JP2004143155A - Ophthalmic solution - Google Patents
Ophthalmic solution Download PDFInfo
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- JP2004143155A JP2004143155A JP2003336255A JP2003336255A JP2004143155A JP 2004143155 A JP2004143155 A JP 2004143155A JP 2003336255 A JP2003336255 A JP 2003336255A JP 2003336255 A JP2003336255 A JP 2003336255A JP 2004143155 A JP2004143155 A JP 2004143155A
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- Prior art keywords
- sodium
- ketotifen fumarate
- eye
- purified water
- adjusted
- Prior art date
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- 239000002997 ophthalmic solution Substances 0.000 title abstract description 4
- 229940054534 ophthalmic solution Drugs 0.000 title abstract description 4
- 229960003630 ketotifen fumarate Drugs 0.000 claims abstract description 26
- 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 claims abstract description 26
- 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 abstract description 14
- 229920002385 Sodium hyaluronate Polymers 0.000 claims abstract description 10
- 229940010747 sodium hyaluronate Drugs 0.000 claims abstract description 10
- 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 claims abstract description 10
- 238000002360 preparation method Methods 0.000 claims description 13
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 3
- 229940009098 aspartate Drugs 0.000 claims description 3
- QDWYPRSFEZRKDK-UHFFFAOYSA-M sodium;sulfamate Chemical compound [Na+].NS([O-])(=O)=O QDWYPRSFEZRKDK-UHFFFAOYSA-M 0.000 claims 1
- 206010015958 Eye pain Diseases 0.000 abstract description 14
- 230000000694 effects Effects 0.000 abstract description 10
- 239000000243 solution Substances 0.000 abstract description 10
- 239000000463 material Substances 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 54
- 239000003889 eye drop Substances 0.000 description 22
- 239000008213 purified water Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 13
- 238000004519 manufacturing process Methods 0.000 description 11
- 229960000686 benzalkonium chloride Drugs 0.000 description 10
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 10
- 238000001914 filtration Methods 0.000 description 9
- 230000003204 osmotic effect Effects 0.000 description 9
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 8
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 8
- 229920000053 polysorbate 80 Polymers 0.000 description 8
- 235000011187 glycerol Nutrition 0.000 description 7
- 230000007794 irritation Effects 0.000 description 7
- 229940068968 polysorbate 80 Drugs 0.000 description 7
- 229940012356 eye drops Drugs 0.000 description 6
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 5
- 238000011156 evaluation Methods 0.000 description 5
- 229940068988 potassium aspartate Drugs 0.000 description 5
- -1 terpenoid compound Chemical class 0.000 description 5
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 4
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- 208000003251 Pruritus Diseases 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000003732 agents acting on the eye Substances 0.000 description 3
- 239000000739 antihistaminic agent Substances 0.000 description 3
- 229960004926 chlorobutanol Drugs 0.000 description 3
- YKZPPPNXRZHVGX-PXYKVGKMSA-L dipotassium;(2s)-2-aminobutanedioate;hydron;hydrate Chemical group [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 3
- 239000006196 drop Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000007803 itching Effects 0.000 description 3
- 229940041616 menthol Drugs 0.000 description 3
- 229940096517 menthol 5 mg Drugs 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229940125702 ophthalmic agent Drugs 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 3
- 229920002567 Chondroitin Polymers 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 230000000172 allergic effect Effects 0.000 description 2
- 230000007815 allergy Effects 0.000 description 2
- 230000003042 antagnostic effect Effects 0.000 description 2
- 239000000043 antiallergic agent Substances 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- DLGJWSVWTWEWBJ-HGGSSLSASA-N chondroitin Chemical compound CC(O)=N[C@@H]1[C@H](O)O[C@H](CO)[C@H](O)[C@@H]1OC1[C@H](O)[C@H](O)C=C(C(O)=O)O1 DLGJWSVWTWEWBJ-HGGSSLSASA-N 0.000 description 2
- 238000013329 compounding Methods 0.000 description 2
- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000005526 vasoconstrictor agent Substances 0.000 description 2
