JP5740906B2 - Ophthalmic agent - Google Patents
Ophthalmic agent Download PDFInfo
- Publication number
- JP5740906B2 JP5740906B2 JP2010235298A JP2010235298A JP5740906B2 JP 5740906 B2 JP5740906 B2 JP 5740906B2 JP 2010235298 A JP2010235298 A JP 2010235298A JP 2010235298 A JP2010235298 A JP 2010235298A JP 5740906 B2 JP5740906 B2 JP 5740906B2
- Authority
- JP
- Japan
- Prior art keywords
- purified water
- sodium hydroxide
- chlorobutanol
- appropriate amount
- added
- 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.)
- Active
Links
- 239000003732 agents acting on the eye Substances 0.000 title claims description 29
- 229940125702 ophthalmic agent Drugs 0.000 title claims description 29
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 claims description 160
- 229960004926 chlorobutanol Drugs 0.000 claims description 80
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 65
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 60
- 239000004327 boric acid Substances 0.000 claims description 60
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 44
- 229930195725 Mannitol Natural products 0.000 claims description 44
- 239000000594 mannitol Substances 0.000 claims description 44
- 235000010355 mannitol Nutrition 0.000 claims description 44
- 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 claims description 29
- 229940046978 chlorpheniramine maleate Drugs 0.000 claims description 29
- 238000002360 preparation method Methods 0.000 claims description 27
- TVQZAMVBTVNYLA-UHFFFAOYSA-N Pranoprofen Chemical compound C1=CC=C2CC3=CC(C(C(O)=O)C)=CC=C3OC2=N1 TVQZAMVBTVNYLA-UHFFFAOYSA-N 0.000 claims description 24
- 229960003101 pranoprofen Drugs 0.000 claims description 24
- 150000005846 sugar alcohols Chemical class 0.000 claims description 22
- 229940079593 drug Drugs 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 16
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 claims description 12
- POJWUDADGALRAB-UHFFFAOYSA-N allantoin Chemical compound NC(=O)NC1NC(=O)NC1=O POJWUDADGALRAB-UHFFFAOYSA-N 0.000 claims description 10
- 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 10
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 9
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 235000010356 sorbitol Nutrition 0.000 claims description 8
- 239000000600 sorbitol Substances 0.000 claims description 8
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 claims description 7
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 7
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 7
- 239000000811 xylitol Substances 0.000 claims description 7
- 235000010447 xylitol Nutrition 0.000 claims description 7
- 229960002675 xylitol Drugs 0.000 claims description 7
- 229960002684 aminocaproic acid Drugs 0.000 claims description 6
- IMZMKUWMOSJXDT-UHFFFAOYSA-N cromoglycic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C(O)=O)O2 IMZMKUWMOSJXDT-UHFFFAOYSA-N 0.000 claims description 6
- 229960003080 taurine Drugs 0.000 claims description 6
- POJWUDADGALRAB-PVQJCKRUSA-N Allantoin Natural products NC(=O)N[C@@H]1NC(=O)NC1=O POJWUDADGALRAB-PVQJCKRUSA-N 0.000 claims description 5
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 5
- BIVBRWYINDPWKA-VLQRKCJKSA-L Glycyrrhizinate dipotassium Chemical compound [K+].[K+].O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C([O-])=O)[C@@H]1O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@H]1O BIVBRWYINDPWKA-VLQRKCJKSA-L 0.000 claims description 5
- 229960000458 allantoin Drugs 0.000 claims description 5
- 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 claims description 5
- 229960000265 cromoglicic acid Drugs 0.000 claims description 5
- 229960002104 cyanocobalamin Drugs 0.000 claims description 5
- 235000000639 cyanocobalamin Nutrition 0.000 claims description 5
- 239000011666 cyanocobalamin Substances 0.000 claims description 5
- 229940101029 dipotassium glycyrrhizinate Drugs 0.000 claims description 5
- 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 claims description 5
- 229960002253 neostigmine methylsulfate Drugs 0.000 claims description 5
- BJORNXNYWNIWEY-UHFFFAOYSA-N tetrahydrozoline hydrochloride Chemical compound Cl.N1CCN=C1C1C2=CC=CC=C2CCC1 BJORNXNYWNIWEY-UHFFFAOYSA-N 0.000 claims description 5
- 229940021790 tetrahydrozoline hydrochloride Drugs 0.000 claims description 5
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 claims description 4
- 229960004172 pyridoxine hydrochloride Drugs 0.000 claims description 4
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 claims description 4
- 239000011764 pyridoxine hydrochloride Substances 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- IKALZAKZWHFNIC-JIZZDEOASA-L dipotassium;(2s)-2-aminobutanedioate Chemical compound [K+].[K+].[O-]C(=O)[C@@H](N)CC([O-])=O IKALZAKZWHFNIC-JIZZDEOASA-L 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- VWWQXMAJTJZDQX-UHFFFAOYSA-N Flavine adenine dinucleotide Natural products C1=NC2=C(N)N=CN=C2N1C(C(O)C1O)OC1COP(O)(=O)OP(O)(=O)OCC(O)C(O)C(O)CN1C2=NC(=O)NC(=O)C2=NC2=C1C=C(C)C(C)=C2 VWWQXMAJTJZDQX-UHFFFAOYSA-N 0.000 claims description 2
- 229960002645 boric acid Drugs 0.000 claims description 2
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 claims 2
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims 1
- 235000008160 pyridoxine Nutrition 0.000 claims 1
- 239000011677 pyridoxine Substances 0.000 claims 1
- IDBYLPRJLWSMAI-UHFFFAOYSA-M sodium;1,2,3,3a,4,5,6,7,8,8a-decahydroazulene-1-sulfonate Chemical compound [Na+].C1CCCCC2C(S(=O)(=O)[O-])CCC21 IDBYLPRJLWSMAI-UHFFFAOYSA-M 0.000 claims 1
- 229940011671 vitamin b6 Drugs 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 351
- 239000008213 purified water Substances 0.000 description 155
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 155
- 239000003889 eye drop Substances 0.000 description 52
- 238000001914 filtration Methods 0.000 description 51
- 239000000243 solution Substances 0.000 description 51
- 230000000052 comparative effect Effects 0.000 description 19
- 230000000694 effects Effects 0.000 description 8
- 239000000872 buffer Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- 230000000087 stabilizing effect Effects 0.000 description 6
- 229910021538 borax Inorganic materials 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- YNQQEYBLVYAWNX-WLHGVMLRSA-N ketotifen fumarate Chemical compound OC(=O)\C=C\C(O)=O.C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 YNQQEYBLVYAWNX-WLHGVMLRSA-N 0.000 description 5
- 229960003630 ketotifen fumarate Drugs 0.000 description 5
- 239000004328 sodium tetraborate Substances 0.000 description 5
- 238000000354 decomposition reaction Methods 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- GEYJUFBPCGDENK-UHFFFAOYSA-M sodium;3,8-dimethyl-5-propan-2-ylazulene-1-sulfonate Chemical compound [Na+].CC(C)C1=CC=C(C)C2=C(S([O-])(=O)=O)C=C(C)C2=C1 GEYJUFBPCGDENK-UHFFFAOYSA-M 0.000 description 4
- 150000003505 terpenes Chemical class 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010015946 Eye irritation Diseases 0.000 description 3
- 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 3
