JP6050454B1 - Aqueous pharmaceutical composition - Google Patents
Aqueous pharmaceutical composition Download PDFInfo
- Publication number
- JP6050454B1 JP6050454B1 JP2015189118A JP2015189118A JP6050454B1 JP 6050454 B1 JP6050454 B1 JP 6050454B1 JP 2015189118 A JP2015189118 A JP 2015189118A JP 2015189118 A JP2015189118 A JP 2015189118A JP 6050454 B1 JP6050454 B1 JP 6050454B1
- Authority
- JP
- Japan
- Prior art keywords
- pharmaceutical composition
- aqueous pharmaceutical
- salt
- dorzolamide
- chlorobutanol
- 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
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 94
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 claims abstract description 94
- 150000003839 salts Chemical class 0.000 claims abstract description 74
- 229960004926 chlorobutanol Drugs 0.000 claims abstract description 46
- 229960003933 dorzolamide Drugs 0.000 claims abstract description 46
- IAVUPMFITXYVAF-XPUUQOCRSA-N dorzolamide Chemical compound CCN[C@H]1C[C@H](C)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 IAVUPMFITXYVAF-XPUUQOCRSA-N 0.000 claims abstract description 46
- OSRUSFPMRGDLAG-QMGYSKNISA-N dorzolamide hydrochloride Chemical compound [Cl-].CC[NH2+][C@H]1C[C@H](C)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 OSRUSFPMRGDLAG-QMGYSKNISA-N 0.000 claims abstract description 10
- 229960002506 dorzolamide hydrochloride Drugs 0.000 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 14
- 208000010412 Glaucoma Diseases 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- 229940124597 therapeutic agent Drugs 0.000 claims description 9
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical group O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 claims description 8
- 239000006196 drop Substances 0.000 claims description 8
- 229960004605 timolol Drugs 0.000 claims description 8
- WLRMANUAADYWEA-NWASOUNVSA-N (S)-timolol maleate Chemical compound OC(=O)\C=C/C(O)=O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 WLRMANUAADYWEA-NWASOUNVSA-N 0.000 claims description 7
- 229960005221 timolol maleate Drugs 0.000 claims description 7
- 239000002876 beta blocker Substances 0.000 claims description 6
- 229940097320 beta blocking agent Drugs 0.000 claims description 6
- 239000003889 eye drop Substances 0.000 claims description 5
- 239000002997 ophthalmic solution Substances 0.000 claims description 4
- 229940054534 ophthalmic solution Drugs 0.000 claims description 3
- 239000006172 buffering agent Substances 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 abstract description 12
- 238000000354 decomposition reaction Methods 0.000 abstract description 6
- -1 inorganic acid salts Chemical class 0.000 description 33
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 239000000654 additive Substances 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 11
- 235000015165 citric acid Nutrition 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 230000000996 additive effect Effects 0.000 description 8
- 239000004359 castor oil Substances 0.000 description 8
- 235000019438 castor oil Nutrition 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 8
- 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 8
- 239000004094 surface-active agent Substances 0.000 description 7
- 239000002562 thickening agent Substances 0.000 description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 239000003963 antioxidant agent Substances 0.000 description 6
- 235000006708 antioxidants Nutrition 0.000 description 6
- 229960000686 benzalkonium chloride Drugs 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 235000014113 dietary fatty acids Nutrition 0.000 description 6
- 239000000194 fatty acid Substances 0.000 description 6
- 229930195729 fatty acid Natural products 0.000 description 6
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 206010030043 Ocular hypertension Diseases 0.000 description 5
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 229920001451 polypropylene glycol Polymers 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 239000012929 tonicity agent Substances 0.000 description 5
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 5
- 239000008215 water for injection Substances 0.000 description 5
- 229920002675 Polyoxyl Polymers 0.000 description 4
- 229920001214 Polysorbate 60 Polymers 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000003078 antioxidant effect Effects 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 230000002335 preservative effect Effects 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 3
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 3
- 239000003002 pH adjusting agent Substances 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 229940068968 polysorbate 80 Drugs 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
