present invention can be remarkably exhibited, the ophthalmic composition according to the present embodiment contains petrolatum, polyvinyl alcohol, flavin adenine dinucleotide sodium, epsilon-aminocaproic acid, alexidine, zinc chloride, menthol, and azulene sulfonic acid. and salts thereof, and at least one selected from the group consisting of berberine and salts thereof.
本実施形態に係る眼科組成物が水を含有する場合、水の含有量としては、本発明による効果をより顕著に奏する観点から、例えば、眼科組成物の総量を基準として、水の含有量が、80w/v%以上100w/v%未満であることが好ましく、85w/v%以上99.5w/v%以下であることがより好ましく、90w/v%以上99.2w/v%以下であることが更に好ましい。 When the ophthalmic composition according to the present embodiment contains water, the water content is, for example, based on the total amount of the ophthalmic composition, from the viewpoint of exhibiting the effects of the present invention more remarkably. , preferably 80 w/v% or more and less than 100 w/v%, more preferably 85 w/v% or more and 99.5 w/v% or less, and 90 w/v% or more and 99.2 w/v% or less is more preferred.
本実施形態に係る眼科組成物に使用される水は、医薬上、薬理学的に(製薬上)又は生理学的に許容されるものであればよい。このような水として、例えば、蒸留水、常水、精製水、滅菌精製水、注射用水及び注射用蒸留水等を挙げることができる。それらの定義は第十七改正日本薬局方に基づく。 The water used in the ophthalmic composition according to this embodiment may be pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Examples of such water include distilled water, ordinary water, purified water, sterile purified water, water for injection, and distilled water for injection. Their definitions are based on the 17th revision of the Japanese Pharmacopoeia.
本実施形態に係る眼科組成物は、所望量の(A)成分、(B)成分、(C)成分、(D)成分、及び必要に応じて他の成分を所望の濃度となるように添加及び混和することにより調製することができる。例えば、精製水でそれらの成分を溶解又は分散させ、所定のpH及び浸透圧に調整し、濾過滅菌等により滅菌処理することで調製できる。 The ophthalmic composition according to the present embodiment contains desired amounts of component (A), component (B), component (C), component (D), and, if necessary, other components at desired concentrations. and blending. For example, it can be prepared by dissolving or dispersing these components in purified water, adjusting to a predetermined pH and osmotic pressure, and sterilizing by filtration sterilization or the like.
本実施形態に係る眼科組成物は、目的に応じて種々の製剤形態をとることができる。製剤形態として、例えば、液剤、ゲル剤、半固形剤(軟膏等)等が挙げられる。 The ophthalmic composition according to this embodiment can take various formulation forms depending on the purpose. Formulations include, for example, liquids, gels, semi-solids (ointments, etc.) and the like.
本実施形態に係る眼科組成物は、例えば、点眼剤(点眼液又は点眼薬ともいう。また、点眼剤にはコンタクトレンズ装用中に点眼可能な点眼剤を含む。)、人工涙液、洗眼剤(洗眼液又は洗眼薬ともいう。また、洗眼剤にはコンタクトレンズ装用中に洗眼可能な洗眼剤を含む。)、コンタクトレンズ用組成物[コンタクトレンズ装着液、コンタクトレンズケア用組成物(コンタクトレンズ消毒剤、コンタクトレンズ用保存剤、コンタクトレンズ用洗浄剤、コンタクトレンズ用洗浄保存剤)、コンタクトレンズパッケージ液等]として用いることができる。なお、「コンタクトレンズ」は、ハードコンタクトレンズ、ソフトコンタクトレンズ(イオン性及び非イオン性の双方を包含し、シリコーンハイドロゲルコンタクトレンズ及び非シリコーンハイドロゲルコンタクトレンズの双方を包含する)を含む。 The ophthalmic composition according to the present embodiment includes, for example, eye drops (also referred to as eye drops or eye drops. Eye drops include eye drops that can be dropped while wearing contact lenses), artificial tears, and eye washes. (Also referred to as eye wash or eye wash. Eye wash includes eye wash that can be washed while wearing contact lenses.), contact lens composition [contact lens wetting solution, contact lens care composition (contact lens disinfectant, contact lens preservative, contact lens cleaning agent, contact lens cleaning and preserving agent), contact lens packaging solution, etc.]. The term "contact lens" includes hard contact lenses and soft contact lenses (both ionic and non-ionic, including both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).
本実施形態に係る眼科組成物は、本発明による効果をより顕著に発揮できることから、点眼剤(コンタクトレンズ装用中に点眼可能な点眼剤を含む。)であることが好ましい。本実施形態に係る眼科組成物が点眼剤である場合、その用法・用量としては、効果を奏し、副作用の少ない用法・用量であれば特に限定されないが、例えば成人(15歳以上)及び7歳以上の小児の場合、1回1~3滴、1~2滴、又は2~3滴を1日2~4回、又は5~6回点眼して用いる方法を例示できる。 The ophthalmic composition according to this embodiment is preferably an eye drop (including an eye drop that can be instilled while wearing contact lenses), since the effects of the present invention can be exhibited more remarkably. When the ophthalmic composition according to the present embodiment is an eye drop, the usage and dosage are not particularly limited as long as they are effective and have few side effects. In the case of children as described above, a method of using 1 to 3 drops, 1 to 2 drops, or 2 to 3 drops at a time, 2 to 4 times, or 5 to 6 times a day can be exemplified.