- 239000004372 Polyvinyl alcohol 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
- 231100000013 eye irritation Toxicity 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 239000007951 isotonicity adjuster Substances 0.000 description 3
- -1 polyoxyethylene monostearate Polymers 0.000 description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 208000024891 symptom Diseases 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
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000172 allergic effect Effects 0.000 description 2
- 230000002421 anti-septic effect Effects 0.000 description 2
- 208000003464 asthenopia Diseases 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
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- 229940062138 glycerin 1000 mg Drugs 0.000 description 2
- 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 2
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- LEAHFJQFYSDGGP-UHFFFAOYSA-K trisodium;dihydrogen phosphate;hydrogen phosphate Chemical compound [Na+].[Na+].[Na+].OP(O)([O-])=O.OP([O-])([O-])=O LEAHFJQFYSDGGP-UHFFFAOYSA-K 0.000 description 2
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- UVZZAUIWJCQWEO-DFWYDOINSA-N (2s)-2-aminopentanedioic acid;sodium Chemical compound [Na].OC(=O)[C@@H](N)CCC(O)=O UVZZAUIWJCQWEO-DFWYDOINSA-N 0.000 description 1
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
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- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- YKZPPPNXRZHVGX-PXYKVGKMSA-L dipotassium;(2s)-2-aminobutanedioate;hydron;hydrate Chemical compound [H+].[H+].O.[K+].[K+].[O-]C(=O)[C@@H](N)CC([O-])=O.[O-]C(=O)[C@@H](N)CC([O-])=O YKZPPPNXRZHVGX-PXYKVGKMSA-L 0.000 description 1
- KFGJICJPSZZEEP-UHFFFAOYSA-L dipotassium;hydrogen phosphate;hydrate Chemical compound O.[K+].[K+].OP([O-])([O-])=O KFGJICJPSZZEEP-UHFFFAOYSA-L 0.000 description 1
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- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
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- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229940068988 potassium aspartate Drugs 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940021651 pyridoxine hydrochloride 100 mg Drugs 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940079839 sodium dehydroacetate Drugs 0.000 description 1
- 235000019259 sodium dehydroacetate Nutrition 0.000 description 1
- 229940010747 sodium hyaluronate Drugs 0.000 description 1
- DSOWAKKSGYUMTF-GZOLSCHFSA-M sodium;(1e)-1-(6-methyl-2,4-dioxopyran-3-ylidene)ethanolate Chemical compound [Na+].C\C([O-])=C1/C(=O)OC(C)=CC1=O DSOWAKKSGYUMTF-GZOLSCHFSA-M 0.000 description 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229940045613 taurine 1000 mg Drugs 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
本発明は、眼科用剤の分野に関する。さらに詳しくは、薬物及びクロロブタノールを含有する眼科用剤において、クロロブタノールの分解による経時的なｐＨの低下を改善することを可能にする技術に関する。 The present invention relates to the field of ophthalmic agents. More specifically, the present invention relates to a technique that makes it possible to improve a decrease in pH over time due to decomposition of chlorobutanol in an ophthalmic agent containing a drug and chlorobutanol.
一般的に、クロルフェニラミンマレイン酸塩、ケトチフェンフマル酸塩、塩酸テトラヒドロゾリン、ネオスチグミンメチル硫酸塩、グリチルリチン酸二カリウム、タウリン、コンドロイチン硫酸ナトリウム、ピリドキシン塩酸塩、Ｌ−アスパラギン酸カリウム、フラビンアデニンジヌクレオチドナトリウム、シアノコバラミン、クロモグリク酸ナトリウム、アラントイン、アズレンスルホン酸ナトリウム、ε−アミノカプロン酸、プラノプロフェン等を配合した眼科用剤においては、眼の疲労感を改善する効果やアレルギー症状による眼掻痒感を緩和する効果が求められる。さらに、コンプライアンスの向上のため、薬物や添加物に由来する眼刺激性の軽減が求められる。 In general, chlorpheniramine maleate, ketotifen fumarate, tetrahydrozoline hydrochloride, neostigmine methyl sulfate, dipotassium glycyrrhizinate, taurine, chondroitin sulfate sodium, pyridoxine hydrochloride, potassium L-aspartate, flavin adenine dinucleotide sodium , Cyanocobalamin, sodium cromoglycate, allantoin, sodium azulene sulfonate, epsilon-aminocaproic acid, pranoprofen, etc., can reduce eye fatigue and allergic symptoms An effect is required. Furthermore, in order to improve compliance, reduction of eye irritation derived from drugs and additives is required.
例えば、クロロブタノールは、眼科用剤に用いられる成分であり、局所麻酔作用を有することから、眼刺激性のある成分と同時に配合することにより、刺激感を軽減することができる。そのような例として、プラノプロフェン及びクロロブタノールを同時配合した製剤が開示されている（特許文献１）。 For example, chlorobutanol is a component used in ophthalmic agents and has a local anesthetic action, so that the irritant feeling can be reduced by blending it simultaneously with a component having eye irritation. As such an example, a preparation containing pranoprofen and chlorobutanol at the same time is disclosed (Patent Document 1).
また、眼科用剤には、眼の疲労感を改善したり、アレルギー症状による眼掻痒感を緩和したりすることを目的として、メントールやカンフル等のテルペノイド類が配合されるが、少量では期待されるほどの効果が得られない。そこで、テルペノイド類を増量すると、テルペノイド類由来の清涼感が強すぎるため、眼刺激感が生じ、かえって使用感が悪くなる問題がある。しかし、テルペノイド類を高濃度で配合した製剤であっても、クロロブタノールを配合することで刺激感のマスキングが可能となり使用感が向上する。このような例として、ケトチフェンフマル酸塩、メントール、及びクロロブタノールを同時配合した製剤が開示されている（特許文献２）。 Ophthalmic preparations contain terpenoids such as menthol and camphor for the purpose of improving eye fatigue and alleviating itching caused by allergic symptoms. The effect is not obtained. Therefore, when the amount of terpenoids is increased, the refreshing feeling derived from the terpenoids is too strong, causing an eye irritation feeling, and on the contrary, there is a problem that the feeling of use becomes worse. However, even in a preparation containing terpenoids at a high concentration, the use of chlorobutanol can mask irritation and improve the feeling of use. As such an example, a preparation containing ketotifen fumarate, menthol, and chlorobutanol is disclosed (Patent Document 2).
また、クロロブタノールは防腐作用を有することから、眼科用剤において広く汎用されており、例えば、ヒアルロン酸ナトリウム、タウリン、Ｌ−アスパラギン酸、ε−アミノカプロン酸、コンドロイチン硫酸ナトリウムから選ばれる１種又は２種以上、及びクロロブタノールを同時配合する製剤が開示されている（特許文献３）。また、プラノプロフェン、クロロブタノール、水溶性高分子を同時配合した製剤が開示されている（特許文献４）。 Moreover, since chlorobutanol has antiseptic action, it is widely used in ophthalmic preparations, for example, one or two selected from sodium hyaluronate, taurine, L-aspartic acid, ε-aminocaproic acid, and sodium chondroitin sulfate. The formulation which mix | blends a seed or more and chlorobutanol simultaneously is disclosed (patent document 3). In addition, a preparation containing pranoprofen, chlorobutanol, and a water-soluble polymer is disclosed (Patent Document 4).
しかしながら、クロロブタノールを配合した眼科用剤は、熱や光によりクロロブタノールが経時的に分解することでｐＨが低下することが知られており、これにより配合成分の不安定化や析出等の問題が生じるという課題があった。また、特許文献４では、プラノプロフェンを溶解させるのに適切なｐＨ（ｐＨ７〜８）ではクロロブタノールが不安定となり速やかに分解してしまうという課題が開示されており、この課題を解決するために、ｐＨ６．５を超える領域でプラノプロフェンを溶解させた後にｐＨを６．５以下に調整するという煩雑な作業を必要としている。 However, ophthalmic preparations formulated with chlorobutanol are known to decrease pH due to degradation of chlorobutanol over time by heat and light, which causes problems such as destabilization and precipitation of the components. There was a problem that occurred. Patent Document 4 discloses a problem that chlorobutanol becomes unstable and quickly decomposes at a pH (pH 7 to 8) appropriate for dissolving pranoprofen. In addition, a complicated operation of adjusting the pH to 6.5 or less after pranoprofen is dissolved in a region exceeding pH 6.5 is required.