- 230000001629 suppression Effects 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 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 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 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 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- KKEYFWRCBNTPAC-UHFFFAOYSA-N Terephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 229960002684 aminocaproic acid Drugs 0.000 description 2
- 239000003945 anionic surfactant Substances 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
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000003093 cationic surfactant Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Chemical class 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000002736 nonionic surfactant Substances 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 229960002920 sorbitol Drugs 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 150000005846 sugar alcohols Chemical class 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 235000010384 tocopherol Nutrition 0.000 description 2
- 229930003799 tocopherol Natural products 0.000 description 2
- 229960001295 tocopherol Drugs 0.000 description 2
- 239000011732 tocopherol Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 229960000281 trometamol Drugs 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- WXHLLJAMBQLULT-UHFFFAOYSA-N 2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-n-(2-methyl-6-sulfanylphenyl)-1,3-thiazole-5-carboxamide;hydrate Chemical compound O.C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1S WXHLLJAMBQLULT-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical compound C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 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
- 208000017667 Chronic Disease Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 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 description 1
- 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 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-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
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 239000001263 FEMA 3042 Substances 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- OMCPLEZZPVJJIS-UHFFFAOYSA-N Hypadil (TN) Chemical compound C1C(O[N+]([O-])=O)COC2=C1C=CC=C2OCC(O)CNC(C)C OMCPLEZZPVJJIS-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 1
- 229920002701 Polyoxyl 40 Stearate Polymers 0.000 description 1
- 229920002696 Polyoxyl 40 castor oil Polymers 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 229920001219 Polysorbate 40 Polymers 0.000 description 1
- 229920002642 Polysorbate 65 Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229920002385 Sodium hyaluronate Polymers 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 239000004147 Sorbitan trioleate Substances 0.000 description 1
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- SZYSLWCAWVWFLT-UTGHZIEOSA-N [(2s,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)-2-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxolan-2-yl]methyl octadecanoate Chemical compound O([C@@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@]1(COC(=O)CCCCCCCCCCCCCCCCC)O[C@H](CO)[C@@H](O)[C@@H]1O SZYSLWCAWVWFLT-UTGHZIEOSA-N 0.000 description 1
- 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 1
- IYKJEILNJZQJPU-UHFFFAOYSA-N acetic acid;butanedioic acid Chemical compound CC(O)=O.OC(=O)CCC(O)=O IYKJEILNJZQJPU-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 239000002160 alpha blocker Substances 0.000 description 1
- 229940124308 alpha-adrenoreceptor antagonist Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 229960004324 betaxolol Drugs 0.000 description 1
- CHDPSNLJFOQTRK-UHFFFAOYSA-N betaxolol hydrochloride Chemical compound [Cl-].C1=CC(OCC(O)C[NH2+]C(C)C)=CC=C1CCOCC1CC1 CHDPSNLJFOQTRK-UHFFFAOYSA-N 0.000 description 1
- 229960002645 boric acid Drugs 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229960001222 carteolol Drugs 0.000 description 1
- LWAFSWPYPHEXKX-UHFFFAOYSA-N carteolol Chemical compound N1C(=O)CCC2=C1C=CC=C2OCC(O)CNC(C)(C)C LWAFSWPYPHEXKX-UHFFFAOYSA-N 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 229940046978 chlorpheniramine maleate Drugs 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 150000005332 diethylamines Chemical class 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 235000019262 disodium citrate Nutrition 0.000 description 1
- 239000002526 disodium citrate Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- CEYULKASIQJZGP-UHFFFAOYSA-L disodium;2-(carboxymethyl)-2-hydroxybutanedioate Chemical compound [Na+].[Na+].[O-]C(=O)CC(O)(C(=O)O)CC([O-])=O CEYULKASIQJZGP-UHFFFAOYSA-L 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000008378 epithelial damage Effects 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229940074391 gallic acid Drugs 0.000 description 1
- 235000004515 gallic acid Nutrition 0.000 description 1