本実施形態に係る眼科組成物は、任意の容器に収容して提供される。本実施形態に係る眼科組成物を収容する容器については特に制限されず、例えば、ガラス製であってもよく、またプラスチック製であってもよい。好ましくはプラスチック製である。プラスチックとしては、例えば、ポリエチレンテレフタレート(PET)、ポリアリレート、ポリエチレンナフタレート、ポリカーボネート、ポリエチレン、ポリプロピレン、ポリイミド及びこれらを構成するモノマーの共重合体、並びにこれら2種以上を混合したものが挙げられる。好ましくは、ポリエチレンテレフタレートである。また、本実施形態に係る眼科組成物を収容する容器は、容器内部を視認できる透明容器であってもよく、容器内部の視認が困難な不透明容器であってもよい。好ましくは透明容器である。ここで、「透明容器」とは、無色透明容器及び有色透明容器の双方が含まれる。 The ophthalmic composition according to this embodiment is provided in an arbitrary container. The container for containing the ophthalmic composition according to this embodiment is not particularly limited, and may be made of glass or plastic, for example. It is preferably made of plastic. Examples of plastics include polyethylene terephthalate (PET), polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, polyimide, copolymers of these monomers, and mixtures of two or more thereof. Preferred is polyethylene terephthalate. Further, the container containing the ophthalmic composition according to the present embodiment may be a transparent container in which the inside of the container is visible, or an opaque container in which the inside of the container is difficult to be seen. A transparent container is preferred. Here, the "transparent container" includes both a colorless transparent container and a colored transparent container.
本実施形態に係る眼科組成物を収容する容器には、ノズルが装着されてもよい。ノズルの材質については特に制限されず、例えば、ガラス製であってもよく、またプラスチック製であってもよい。好ましくはプラスチック製である。プラスチックとしては、例えば、ポリブチレンテレフタレート、ポリエチレン、ポリプロピレン、ポリエチレンテレフタレート、ポリエチレンナフタレート及びこれらを構成するモノマーの共重合体、並びにこれら2種以上を混合したものが挙げられる。ノズルの材質としては、本発明の効果をより一層高めるという観点から、ポリプロピレン、ポリエチレン、ポリエチレンテレフタレート、ポリブチレンテレフタレート、ポリエチレンナフタレートが好ましく、ポリエチレンがより好ましい。 A nozzle may be attached to the container containing the ophthalmic composition according to the present embodiment. The material of the nozzle is not particularly limited, and may be, for example, glass or plastic. It is preferably made of plastic. Examples of plastics include polybutylene terephthalate, polyethylene, polypropylene, polyethylene terephthalate, polyethylene naphthalate, copolymers of monomers constituting these, and mixtures of two or more of these. From the viewpoint of further enhancing the effects of the present invention, the nozzle material is preferably polypropylene, polyethylene, polyethylene terephthalate, polybutylene terephthalate, or polyethylene naphthalate, and more preferably polyethylene.
本実施形態に係る眼科組成物を収容する容器は、複数回の使用量が収容されるマルチドーズ型であってもよく、単回の使用量が収容されるユニットドーズ型であってもよい。 The container containing the ophthalmic composition according to the present embodiment may be of a multi-dose type that accommodates multiple doses, or may be of a unit dose type that accommodates a single dose.
本実施形態に係る眼科組成物は、内容積が4~30mLである容器に充填されてなることが好ましく、内容積が5~20mLである容器に充填されてなることがより好ましく、内容積が6~16mLである容器に充填されてなることが更に好ましく、内容積が10~15mLである容器に充填されてなることが更により好ましい。また、内容積が0.1~3mLである容器に充填されてもよく、内容積が0.2~1mLである容器に充填されてもよい。 The ophthalmic composition according to the present embodiment is preferably filled in a container having an internal volume of 4 to 30 mL, more preferably filled in a container having an internal volume of 5 to 20 mL. More preferably, it is packed in a container of 6 to 16 mL, and even more preferably packed in a container with an internal volume of 10 to 15 mL. Also, it may be filled in a container with an internal volume of 0.1 to 3 mL, or may be filled in a container with an internal volume of 0.2 to 1 mL.
本実施形態に係る眼科組成物は、後述の試験例において確認されているとおり、滴下量のばらつきを抑制する効果に加えて、目に製剤を入れた時の粘度によらず(高粘度製剤であっても)瞬きをしやすくする効果及び/又は瞬き時の違和感を抑制する効果、使用後の容器への液残りを低減させる効果、昼光、紫外線及び熱による粘度変化を抑制する効果及び紫外線による製剤の着色を抑制する効果を奏する。 As confirmed in the test examples described later, the ophthalmic composition according to the present embodiment has the effect of suppressing variations in the amount of drops, and is independent of the viscosity when the formulation is applied to the eye (high viscosity formulations). Effect of making it easier to blink and / or effect of suppressing discomfort when blinking, effect of reducing liquid residue in the container after use, effect of suppressing viscosity change due to daylight, ultraviolet rays and heat and ultraviolet rays There is an effect of suppressing the coloring of the formulation due to.
