JPWO2014119643A1 - 澄明な水性液剤 - Google Patents
澄明な水性液剤 Download PDFInfo
- Publication number
- JPWO2014119643A1 JPWO2014119643A1 JP2014559730A JP2014559730A JPWO2014119643A1 JP WO2014119643 A1 JPWO2014119643 A1 JP WO2014119643A1 JP 2014559730 A JP2014559730 A JP 2014559730A JP 2014559730 A JP2014559730 A JP 2014559730A JP WO2014119643 A1 JPWO2014119643 A1 JP WO2014119643A1
- Authority
- JP
- Japan
- Prior art keywords
- aqueous liquid
- benzalkonium chloride
- alkyl group
- liquid preparation
- carbon atoms
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000007864 aqueous solution Substances 0.000 title claims description 36
- 239000007788 liquid Substances 0.000 claims abstract description 93
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 60
- 238000002360 preparation method Methods 0.000 claims abstract description 60
- 229960000686 benzalkonium chloride Drugs 0.000 claims abstract description 53
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims abstract description 53
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 42
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 13
- 239000002253 acid Substances 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 23
- 239000003889 eye drop Substances 0.000 claims description 17
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 238000002834 transmittance Methods 0.000 claims description 11
- 229920001664 tyloxapol Polymers 0.000 claims description 10
- MDYZKJNTKZIUSK-UHFFFAOYSA-N tyloxapol Chemical group O=C.C1CO1.CC(C)(C)CC(C)(C)C1=CC=C(O)C=C1 MDYZKJNTKZIUSK-UHFFFAOYSA-N 0.000 claims description 10
- 229960004224 tyloxapol Drugs 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 9
- 239000004094 surface-active agent Substances 0.000 claims description 8
- 229940012356 eye drops Drugs 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 abstract description 2
- 229940126062 Compound A Drugs 0.000 description 27
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 27
- 235000002639 sodium chloride Nutrition 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- -1 oxy Acetic acid Chemical compound 0.000 description 11
- 238000002156 mixing Methods 0.000 description 10
- 239000000872 buffer Substances 0.000 description 7
- 239000002997 ophthalmic solution Substances 0.000 description 7
- 229940054534 ophthalmic solution Drugs 0.000 description 7
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 3
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- 206010065062 Meibomian gland dysfunction Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000001270 agonistic effect Effects 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 3
- 239000004327 boric acid Substances 0.000 description 3
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- 238000011049 filling Methods 0.000 description 3
- 239000007951 isotonicity adjuster Substances 0.000 description 3
- 239000003002 pH adjusting agent Substances 0.000 description 3
- 239000001509 sodium citrate Substances 0.000 description 3
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 3