- LRBQNJMCXXYXIU-QWKBTXIPSA-N gallotannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@H]2[C@@H]([C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-QWKBTXIPSA-N 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 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
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229960003630 ketotifen fumarate Drugs 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 229950000754 nipradilol Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229960002969 oleic acid Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 239000000734 parasympathomimetic agent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229940113116 polyethylene glycol 1000 Drugs 0.000 description 1
- 229920000139 polyethylene terephthalate Polymers 0.000 description 1
- 239000005020 polyethylene terephthalate Substances 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 1
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010988 polyoxyethylene sorbitan tristearate Nutrition 0.000 description 1
- 239000001816 polyoxyethylene sorbitan tristearate Substances 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229940099429 polyoxyl 40 stearate Drugs 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229940101027 polysorbate 40 Drugs 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229940099511 polysorbate 65 Drugs 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 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
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- AVTYONGGKAJVTE-OLXYHTOASA-L potassium L-tartrate Chemical compound [K+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O AVTYONGGKAJVTE-OLXYHTOASA-L 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000001472 potassium tartrate Substances 0.000 description 1
- 229940111695 potassium tartrate Drugs 0.000 description 1
- 235000011005 potassium tartrates Nutrition 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 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 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- 239000004320 sodium erythorbate Substances 0.000 description 1
- 235000010352 sodium erythorbate Nutrition 0.000 description 1
- 229940010747 sodium hyaluronate 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
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- RBWSWDPRDBEWCR-RKJRWTFHSA-N sodium;(2r)-2-[(2r)-3,4-dihydroxy-5-oxo-2h-furan-2-yl]-2-hydroxyethanolate Chemical compound [Na+].[O-]C[C@@H](O)[C@H]1OC(=O)C(O)=C1O RBWSWDPRDBEWCR-RKJRWTFHSA-N 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
- 239000012453 solvate Substances 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
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-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
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- 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
Abstract
【課題】クロロブタノールを含み、かつ、経時的なｐＨ低下又は有効成分の分解が抑制された水性医薬組成物等を提供すること。【解決手段】本発明に係る水性医薬組成物は、ドルゾラミド又はその塩と、クロロブタノールとを含有する。ｐＨは４．０〜８．０であることが好ましい。また、６０℃の保存による、１４日間平均ｐＨ低下値が０．０４６／日以下であることも好ましい。ドルゾラミド又はその塩は、ドルゾラミド塩酸塩であることが好ましい。【選択図】なしThe present invention provides an aqueous pharmaceutical composition containing chlorobutanol, in which pH decrease over time or decomposition of an active ingredient is suppressed. An aqueous pharmaceutical composition according to the present invention contains dorzolamide or a salt thereof and chlorobutanol. The pH is preferably 4.0 to 8.0. Moreover, it is also preferable that the average pH drop value for 14 days by storage at 60 ° C. is 0.046 / day or less. Dorzolamide or a salt thereof is preferably Dorzolamide hydrochloride. [Selection figure] None
Description
本発明は、ドルゾラミド又はその塩及びクロロブタノールを含有する水性医薬組成物に関する。 The present invention relates to an aqueous pharmaceutical composition containing dorzolamide or a salt thereof and chlorobutanol.
点眼液を始めとする水性医薬組成物は、菌類等の繁殖を防止するため、一定以上の保存効力が要求される。塩化ベンザルコニウムは水溶性であり、化学的に安定で、他の保存剤と比較しても保存効力が高いので、汎用的に水性医薬組成物に使用される。しかし、塩化ベンザルコニウムには細胞障害性があり、曝露量が増えると角膜上皮障害を引き起こす可能性が増大する（非特許文献１）。そのため、特に塩化ベンザルコニウムに過敏な反応を示す患者や重度の角膜上皮障害を有する患者には、塩化ベンザルコニウムを全く含有しない水性医薬組成物の開発が望まれている。 Aqueous pharmaceutical compositions including ophthalmic solutions are required to have a certain level of preservation efficacy in order to prevent the growth of fungi and the like. Benzalkonium chloride is water-soluble, chemically stable, and has a high preservative effect compared to other preservatives, so it is generally used in aqueous pharmaceutical compositions. However, benzalkonium chloride has cytotoxicity, and the possibility of causing corneal epithelial damage increases with increasing exposure (Non-patent Document 1). Therefore, the development of an aqueous pharmaceutical composition that does not contain benzalkonium chloride at all is desired particularly for patients who are hypersensitive to benzalkonium chloride and patients with severe corneal epithelial disorders.