従来、製剤のｐＨ低下を抑制する方法として、リン酸塩緩衝剤（例えば、リン酸二水素ナトリウム−リン酸水素二ナトリウム等）、ホウ酸緩衝剤（ホウ酸−ホウ砂）などを添加する方法が知られているが、その抑制効果は十分なものではなかった（「緩衝液の選択と応用」Ｄ．Ｄ．ペリン著 講談社サイエンティフィック）。 Conventionally, as a method for suppressing a decrease in pH of a preparation, a method of adding a phosphate buffer (for example, sodium dihydrogen phosphate-disodium hydrogen phosphate), a borate buffer (boric acid-borax), or the like. However, its inhibitory effect was not sufficient ("Selection and application of buffer solution" by D. Perrin Kodansha Scientific).
したがって、本発明は、薬物及びクロロブタノールを含有する眼科用剤において、クロロブタノールの分解による経時的なｐＨの低下を抑制することを課題とする。 Therefore, an object of the present invention is to suppress a decrease in pH over time due to decomposition of chlorobutanol in an ophthalmic preparation containing a drug and chlorobutanol.
本発明者らは、かかる課題を解決するために種々検討した結果、薬物及びクロロブタノールを含有する眼科用剤に、さらにホウ酸と糖アルコールを配合することにより、眼科用剤のｐＨ低下を抑制できることを見出し、本発明を完成した。 As a result of various investigations to solve such problems, the present inventors have suppressed the decrease in pH of the ophthalmic agent by further adding boric acid and sugar alcohol to the ophthalmic agent containing the drug and chlorobutanol. The present invention has been completed by finding out what can be done.
すなわち本発明は、
（１）薬物、クロロブタノール、ホウ酸及び糖アルコールを含有し、該薬物が、クロルフェニラミンマレイン酸塩、ケトチフェンフマル酸塩、塩酸テトラヒドロゾリン、ネオスチグミンメチル硫酸塩、グリチルリチン酸二カリウム、タウリン、コンドロイチン硫酸ナトリウム、ピリドキシン塩酸塩、Ｌ−アスパラギン酸カリウム、フラビンアデニンジヌクレオチドナトリウム、シアノコバラミン、クロモグリク酸ナトリウム、アラントイン、アズレンスルホン酸ナトリウム、ε−アミノカプロン酸、プラノプロフェンから選ばれる１種以上である眼科用剤、
（２）糖アルコールが、マンニトール、ソルビトール又はキシリトールである、（１）に記載の眼科用剤、
（３）糖アルコールが、眼科用剤全体の０．１ｗ／ｖ%〜５．０ｗ／ｖ%である、（１）又は（２）に記載の眼科用剤、
（４）ホウ酸が、眼科用剤全体の０．１ｗ／ｖ%〜２．０ｗ／ｖ%である、（１）〜（３）のいずれかに記載の眼科用剤、
（５）クロロブタノール含有眼科用剤に、ホウ酸及び糖アルコールを添加することにより、眼科用剤のｐＨ低下を抑制する方法、
（６）糖アルコールが、マンニトール、ソルビトール又はキシリトールである、（５）に記載の眼科用剤のｐＨ低下を抑制する方法である。
That is, the present invention
(1) Contains a drug, chlorobutanol, boric acid and sugar alcohol, and the drug is chlorpheniramine maleate, ketotifen fumarate, tetrahydrozoline hydrochloride, neostigmine methyl sulfate, dipotassium glycyrrhizinate, taurine, chondroitin sulfate Ophthalmic preparation which is at least one selected from sodium, pyridoxine hydrochloride, potassium L-aspartate, sodium flavin adenine dinucleotide, cyanocobalamin, cromoglycate sodium, allantoin, sodium azulenesulfonate, ε-aminocaproic acid, and pranoprofen ,
(2) The ophthalmic agent according to (1), wherein the sugar alcohol is mannitol, sorbitol or xylitol,
(3) The ophthalmic agent according to (1) or (2), wherein the sugar alcohol is 0.1 w / v% to 5.0 w / v% of the entire ophthalmic agent,
(4) The ophthalmic agent according to any one of (1) to (3), wherein boric acid is 0.1 w / v% to 2.0 w / v% of the entire ophthalmic agent,
(5) A method for suppressing a decrease in pH of the ophthalmic agent by adding boric acid and a sugar alcohol to the chlorobutanol-containing ophthalmic agent,
(6) The method for suppressing a decrease in pH of the ophthalmic agent according to (5), wherein the sugar alcohol is mannitol, sorbitol, or xylitol.
本発明により、薬物及びクロロブタノールを含有する眼科用剤において、クロロブタノールの分解による経時的なｐＨの低下を抑制することが可能となった。 According to the present invention, in an ophthalmic preparation containing a drug and chlorobutanol, it has become possible to suppress a decrease in pH over time due to decomposition of chlorobutanol.
本発明の眼科用剤における薬物としては、クロルフェニラミンマレイン酸塩、ケトチフェンフマル酸塩、塩酸テトラヒドロゾリン、ネオスチグミンメチル硫酸塩、グリチルリチン酸二カリウム、タウリン、コンドロイチン硫酸ナトリウム、ピリドキシン塩酸塩、Ｌ−アスパラギン酸カリウム、フラビンアデニンジヌクレオチドナトリウム、シアノコバラミン、クロモグリク酸ナトリウム、アラントイン、アズレンスルホン酸ナトリウム、ε−アミノカプロン酸、プラノプロフェン等が好ましく、これらを単独で又は２種以上の薬物を組み合わせて使用することが可能である。 Examples of the drug in the ophthalmic preparation of the present invention include chlorpheniramine maleate, ketotifen fumarate, tetrahydrozoline hydrochloride, neostigmine methyl sulfate, dipotassium glycyrrhizinate, taurine, sodium chondroitin sulfate, pyridoxine hydrochloride, L-aspartic acid Potassium, flavin adenine dinucleotide sodium, cyanocobalamin, sodium cromoglycate, allantoin, sodium azulenesulfonate, ε-aminocaproic acid, pranoprofen, etc. are preferable, and these may be used alone or in combination of two or more kinds of drugs. Is possible.
本発明の眼科用剤における薬物の配合濃度は、特に制限されるものではなく、適用する疾病の症状に応じて適宜増減することができるが、治療効果の点から、眼科用剤全体の０．００１〜１０．０ｗ／ｖ%であることが好ましく、０．００５〜５．０ｗ／ｖ%であることが更に好ましい。 The compounding concentration of the drug in the ophthalmic preparation of the present invention is not particularly limited, and can be appropriately increased or decreased depending on the symptoms of the disease to be applied. It is preferably 001 to 10.0 w / v%, and more preferably 0.005 to 5.0 w / v%.
また、本発明のクロロブタノールの配合濃度は必要に応じて適宜選択することができるが、使用感及び防腐作用向上の点から、眼科用剤全体の０．００１〜０．４ｗ／ｖ％であることが好ましく、０．０１〜０．４ｗ／ｖ%であることが更に好ましい。 Moreover, the compounding concentration of the chlorobutanol of the present invention can be appropriately selected as necessary, but is 0.001 to 0.4 w / v% of the whole ophthalmic preparation from the viewpoint of improvement in feeling of use and antiseptic action. It is preferably 0.01 to 0.4 w / v%.