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- CIVCELMLGDGMKZ-UHFFFAOYSA-N 2,4-dichloro-6-methylpyridine-3-carboxylic acid Chemical compound CC1=CC(Cl)=C(C(O)=O)C(Cl)=N1 CIVCELMLGDGMKZ-UHFFFAOYSA-N 0.000 description 1
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 1
- SNPLKNRPJHDVJA-ZETCQYMHSA-N D-panthenol Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCCO SNPLKNRPJHDVJA-ZETCQYMHSA-N 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- BIVBRWYINDPWKA-VLQRKCJKSA-L Glycyrrhizinate dipotassium Chemical compound [K+].[K+].O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C([O-])=O)[C@@H]1O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@H]1O BIVBRWYINDPWKA-VLQRKCJKSA-L 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 235000014435 Mentha Nutrition 0.000 description 1
- 241001072983 Mentha Species 0.000 description 1
- DJDFFEBSKJCGHC-UHFFFAOYSA-N Naphazoline Chemical compound Cl.C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 DJDFFEBSKJCGHC-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 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 description 1
- HFWPXARYYXLTQE-UHFFFAOYSA-N [Mg].[K].[K] Chemical compound [Mg].[K].[K] HFWPXARYYXLTQE-UHFFFAOYSA-N 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 229960002684 aminocaproic acid Drugs 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 230000001139 anti-pruritic effect Effects 0.000 description 1
- 229940124623 antihistamine drug Drugs 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- PEEKVIHQOHJITP-UHFFFAOYSA-N boric acid;propane-1,2,3-triol Chemical compound OB(O)O.OCC(O)CO PEEKVIHQOHJITP-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 229940046978 chlorpheniramine maleate Drugs 0.000 description 1
- 229940006423 chondroitin sulfate sodium Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 229960002104 cyanocobalamin Drugs 0.000 description 1
- 235000000639 cyanocobalamin Nutrition 0.000 description 1
- 239000011666 cyanocobalamin Substances 0.000 description 1
- 229960000525 diphenhydramine hydrochloride Drugs 0.000 description 1
- 229940101029 dipotassium glycyrrhizinate Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002444 effect on eosinophils Effects 0.000 description 1
- 230000001210 effect on neutrophils Effects 0.000 description 1
- 210000003979 eosinophil Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- FVTCRASFADXXNN-SCRDCRAPSA-N flavin mononucleotide Chemical compound OP(=O)(O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O FVTCRASFADXXNN-SCRDCRAPSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 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 1
- 229960001340 histamine Drugs 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 150000002617 leukotrienes Chemical class 0.000 description 1
- SWHAQEYMVUEVNF-UHFFFAOYSA-N magnesium potassium Chemical compound [Mg].[K] SWHAQEYMVUEVNF-UHFFFAOYSA-N 0.000 description 1
- 229940033165 menthol 3 mg Drugs 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 229960004760 naphazoline hydrochloride Drugs 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 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 1
- 229960002253 neostigmine methylsulfate Drugs 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229940101267 panthenol Drugs 0.000 description 1
- 235000020957 pantothenol Nutrition 0.000 description 1
- 239000011619 pantothenol Substances 0.000 description 1
- OCYSGIYOVXAGKQ-FVGYRXGTSA-N phenylephrine hydrochloride Chemical compound [H+].[Cl-].CNC[C@H](O)C1=CC=CC(O)=C1 OCYSGIYOVXAGKQ-FVGYRXGTSA-N 0.000 description 1
- 229960003733 phenylephrine hydrochloride Drugs 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 1
- 229960004172 pyridoxine hydrochloride Drugs 0.000 description 1
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 description 1
- 239000011764 pyridoxine hydrochloride Substances 0.000 description 1
- 229950001574 riboflavin phosphate Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- 239000004328 sodium tetraborate Substances 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- BJORNXNYWNIWEY-UHFFFAOYSA-N tetrahydrozoline hydrochloride Chemical compound Cl.N1CCN=C1C1C2=CC=CC=C2CCC1 BJORNXNYWNIWEY-UHFFFAOYSA-N 0.000 description 1
- 229940021790 tetrahydrozoline hydrochloride Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は、フマル酸ケトチフェンを配合する眼科用剤に関する。 The present invention relates to an ophthalmic agent containing ketotifen fumarate.