一方、クロロブタノールは、塩化ベンザルコニウムほど保存効力が高くないが安全性が比較的改善されるので、水性医薬組成物の保存剤として使用される。しかし、クロロブタノールは中性付近で熱・光分解しやすいので、水性医薬組成物の経時的なｐＨ低下や有効成分の分解といった課題を有することが知られている。 On the other hand, chlorobutanol is used as a preservative for aqueous pharmaceutical compositions because it is not as effective as benzalkonium chloride but has a relatively improved safety. However, since chlorobutanol is easily thermally and photodegraded near neutrality, it is known that it has problems such as a decrease in pH of an aqueous pharmaceutical composition over time and decomposition of active ingredients.
本発明は、クロロブタノールを含み、かつ、経時的なｐＨ低下又は有効成分の分解が抑制された水性医薬組成物、及びクロロブタノールを含む水性医薬組成物の経時的なｐＨ低下又は有効成分の分解を抑制する方法等を提供することを目的とする。 The present invention relates to an aqueous pharmaceutical composition containing chlorobutanol, in which pH decrease over time or decomposition of an active ingredient is suppressed, and a pH reduction over time of an aqueous pharmaceutical composition containing chlorobutanol or decomposition of an active ingredient It aims at providing the method etc. which suppress this.
本発明者らは、ドルゾラミド又はその塩が、クロロブタノールを含む水性医薬組成物の経時的なｐＨ低下又は有効成分の分解を抑制することを見出し、本発明を完成するに至った。具体的に、本発明は以下の通りである。 The present inventors have found that dorzolamide or a salt thereof suppresses a decrease in pH over time or decomposition of an active ingredient of an aqueous pharmaceutical composition containing chlorobutanol, and has completed the present invention. Specifically, the present invention is as follows.
（１） ドルゾラミド又はその塩と、クロロブタノールとを含有する水性医薬組成物。 (1) An aqueous pharmaceutical composition containing dorzolamide or a salt thereof and chlorobutanol.
（２） ｐＨが４．０〜８．０である、（１）に記載の水性医薬組成物。 (2) The aqueous pharmaceutical composition according to (1), wherein the pH is 4.0 to 8.0.
（３） ６０℃での保存による、１４日間平均ｐＨ低下値が０．０４６／日以下である、（１）又は（２）のいずれか一項に記載の水性医薬組成物。 (3) The aqueous pharmaceutical composition according to any one of (1) and (2), wherein a 14-day average pH decrease value after storage at 60 ° C. is 0.046 / day or less.
（４） ドルゾラミド又はその塩がドルゾラミド塩酸塩である、（１）〜（３）のいずれか一項に記載の水性医薬組成物。 (4) The aqueous pharmaceutical composition according to any one of (1) to (3), wherein dorzolamide or a salt thereof is dorzolamide hydrochloride.
（５） ドルゾラミド又はその塩の含有量が０．１〜５％（ｗ／ｖ）である、（１）〜（４）のいずれか一項に記載の水性医薬組成物。 (5) The aqueous pharmaceutical composition according to any one of (1) to (4), wherein the content of dorzolamide or a salt thereof is 0.1 to 5% (w / v).
（６） ドルゾラミド又はその塩の含有量が、１〜２％（ｗ／ｖ）である、（５）に記載の水性医薬組成物。 (6) The aqueous pharmaceutical composition according to (5), wherein the content of dorzolamide or a salt thereof is 1 to 2% (w / v).
（７） クロロブタノールの含有量が０．０１〜５％（ｗ／ｖ）である、（１）〜（６）のいずれか一項に記載の水性医薬組成物。 (7) The aqueous pharmaceutical composition according to any one of (1) to (6), wherein the content of chlorobutanol is 0.01 to 5% (w / v).
（８） クロロブタノールの含有量に対するドルゾラミド又はその塩の含有量の質量比が１．０〜１０．０である、（１）〜（７）のいずれか一項に記載の水性医薬組成物。 (8) The aqueous pharmaceutical composition according to any one of (1) to (7), wherein the mass ratio of the content of dorzolamide or a salt thereof to the content of chlorobutanol is 1.0 to 10.0.
（９） さらに緩衝剤（好ましくはクエン酸又はその塩を含む）を含有する、（１）〜（８）のいずれか一項に記載の水性医薬組成物。 (9) The aqueous pharmaceutical composition according to any one of (1) to (8), further comprising a buffer (preferably containing citric acid or a salt thereof).