以下、試験例に基づいて本発明を具体的に説明するが、本発明はこれらに限定されるものではない。なお、表中の試験溶液の全量はいずれも100mLである。pH調整剤としては塩酸又は水酸化ナトリウムを使用した。 The present invention will be specifically described below based on test examples, but the present invention is not limited to these. In addition, the total amount of the test solution in the table is 100 mL. Hydrochloric acid or sodium hydroxide was used as a pH adjuster.
〔試験例1:滴下量のばらつき評価〕
表1及び2に示す組成で常法に従い各眼科組成物を調製し、試験溶液とした。表1及び2における各成分の単位はw/v%である。なお、試験例1及び以下の試験例、並びに製剤例においては、コンドロイチン硫酸ナトリウムは局外規コンドロイチン硫酸ナトリウム(重量平均分子量約2万5000、マルハニチロ株式会社製)を使用した。次に、調製した各眼科組成物を内容積10mLのポリエチレンテレフタレート製点眼容器に5mL充填し、この容器にポリエチレン製ノズルを装着した。ポリエチレン製ノズルとしては、30~50μLの滴下に適したノズルを使用した。この容器入り点眼剤を水平方向に向けた状態で滴下した場合の1滴滴下毎の滴下重量を測定した。この操作を10回繰り返すことによって求めた平均滴下量(AVG:mg)及び標準偏差(SD:mg)から、下記式1によって滴下量のばらつき(変動係数CV:%)を算出した。得られた各変動係数を用いて、試験溶液1に対する試験溶液2~9の滴下量のばらつき改善率を下記式2に基づき算出し、試験溶液10に対する試験溶液11~14の滴下量のばらつき改善率を下記式3に基づき算出した。結果を表1及び2に示す。
[式1]滴下量のばらつき(変動係数CV:%)=(SD/AVG)×100
[式2]滴下量のばらつき改善率(%)={(試験溶液1の変動係数-試験溶液2~9の変動係数)/試験溶液1の変動係数}×100
[式3]滴下量のばらつき改善率(%)={(試験溶液10の変動係数-試験溶液11~14の変動係数)/試験溶液10の変動係数}×100
[Test Example 1: Evaluation of Variation in Dropping Amount]
Each ophthalmic composition was prepared according to a conventional method with the composition shown in Tables 1 and 2, and used as a test solution. The unit of each component in Tables 1 and 2 is w/v%. In Test Example 1, the following test examples, and formulation examples, chondroitin sulfate sodium chondroitin sulfate (weight average molecular weight of about 25,000, manufactured by Maruha Nichiro Co., Ltd.) was used as sodium chondroitin sulfate. Next, 5 mL of each of the prepared ophthalmic compositions was filled in a polyethylene terephthalate eye drop container having an inner volume of 10 mL, and a polyethylene nozzle was attached to the container. As a polyethylene nozzle, a nozzle suitable for dropping 30 to 50 μL was used. The drop weight of each drop was measured when the eye drops contained in the container were dropped in the horizontal direction. From the average drop amount (AVG: mg) and the standard deviation (SD: mg) obtained by repeating this operation 10 times, the dispersion of the drop amount (variation coefficient CV: %) was calculated by the following formula 1. Using the obtained coefficients of variation, the variation improvement rate of the dropping amount of the test solutions 2 to 9 relative to the test solution 1 is calculated based on the following formula 2, and the variation in the dropping amount of the test solutions 11 to 14 relative to the test solution 10 is improved. The ratio was calculated based on Equation 3 below. Results are shown in Tables 1 and 2.
[Formula 1] Variation in dropping amount (variation coefficient CV: %) = (SD / AVG) × 100
[Formula 2] Drop amount variation improvement rate (%) = {(variation coefficient of test solution 1-variation coefficient of test solutions 2 to 9)/variation coefficient of test solution 1} × 100
[Formula 3] Drop amount variation improvement rate (%) = {(coefficient of variation of test solution 10 - coefficient of variation of test solutions 11 to 14) / coefficient of variation of test solution 10} x 100
コンドロイチン硫酸ナトリウム及びネオスチグミンメチル硫酸塩に加えて、クロルフェニラミンマレイン酸塩又は塩酸テトラヒドロゾリンを更に含む試験溶液2及び5、並びに試験溶液2においてホウ酸とホウ砂に代えてリン酸水素ナトリウム水和物又はEDTAを含む試験溶液3、4、6及び8では、コンドロイチン硫酸ナトリウム及びネオスチグミンメチル硫酸塩を含む試験溶液1と比較して滴下量のばらつきが顕著に改善することが確認された。また、コンドロイチン硫酸ナトリウム及びネオスチグミンメチル硫酸塩に加えて、クロルフェニラミンマレイン酸塩及び塩酸テトラヒドロゾリンを更に含む試験溶液7及び9ではより一層顕著に滴下量のばらつきが顕著に改善することが確認された。 In addition to sodium chondroitin sulfate and neostigmine methyl sulfate, test solutions 2 and 5 further containing chlorpheniramine maleate or tetrahydrozoline hydrochloride, and sodium hydrogen phosphate hydrate instead of boric acid and borax in test solution 2 Alternatively, it was confirmed that test solutions 3, 4, 6 and 8 containing EDTA significantly improved the variability of the drop amount compared to test solution 1 containing sodium chondroitin sulfate and neostigmine methylsulfate. In addition, it was confirmed that test solutions 7 and 9 further containing chlorpheniramine maleate and tetrahydrozoline hydrochloride in addition to sodium chondroitin sulfate and neostigmine methylsulfate significantly improved the variation in the drop amount. .