フマル酸ケトチフェンは、アレルギー反応の際、ヒスタミンなどの遊離抑制作用・直接拮抗作用を有し、ロイコトリエンの産生と遊離抑制・拮抗作用を有しており、また、好中球・好酸球などの炎症細胞の遊走・浸潤抑制作用、活性酸素産生抑制作用を示すことが知られ、アレルギー症状の予防のため、点眼液や点鼻液等として臨床的に広く用いられている。 Ketotifen fumarate has an inhibitory action and a direct antagonistic action on histamine and the like during an allergic reaction, has a leukotriene production and release inhibitory and antagonistic action, and also has an effect on neutrophils and eosinophils. It is known to exhibit an inhibitory effect on the migration and infiltration of inflammatory cells and an active oxygen production, and is widely used clinically as eye drops, nasal drops and the like for preventing allergic symptoms.
フマル酸ケトチフェンを含有する眼科用剤とした場合は、点眼時に眼痛を生じることが知られている。点眼時の眼痛を除去し、速効的な鎮痒効果を有するいくつかの点眼剤が開示されている。たとえば、フマル酸ケトチフェン等の抗アレルギー薬と抗ヒスタミン薬及びメントール等のテルペノイド類を配合した点眼剤がある（特許文献１）。また、フマル酸ケトチフェン等の抗アレルギー薬と抗ヒスタミン薬、血管収縮薬及びメントール等のテルペノイド化合物を配合する点眼剤がある（特許文献２）。 It is known that ophthalmic preparations containing ketotifen fumarate cause eye pain when instilled. Several eye drops have been disclosed which eliminate eye pain during eye drops and have a rapid antipruritic effect. For example, there is an eye drop in which an antiallergic drug such as ketotifen fumarate and an antihistamine drug and a terpenoid such as menthol are blended (Patent Document 1). Further, there is an eye drop containing an antiallergic drug such as ketotifen fumarate and an antihistamine, a vasoconstrictor, and a terpenoid compound such as menthol (Patent Document 2).
コンドロイチン硫酸ナトリウム及びヒアルロン酸ナトリウムは、角膜表面の保護成分として、眼科用剤に使用されているが、フマル酸ケトチフェンとコンドロイチン硫酸ナトリウム又はヒアルロン酸ナトリウムを配合した眼科用剤は知られていない。 ナ ト リ ウ ム Sodium chondroitin sulfate and sodium hyaluronate are used in ophthalmic preparations as protective components on the surface of the cornea, but no ophthalmic preparation containing ketotifen fumarate and sodium chondroitin sulfate or sodium hyaluronate is known.
本発明は、フマル酸ケトチフェンを配合する眼科用剤において、眼痛を防止し、しかも使用感の優れたものを提供することである。 The present invention is to provide an ophthalmic preparation containing ketotifen fumarate, which prevents eye pain and has an excellent feeling upon use.
本発明者らは、かかる課題を解決するために鋭意研究した結果、（ａ）フマル酸ケトチフェン及び（ｂ）コンドロイチン硫酸ナトリウム及びヒアルロン酸ナトリウムから選ばれる１種以上を配合する眼科用剤が、意外にも、点眼時の眼痛を防止し、また、花粉などによるアレルギー発生時のかゆみ等の不快感を抑えることを見出し、本発明を完成した。 The present inventors have conducted intensive studies in order to solve such problems, and as a result, an ophthalmic agent containing (a) ketotifen fumarate and (b) one or more selected from sodium chondroitin sulfate and sodium hyaluronate has been unexpectedly obtained. In addition, they have found that they can prevent eye pain when instilled and suppress discomfort such as itching when allergy occurs due to pollen and the like, and thus completed the present invention.
本発明の点眼剤は、フマル酸ケトチフェンの点眼時の眼痛防止ができ、花粉などによるかゆみ等の不快感を改善することができる眼科用剤である。 The ophthalmic preparation of the present invention is an ophthalmic preparation which can prevent eye pain when ketotifen fumarate is instilled and can reduce discomfort such as itching due to pollen and the like.
本発明は、（ａ）フマル酸ケトチフェン及び（ｂ）コンドロイチン硫酸ナトリウム及びヒアルロン酸ナトリウムから選ばれる１種以上を配合する点眼用剤である。 The present invention is an ophthalmic solution containing (a) ketotifen fumarate and (b) one or more selected from sodium chondroitin sulfate and sodium hyaluronate.