（１０） さらに粘稠剤（好ましくはヒドロキシエチルセルロースを含む）を含有する、（１）〜（９）のいずれか一項に記載の水性医薬組成物。 (10) The aqueous pharmaceutical composition according to any one of (1) to (9), further comprising a thickening agent (preferably containing hydroxyethyl cellulose).
（１１） さらに界面活性化剤（好ましくはポリソルベート８０を含む）を含有する、（１）〜（１０）のいずれか一項に記載の水性医薬組成物。 (11) The aqueous pharmaceutical composition according to any one of (1) to (10), further comprising a surfactant (preferably containing polysorbate 80).
（１２） 緑内障又は高眼圧症の治療に用いられる、（１）〜（１１）のいずれか一項に記載の水性医薬組成物。 (12) The aqueous pharmaceutical composition according to any one of (1) to (11), which is used for the treatment of glaucoma or ocular hypertension.
（１３） さらに、ドルゾラミドとは別の緑内障治療剤を治療上有効な量で含む、（１）〜（１２）のいずれか一項に記載の水性医薬組成物。 (13) The aqueous pharmaceutical composition according to any one of (1) to (12), further comprising a therapeutically effective amount of a glaucoma therapeutic agent different from dorzolamide.
（１４） 前記別の緑内障治療剤がβ遮断薬である、（１３）に記載の水性医薬組成物。 (14) The aqueous pharmaceutical composition according to (13), wherein the another therapeutic agent for glaucoma is a β-blocker.
（１５） 前記β遮断薬がチモロール又はその塩である、（１４）に記載の水性医薬組成物。 (15) The aqueous pharmaceutical composition according to (14), wherein the β-blocker is timolol or a salt thereof.
（１６） チモロール又はその塩がチモロールマレイン酸塩である、（１５）に記載の水性医薬組成物。
(16) The aqueous pharmaceutical composition according to (15), wherein timolol or a salt thereof is timolol maleate.
（１７） 室温で保管される、（１）〜（１６）のいずれか一項に記載の水性医薬組成物。 (17) The aqueous pharmaceutical composition according to any one of (1) to (16), which is stored at room temperature.
（１８） ドルゾラミド又はその塩及びクロロブタノールを含有する、ｐＨ４．０〜８．０の水性点眼剤。 (18) A pH 4.0 to 8.0 aqueous eye drop containing dorzolamide or a salt thereof and chlorobutanol.
（１９） ドルゾラミド又はその塩及びクロロブタノールを含有し、６０℃での保存による、１４日間平均ｐＨ低下値が０．０４６／日以下である、水性点眼剤。 (19) An aqueous ophthalmic solution containing dorzolamide or a salt thereof and chlorobutanol and having a 14-day average pH decrease value of 0.046 / day or less by storage at 60 ° C.
（２０） クロロブタノールを含有する水性医薬組成物にドルゾラミド又はその塩を含有させる、クロロブタノールの分解抑制方法。 (20) A method for inhibiting degradation of chlorobutanol, wherein dorzolamide or a salt thereof is contained in an aqueous pharmaceutical composition containing chlorobutanol.
（２１） クロロブタノールを含有する水性医薬組成物にドルゾラミド又はその塩を含有させる、水性医薬組成物の経時的ｐＨ低下の抑制方法。 (21) A method for suppressing a decrease in pH over time of an aqueous pharmaceutical composition, wherein dorzolamide or a salt thereof is contained in an aqueous pharmaceutical composition containing chlorobutanol.
（２２） クロロブタノールを含有する水性医薬組成物にドルゾラミド又はその塩を含有させる、水性医薬組成物の保存効力の向上方法。 (22) A method for improving the storage efficacy of an aqueous pharmaceutical composition, wherein dorzolamide or a salt thereof is contained in an aqueous pharmaceutical composition containing chlorobutanol.
（２３） （１）〜（１７）のいずれか一項に記載の水性医薬組成物を、患者の眼に局所投与する、緑内障又は高眼圧症の治療方法。 (23) A method for treating glaucoma or ocular hypertension, wherein the aqueous pharmaceutical composition according to any one of (1) to (17) is locally administered to a patient's eye.
なお、前記（１）から（２３）の各構成は、任意に２以上を選択して組み合わせることができる。 Note that two or more of the configurations (1) to (23) can be arbitrarily selected and combined.