コンドロイチン硫酸ナトリウム及びシアノコバラミンに加えて、塩酸テトラヒドロゾリン、クロルフェニラミンマレイン酸塩、ネオスチグミン硫酸塩又は塩酸ナファゾリンを更に含む試験溶液11~14では、コンドロイチン硫酸ナトリウム及びシアノコバラミンを含む試験溶液10と比較して滴下量のばらつきが顕著に改善することが確認された。 In addition to sodium chondroitin sulfate and cyanocobalamin, test solutions 11 to 14 further containing tetrahydrozoline hydrochloride, chlorpheniramine maleate, neostigmine sulfate, or naphazoline hydrochloride were dropped compared to test solution 10 containing sodium chondroitin sulfate and cyanocobalamin. It was confirmed that the variation in amount was remarkably improved.
〔試験例2:点眼瓶内の残液量の測定試験〕
表3に示す組成で常法に従い各眼科組成物を調製し、試験溶液とした。表3における各成分の単位はw/v%である。10mL容量のPET製の点眼瓶の風袋の重量を測定し、各眼科組成物を5mL充填した。次に充填した各眼科組成物を出し切った後の各点眼瓶の重量を測定し、下記式4及び5に従って、残液量(g)及び試験溶液1の残液量に対する残液量の改善率(%)を算出した。結果を表3に示す。
(式4)残液量(g)=眼科組成物を出し切った後の点眼瓶の重量-点眼瓶の風袋の重量
(式5)残液量の改善率(%)={1-(各試験溶液の残液量/試験溶液1の残液量)}×100
[Test Example 2: Measurement test of the amount of residual liquid in the eyedropper bottle]
Each ophthalmic composition was prepared according to a conventional method with the composition shown in Table 3 and used as a test solution. The unit of each component in Table 3 is w/v%. A 10 mL PET eye dropper bottle was tared and filled with 5 mL of each ophthalmic composition. Next, the weight of each ophthalmic composition filled in each ophthalmic composition was drained, and the weight of each eyedropper bottle was measured. (%) was calculated. Table 3 shows the results.
(Formula 4) Remaining liquid amount (g) = Weight of eyedropper bottle after the ophthalmic composition has been drained - Tare weight of eyedropper bottle (Formula 5) Improvement rate of residual liquid amount (%) = {1 - (each test Remaining liquid volume of solution/Remaining liquid volume of test solution 1)} × 100
コンドロイチン硫酸ナトリウム及びネオスチグミンメチル硫酸塩に加えて、クロルフェニラミンマレイン酸塩を更に含む試験溶液2、及び試験溶液2においてホウ酸とホウ砂に代えてEDTAを含む試験溶液3では、コンドロイチン硫酸ナトリウム及びネオスチグミンメチル硫酸塩を含む試験溶液1と比較して残液量が減少し、点眼瓶中の眼科組成物が使い切りやすくなることが確認された。また、コンドロイチン硫酸ナトリウム及びネオスチグミンメチル硫酸塩に加えて、クロルフェニラミンマレイン酸塩及び塩酸テトラヒドロゾリン、又はシアノコバラミンを更に含む試験溶液9、15及び16ではより一層顕著に残液量が顕著に減少し、点眼瓶中の眼科組成物がより一層使い切りやすくなることが確認された。 In addition to sodium chondroitin sulfate and neostigmine methyl sulfate, test solution 2 further containing chlorpheniramine maleate, and test solution 3 containing EDTA instead of boric acid and borax in test solution 2, sodium chondroitin sulfate and Compared to test solution 1 containing neostigmine methylsulfate, the amount of residual liquid was reduced, and it was confirmed that the ophthalmic composition in the eyedropper bottle can be used up easily. In addition, in addition to sodium chondroitin sulfate and neostigmine methyl sulfate, test solutions 9, 15 and 16 further containing chlorpheniramine maleate and tetrahydrozoline hydrochloride, or cyanocobalamin significantly reduced the residual liquid volume, It was confirmed that the ophthalmic composition in the eyedropper bottle is much easier to use up.