- 235000011083 sodium citrates Nutrition 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
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- PMNLUUOXGOOLSP-UHFFFAOYSA-N 2-mercaptopropanoic acid Chemical compound CC(S)C(O)=O PMNLUUOXGOOLSP-UHFFFAOYSA-N 0.000 description 2
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- OVBJJZOQPCKUOR-UHFFFAOYSA-L EDTA disodium salt dihydrate Chemical compound O.O.[Na+].[Na+].[O-]C(=O)C[NH+](CC([O-])=O)CC[NH+](CC([O-])=O)CC([O-])=O OVBJJZOQPCKUOR-UHFFFAOYSA-L 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 108010015181 PPAR delta Proteins 0.000 description 2
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- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 229910021538 borax Inorganic materials 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 239000006196 drop Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
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- 235000011187 glycerol Nutrition 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
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- 239000011347 resin Substances 0.000 description 2
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
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- 229940037001 sodium edetate Drugs 0.000 description 2
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- 239000004328 sodium tetraborate Substances 0.000 description 2
- 235000010339 sodium tetraborate Nutrition 0.000 description 2
- GNBVPFITFYNRCN-UHFFFAOYSA-M sodium thioglycolate Chemical compound [Na+].[O-]C(=O)CS GNBVPFITFYNRCN-UHFFFAOYSA-M 0.000 description 2
- 229940046307 sodium thioglycolate Drugs 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
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- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 1
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 description 1
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 1
- 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
- OOSZCNKVJAVHJI-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]piperazine Chemical compound C1=CC(F)=CC=C1CN1CCNCC1 OOSZCNKVJAVHJI-UHFFFAOYSA-N 0.000 description 1
- IHPYMWDTONKSCO-UHFFFAOYSA-N 2,2'-piperazine-1,4-diylbisethanesulfonic acid Chemical compound OS(=O)(=O)CCN1CCN(CCS(O)(=O)=O)CC1 IHPYMWDTONKSCO-UHFFFAOYSA-N 0.000 description 1
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- OCBHHZMJRVXXQK-UHFFFAOYSA-M benzyl-dimethyl-tetradecylazanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 OCBHHZMJRVXXQK-UHFFFAOYSA-M 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- CKDOCTFBFTVPSN-UHFFFAOYSA-N borneol Natural products C1CC2(C)C(C)CC1C2(C)C CKDOCTFBFTVPSN-UHFFFAOYSA-N 0.000 description 1
- 229940116229 borneol Drugs 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229930008380 camphor Natural products 0.000 description 1
- 229960000846 camphor Drugs 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- SXPWTBGAZSPLHA-UHFFFAOYSA-M cetalkonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 SXPWTBGAZSPLHA-UHFFFAOYSA-M 0.000 description 1
- 229960000228 cetalkonium chloride Drugs 0.000 description 1