本発明によれば、クロロブタノールを含む水性医薬組成物の経時的なｐＨ低下又は有効成分の分解を抑制することができる。 ADVANTAGE OF THE INVENTION According to this invention, the time-dependent pH fall or decomposition | disassembly of an active ingredient of the aqueous | water-based pharmaceutical composition containing a chlorobutanol can be suppressed.
以下、本発明の実施形態を説明するが、これらに本発明が限定されるものではない。 Hereinafter, although embodiment of this invention is described, this invention is not limited to these.
本発明の水性医薬組成物において、含有されるドルゾラミドは、化学名（４Ｓ，６Ｓ）−４−Ｅｔｈｙｌａｍｉｎｏ−６−ｍｅｔｈｙｌ−５，６−ｄｉｈｙｄｒｏ−４Ｈ−ｔｈｉｅｎｏ［２，３−ｂ］ｔｈｉｏｐｙｒａｎ−２−ｓｕｌｆｏｎａｍｉｄｅ−７，７−ｄｉｏｘｉｄｅで表される化合物である。 In the aqueous pharmaceutical composition of the present invention, the contained dorzolamide has the chemical name (4S, 6S) -4-Ethylamino-6-methyl-5,6-dihydro-4H-thieno [2,3-b] thiopyran-2. It is a compound represented by -sulfonamide-7,7-dioxide.
本発明の水性医薬組成物において、含有されるドルゾラミドは塩であってもよく、医薬として許容される塩であれば特に制限はない。塩としては無機酸との塩、有機酸との塩、四級アンモニウム塩、ハロゲンイオンとの塩、アルカリ金属との塩、アルカリ土類金属との塩、金属塩、有機アミンとの塩等が挙げられる。 In the aqueous pharmaceutical composition of the present invention, the contained dorzolamide may be a salt, and is not particularly limited as long as it is a pharmaceutically acceptable salt. Salts include inorganic acid salts, organic acid salts, quaternary ammonium salts, halogen ion salts, alkali metal salts, alkaline earth metal salts, metal salts, organic amine salts, etc. Can be mentioned.
無機酸の塩としては、塩酸、臭化水素酸、ヨウ化水素酸、硝酸、硫酸、リン酸等との塩が挙げられる。 Examples of inorganic acid salts include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
有機酸との塩としては、酢酸、シュウ酸、フマル酸、マレイン酸、コハク酸、リンゴ酸、クエン酸、酒石酸、アジピン酸、グルコン酸、グルコヘプト酸、グルクロン酸、テレフタル酸、メタンスルホン酸、アラニン、乳酸、馬尿酸、１，２−エタンジスルホン酸、イセチオン酸、ラクトビオン酸、オレイン酸、没食子酸、パモ酸、ポリガラクツロン酸、ステアリン酸、タンニン酸、トリフルオロメタンスルホン酸、ベンゼンスルホン酸、ｐ−トルエンスルホン酸、硫酸ラウリル、硫酸メチル、ナフタレンスルホン酸、スルホサリチル酸等との塩が挙げられる。 Salts with organic acids include acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine , Lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p- Examples thereof include salts with toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid and the like.
四級アンモニウム塩としては、臭化メチル、ヨウ化メチル等との塩が挙げられる。 Examples of quaternary ammonium salts include salts with methyl bromide, methyl iodide and the like.
ハロゲンイオンとの塩としては、塩化物イオン、臭化物イオン、ヨウ化物イオン等との塩が挙げられる。 Examples of salts with halogen ions include salts with chloride ions, bromide ions, iodide ions and the like.
アルカリ金属との塩としては、リチウム、ナトリウム、カリウム等との塩が挙げられる。 Examples of the salt with an alkali metal include salts with lithium, sodium, potassium and the like.
アルカリ土類金属との塩としては、カルシウム、マグネシウム等との塩が挙げられる。 Examples of the salt with alkaline earth metal include salts with calcium, magnesium and the like.
金属塩としては、鉄、亜鉛等との塩が挙げられる。 Examples of the metal salt include salts with iron, zinc and the like.