〔試験例3:光照射による粘度安定性試験〕
表4及び5に示す組成で常法に従い各眼科組成物を調製し、試験溶液とした。表4及び5における各成分の単位はw/v%である。10mL容量のガラスヘッドスペースバイアル(ジーエルサイエンス社)に各眼科組成物を10mLずつ充填し、光安定性試験装置(LT-120A-WCD(ナガノサイエンス社製))にて、D65蛍光ランプを光源として、室温25℃の下、照度4000lx/hで積算照度120万lxとなるまで照射した。照射前後の各眼科組成物(600μL)について、レオメーター(MCR302(AntonPaar社))にて、コーンプレート型測定治具(CP50-1、d:0.102mm)を用いて、34℃でのせん断速度(1~10000(1/s))に対する粘度を測定した。そして、せん断速度10000(1/s)での粘度(mPa・s)を用いて、下記式6、7に従い、試験前後の粘度安定性を評価した。結果を表4及び5に示す。なお、粘度変化率の絶対値が小さい程、光照射による粘度変化が生じず、眼科組成物が物性的に同等に保たれていることを示す。
(式6)粘度変化率(%)={(各眼科組成物の光照射前粘度-各眼科組成物の光照射後粘度)/各眼科組成物の光照射前粘度}×100
(式7)粘度変化改善率(%)={(試験溶液1(表5では試験溶液10)の粘度変化率-各試験溶液の粘度変化率)/試験溶液1(表5では試験溶液10)の粘度変化率}×100
[Test Example 3: Viscosity stability test by light irradiation]
Each ophthalmic composition was prepared according to a conventional method with the composition shown in Tables 4 and 5, and used as a test solution. The unit of each component in Tables 4 and 5 is w/v%. 10 mL of each ophthalmic composition was filled in a 10 mL capacity glass headspace vial (GL Sciences Inc.) and tested with a photostability tester (LT-120A-WCD (manufactured by Nagano Sciences)) using a D65 fluorescent lamp as a light source. , at a room temperature of 25° C., irradiation was performed at an illuminance of 4000 lx/h until an integrated illuminance of 1,200,000 lx. Each ophthalmic composition (600 μL) before and after irradiation was subjected to shearing at 34° C. using a cone-plate measuring jig (CP50-1, d: 0.102 mm) with a rheometer (MCR302 (AntonPaar)). Viscosity was measured against speed (1-10000 (1/s)). Then, using the viscosity (mPa·s) at a shear rate of 10000 (1/s), the viscosity stability before and after the test was evaluated according to Equations 6 and 7 below. Results are shown in Tables 4 and 5. The smaller the absolute value of the viscosity change rate, the less the viscosity change due to light irradiation, and the more the ophthalmic composition maintains the same physical properties.
(Formula 6) Viscosity change rate (%) = {(Viscosity of each ophthalmic composition before light irradiation - Viscosity of each ophthalmic composition after light irradiation)/Viscosity of each ophthalmic composition before light irradiation} x 100
(Formula 7) Viscosity change improvement rate (%) = {(viscosity change rate of test solution 1 (test solution 10 in Table 5) - viscosity change rate of each test solution) / test solution 1 (test solution 10 in Table 5) Viscosity change rate} × 100
コンドロイチン硫酸ナトリウム及びネオスチグミンメチル硫酸塩に加えて、クロルフェニラミンマレイン酸塩を更に含む試験溶液2及び4では、コンドロイチン硫酸ナトリウム及びネオスチグミンメチル硫酸塩を含む試験溶液1と比較してD65蛍光ランプを光源として用いた場合の粘度変化率が低下し、光(昼光)照射による眼科組成物の安定性が向上することが確認された。また、コンドロイチン硫酸ナトリウム及びシアノコバラミンに加えて、塩酸テトラヒドロゾリン、クロルフェニラミンマレイン酸塩、ネオスチグミンメチル硫酸塩又は塩酸ナファゾリンを更に含む試験溶液11、12、13及び14では、コンドロイチン硫酸ナトリウム及びシアノコバラミンを含む試験溶液10と比較してD65蛍光ランプを光源として用いた場合の粘度変化率が低下し、光(昼光)照射による眼科組成物の安定性が向上することが確認された。 In addition to sodium chondroitin sulfate and neostigmine methylsulfate, test solutions 2 and 4, which also contain chlorpheniramine maleate, were compared to test solution 1, which contained sodium chondroitin sulfate and neostigmine methylsulfate, using a D65 fluorescent lamp as the light source. It was confirmed that the viscosity change rate when used as is reduced and the stability of the ophthalmic composition due to light (daylight) irradiation is improved. In addition to sodium chondroitin sulfate and cyanocobalamin, test solutions 11, 12, 13 and 14 further containing tetrahydrozoline hydrochloride, chlorpheniramine maleate, neostigmine methylsulfate or naphazoline hydrochloride were tested with sodium chondroitin sulfate and cyanocobalamin. It was confirmed that the viscosity change rate was lower when a D65 fluorescent lamp was used as the light source compared to solution 10, and the stability of the ophthalmic composition against light (daylight) irradiation was improved.