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- KXKPYJOVDUMHGS-OSRGNVMNSA-N chondroitin sulfate Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](OS(O)(=O)=O)[C@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](C(O)=O)O1 KXKPYJOVDUMHGS-OSRGNVMNSA-N 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 229920006026 co-polymeric resin Polymers 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000002826 coolant Substances 0.000 description 1
- 229960001305 cysteine hydrochloride Drugs 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- DTGKSKDOIYIVQL-UHFFFAOYSA-N dl-isoborneol Natural products C1CC2(C)C(O)CC1C2(C)C DTGKSKDOIYIVQL-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- HQQADJVZYDDRJT-UHFFFAOYSA-N ethene;prop-1-ene Chemical group C=C.CC=C HQQADJVZYDDRJT-UHFFFAOYSA-N 0.000 description 1
- 239000010642 eucalyptus oil Substances 0.000 description 1
- 229940044949 eucalyptus oil Drugs 0.000 description 1
- 231100000013 eye irritation Toxicity 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 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
- 239000007952 growth promoter Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229920001903 high density polyethylene Polymers 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000004700 high-density polyethylene Substances 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229920001684 low density polyethylene Polymers 0.000 description 1
- 239000004702 low-density polyethylene Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 210000004175 meibomian gland Anatomy 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- HWPKGOGLCKPRLZ-UHFFFAOYSA-M monosodium citrate Chemical compound [Na+].OC(=O)CC(O)(C([O-])=O)CC(O)=O HWPKGOGLCKPRLZ-UHFFFAOYSA-M 0.000 description 1
- 239000002524 monosodium citrate Substances 0.000 description 1
- 235000018342 monosodium citrate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 229940066429 octoxynol Drugs 0.000 description 1
- 229920002113 octoxynol Polymers 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229920005668 polycarbonate resin Polymers 0.000 description 1
- 239000004431 polycarbonate resin Substances 0.000 description 1
- 229920013716 polyethylene resin Polymers 0.000 description 1
- 229920000139 polyethylene terephthalate Polymers 0.000 description 1
- 239000005020 polyethylene terephthalate Substances 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229940099429 polyoxyl 40 stearate Drugs 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229940074545 sodium dihydrogen phosphate dihydrate Drugs 0.000 description 1
- 239000000176 sodium gluconate Substances 0.000 description 1
- 235000012207 sodium gluconate Nutrition 0.000 description 1
- 229940005574 sodium gluconate Drugs 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- SFVFIFLLYFPGHH-UHFFFAOYSA-M stearalkonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 SFVFIFLLYFPGHH-UHFFFAOYSA-M 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Ophthalmology & Optometry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Description