本発明で、フマル酸ケトチフェンの配合量は、薬効と副作用を考慮し、0.00138−0.138w/v%が好ましい。 で In the present invention, the compounding amount of ketotifen fumarate is preferably 0.00138 to 0.138 w / v% in consideration of the efficacy and side effects.
コンドロイチン硫酸ナトリウムの配合量は、眼痛防止効果や使用感を考慮し、0.01−3.0w/v%が好ましい。 The amount of sodium chondroitin sulfate is preferably 0.01-3.0 w / v% in consideration of the effect of preventing eye pain and feeling during use.
ヒアルロン酸ナトリウム配合量は、眼痛防止効果や使用感を考慮し、0.01−0.3w/v%が好ましい。 ナ ト リ ウ ム The amount of sodium hyaluronate is preferably 0.01-0.3 w / v% in consideration of the effect of preventing eye pain and feeling during use.
コンドロイチン硫酸ナトリウムとヒアルロン酸ナトリウムの配合量が下限を下回るとフマル酸ケトチフェンの眼痛の防止効果及び花粉などによるかゆみ等のアレルギー症状の除去効果が低い。フマル酸ケトチフェンの配合量が0.138w/v%を上回る場合は、眼痛を防止することができない。また、コンドロイチン硫酸ナトリウムとヒアルロン酸ナトリウムの配合量が上限を上回る場合は、粘性等により使用感が悪くなるため好ましくない。 る と If the blending amount of sodium chondroitin sulfate and sodium hyaluronate is below the lower limit, the effect of ketotifen fumarate for preventing eye pain and the effect of removing allergic symptoms such as itching due to pollen and the like are low. If the compounding amount of ketotifen fumarate exceeds 0.138 w / v%, eye pain cannot be prevented. Further, when the blending amount of sodium chondroitin sulfate and sodium hyaluronate exceeds the upper limit, the feeling of use is deteriorated due to viscosity and the like, which is not preferable.
また、更にアスパラギン酸塩及びアミノエチルスルホン酸から選ばれる１種以上を配合することにより、眼痛防止効果や異物の除去によるアレルギー発症時の不快感改善効果を高めることができる。
アスパラギン酸塩とは、アスパラギン酸カリウム、アスパラギン酸マグネシウム・カリウム等である。
Further, by blending at least one selected from aspartate and aminoethylsulfonic acid, the effect of preventing eye pain and the effect of improving discomfort at the onset of allergy by removing foreign substances can be enhanced.
Aspartate is potassium aspartate, magnesium potassium potassium aspartate, and the like.
本発明の眼科用剤には、眼痛を起こさない範囲で、必要に応じて、医薬上許容される他の成分を配合することができ、例えば、イプシロンアミノカプロン酸、グリチルリチン酸二カリウム等の抗炎症薬、マレイン酸クロルフェニラミン、塩酸ジフェンヒドラミン等の抗ヒスタミン薬、塩酸テトラヒドロゾリン、塩酸フェニレフリン、塩酸ナファゾリン等の血管収縮薬、塩酸ピリドキシン、リン酸リボフラビン、シアノコバラミン、パンテノール、酢酸トコフェノール、フラビンアデニンジヌクレオチドナトリウム等のビタミン類、メチル硫酸ネオスチグミン等のピント調節薬、塩化ナトリウム、塩化カリウム等の無機塩、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンソルビタンモノオレート等の界面活性剤、メントール、カンフル、ユーカリ油等の精油、その他基剤成分として、クロロブタノール、ホウ砂、ホウ酸、塩化ベンザルコニウム、パラオキシ安息香酸エステル（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）等を挙げることができる。 The ophthalmic preparation of the present invention may optionally contain other pharmaceutically acceptable components within a range that does not cause ocular pain. For example, antioxidants such as epsilon aminocaproic acid and dipotassium glycyrrhizinate may be used. Inflammatory drugs, antihistamines such as chlorpheniramine maleate, diphenhydramine hydrochloride, vasoconstrictors such as tetrahydrozoline hydrochloride, phenylephrine hydrochloride, naphazoline hydrochloride, pyridoxine hydrochloride, riboflavin phosphate, cyanocobalamin, panthenol, tocophenol acetate, flavin adenine diamine Vitamins such as nucleotide sodium, focus modifiers such as neostigmine methyl sulfate, inorganic salts such as sodium chloride and potassium chloride, surfactants such as polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monooleate, menthol, camphor Chlorobutanol, borax, boric acid, benzalkonium chloride, paraoxybenzoic acid esters (methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, paraoxybenzoic acid) Butyl, etc.).