〔試験例4:紫外線照射による粘度安定性試験〕
表6及び7に示す組成で常法に従い調製した各眼科組成物をガラス瓶(10mL)に10mL充填し、35℃において、SUNTESTER XLS+(東洋精機社製、1700W キセノン空冷ランプ光源)を用いて、紫外光照度765(W/m2)、48時間(試験溶液10、12、14)または96時間(試験溶液1、2、3、4、5、7、15)照射した。各眼科組成物を25℃で十分に恒温化させた後、上記と同様に粘度を測定し、せん断速度1000(1/s)での粘度(mPa・s)を用いて、試験前後の粘度安定性を評価した。結果を表6及び7に示す。
[Test Example 4: Viscosity stability test by UV irradiation]
A glass bottle (10 mL) was filled with 10 mL of each ophthalmic composition having the composition shown in Tables 6 and 7 and prepared according to a conventional method. Light intensity of 765 (W/m2), irradiation for 48 hours (test solutions 10, 12, 14) or 96 hours (test solutions 1, 2, 3, 4, 5, 7, 15). After sufficiently isothermalizing each ophthalmic composition at 25 ° C., the viscosity was measured in the same manner as above, and the viscosity (mPa s) at a shear rate of 1000 (1 / s) was used to determine the viscosity stability before and after the test. evaluated the sex. Results are shown in Tables 6 and 7.
コンドロイチン硫酸ナトリウム及びネオスチグミンメチル硫酸塩に加えて、クロルフェニラミンマレイン酸塩を更に含む試験溶液2及び4では、コンドロイチン硫酸ナトリウム及びネオスチグミンメチル硫酸塩を含む試験溶液1と比較してD65蛍光ランプを光源として用いた場合の粘度変化が抑制され、光(昼光)照射による眼科組成物の安定性が向上することが確認された。また、コンドロイチン硫酸ナトリウム及びネオスチグミンメチル硫酸塩に加えて、クロルフェニラミンマレイン酸塩を更に含む試験溶液2、3、4及び15、コンドロイチン硫酸ナトリウム及びネオスチグミンメチル硫酸塩に加えて、塩酸テトラヒドロゾリンを更に含む試験溶液5、コンドロイチン硫酸ナトリウム及びネオスチグミンメチル硫酸塩に加えて、クロルフェニラミンマレイン酸塩と塩酸テトラヒドロゾリンを更に含む試験溶液7では、コンドロイチン硫酸ナトリウム及びネオスチグミンメチル硫酸塩を含む試験溶液1と比較してキセノンランプを光源として用いた場合の粘度変化が抑制され、光(紫外線)照射による眼科組成物の安定性が向上することが確認された。さらに、コンドロイチン硫酸ナトリウム及びシアノコバラミンに加えて、クロルフェニラミンマレイン酸塩、塩酸ナファゾリンをそれぞれ更に含む試験溶液12及び14では、コンドロイチン硫酸ナトリウム及びシアノコバラミンを含む試験溶液10と比較してキセノンランプを光源として用いた場合の粘度変化が抑制され、光(紫外線)照射による眼科組成物の安定性が向上することが確認された。 In addition to sodium chondroitin sulfate and neostigmine methylsulfate, test solutions 2 and 4, which also contain chlorpheniramine maleate, were compared to test solution 1, which contained sodium chondroitin sulfate and neostigmine methylsulfate, using a D65 fluorescent lamp as the light source. It was confirmed that the viscosity change when used as is suppressed, and the stability of the ophthalmic composition due to light (daylight) irradiation is improved. In addition to sodium chondroitin sulfate and neostigmine methylsulfate, test solutions 2, 3, 4 and 15 further containing chlorpheniramine maleate, and sodium chondroitin sulfate and neostigmine methylsulfate further containing tetrahydrozoline hydrochloride In addition to test solution 5, sodium chondroitin sulfate and neostigmine methylsulfate, test solution 7 further containing chlorpheniramine maleate and tetrahydrozoline hydrochloride compared to test solution 1 containing sodium chondroitin sulfate and neostigmine methylsulfate. It was confirmed that the viscosity change is suppressed when a xenon lamp is used as a light source, and the stability of the ophthalmic composition is improved by light (ultraviolet) irradiation. Furthermore, in addition to sodium chondroitin sulfate and cyanocobalamin, test solutions 12 and 14 further containing chlorpheniramine maleate and naphazoline hydrochloride, respectively, were compared with test solution 10 containing sodium chondroitin sulfate and cyanocobalamin using a xenon lamp as a light source. It was confirmed that the change in viscosity when used was suppressed, and the stability of the ophthalmic composition against light (ultraviolet) irradiation was improved.