さらに、本発明のホウ酸の配合濃度は、ｐＨ低下抑制効果の点から、眼科用剤全体の０．０１〜２．０ｗ／ｖ%であることが好ましく、０．１〜２．０ｗ／ｖ%であることが更に好ましい。また、別の表現に言い換えたとき、クロロブタノール１質量部に対して１．５〜１００質量部であることが好ましく、２〜４０質量部であることが更に好ましい。 Furthermore, the blending concentration of the boric acid of the present invention is preferably 0.01 to 2.0 w / v% of the whole ophthalmic agent from the viewpoint of the effect of suppressing pH decrease, and is preferably 0.1 to 2.0 w / v. More preferably, it is%. In other words, it is preferably 1.5 to 100 parts by mass, more preferably 2 to 40 parts by mass with respect to 1 part by mass of chlorobutanol.
本発明における好ましい糖アルコールは、マンニトール、ソルビトール又はキシリトールであり、これらを単独で又は２種以上組み合わせて使用することが可能である。なかでもマンニトールが最も好ましい。本発明で用いる糖アルコールは、眼科用剤において本来等張化剤として用いられる成分であるが、ホウ酸と組み合わせて使用することで、薬物及びクロロブタノールを含有する眼科用剤のｐＨ低下を抑制することが可能である。他の等張化成分ではｐＨの安定化効果は得られず、糖アルコールに特異的な効果であった。 The preferred sugar alcohol in the present invention is mannitol, sorbitol or xylitol, and these can be used alone or in combination of two or more. Of these, mannitol is most preferable. The sugar alcohol used in the present invention is a component that is originally used as an isotonic agent in ophthalmic preparations, but it is used in combination with boric acid to suppress a decrease in pH of an ophthalmic preparation containing a drug and chlorobutanol. Is possible. With other isotonic components, the effect of stabilizing the pH was not obtained, and the effect was specific to sugar alcohol.
さらに、本発明の糖アルコールの配合濃度は、ｐＨ低下抑制効果の面から、眼科用剤全体の０．０１〜５．０ｗ／ｖ%であることが好ましく、０．１〜５．０ｗ／ｖ%であることが更に好ましい。特に好ましくは、眼科用剤全体の０．２５〜５．０ｗ／ｖ%である。また、別の表現に言い換えたとき、クロロブタノール１質量部に対して１〜２００質量部であることが好ましく、２〜１００質量部であることが更に好ましい。特に好ましくは、クロロブタノール１質量部に対して５〜１００質量部である。 Furthermore, the blending concentration of the sugar alcohol of the present invention is preferably 0.01 to 5.0 w / v% of the whole ophthalmic agent from the viewpoint of the effect of suppressing pH decrease, and preferably 0.1 to 5.0 w / v. More preferably, it is%. Particularly preferred is 0.25 to 5.0 w / v% of the whole ophthalmic preparation. In other words, it is preferably 1 to 200 parts by mass, more preferably 2 to 100 parts by mass with respect to 1 part by mass of chlorobutanol. Especially preferably, it is 5-100 mass parts with respect to 1 mass part of chlorobutanol.
本発明の眼科用剤のｐＨは、眼科用剤として使用可能なｐＨの範囲であれば特に制限はなく、通常はｐＨ４〜９の範囲で調整される。なお、薬物がプラノプロフェンの場合は、薬物の溶解性の観点からｐＨ６．５以上が好ましく、また、ｐＨ６．５以上においてクロロブタノールの分解によるｐＨ低下という解決すべき課題が顕著に発現する。 The pH of the ophthalmic agent of the present invention is not particularly limited as long as it is in a pH range that can be used as an ophthalmic agent, and is usually adjusted in the range of pH 4 to 9. In the case where the drug is pranoprofen, pH 6.5 or higher is preferable from the viewpoint of drug solubility, and the problem to be solved such as pH reduction due to decomposition of chlorobutanol is remarkably exhibited at pH 6.5 or higher.
本発明の眼科用剤には、さらにホウ酸以外の緩衝剤、糖アルコール以外の等張化剤、溶解補助剤、防腐剤、粘稠剤、ｐＨ調整剤のような各種の添加剤を適宜添加してもよい。 Various additives such as buffering agents other than boric acid, isotonic agents other than sugar alcohols, solubilizers, preservatives, thickeners, and pH adjusters are appropriately added to the ophthalmic agent of the present invention. May be.
緩衝剤としては、例えばリン酸塩緩衝剤（リン酸二水素ナトリウム−リン酸水素二ナトリウム、リン酸二水素カリウム−水酸化カリウム等）、酒石酸塩緩衝剤（酒石酸−酒石酸ナトリウム）、アミノ酸（グルタミン酸ナトリウム）等が挙げられる。 Examples of the buffer include phosphate buffer (sodium dihydrogen phosphate-disodium hydrogen phosphate, potassium dihydrogen phosphate-potassium hydroxide, etc.), tartrate buffer (tartaric acid-sodium tartrate), amino acid (glutamic acid) Sodium) and the like.
等張化剤としては、グルコース等の糖類、グリセリン、プロピレングリコール等の多価アルコール類、塩化ナトリウム、塩化カリウム等の無機塩類、が挙げられる。 Examples of the isotonic agent include sugars such as glucose, polyhydric alcohols such as glycerin and propylene glycol, and inorganic salts such as sodium chloride and potassium chloride.
溶解補助剤としては、ポリオキシエチレンソルビタンモノオレート（ポリソルベート80）、ポリオキシエチレンモノステアレート、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等の非イオン性界面活性剤、ポリエチレングリコール等が挙げられる。 Examples of solubilizers include nonionic surfactants such as polyoxyethylene sorbitan monooleate (polysorbate 80), polyoxyethylene monostearate, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and polyethylene glycol. It is done.
防腐剤としては、ベンザルコニウム塩化物、ベンゼトニウム塩化物、セチルピリジニウム塩化物等の第四級アンモニウム塩、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等のパラオキシ安息香酸エステル類、ベンジルアルコール、フェネチルアルコール、ソルビン酸及びそれらの塩、チメロサール、デヒドロ酢酸ナトリウム等が挙げられる。 Preservatives include quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, paraoxybenzoates such as methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, and butyl paraoxybenzoate. Acid esters, benzyl alcohol, phenethyl alcohol, sorbic acid and their salts, thimerosal, sodium dehydroacetate and the like.
粘稠剤としては、ポリビニルピロリドン、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、メチルセルロース、ヒプロメロース、カルボキシメチルセルロース及びそれらの塩等が挙げられる。 Examples of the thickener include polyvinyl pyrrolidone, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hypromellose, carboxymethyl cellulose, and salts thereof.
ｐＨ調整剤としては、塩酸、リン酸、酢酸、酒石酸、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム及び炭酸水素ナトリウム等が挙げられる。 Examples of the pH adjuster include hydrochloric acid, phosphoric acid, acetic acid, tartaric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate.
本発明の眼科用剤を点眼剤とした場合、１日１回〜数回、１回１滴〜数滴を投与することができる。 When the ophthalmic preparation of the present invention is used as an eye drop, 1 to several drops can be administered once to several times a day.
以下に、実施例、比較例及び試験例を示し、本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail with reference to Examples, Comparative Examples and Test Examples.