本願発明の眼科用剤とは、点眼剤又は洗眼剤である。 眼 The ophthalmic preparation of the present invention is an eye drop or an eyewash.
本発明の眼科用剤は、従来の方法で点眼剤又は洗眼剤として製造することができ、点眼剤とした際は、１日数回、１回１滴から数滴投与することができ、洗眼剤とした際は、１日数回、眼の洗浄をすることができる。 The ophthalmic preparation of the present invention can be produced as an eye drop or an eye wash by a conventional method. When used as an eye drop, it can be administered several times a day, from one drop to several drops at a time. Then, the eyes can be washed several times a day.
以下に、本発明を実施例及び試験例を示し、詳細に説明する。 本 Hereinafter, the present invention will be described in detail with reference to Examples and Test Examples.
実施例１
処方 100mL中
フマル酸ケトチフェン 69mg
コンドロイチン硫酸ナトリウム 250mg
アミノエチルスルホン酸 1000mg
ｌ−メントール 5mg
ｄｌ−カンフル 5mg
ハッカ油 10mg
クロロブタノール 150mg
ホウ酸 500mg
グリセリン 1150mg
エデト酸ナトリウム 5mg
ポリソルベート８０ 100mg
塩化ベンザルコニウム 5mg
水酸化ナトリウム 適量
精製水 全量100mL
製造方法
精製水（85mL）に各成分を溶解し、水酸化ナトリウムでｐＨを5.6に調整した後、全量を100mLとした。その後ろ過滅菌を行い、無菌の点眼剤とした。この点眼剤の浸透圧は288mOsmであった。
Example 1
Prescription 100ml ketotifen fumarate 69mg
Sodium chondroitin sulfate 250mg
Aminoethylsulfonic acid 1000mg
l-menthol 5mg
dl-camphor 5mg
Mentha oil 10mg
Chlorobutanol 150mg
Boric acid 500mg
Glycerin 1150mg
Sodium edetate 5mg
Polysorbate 80 100mg
Benzalkonium chloride 5mg
Appropriate amount of sodium hydroxide Purified water 100mL
Production Method Each component was dissolved in purified water (85 mL), the pH was adjusted to 5.6 with sodium hydroxide, and the total amount was adjusted to 100 mL. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop. The osmotic pressure of this eye drop was 288 mOsm.
実施例２
処方 100mL中
フマル酸ケトチフェン 69mg
コンドロイチン硫酸ナトリウム 500mg
クロロブタノール 150mg
グリセリン 2500mg
ポリソルベート８０ 100mg
塩化ベンザルコニウム 5mg
水酸化ナトリウム 適量
精製水 全量100mL
製造方法
精製水（85mL）に各成分を溶解し、水酸化ナトリウムでｐＨを5.5に調整した後、全量を100mLとした。その後ろ過滅菌を行い、無菌の点眼剤とした。この点眼剤の浸透圧は258mOsmであった。
Example 2
Prescription 100ml ketotifen fumarate 69mg
500mg sodium chondroitin sulfate
Chlorobutanol 150mg
Glycerin 2500mg
Polysorbate 80 100mg
Benzalkonium chloride 5mg
Appropriate amount of sodium hydroxide Purified water 100mL
Production Method Each component was dissolved in purified water (85 mL), the pH was adjusted to 5.5 with sodium hydroxide, and the total amount was adjusted to 100 mL. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop. The osmotic pressure of this eye drop was 258 mOsm.