有機アミンとの塩としては、トリエチレンジアミン、２−アミノエタノール、２，２−イミノビス（エタノール）、１−デオキシ−１−（メチルアミノ）−２−Ｄ−ソルビトール、２−アミノ−２−（ヒドロキシメチル）−１，３−プロパンジオール、プロカイン、Ｎ，Ｎ−ビス（フェニルメチル）−１，２−エタンジアミン等との塩が挙げられる。 Examples of salts with organic amines include triethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy-1- (methylamino) -2-D-sorbitol, 2-amino-2- (hydroxy And salts with methyl) -1,3-propanediol, procaine, N, N-bis (phenylmethyl) -1,2-ethanediamine and the like.
ドルゾラミドの塩としては、一塩酸塩（ドルゾラミド塩酸塩）が特に好ましい。 As the salt of dorzolamide, monohydrochloride (dorzolamide hydrochloride) is particularly preferable.
本発明の水性医薬組成物において、含有されるドルゾラミド又はその塩は、水和物又は溶媒和物の形態をとってもよい。 In the aqueous pharmaceutical composition of the present invention, the contained dorzolamide or a salt thereof may take the form of a hydrate or a solvate.
本発明の水性医薬組成物において、含有されるドルゾラミド又はその塩の含有量は、所望のクロロブタノールの分解抑制、水性医薬組成物の経時的ｐＨ低下の抑制、又は水性医薬組成物の保存効力の向上を奏するのに十分な量であれば特に制限されないが、０．１〜５％（ｗ／ｖ）が好ましく、０．２〜３％（ｗ／ｖ）がより好ましく、０．５〜２．５％（ｗ／ｖ）がさらに好ましく、１〜２％（ｗ／ｖ）がさらにより好ましく、１％（ｗ／ｖ）が特に好ましい。なお、本発明の水性医薬組成物においてドルゾラミドの塩が含有される場合、これらの値はフリーのドルゾラミドに換算した含量である。 In the aqueous pharmaceutical composition of the present invention, the content of dorzolamide or a salt thereof is sufficient to suppress the degradation of the desired chlorobutanol, suppress the pH drop over time of the aqueous pharmaceutical composition, or preserve the storage efficacy of the aqueous pharmaceutical composition. The amount is not particularly limited as long as the amount is sufficient to improve, but is preferably 0.1 to 5% (w / v), more preferably 0.2 to 3% (w / v), and 0.5 to 2 0.5% (w / v) is more preferred, 1-2% (w / v) is even more preferred, and 1% (w / v) is particularly preferred. In addition, when the salt of a dorzolamide contains in the aqueous | water-based pharmaceutical composition of this invention, these values are the content converted into the free dorzolamide.
本発明の水性医薬組成物において、後述のクロロブタノールの含有量に対するドルゾラミド又はその塩の含有量の質量比は、所望のクロロブタノールの分解抑制、水性医薬組成物の経時的ｐＨ低下の抑制、又は水性医薬組成物の保存効力の向上を奏する観点で、１．０〜１０．０であることが好ましく、１．５〜７．５であることがより好ましい。なお、本発明の水性医薬組成物においてドルゾラミドの塩が含有される場合、これらの値はフリーのドルゾラミドに換算した質量比である。 In the aqueous pharmaceutical composition of the present invention, the mass ratio of the content of dorzolamide or a salt thereof to the content of chlorobutanol described below is the desired suppression of degradation of chlorobutanol, suppression of the pH drop over time of the aqueous pharmaceutical composition, or From the viewpoint of improving the storage efficacy of the aqueous pharmaceutical composition, it is preferably 1.0 to 10.0, and more preferably 1.5 to 7.5. In addition, when the salt of dorzolamide is contained in the aqueous pharmaceutical composition of the present invention, these values are mass ratios converted to free dorzolamide.
本発明の水性医薬組成物において、含有されるクロロブタノールは、化学名１，１，１−Ｔｒｉｃｈｌｏｒｏ−２−ｍｅｔｈｙｌ−２−ｐｒｏｐａｎｏｌで表される化合物である。 In the aqueous pharmaceutical composition of the present invention, the chlorobutanol contained is a compound represented by the chemical name 1,1,1-Trichloro-2-methyl-2-propanol.