（実施例１）
処方 １００ｍＬ中
クロルフェニラミンマレイン酸塩 ３０ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １０００ｍｇ
ソルビトール ８６０ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
Example 1
Formula 100ml chlorpheniramine maleate 30mg
Chlorobutanol 50mg
Boric acid 1000mg
Sorbitol 860mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例２）
処方 １００ｍＬ中
クロルフェニラミンマレイン酸塩 ３０ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １０００ｍｇ
キシリトール １０００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 2)
Formula 100ml chlorpheniramine maleate 30mg
Chlorobutanol 50mg
Boric acid 1000mg
Xylitol 1000mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例３）
処方 １００ｍＬ中
クロルフェニラミンマレイン酸塩 ３０ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １０００ｍｇ
マンニトール ２５０ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 3)
Formula 100ml chlorpheniramine maleate 30mg
Chlorobutanol 50mg
Boric acid 1000mg
Mannitol 250mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例４）
処方 １００ｍＬ中
クロルフェニラミンマレイン酸塩 ３０ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １０００ｍｇ
マンニトール ５００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
Example 4
Formula 100ml chlorpheniramine maleate 30mg
Chlorobutanol 50mg
Boric acid 1000mg
Mannitol 500mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例５）
処方 １００ｍＬ中
クロルフェニラミンマレイン酸塩 ３０ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １０００ｍｇ
マンニトール ５０００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 5)
Formula 100ml chlorpheniramine maleate 30mg
Chlorobutanol 50mg
Boric acid 1000mg
Mannitol 5000mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例６）
処方 １００ｍＬ中
クロルフェニラミンマレイン酸塩 ３０ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １００ｍｇ
マンニトール １０００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 6)
Formula 100ml chlorpheniramine maleate 30mg
Chlorobutanol 50mg
Boric acid 100mg
Mannitol 1000mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例７）
処方 １００ｍＬ中
クロルフェニラミンマレイン酸塩 ３０ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １００ｍｇ
マンニトール １５００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 7)
Formula 100ml chlorpheniramine maleate 30mg
Chlorobutanol 50mg
Boric acid 100mg
Mannitol 1500mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例８）
処方 １００ｍＬ中
クロルフェニラミンマレイン酸塩 ３０ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １００ｍｇ
マンニトール ５０００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 8)
Formula 100ml chlorpheniramine maleate 30mg
Chlorobutanol 50mg
Boric acid 100mg
Mannitol 5000mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例９）
処方 １００ｍＬ中
クロルフェニラミンマレイン酸塩 ３０ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 ２０００ｍｇ
マンニトール ２５０ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
Example 9
Formula 100ml chlorpheniramine maleate 30mg
Chlorobutanol 50mg
Boric acid 2000mg
Mannitol 250mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例１０）
処方 １００ｍＬ中
クロルフェニラミンマレイン酸塩 ３０ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 ２０００ｍｇ
マンニトール １０００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 10)
Formula 100ml chlorpheniramine maleate 30mg
Chlorobutanol 50mg
Boric acid 2000mg
Mannitol 1000mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例１１）
処方 １００ｍＬ中
クロルフェニラミンマレイン酸塩 ３０ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 ２０００ｍｇ
マンニトール ５０００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 11)
Formula 100ml chlorpheniramine maleate 30mg
Chlorobutanol 50mg
Boric acid 2000mg
Mannitol 5000mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例１２）
処方 １００ｍＬ中
クロルフェニラミンマレイン酸塩 ３０ｍｇ
クロロブタノール ２００ｍｇ
ホウ酸 １０００ｍｇ
マンニトール ２０００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 12)
Formula 100ml chlorpheniramine maleate 30mg
Chlorobutanol 200mg
Boric acid 1000mg
Mannitol 2000mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例１３）
処方 １００ｍＬ中
クロルフェニラミンマレイン酸塩 ３０ｍｇ
クロロブタノール ４００ｍｇ
ホウ酸 １０００ｍｇ
マンニトール ５０００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 13)
Formula 100ml chlorpheniramine maleate 30mg
Chlorobutanol 400mg
Boric acid 1000mg
Mannitol 5000mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例１４）
処方 １００ｍＬ中
クロルフェニラミンマレイン酸塩 ３０ｍｇ
クロロブタノール ４００ｍｇ
ホウ酸 ２０００ｍｇ
マンニトール ２５００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 14)
Formula 100ml chlorpheniramine maleate 30mg
Chlorobutanol 400mg
Boric acid 2000mg
Mannitol 2500mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例１５）
処方 １００ｍＬ中
クロルフェニラミンマレイン酸塩 ３０ｍｇ
クロロブタノール ４００ｍｇ
ホウ酸 ２０００ｍｇ
マンニトール ５０００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 15)
Formula 100ml chlorpheniramine maleate 30mg
Chlorobutanol 400mg
Boric acid 2000mg
Mannitol 5000mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例１６）
処方 １００ｍＬ中
ケトチフェンフマル酸塩 ６９ｍｇ
クロロブタノール ４００ｍｇ
ホウ酸 ２０００ｍｇ
マンニトール ５０００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 16)
Formulation 100mg ketotifen fumarate 69mg
Chlorobutanol 400mg
Boric acid 2000mg
Mannitol 5000mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例１７）
処方 １００ｍＬ中
ネオスチグミンメチル硫酸塩 ５ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １０００ｍｇ
マンニトール ２０００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 17)
Prescription Neostigmine Methyl Sulfate 5mg in 100mL
Chlorobutanol 50mg
Boric acid 1000mg
Mannitol 2000mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例１８）
処方 １００ｍＬ中
塩酸テトラヒドロゾリン ５０ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １０００ｍｇ
マンニトール ２０００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 18)
Formula 100ml Tetrahydrozoline Hydrochloride 50mg
Chlorobutanol 50mg
Boric acid 1000mg
Mannitol 2000mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例１９）
処方 １００ｍＬ中
グリチルリチン酸二カリウム ２５０ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １０００ｍｇ
マンニトール ２０００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 19)
Formula 100ml dipotassium glycyrrhizinate 250mg
Chlorobutanol 50mg
Boric acid 1000mg
Mannitol 2000mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例２０）
処方 １００ｍＬ中
タウリン １０００ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １０００ｍｇ
マンニトール ２０００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 20)
Formula 100mg Taurine 1000mg
Chlorobutanol 50mg
Boric acid 1000mg
Mannitol 2000mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例２１）
処方 １００ｍＬ中
コンドロイチン硫酸ナトリウム ５００ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １０００ｍｇ
マンニトール ２０００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 21)
Prescription 100 mg sodium chondroitin sulfate 500 mg
Chlorobutanol 50mg
Boric acid 1000mg
Mannitol 2000mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例２２）
処方 １００ｍＬ中
ピリドキシン塩酸塩 １００ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １０００ｍｇ
マンニトール ２０００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 22)
Formula 100ml pyridoxine hydrochloride 100mg
Chlorobutanol 50mg
Boric acid 1000mg
Mannitol 2000mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例２３）
処方 １００ｍＬ中