〔試験例5:紫外線照射による外観(色)の変化抑制試験〕
表8に示す組成で常法に従い各眼科組成物を調製し、試験溶液とした。表8における各成分の単位はw/v%である。各眼科組成物をガラス瓶(10mL)に10mL充填し、35℃において、SUNTESTER XLS+(東洋精機社製、1700W キセノン空冷ランプ光源)を用いて、紫外光照度765(W/m2)、48時間照射した。その後、各眼科組成物を25℃で十分に恒温化させ、分光測色計(CM3500d:コニカミノルタ社製)を用いて、紫外線照射前後の各眼科組成物の色差(L、a、b値)を測定し、下記式7に従って紫外線照射前後での眼科組成物の外観(色)の変化(ΔE*ab)を算出し、さらに下記式8、9に従って、色差変化低下率を算出した。なお、ΔE値が小さいほど、眼科組成物の外観(色)の変化(着色)が抑制されていることを表す。結果を表8に示す。
(式8)ΔE*ab=〔(ΔL*)×2+(Δa*)×2+(Δb*)×2〕×1/2
(式9)色差変化低下率(%)={1-(各試験溶液のΔE*ab)/試験溶液10のΔE*ab}×100
[Test Example 5: Appearance (color) change suppression test due to ultraviolet irradiation]
Each ophthalmic composition was prepared according to a conventional method with the composition shown in Table 8 and used as a test solution. The unit of each component in Table 8 is w/v%. 10 mL of each ophthalmic composition was filled in a glass bottle (10 mL) and irradiated at 35° C. for 48 hours at an ultraviolet light illuminance of 765 (W/m 2 ) using SUNTESTER XLS+ (manufactured by Toyo Seiki Co., Ltd., 1700 W xenon air-cooled lamp light source). . After that, each ophthalmic composition was sufficiently thermostated at 25° C., and the color difference (L, a, b values) of each ophthalmic composition before and after ultraviolet irradiation was measured using a spectrophotometer (CM3500d: manufactured by Konica Minolta Co., Ltd.). was measured, the change in appearance (color) of the ophthalmic composition before and after UV irradiation (ΔE*ab) was calculated according to the following formula 7, and the color difference change reduction rate was calculated according to the following formulas 8 and 9. Note that the smaller the ΔE value, the more suppressed the change (coloring) in the appearance (color) of the ophthalmic composition. Table 8 shows the results.
(Formula 8) ΔE*ab = [(ΔL*) x 2 + (Δa*) x 2 + (Δb*) x 2] x 1/2
(Formula 9) Color difference change reduction rate (%) = {1-(ΔE*ab of each test solution)/ΔE*ab of test solution 10} × 100
コンドロイチン硫酸ナトリウム及びシアノコバラミンに加えて、塩酸テトラヒドロゾリン、クロルフェニラミンマレイン酸塩、ネオスチグミン硫酸塩又は塩酸ナファゾリンを更に含む試験溶液11~14では、コンドロイチン硫酸ナトリウム及びシアノコバラミンを含む試験溶液10と比較して、紫外線照射による製剤の着色が抑制されることが確認された。 In addition to sodium chondroitin sulfate and cyanocobalamin, test solutions 11 to 14 further containing tetrahydrozoline hydrochloride, chlorpheniramine maleate, neostigmine sulfate, or naphazoline hydrochloride compared to test solution 10 containing sodium chondroitin sulfate and cyanocobalamin: It was confirmed that the coloring of the formulation due to ultraviolet irradiation was suppressed.
〔試験例6:光照射による外観(色)の変化抑制試験〕
表9に示す組成で常法に従い各眼科組成物を調製し、試験溶液とした。表9における各成分の単位は表中に明記したもの以外はw/v%である。10mL容量のガラスヘッドスペースバイアルに各眼科組成物を10mL充填し、60℃の恒温庫にて3週間静置保管した。その後、各眼科組成物を25℃で十分に恒温化させ、分光測色計(CM3500d:コニカミノルタ社製)を用いて、熱加速試験前後の各眼科組成物の色差(L、a、b値)を測定し、下記式9に従って熱加速試験前後での眼科組成物の外観(透明度)の変化(ΔE*ab)を算出し、さらに下記式10に従って透明度差変化低下率を算出した。結果を表9に示す。なお、ΔE*ab値が小さいほど、製剤の外観(透明度)の変化が抑制されていることを示す。
(式9)ΔE*ab=〔(ΔL*)×2+(Δa*)×2+(Δb*)×2〕×1/2
(式10)透明度差変化低下率(%)={1-(対応する試験溶液のΔE*ab)/試験溶液10のΔE*ab}×100
[Test Example 6: Appearance (color) change suppression test due to light irradiation]
Each ophthalmic composition was prepared according to a conventional method with the composition shown in Table 9, and used as a test solution. The unit of each component in Table 9 is w/v% unless specified in the table. 10 mL of each ophthalmic composition was filled in a 10-mL glass headspace vial, and stored in a thermostat at 60°C for 3 weeks. After that, each ophthalmic composition was sufficiently thermostated at 25° C., and a spectrophotometer (CM3500d: manufactured by Konica Minolta) was used to measure the color difference (L, a, b values) ) was measured, the change (ΔE*ab) in the appearance (transparency) of the ophthalmic composition before and after the thermal acceleration test was calculated according to the following formula 9, and the transparency difference change reduction rate was calculated according to the following formula 10. Table 9 shows the results. It should be noted that the smaller the ΔE*ab value, the more suppressed the change in appearance (transparency) of the formulation.