[1](3−{2−[4−イソプロピル−2−(4−トリフルオロメチル)フェニル−5−チアゾリル]エチル}−5−メチル−1,2−ベンズイソキサゾール−6−イル)オキシ酢酸又はその製剤学的に許容される塩、及び式:
[2](3−{2−[4−イソプロピル−2−(4−トリフルオロメチル)フェニル−5−チアゾリル]エチル}−5−メチル−1,2−ベンズイソキサゾール−6−イル)オキシ酢酸又はその製剤学的に許容される塩の水性液剤全量に対する下限濃度が0.0002w/v%で、上限濃度が0.05w/v%の範囲から選択される、上記[1]記載の水性液剤、
[3]Rが炭素数8のアルキル基であるベンザルコニウム塩化物を含有し、該ベンザルコニウム塩化物の水性液剤全量に対する濃度が0.05w/v%未満、又は0.1w/v%よりも高い範囲から選択される、上記[1]又は[2]に記載の水性液剤、
[4]Rが炭素数10のアルキル基であるベンザルコニウム塩化物を含有し、該ベンザルコニウム塩化物の水性液剤全量に対する濃度が0.05w/v%未満、又は0.1w/v%よりも高い範囲から選択される、上記[1]又は[2]に記載の水性液剤、
[5]Rが炭素数12のアルキル基であるベンザルコニウム塩化物を含有し、該ベンザルコニウム塩化物の水性液剤全量に対する濃度が0.003w/v%未満、又は0.01w/v%よりも高い範囲から選択される、上記[1]又は[2]に記載の水性液剤、
[6]Rが炭素数14のアルキル基であるベンザルコニウム塩化物を含有し、該ベンザルコニウム塩化物の水性液剤全量に対する濃度が0.001w/v%未満、又は0.002w/v%よりも高い範囲から選択される、上記[1]又は[2]に記載の水性液剤、
[7]Rが炭素数16のアルキル基であるベンザルコニウム塩化物を含有し、該ベンザルコニウム塩化物の水性液剤全量に対する濃度が0.001w/v%以外の範囲から選択される、上記[1]又は[2]に記載の水性液剤、
[8]ベンザルコニウム塩化物のRが炭素数18のアルキル基である、上記[1]又は[2]に記載の水性液剤、
[9]ベンザルコニウム塩化物として、Rが炭素数12のアルキル基であるベンザルコニウム塩化物とRが炭素数14のアルキル基であるベンザルコニウム塩化物とを共に含み、且つ該ベンザルコニウム塩化物の水性液剤全量に対する合計濃度が0.001w/v%未満、又は0.002w/v%よりも高い範囲から選択される、上記[1]又は[2]に記載の水性液剤、
[10]さらに界面活性剤を含有する、上記[1]〜[9]のいずれかに記載の水性液剤、
[11]界面活性剤がチロキサポールである、上記[10]記載の水性液剤、
[12]眼科用である、上記[1]〜[11]のいずれかに記載の水性液剤、
[13]点眼剤である、上記[12]記載の水性液剤、
[14](3−{2−[4−イソプロピル−2−(4−トリフルオロメチル)フェニル−5−チアゾリル]エチル}−5−メチル−1,2−ベンズイソキサゾール−6−イル)オキシ酢酸又はその製剤学的に許容される塩、式:
[15](3−{2−[4−イソプロピル−2−(4−トリフルオロメチル)フェニル−5−チアゾリル]エチル}−5−メチル−1,2−ベンズイソキサゾール−6−イル)オキシ酢酸又はその製剤学的に許容される塩を含有する水性液剤において、式:
[16]Rが炭素数8のアルキル基であるベンザルコニウム塩化物を水性液剤全量に対して0.05w/v%未満、又は0.1w/v%よりも高い濃度になるよう配合することを特徴とする、上記[15]記載の方法、
[17]Rが炭素数10のアルキル基であるベンザルコニウム塩化物を水性液剤全量に対して0.05w/v%未満、又は0.1w/v%よりも高い濃度になるよう配合することを特徴とする、上記[15]記載の方法、
[18]Rが炭素数12のアルキル基であるベンザルコニウム塩化物を水性液剤全量に対して0.003w/v%未満、又は0.01w/v%よりも高い濃度になるよう配合することを特徴とする、上記[15]記載の方法、
[19]Rが炭素数14のアルキル基であるベンザルコニウム塩化物を水性液剤全量に対して0.001w/v%未満、又は0.002w/v%よりも高い濃度になるよう配合することを特徴とする、上記[15]記載の方法、
[20]Rが炭素数16のアルキル基であるベンザルコニウム塩化物を水性液剤全量に対して0.001w/v%以外の濃度になるよう配合することを特徴とする、上記[15]記載の方法、
[21]Rが炭素数18のアルキル基であるベンザルコニウム塩化物を配合することを特徴とする、上記[15]記載の方法、および
[22]Rが炭素数12のアルキル基であるベンザルコニウム塩化物とRが炭素数14のアルキル基であるベンザルコニウム塩化物とを共に含む混合物を水性液剤全量に対して0.001w/v%未満、又は0.002w/v%よりも高い濃度になるよう配合することを特徴とする、上記[15]記載の方法、
に関する。
RがC8H17〜C18H37のいずれかのアルキル基(具体的には、例えば、C10H21、C12H25、C14H29、C16H33、C18H37等)である化合物は、それぞれ単一化合物として市販されている。例えば、Benzyldimethyldecylammonium chloride(R=C10H21)(SIGMA−ALDRICH)、Benzyldimethyldodecylammonium chloride(R=C12H25)(Fluka)、Benzyldimethyltetradecylammonium chloride(R=C14H29)(Fluka)、Benzyldimethylhexadecylammonium chloride,hydrate(R=C16H33)(Acros Organics)、Benzyldimethylstearylammonium chloride,hydrate(R=C18H37)(東京化成工業株式会社製)等として入手できる。
化合物Aの水性液剤を下記処方にしたがって調製した。精製水にリン酸二水素ナトリウム二水和物あるいはホウ酸を溶解し、水酸化ナトリウムを加えてpHを7.5あるいは8.5に調整した。この液に化合物Aを加えて完全に溶解させた。このとき必要に応じて加温(約60℃〜80℃)及び超音波処理(42kHz,1分)をした。次に、BAKを加えた後、規定量まで精製水を加えて水性液剤を調製した。その水性液剤をガラスアンプルに充填し、色調(白色の背景を使用)及び澄明性(黒色又は白色の背景を使用)を肉眼で観察した。また、自記分光光度計(U−3000、U−3010、日立製作所)を用いて波長600nmにおける該水性液剤の光線透過率を測定した。濁りの基準として、肉眼観察の結果から透過率が98.0%以上の状態を無色澄明とし、透過率が98.0%未満の状態を白濁として評価した。