実施例３
処方 100mL中
フマル酸ケトチフェン 69mg
コンドロイチン硫酸ナトリウム 500mg
グリセリン 2200mg
アスパラギン酸カリウム 1000mg
メントール 5mg
ポリソルベート８０ 100mg
塩化ベンザルコニウム 5mg
水酸化ナトリウム 適量
精製水 全量100mL
製造方法
精製水（85mL）に各成分を溶解し、水酸化ナトリウムでｐＨを5.3に調整した後、全量を100mLとした。その後ろ過滅菌を行い、無菌の点眼剤とした。この点眼剤の浸透圧は282mOsmであった。
Example 3
Prescription 100ml ketotifen fumarate 69mg
500mg sodium chondroitin sulfate
Glycerin 2200mg
Potassium aspartate 1000mg
Menthol 5mg
Polysorbate 80 100mg
Benzalkonium chloride 5mg
Appropriate amount of sodium hydroxide Purified water 100mL
Production method Each component was dissolved in purified water (85 mL), the pH was adjusted to 5.3 with sodium hydroxide, and the total amount was adjusted to 100 mL. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop. The osmotic pressure of this eye drop was 282 mOsm.
実施例４
処方 100mL中
フマル酸ケトチフェン 69mg
コンドロイチン硫酸ナトリウム 500mg
アミノエチルスルホン酸 1000mg
グリセリン 2200mg
メントール 5mg
クロロブタノール 150mg
ポリソルベート８０ 100mg
塩化ベンザルコニウム 5mg
水酸化ナトリウム 適量
精製水 全量100mL
製造方法
精製水（85mL）に各成分を溶解し、水酸化ナトリウムでｐＨを5.3に調整した後、全量を100mLとした。その後ろ過滅菌を行い、無菌の点眼剤とした。この点眼剤の浸透圧は280mOsmであった。
Example 4
Prescription 100ml ketotifen fumarate 69mg
500mg sodium chondroitin sulfate
Aminoethylsulfonic acid 1000mg
Glycerin 2200mg
Menthol 5mg
Chlorobutanol 150mg
Polysorbate 80 100mg
Benzalkonium chloride 5mg
Appropriate amount of sodium hydroxide Purified water 100mL
Production method Each component was dissolved in purified water (85 mL), the pH was adjusted to 5.3 with sodium hydroxide, and the total amount was adjusted to 100 mL. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop. The osmotic pressure of this eye drop was 280 mOsm.
実施例５〜１０
表１に示した実施例５〜１０の点眼剤を実施例１と同様の方法で製造した。
Examples 5 to 10
The eye drops of Examples 5 to 10 shown in Table 1 were produced in the same manner as in Example 1.
実施例１１
処方 100mL中
フマル酸ケトチフェン 6.9mg
コンドロイチン硫酸ナトリウム 50mg
グリセリン 2500mg
ポリソルベート８０ 10mg
塩化ベンザルコニウム 5mg
水酸化ナトリウム 適量
精製水 全量100mL
製造方法
精製水（85mL）に各成分を溶解し、水酸化ナトリウムでｐＨを6.7に調整した後、全量を100mLとした。その後ろ過滅菌を行い、無菌の洗眼剤とした。この洗眼剤の浸透圧は237mOsmであった。
Example 11
Prescription 100mL Ketotifen fumarate 6.9mg
Chondroitin sodium sulfate 50mg
Glycerin 2500mg
Polysorbate 80 10mg
Benzalkonium chloride 5mg
Appropriate amount of sodium hydroxide Purified water 100mL
Production Method Each component was dissolved in purified water (85 mL), the pH was adjusted to 6.7 with sodium hydroxide, and the total amount was adjusted to 100 mL. Thereafter, the solution was sterilized by filtration to obtain a sterile eyewash. The osmotic pressure of this eyewash was 237 mOsm.