(Formula 9) ΔE * ab = [(ΔL *) × 2 + (Δa *) × 2 + (Δb *) × 2] × 1/2
(Formula 10) Transparency difference change reduction rate (%) = {1-(ΔE*ab of corresponding test solution)/ΔE*ab of test solution 10} × 100
コンドロイチン硫酸ナトリウム及びシアノコバラミンに加えて、塩酸テトラヒドロゾリン、クロルフェニラミンマレイン酸塩、ネオスチグミン硫酸塩又は塩酸ナファゾリンを更に含む試験溶液11~14では、コンドロイチン硫酸ナトリウム及びシアノコバラミンを含む試験溶液10と比較して、光照射による製剤の着色が抑制されることが確認された。 In addition to sodium chondroitin sulfate and cyanocobalamin, test solutions 11 to 14 further containing tetrahydrozoline hydrochloride, chlorpheniramine maleate, neostigmine sulfate, or naphazoline hydrochloride compared to test solution 10 containing sodium chondroitin sulfate and cyanocobalamin: It was confirmed that the coloring of the formulation due to light irradiation was suppressed.
〔製剤例〕
下記表10及び11に記載の処方で、常法により点眼剤を調製した。なお、各成分量の単位は、表中に明記したもの以外はw/v%である。いずれも、ポリエチレンテレフタレート製の容器に充填し、それぞれの処方において、低密度ポリエチレン製のノズルを装着したもの、キャップ装着時(保存時)において内容液と接液する可能性のある壁面の全部がポリブチレンテレフタレート製のノズルを装着したもの、内容液と接液する可能性のある壁面の一部がポリエチレンテレフタレート製のノズルを装着したもの、内容液と接液する可能性のある壁面の一部がポリエチレンナフタレート製のノズルを装着したもの、を調製した。
[Formulation example]
Eye drops were prepared by a conventional method according to the formulations shown in Tables 10 and 11 below. In addition, the unit of each component amount is w/v % except for those specified in the table. All of them are packed in a container made of polyethylene terephthalate, and each formulation has a low-density polyethylene nozzle attached, and all the walls that may come into contact with the content liquid when the cap is attached (during storage) Those with polybutylene terephthalate nozzles, those with polyethylene terephthalate nozzles on the part of the wall that may come in contact with the liquid content, and the part of the wall that may come in contact with the liquid was equipped with a nozzle made of polyethylene naphthalate.
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JP2005247803A (en) * | 2004-03-08 | 2005-09-15 | Zeria Pharmaceut Co Ltd | Eye drop and container of the same |
JP2005247799A (en) * | 2004-03-08 | 2005-09-15 | Zeria Pharmaceut Co Ltd | Eye drop |
JP2005247798A (en) * | 2004-03-08 | 2005-09-15 | Zeria Pharmaceut Co Ltd | Eye drop |
JP2005247795A (en) * | 2004-03-08 | 2005-09-15 | Zeria Pharmaceut Co Ltd | Stable eye drops |
JP2006151828A (en) * | 2004-11-25 | 2006-06-15 | Zeria Pharmaceut Co Ltd | Ophthalmological composition |
JP2015052023A (en) * | 2009-12-02 | 2015-03-19 | ロート製薬株式会社 | Ophthalmic composition for silicone hydrogel contact lens |
JP2019199469A (en) * | 2018-05-09 | 2019-11-21 | ロート製薬株式会社 | Aqueous ophthalmic composition |
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JPH01224321A (en) * | 1988-03-02 | 1989-09-07 | Taisho Pharmaceut Co Ltd | Ophthalmic preparation |
JPH0283318A (en) * | 1988-09-20 | 1990-03-23 | Zeria Pharmaceut Co Ltd | Stable eye drop |
JP2000143501A (en) * | 1998-11-12 | 2000-05-23 | Zeria Pharmaceut Co Ltd | Sulfa drug-containing ophthalmic solution |
JP2001278788A (en) * | 2000-03-30 | 2001-10-10 | Zeria Pharmaceut Co Ltd | Stable liquid preparation formulated with allantoin |
WO2003053472A1 (en) * | 2001-12-21 | 2003-07-03 | Senju Pharmaceutical Co., Ltd. | Eye drops |
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JP2005247799A (en) * | 2004-03-08 | 2005-09-15 | Zeria Pharmaceut Co Ltd | Eye drop |
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JP2005247795A (en) * | 2004-03-08 | 2005-09-15 | Zeria Pharmaceut Co Ltd | Stable eye drops |
JP2006151828A (en) * | 2004-11-25 | 2006-06-15 | Zeria Pharmaceut Co Ltd | Ophthalmological composition |
JP2015052023A (en) * | 2009-12-02 | 2015-03-19 | ロート製薬株式会社 | Ophthalmic composition for silicone hydrogel contact lens |
JP2019199469A (en) * | 2018-05-09 | 2019-11-21 | ロート製薬株式会社 | Aqueous ophthalmic composition |
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