表1〜7に示されるように、配合するBAKの種類により白濁の生じない濃度範囲が異なることが分かった。すなわち、BAKとして、BAK−C10を用いた場合には、0.01w/v%以下又は0.5w/v%以上の濃度で配合した場合に無色澄明な水性液剤が得られた(表1)。BAK−C12を用いた場合には、0.002w/v%以下又は0.02w/v%以上の濃度で配合した場合に無色澄明な水性液剤が得られた(表2〜表4)。BAK−C14を用いた場合には、0.0005w/v%以上0.001w/v%未満又は0.005w/v%以上の濃度で配合した場合に無色澄明な水性液剤が得られた(表5)。BAK−C16を用いた場合には、0.0005w/v%又は0.002w/v%以上の濃度で配合した場合に無色澄明な水性液剤が得られた(表6)。BAK−C18を用いた場合には、いずれの濃度で配合した場合にも無色澄明な水性液剤が得られた(表7)。表2〜表4の結果によれば、水性液剤のpHが7.5〜8.5の範囲では、pHの変化や化合物Aの配合濃度の変化にかかわらず、同様の濃度のBAK−C12の配合により無色澄明な水性液剤が得られることが分かった。
実験例1と同様の方法により下記の化合物A含有水性液剤を調製し、その色調及び澄明性を肉眼で観察するとともに、波長600nmにおける該水性液剤の透過率を測定し、評価した。
表8の結果によれば、BAK−C12/C14を使用した場合にも、前記したBAK−C12又はBAK−C14を各々単独で配合した場合と外観が類似する水性液剤が得られることが分かった。
精製水にチロキサポールを加えて溶解させた以外は、実験例1と同様の方法により下記の化合物A含有水性液剤を調製し、その色調及び澄明性を肉眼で観察するとともに、波長600nmにおける該水性液剤の透過率を測定、評価した。
サニゾールC(花王株式会社製、製造番号:4888)
オスバンS(日本製薬株式会社製、製造番号:S277)
Benzalkonium Chloride Solution 50% Ph.Eur.,USP/NF(FeF Chemicals A/S製、Batch No.:209634)
カラム:YMC−Triart C8(YMC) 3.0mmφ×150mm
カラム温度:40℃付近の一定温度
移動相:(A液)100mM リン酸緩衝液(pH5.5)/アセトニトリル混液(60:40)、(B液)水/アセトニトリル混液(1:4)
グラジエント溶出条件:
検出器:紫外吸光光度計(測定波長:214nm)
BAKとしてBAK−C12/C14とは異なる混合比率の市販品を使用しても同様の結果が得られた(表11、実施例36)。また、チロキサポールを添加することで、化合物Aの濃度を上げてもBAK混合物の種類に依らず、澄明性を維持できることが分かった(表11、12)。
Claims (22)
- (3−{2−[4−イソプロピル−2−(4−トリフルオロメチル)フェニル−5−チアゾリル]エチル}−5−メチル−1,2−ベンズイソキサゾール−6−イル)オキシ酢酸又はその製剤学的に許容される塩、及び式:
- (3−{2−[4−イソプロピル−2−(4−トリフルオロメチル)フェニル−5−チアゾリル]エチル}−5−メチル−1,2−ベンズイソキサゾール−6−イル)オキシ酢酸又はその製剤学的に許容される塩の水性液剤全量に対する下限濃度が0.0002w/v%で、上限濃度が0.05w/v%の範囲から選択される、請求項1記載の水性液剤。
- Rが炭素数8のアルキル基であるベンザルコニウム塩化物を含有し、該ベンザルコニウム塩化物の水性液剤全量に対する濃度が0.05w/v%未満、又は0.1w/v%よりも高い範囲から選択される、請求項1又は2に記載の水性液剤。
- Rが炭素数10のアルキル基であるベンザルコニウム塩化物を含有し、該ベンザルコニウム塩化物の水性液剤全量に対する濃度が0.05w/v%未満、又は0.1w/v%よりも高い範囲から選択される、請求項1又は2に記載の水性液剤。
- Rが炭素数12のアルキル基であるベンザルコニウム塩化物を含有し、該ベンザルコニウム塩化物の水性液剤全量に対する濃度が0.003w/v%未満、又は0.01w/v%よりも高い範囲から選択される、請求項1又は2に記載の水性液剤。
- Rが炭素数14のアルキル基であるベンザルコニウム塩化物を含有し、該ベンザルコニウム塩化物の水性液剤全量に対する濃度が0.001w/v%未満、又は0.002w/v%よりも高い範囲から選択される、請求項1又は2に記載の水性液剤。
- Rが炭素数16のアルキル基であるベンザルコニウム塩化物を含有し、該ベンザルコニウム塩化物の水性液剤全量に対する濃度が0.001w/v%以外の範囲から選択される、請求項1又は2に記載の水性液剤。
- ベンザルコニウム塩化物のRが炭素数18のアルキル基である、請求項1又は2に記載の水性液剤。
- ベンザルコニウム塩化物として、Rが炭素数12のアルキル基であるベンザルコニウム塩化物とRが炭素数14のアルキル基であるベンザルコニウム塩化物とを共に含み、且つ該ベンザルコニウム塩化物の水性液剤全量に対する合計濃度が0.001w/v%未満、又は0.002w/v%よりも高い範囲から選択される、請求項1又は2に記載の水性液剤。
- さらに界面活性剤を含有する、請求項1〜9のいずれか1項に記載の水性液剤。
- 界面活性剤がチロキサポールである、請求項10記載の水性液剤。
- 眼科用である、請求項1〜11のいずれか1項に記載の水性液剤。
- 点眼剤である、請求項12記載の水性液剤。
- (3−{2−[4−イソプロピル−2−(4−トリフルオロメチル)フェニル−5−チアゾリル]エチル}−5−メチル−1,2−ベンズイソキサゾール−6−イル)オキシ酢酸又はその製剤学的に許容される塩、式:
- (3−{2−[4−イソプロピル−2−(4−トリフルオロメチル)フェニル−5−チアゾリル]エチル}−5−メチル−1,2−ベンズイソキサゾール−6−イル)オキシ酢酸又はその製剤学的に許容される塩を含有する水性液剤において、式:
- Rが炭素数8のアルキル基であるベンザルコニウム塩化物を水性液剤全量に対して0.05w/v%未満、又は0.1w/v%よりも高い濃度になるよう配合することを特徴とする、請求項15に記載の方法。
- Rが炭素数10のアルキル基であるベンザルコニウム塩化物を水性液剤全量に対して0.05w/v%未満、又は0.1w/v%よりも高い濃度になるよう配合することを特徴とする、請求項15に記載の方法。
- Rが炭素数12のアルキル基であるベンザルコニウム塩化物を水性液剤全量に対して0.003w/v%未満、又は0.01w/v%よりも高い濃度になるよう配合することを特徴とする、請求項15に記載の方法。
- Rが炭素数14のアルキル基であるベンザルコニウム塩化物を水性液剤全量に対して0.001w/v%未満、又は0.002w/v%よりも高い濃度になるよう配合することを特徴とする、請求項15に記載の方法。
- Rが炭素数16のアルキル基であるベンザルコニウム塩化物を水性液剤全量に対して0.001w/v%以外の濃度になるよう配合することを特徴とする、請求項15に記載の方法。
- Rが炭素数18のアルキル基であるベンザルコニウム塩化物を配合することを特徴とする、請求項15に記載の方法。
- Rが炭素数12のアルキル基であるベンザルコニウム塩化物とRが炭素数14のアルキル基であるベンザルコニウム塩化物とを共に含む混合物を水性液剤全量に対して0.001w/v%未満、又は0.002w/v%よりも高い濃度になるよう配合することを特徴とする、請求項15に記載の方法。
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