実施例１２
処方 100mL中
フマル酸ケトチフェン 6.9mg
コンドロイチン硫酸ナトリウム 10mg
アスパラギン酸カリウム 50mg
アミノエチルスルホン酸 50mg
メントール 3mg
塩化ナトリウム 850mg
ポリソルベート８０ 10mg
塩化ベンザルコニウム 5mg
水酸化ナトリウム 適量
精製水 全量100mL
製造方法
精製水（85mL）に各成分を溶解し、水酸化ナトリウムでｐＨを6.2に調整した後、全量を100mLとした。その後ろ過滅菌を行い、無菌の洗眼剤とした。この洗眼剤の浸透圧は280mOsmであった。
Example 12
Prescription 100mL Ketotifen fumarate 6.9mg
Chondroitin sulfate sodium 10mg
Potassium aspartate 50mg
Aminoethylsulfonic acid 50mg
Menthol 3mg
Sodium chloride 850mg
Polysorbate 80 10mg
Benzalkonium chloride 5mg
Appropriate amount of sodium hydroxide Purified water 100mL
Production Method Each component was dissolved in purified water (85 mL), the pH was adjusted to 6.2 with sodium hydroxide, and the total amount was adjusted to 100 mL. Thereafter, the solution was sterilized by filtration to obtain a sterile eyewash. The osmotic pressure of this eyewash was 280 mOsm.
実施例１３
処方 100mL中
フマル酸ケトチフェン 1.38mg
コンドロイチン硫酸ナトリウム 25mg
アスパラギン酸マグネシウム・カリウム 100mg
ホウ酸 250mg
グリセリン 1900mg
ポリソルベート８０ 10mg
塩化ベンザルコニウム 5mg
水酸化ナトリウム 適量
精製水 全量100mL
製造方法
精製水（85mL）に各成分を溶解し、水酸化ナトリウムでｐＨを6.5に調整した後、全量を100mLとした。その後ろ過滅菌を行い、無菌の洗眼剤とした。この洗眼剤の浸透圧は270mOsmであった。
Example 13
Formulation Ketotifen fumarate 1.38mg in 100mL
Chondroitin sodium sulfate 25mg
Magnesium potassium aspartate 100mg
250mg boric acid
Glycerin 1900mg
Polysorbate 80 10mg
Benzalkonium chloride 5mg
Appropriate amount of sodium hydroxide Purified water 100mL
Production Method Each component was dissolved in purified water (85 mL), the pH was adjusted to 6.5 with sodium hydroxide, and the total amount was adjusted to 100 mL. Thereafter, the solution was sterilized by filtration to obtain a sterile eyewash. The osmotic pressure of this eyewash was 270 mOsm.
比較例１
処方 100mL中
フマル酸ケトチフェン 69mg
グリセリン 2500mg
塩化ベンザルコニウム 5mg
水酸化ナトリウム 適量
精製水 全量100mL
製造方法
精製水（85mL）に各成分を溶解し、水酸化ナトリウムでｐＨを5.7に調整した後、全量を100mLとした。その後ろ過滅菌を行い、無菌の点眼剤とした。この点眼剤の浸透圧は247mOsmであった。
Comparative Example 1
Prescription 100ml ketotifen fumarate 69mg
Glycerin 2500mg
Benzalkonium chloride 5mg
Appropriate amount of sodium hydroxide Purified water 100mL
Production Method Each component was dissolved in purified water (85 mL), the pH was adjusted to 5.7 with sodium hydroxide, and the total amount was adjusted to 100 mL. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop. The osmotic pressure of this eye drop was 247 mOsm.
比較例２
処方 100mL中
フマル酸ケトチフェン 6.9mg
グリセリン 2500mg
塩化ベンザルコニウム 5mg
水酸化ナトリウム 適量
精製水 全量100mL
製造方法
精製水（85mL）に各成分を溶解し、水酸化ナトリウムでｐＨを6.4に調節した後、全量を100mLとした。その後ろ過滅菌を行い、無菌の洗眼剤とした。この洗眼剤の浸透圧は237mOsmであった。
Comparative Example 2
Prescription 100mL Ketotifen fumarate 6.9mg
Glycerin 2500mg
Benzalkonium chloride 5mg
Appropriate amount of sodium hydroxide Purified water 100mL
Production Method Each component was dissolved in purified water (85 mL), the pH was adjusted to 6.4 with sodium hydroxide, and the total amount was adjusted to 100 mL. Thereafter, the solution was sterilized by filtration to obtain a sterile eyewash. The osmotic pressure of this eyewash was 237 mOsm.