Ｌ−アスパラギン酸カリウム １０００ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １０００ｍｇ
マンニトール ２０００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 23)
Formulation 100 mg L-potassium potassium aspartate in 100 mL
Chlorobutanol 50mg
Boric acid 1000mg
Mannitol 2000mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例２４）
処方 １００ｍＬ中
フラビンアデニンジヌクレオチドナトリウム ５０ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １０００ｍｇ
マンニトール ２０００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 24)
Formulation 100mg Flavin Adenine Dinucleotide Sodium 50mg
Chlorobutanol 50mg
Boric acid 1000mg
Mannitol 2000mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例２５）
処方 １００ｍＬ中
シアノコバラミン ２０ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １０００ｍｇ
マンニトール ２０００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 25)
Formula 100ml cyanocobalamin 20mg
Chlorobutanol 50mg
Boric acid 1000mg
Mannitol 2000mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例２６）
処方 １００ｍＬ中
クロモグリク酸ナトリウム １０００ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １０００ｍｇ
マンニトール ２０００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 26)
Prescription Sodium cromoglycate 1000mg in 100mL
Chlorobutanol 50mg
Boric acid 1000mg
Mannitol 2000mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例２７）
処方 １００ｍＬ中
アラントイン ３００ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １０００ｍｇ
マンニトール ２０００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 27)
Allantoin 300mg in 100mL
Chlorobutanol 50mg
Boric acid 1000mg
Mannitol 2000mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例２８）
処方 １００ｍＬ中
アズレンスルホン酸ナトリウム ２０ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １０００ｍｇ
マンニトール ２０００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 28)
Prescription 100 mg of sodium azulene sulfonate in 100 mL
Chlorobutanol 50mg
Boric acid 1000mg
Mannitol 2000mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例２９）
処方 １００ｍＬ中
ε−アミノカプロン酸 ５０００ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １０００ｍｇ
マンニトール ２０００ｍｇ
塩酸 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、塩酸を適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 29)
Formulation 100 mg ε-aminocaproic acid 5000 mg
Chlorobutanol 50mg
Boric acid 1000mg
Mannitol 2000mg
Hydrochloric acid appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of hydrochloric acid was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（比較例１）
処方 １００ｍＬ中
クロルフェニラミンマレイン酸塩 ３０ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １０００ｍｇ
マンニトール １００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Comparative Example 1)
Formula 100ml chlorpheniramine maleate 30mg
Chlorobutanol 50mg
Boric acid 1000mg
Mannitol 100mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（比較例２）
処方 １００ｍＬ中
クロルフェニラミンマレイン酸塩 ３０ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １０００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Comparative Example 2)
Formula 100ml chlorpheniramine maleate 30mg
Chlorobutanol 50mg
Boric acid 1000mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（比較例３）
処方 １００ｍＬ中
クロルフェニラミンマレイン酸塩 ３０ｍｇ
クロロブタノール ５０ｍｇ
ソルビトール ８６０ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Comparative Example 3)
Formula 100ml chlorpheniramine maleate 30mg
Chlorobutanol 50mg
Sorbitol 860mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（比較例４）
処方 １００ｍＬ中
クロルフェニラミンマレイン酸塩 ３０ｍｇ
クロロブタノール ５０ｍｇ
キシリトール １０００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Comparative Example 4)
Formula 100ml chlorpheniramine maleate 30mg
Chlorobutanol 50mg
Xylitol 1000mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（比較例５）
処方 １００ｍＬ中
クロルフェニラミンマレイン酸塩 ３０ｍｇ
クロロブタノール ５０ｍｇ
マンニトール １０００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Comparative Example 5)
Formula 100ml chlorpheniramine maleate 30mg
Chlorobutanol 50mg
Mannitol 1000mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（比較例６）
処方 １００ｍＬ中
クロルフェニラミンマレイン酸塩 ３０ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １０００ｍｇ
グリセリン １０００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Comparative Example 6)
Formula 100ml chlorpheniramine maleate 30mg
Chlorobutanol 50mg
Boric acid 1000mg
Glycerin 1000mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（比較例７）
処方 １００ｍＬ中
クロルフェニラミンマレイン酸塩 ３０ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １０００ｍｇ
塩化ナトリウム ９００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Comparative Example 7)
Formula 100ml chlorpheniramine maleate 30mg
Chlorobutanol 50mg
Boric acid 1000mg
Sodium chloride 900mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（比較例８）
処方 １００ｍＬ中
クロルフェニラミンマレイン酸塩 ３０ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １０００ｍｇ
ホウ砂 ４００ｍｇ
水酸化ナトリウム 適量
精製水 全１００ｍＬ
精製水に各成分を溶解後、水酸化ナトリウムを適量添加しｐＨを５．５に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Comparative Example 8)
Formula 100ml chlorpheniramine maleate 30mg
Chlorobutanol 50mg
Boric acid 1000mg
Borax 400mg
Sodium hydroxide appropriate amount purified water 100mL
After each component was dissolved in purified water, an appropriate amount of sodium hydroxide was added to adjust the pH to 5.5, and the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（試験例１）
実施例及び比較例で得た眼科用剤を６５℃で７日保存した時のｐＨを測定した。結果を表１−１から１−８に示した。処方の数値は「ｍｇ／１００ｍＬ」で示した。
(Test Example 1)
The pH when the ophthalmic preparations obtained in Examples and Comparative Examples were stored at 65 ° C. for 7 days was measured. The results are shown in Tables 1-1 to 1-8. The numerical value of the prescription was shown as “mg / 100 mL”.
本発明にかかる実施例１〜２９の眼科用剤は、比較例の眼科用剤と比較してｐＨの低下が抑制された。本発明で用いる糖アルコールは、等張化剤として用いられる成分であるが、他の等張化成分（グリセリン、塩化ナトリウム）ではｐＨの安定化効果は得られず、糖アルコールに特異的な効果であった。また、本発明の眼科用剤は、一般的な緩衝剤であるホウ酸緩衝剤（ホウ酸−ホウ砂）と比較してｐＨを安定化する効果が高かった。
（実施例３０）
処方 １００ｍＬ中
プラノプロフェン ５０ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １０００ｍｇ
ソルビトール ８６０ｍｇ
水酸化ナトリウム 適量
塩酸 適量
精製水 全１００ｍＬ
精製水にプラノプロフェン及び水酸化ナトリウムを添加し溶解した。その後各成分を添加・溶解し、水酸化ナトリウム及び塩酸を適量添加しｐＨを７．０に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
In the ophthalmic preparations of Examples 1 to 29 according to the present invention, a decrease in pH was suppressed as compared with the ophthalmic preparation of the comparative example. The sugar alcohol used in the present invention is a component used as a tonicity agent, but other isotonic components (glycerin, sodium chloride) do not provide a pH stabilizing effect and are specific to the sugar alcohol. Met. In addition, the ophthalmic agent of the present invention had a higher effect of stabilizing the pH than a boric acid buffer (boric acid-borax) which is a general buffer.
(Example 30)
Formula 100mg of pranoprofen 50mg
Chlorobutanol 50mg
Boric acid 1000mg
Sorbitol 860mg
Sodium hydroxide appropriate amount hydrochloric acid appropriate amount purified water 100mL
Puranoprofen and sodium hydroxide were added to purified water and dissolved. Thereafter, each component was added and dissolved, and sodium hydroxide and hydrochloric acid were added in appropriate amounts to adjust the pH to 7.0, and then the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例３１）
処方 １００ｍＬ中
プラノプロフェン ５０ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 ２０００ｍｇ
マンニトール １００ｍｇ
水酸化ナトリウム 適量
塩酸 適量
精製水 全１００ｍＬ
精製水にプラノプロフェン及び水酸化ナトリウムを添加し溶解した。その後各成分を添加・溶解し、水酸化ナトリウム及び塩酸を適量添加しｐＨを７．０に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 31)
Formula 100mg of pranoprofen 50mg
Chlorobutanol 50mg
Boric acid 2000mg
Mannitol 100mg
Sodium hydroxide appropriate amount hydrochloric acid appropriate amount purified water 100mL
Puranoprofen and sodium hydroxide were added to purified water and dissolved. Thereafter, each component was added and dissolved, and sodium hydroxide and hydrochloric acid were added in appropriate amounts to adjust the pH to 7.0, and then the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例３２）
処方 １００ｍＬ中
プラノプロフェン ５０ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 ２０００ｍｇ
マンニトール ２５０ｍｇ
水酸化ナトリウム 適量
塩酸 適量
精製水 全１００ｍＬ
精製水にプラノプロフェン及び水酸化ナトリウムを添加し溶解した。その後各成分を添加・溶解し、水酸化ナトリウム及び塩酸を適量添加しｐＨを７．０に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 32)
Formula 100mg of pranoprofen 50mg
Chlorobutanol 50mg
Boric acid 2000mg
Mannitol 250mg
Sodium hydroxide appropriate amount hydrochloric acid appropriate amount purified water 100mL
Puranoprofen and sodium hydroxide were added to purified water and dissolved. Thereafter, each component was added and dissolved, and sodium hydroxide and hydrochloric acid were added in appropriate amounts to adjust the pH to 7.0, and then the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例３３）
処方 １００ｍＬ中
プラノプロフェン ５０ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １０００ｍｇ
マンニトール ２５０ｍｇ
水酸化ナトリウム 適量
塩酸 適量
精製水 全１００ｍＬ
精製水にプラノプロフェン及び水酸化ナトリウムを添加し溶解した。その後各成分を添加・溶解し、水酸化ナトリウム及び塩酸を適量添加しｐＨを７．０に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 33)
Formula 100mg of pranoprofen 50mg
Chlorobutanol 50mg
Boric acid 1000mg
Mannitol 250mg
Sodium hydroxide appropriate amount hydrochloric acid appropriate amount purified water 100mL
Puranoprofen and sodium hydroxide were added to purified water and dissolved. Thereafter, each component was added and dissolved, and sodium hydroxide and hydrochloric acid were added in appropriate amounts to adjust the pH to 7.0, and then the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例３４）
処方 １００ｍＬ中
プラノプロフェン ５０ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １０００ｍｇ
マンニトール ５０００ｍｇ
水酸化ナトリウム 適量
塩酸 適量
精製水 全１００ｍＬ
精製水にプラノプロフェン及び水酸化ナトリウムを添加し溶解した。その後各成分を添加・溶解し、水酸化ナトリウム及び塩酸を適量添加しｐＨを７．０に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 34)
Formula 100mg of pranoprofen 50mg
Chlorobutanol 50mg
Boric acid 1000mg
Mannitol 5000mg
Sodium hydroxide appropriate amount hydrochloric acid appropriate amount purified water 100mL
Puranoprofen and sodium hydroxide were added to purified water and dissolved. Thereafter, each component was added and dissolved, and sodium hydroxide and hydrochloric acid were added in appropriate amounts to adjust the pH to 7.0, and then the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例３５）
処方 １００ｍＬ中
プラノプロフェン ５０ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １００ｍｇ
マンニトール １０００ｍｇ
水酸化ナトリウム 適量
塩酸 適量
精製水 全１００ｍＬ
精製水にプラノプロフェン及び水酸化ナトリウムを添加し溶解した。その後各成分を添加・溶解し、水酸化ナトリウム及び塩酸を適量添加しｐＨを７．０に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 35)
Formula 100mg of pranoprofen 50mg
Chlorobutanol 50mg
Boric acid 100mg
Mannitol 1000mg
Sodium hydroxide appropriate amount hydrochloric acid appropriate amount purified water 100mL
Puranoprofen and sodium hydroxide were added to purified water and dissolved. Thereafter, each component was added and dissolved, and sodium hydroxide and hydrochloric acid were added in appropriate amounts to adjust the pH to 7.0, and then the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例３６）
処方 １００ｍＬ中
プラノプロフェン ５０ｍｇ
クロロブタノール ４００ｍｇ
ホウ酸 １０００ｍｇ
マンニトール ５０００ｍｇ
水酸化ナトリウム 適量
塩酸 適量
精製水 全１００ｍＬ
精製水にプラノプロフェン及び水酸化ナトリウムを添加し溶解した。その後各成分を添加・溶解し、水酸化ナトリウム及び塩酸を適量添加しｐＨを７．０に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 36)
Formula 100mg of pranoprofen 50mg
Chlorobutanol 400mg
Boric acid 1000mg
Mannitol 5000mg
Sodium hydroxide appropriate amount hydrochloric acid appropriate amount purified water 100mL
Puranoprofen and sodium hydroxide were added to purified water and dissolved. Thereafter, each component was added and dissolved, and sodium hydroxide and hydrochloric acid were added in appropriate amounts to adjust the pH to 7.0, and then the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例３７）
処方 １００ｍＬ中
プラノプロフェン ５０ｍｇ
クロロブタノール ２００ｍｇ
ホウ酸 ５００ｍｇ
マンニトール １０００ｍｇ
水酸化ナトリウム 適量
塩酸 適量
精製水 全１００ｍＬ
精製水にプラノプロフェン及び水酸化ナトリウムを添加し溶解した。その後各成分を添加・溶解し、水酸化ナトリウム及び塩酸を適量添加しｐＨを７．０に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 37)
Formula 100mg of pranoprofen 50mg
Chlorobutanol 200mg
Boric acid 500mg
Mannitol 1000mg
Sodium hydroxide appropriate amount hydrochloric acid appropriate amount purified water 100mL
Puranoprofen and sodium hydroxide were added to purified water and dissolved. Thereafter, each component was added and dissolved, and sodium hydroxide and hydrochloric acid were added in appropriate amounts to adjust the pH to 7.0, and then the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（実施例３８）
処方 １００ｍＬ中
プラノプロフェン ５０ｍｇ
クロモグリク酸ナトリウム １０００ｍｇ
クロルフェニラミンマレイン酸塩 １５ｍｇ
クロロブタノール ５０ｍｇ
ホウ酸 １０００ｍｇ
マンニトール ５０００ｍｇ
水酸化ナトリウム 適量
塩酸 適量
精製水 全１００ｍＬ
精製水にプラノプロフェン及び水酸化ナトリウムを添加し溶解した。その後各成分を添加・溶解し、水酸化ナトリウム及び塩酸を適量添加しｐＨを７．０に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Example 38)
Formula 100mg of pranoprofen 50mg
Sodium cromoglycate 1000mg
Chlorpheniramine maleate 15mg
Chlorobutanol 50mg
Boric acid 1000mg
Mannitol 5000mg
Sodium hydroxide appropriate amount hydrochloric acid appropriate amount purified water 100mL
Puranoprofen and sodium hydroxide were added to purified water and dissolved. Thereafter, each component was added and dissolved, and sodium hydroxide and hydrochloric acid were added in appropriate amounts to adjust the pH to 7.0, and then the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（比較例９）
処方 １００ｍＬ中
プラノプロフェン ５０ｍｇ
クロロブタノール ４００ｍｇ
ホウ酸 １０００ｍｇ
水酸化ナトリウム 適量
塩酸 適量
精製水 全１００ｍＬ
精製水にプラノプロフェン及び水酸化ナトリウムを添加し溶解した。その後各成分を添加・溶解し、水酸化ナトリウム及び塩酸を適量添加しｐＨを７．０に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Comparative Example 9)
Formula 100mg of pranoprofen 50mg
Chlorobutanol 400mg
Boric acid 1000mg
Sodium hydroxide appropriate amount hydrochloric acid appropriate amount purified water 100mL
Puranoprofen and sodium hydroxide were added to purified water and dissolved. Thereafter, each component was added and dissolved, and sodium hydroxide and hydrochloric acid were added in appropriate amounts to adjust the pH to 7.0, and then the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（比較例１０）