試験例１
方法：
健常者10名に対し、自覚症状として目に異物感等の不快感を感じた時に、実施例１〜４及び比較例１の点眼剤、並びに実施例１１、１２及び比較例２の洗眼剤を使用し、使用時の刺激感（眼痛）及び不快感の改善持続時間を評価した。なお、各点眼剤は１〜２滴ずつ両眼に点眼し、各洗眼剤はプラスチック製の専用カップに約５ｍＬを入れて洗眼を行った。評価基準は、下記の通りである。各被験者の評価の平均を求め、その平均点で評価した。本発明の実施例は、刺激と不快感を抑制することが示された。
＜評価基準＞
Ａ：刺激性評価
４：刺激を感じない
３：ほとんど刺激を感じない
２：刺激を感じる
１：強い刺激を感じる
◎：３．３〜４点
○：２．５〜３．２点
△：１．８〜２．４点
×：１〜１．７点
Ｂ：不快感改善効果
４：１０分以上
３：５〜１０分
２：１〜５分
１：１分以下
◎：３．３〜４点
○：２．５〜３．２点
△：１．８〜２．４点
×：１〜１．７点
Test example 1
Method:
For 10 healthy subjects, when they felt discomfort such as a foreign body sensation in their eyes as a subjective symptom, they applied the eye drops of Examples 1 to 4 and Comparative Example 1 and the eyewash of Examples 11, 12 and Comparative Example 2. It was used to evaluate the duration of improvement in irritation (eye pain) and discomfort during use. In addition, each eyedrop was applied to both eyes by one to two drops, and each eyewash was washed by putting about 5 mL into a plastic exclusive cup. The evaluation criteria are as follows. The average of the evaluation of each subject was obtained, and the evaluation was made based on the average score. Examples of the present invention have been shown to reduce irritation and discomfort.
<Evaluation criteria>
A: Irritation evaluation 4: I do not feel irritation 3: I hardly feel irritation 2: I feel irritation 1: I feel a strong irritation ◎: 3.3-4 points ○: 2.5-3.2 points △: 1 0.8 to 2.4 points ×: 1 to 1.7 points B: discomfort improvement effect 4: 10 minutes or more 3: 5 to 10 minutes 2: 1 to 5 minutes 1: 1 minute or less ：: 3.3 to 4 Points ○: 2.5 to 3.2 points △: 1.8 to 2.4 points ×: 1 to 1.7 points
本発明の点眼用剤は、（ａ）フマル酸ケトチフェン及び（ｂ）コンドロイチン硫酸ナトリウム及びヒアルロン酸ナトリウムから選ばれる１種以上を含有する眼科用剤であり、眼痛防止及び異物除去効果を有しており、極めて有用な眼科用剤であり、点眼剤または洗眼剤として用いることができる。 The ophthalmic preparation of the present invention is an ophthalmic preparation containing (a) ketotifen fumarate and (b) one or more selected from sodium chondroitin sulfate and sodium hyaluronate, and has an effect of preventing eye pain and removing foreign substances. It is a very useful ophthalmic agent and can be used as eye drops or eyewash.
Claims (2)
The ophthalmic preparation according to claim 1, further comprising one or more selected from aspartate and sodium aminosulfonate.
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| JP2006321787A (en) * | 2005-04-19 | 2006-11-30 | Daiichi Sankyo Healthcare Co Ltd | Medicinal preparation to be applied to local mucous membrane containing ketotifen fumarate |
| CN100586440C (en) * | 2007-08-03 | 2010-02-03 | 杨文龙 | Aspartic vitamin eye drops and preparation method thereof |
| JP2012144570A (en) * | 2005-04-19 | 2012-08-02 | Daiichi Sankyo Healthcare Co Ltd | Medicinal preparation to be applied to local mucous membrane containing ketotifen fumarate |
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| JP2005187354A (en) * | 2003-12-25 | 2005-07-14 | Lion Corp | Aqueous external preparation composition |
| JP2006321787A (en) * | 2005-04-19 | 2006-11-30 | Daiichi Sankyo Healthcare Co Ltd | Medicinal preparation to be applied to local mucous membrane containing ketotifen fumarate |
| JP2012144570A (en) * | 2005-04-19 | 2012-08-02 | Daiichi Sankyo Healthcare Co Ltd | Medicinal preparation to be applied to local mucous membrane containing ketotifen fumarate |
| CN100586440C (en) * | 2007-08-03 | 2010-02-03 | 杨文龙 | Aspartic vitamin eye drops and preparation method thereof |
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