処方 １００ｍＬ中
プラノプロフェン ５０ｍｇ
クロロブタノール ４００ｍｇ
マンニトール ５０００ｍｇ
水酸化ナトリウム 適量
塩酸 適量
精製水 全１００ｍＬ
精製水にプラノプロフェン及び水酸化ナトリウムを添加し溶解した。その後各成分を添加・溶解し、水酸化ナトリウム及び塩酸を適量添加しｐＨを７．０に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Comparative Example 10)
Formula 100mg of pranoprofen 50mg
Chlorobutanol 400mg
Mannitol 5000mg
Sodium hydroxide appropriate amount hydrochloric acid appropriate amount purified water 100mL
Puranoprofen and sodium hydroxide were added to purified water and dissolved. Thereafter, each component was added and dissolved, and sodium hydroxide and hydrochloric acid were added in appropriate amounts to adjust the pH to 7.0, and then the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（比較例１１）
処方 １００ｍＬ中
プラノプロフェン ５０ｍｇ
クロロブタノール ４００ｍｇ
ホウ酸 １０００ｍｇ
グリセリン １０００ｍｇ
水酸化ナトリウム 適量
塩酸 適量
精製水 全１００ｍＬ
精製水にプラノプロフェン及び水酸化ナトリウムを添加し溶解した。その後各成分を添加・溶解し、水酸化ナトリウム及び塩酸を適量添加しｐＨを７．０に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Comparative Example 11)
Formula 100mg of pranoprofen 50mg
Chlorobutanol 400mg
Boric acid 1000mg
Glycerin 1000mg
Sodium hydroxide appropriate amount hydrochloric acid appropriate amount purified water 100mL
Puranoprofen and sodium hydroxide were added to purified water and dissolved. Thereafter, each component was added and dissolved, and sodium hydroxide and hydrochloric acid were added in appropriate amounts to adjust the pH to 7.0, and then the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（比較例１２）
処方 １００ｍＬ中
プラノプロフェン ５０ｍｇ
クロロブタノール ４００ｍｇ
ホウ酸 １０００ｍｇ
ホウ砂 ４００ｍｇ
水酸化ナトリウム 適量
塩酸 適量
精製水 全１００ｍＬ
精製水にプラノプロフェン及び水酸化ナトリウムを添加し溶解した。その後各成分を添加・溶解し、水酸化ナトリウム及び塩酸を適量添加しｐＨを７．０に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Comparative Example 12)
Formula 100mg of pranoprofen 50mg
Chlorobutanol 400mg
Boric acid 1000mg
Borax 400mg
Sodium hydroxide appropriate amount hydrochloric acid appropriate amount purified water 100mL
Puranoprofen and sodium hydroxide were added to purified water and dissolved. Thereafter, each component was added and dissolved, and sodium hydroxide and hydrochloric acid were added in appropriate amounts to adjust the pH to 7.0, and then the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（比較例１３）
処方 １００ｍＬ中
プラノプロフェン ５０ｍｇ
クロロブタノール ２００ｍｇ
ホウ酸 ５００ｍｇ
ポリビニルアルコール １０００ｍｇ
水酸化ナトリウム 適量
塩酸 適量
精製水 全１００ｍＬ
精製水にプラノプロフェン及び水酸化ナトリウムを添加し溶解した。その後各成分を添加・溶解し、水酸化ナトリウム及び塩酸を適量添加しｐＨを７．０に調整後、精製水で全量を正確に１００ｍＬとした。その後ろ過滅菌を行い、無菌の点眼剤とした。
(Comparative Example 13)
Formula 100mg of pranoprofen 50mg
Chlorobutanol 200mg
Boric acid 500mg
Polyvinyl alcohol 1000mg
Sodium hydroxide appropriate amount hydrochloric acid appropriate amount purified water 100mL
Puranoprofen and sodium hydroxide were added to purified water and dissolved. Thereafter, each component was added and dissolved, and sodium hydroxide and hydrochloric acid were added in appropriate amounts to adjust the pH to 7.0, and then the total amount was accurately adjusted to 100 mL with purified water. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop.
（比較例１４）
処方 １００ｍＬ中
プラノプロフェン ５０ｍｇ
クロロブタノール ２００ｍｇ
ホウ酸 １０００ｍｇ
ポリビニルアルコール ２０００ｍｇ
水酸化ナトリウム 適量
塩酸 適量
精製水 全１００ｍＬ
精製水にプラノプロフェン及び水酸化ナトリウムを添加し溶解した。その後各成分を添加したが、溶解しなかった。
(Comparative Example 14)
Formula 100mg of pranoprofen 50mg
Chlorobutanol 200mg
Boric acid 1000mg
Polyvinyl alcohol 2000mg
Sodium hydroxide appropriate amount hydrochloric acid appropriate amount purified water 100mL
Puranoprofen and sodium hydroxide were added to purified water and dissolved. Each component was then added but did not dissolve.
（試験例２）
実施例及び比較例で得た眼科用剤を６５℃で４日保存した時のｐＨを測定した。実施例９のみ６５℃で７日保存した時のｐＨを測定した。結果を表２−１から２−３に示した。処方の数値は「ｍｇ／１００ｍＬ」で示した。
(Test Example 2)
The pH when the ophthalmic preparations obtained in Examples and Comparative Examples were stored at 65 ° C. for 4 days was measured. Only Example 9 was measured for pH when stored at 65 ° C. for 7 days. The results are shown in Tables 2-1 to 2-3. The numerical value of the prescription was shown as “mg / 100 mL”.
本発明にかかる実施例３０〜３８の眼科用剤は、比較例の眼科用剤と比較してｐＨの低下が抑制された。本発明で用いる糖アルコールは、等張化剤として用いられる成分であるが、他の等張化成分（グリセリン）ではｐＨの安定化効果は得られなかった。また、特許文献４の発明構成要件である水溶性高分子のポリビニルアルコールにはｐＨの安定化効果は認められず、糖アルコールに特異的な効果であった。さらに、本発明の眼科用剤は、一般的な緩衝剤であるホウ酸緩衝剤（ホウ酸−ホウ砂）と比較してｐＨを安定化する効果が高かった。
As for the ophthalmic agent of Examples 30-38 concerning this invention, the fall of pH was suppressed compared with the ophthalmic agent of the comparative example. The sugar alcohol used in the present invention is a component used as a tonicity agent, but other isotonic components (glycerin) did not provide a pH stabilizing effect. In addition, the water-soluble polymer polyvinyl alcohol, which is the constituent element of the invention of Patent Document 4, was not effective in stabilizing the pH and was specific to the sugar alcohol. Furthermore, the ophthalmic preparation of the present invention had a higher effect of stabilizing the pH than a boric acid buffer (boric acid-borax) which is a general buffer.
本発明により、薬物とクロロブタノールを配合することにより生じるｐＨ低下を抑制することができる極めて有用な眼科用剤を提供することが可能となった。 According to the present invention, it has become possible to provide a very useful ophthalmic agent that can suppress a decrease in pH caused by blending a drug and chlorobutanol.
Claims (5)
該薬物が、クロルフェニラミンマレイン酸塩、塩酸テトラヒドロゾリン、ネオスチグミンメチル硫酸塩、グリチルリチン酸二カリウム、タウリン、コンドロイチン硫酸ナトリウム、ピリドキシン塩酸塩、Ｌ−アスパラギン酸カリウム、フラビンアデニンジヌクレオチドナトリウム、シアノコバラミン、クロモグリク酸ナトリウム、アラントイン、アズレンスルホン酸ナトリウム、ε−アミノカプロン酸、プラノプロフェンから選ばれる１種以上であり、
糖アルコールが、眼科用剤全体の０．２５ｗ／ｖ％〜５．０ｗ／ｖ%である眼科用剤（ただし、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、タウリン、コンドロイチン硫酸ナトリウム、ピリドキシン塩酸塩及びε−アミノカプロン酸を同時に配合する眼科用剤を除く）。 Contains drugs, chlorobutanol, boric acid and sugar alcohol,
The drug is chlorpheniramine maleate , tetrahydrozoline hydrochloride, neostigmine methyl sulfate, dipotassium glycyrrhizinate, taurine, sodium chondroitin sulfate, pyridoxine hydrochloride, potassium L-aspartate, sodium flavin adenine dinucleotide, cyanocobalamin, cromoglycic acid sodium, allantoin, azulene sodium sulfonate, .epsilon.-aminocaproic acid, der least one member selected from pranoprofen is,
Sugar alcohol, ophthalmic agents overall 0.25w / v% ~5.0w / v% der Ru ophthalmic agent (although, chlorpheniramine maleate, Neosuchi gummy emission methyl sulfate, taurine, sodium chondroitin sulfate, pyridoxine Except for ophthalmic preparations containing both hydrochloride and ε-aminocaproic acid) .
糖アルコールが、眼科用剤全体の０．２５ｗ／ｖ％〜５．０ｗ／ｖ%である方法。 By adding boric acid and sugar alcohol to the chlorobutanol-containing ophthalmic agent, it is a method of suppressing the pH drop of the ophthalmic agent ,
The method whose sugar alcohol is 0.25 w / v%-5.0 w / v% of the whole ophthalmic preparation .
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