本発明の水性医薬組成物において、含有されるクロロブタノールの含有量は、０．０１〜５％（ｗ／ｖ）が好ましく、０．１〜１％（ｗ／ｖ）がより好ましく、０．２〜０．５％（ｗ／ｖ）がさらに好ましく、０．４％（ｗ／ｖ）が特に好ましい。 In the aqueous pharmaceutical composition of the present invention, the content of chlorobutanol contained is preferably 0.01 to 5% (w / v), more preferably 0.1 to 1% (w / v), and 2 to 0.5% (w / v) is more preferable, and 0.4% (w / v) is particularly preferable.
本発明の水性医薬組成物には、眼科用製剤としての要件を満たすために必要に応じて医薬品の添加剤を用いることができ、具体的には緩衝剤、粘稠剤、界面活性化剤、等張化剤、抗酸化剤、ｐＨ調整化剤等を加えることができる。これらは、それぞれ１種単独又は２種以上を適宜組み合わせて用いることができ、適量を配合することができる。 In the aqueous pharmaceutical composition of the present invention, additives for pharmaceuticals can be used as necessary in order to satisfy the requirements as an ophthalmic preparation. Specifically, a buffer, a thickener, a surfactant, Tonicity agents, antioxidants, pH adjusting agents and the like can be added. These can be used individually by 1 type or in combination of 2 or more types, respectively, and can mix | blend suitable amount.
本発明の水性医薬組成物に用いることができる緩衝剤の例としては、リン酸又はその塩、クエン酸又はその塩、酢酸又はその塩、炭酸又はその塩、酒石酸又はその塩、ε−アミノカプロン酸、トロメタモール等が挙げられる。リン酸塩としては、リン酸ナトリウム、リン酸二水素ナトリウム、リン酸水素二ナトリウム、リン酸カリウム、リン酸二水素カリウム、リン酸水素二カリウム等が挙げられ、クエン酸塩としては、クエン酸ナトリウム、クエン酸二ナトリウム等が挙げられ、酢酸塩としては、酢酸ナトリウム、酢酸カリウム等が挙げられ、炭酸塩としては、炭酸ナトリウム、炭酸水素ナトリウム等が挙げられ、酒石酸塩としては、酒石酸ナトリウム、酒石酸カリウム等が挙げられる。クエン酸又はその塩が好ましく、クエン酸ナトリウムが特に好ましい。 Examples of buffers that can be used in the aqueous pharmaceutical composition of the present invention include phosphoric acid or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, carbonic acid or a salt thereof, tartaric acid or a salt thereof, ε-aminocaproic acid And trometamol. Examples of the phosphate include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and the citrate includes citric acid. Sodium, disodium citrate and the like can be mentioned. Examples of the acetate include sodium acetate and potassium acetate. Examples of the carbonate include sodium carbonate and sodium bicarbonate. Examples of the tartrate include sodium tartrate, Examples include potassium tartrate. Citric acid or a salt thereof is preferred, and sodium citrate is particularly preferred.
本発明の水性医薬組成物に緩衝剤を配合する場合の緩衝剤の含有量は、緩衝剤の種類などにより適宜調整することができるが、０．００１〜１０％（ｗ／ｖ）が好ましく、０．０１％〜５％（ｗ／ｖ）がより好ましく、０．１〜３％（ｗ／ｖ）がさらに好ましく、０．２〜２％（ｗ／ｖ）が最も好ましい。ただし、緩衝剤は、添加剤使用の最小化の観点では、含まれない又は上記量未満で含まれてもよい。クエン酸又はその塩は、添加剤使用の最小化の観点では、０．３％（ｗ／ｖ）未満の量で含まれることが好ましく、含まれない又は０．００２％（ｗ／ｖ）未満の量で含まれることがさらに好ましい。また、トロメタモールは、添加剤使用の最小化の観点では、含まれない又は０．１％（ｗ／ｖ）未満の量で含まれることが好ましい。 The content of the buffer when blending the buffer with the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the buffer, etc., but is preferably 0.001 to 10% (w / v), 0.01% to 5% (w / v) is more preferable, 0.1 to 3% (w / v) is more preferable, and 0.2 to 2% (w / v) is most preferable. However, the buffering agent is not included or may be included in less than the above amount from the viewpoint of minimizing the use of the additive. Citric acid or a salt thereof is preferably included in an amount of less than 0.3% (w / v), or not included or less than 0.002% (w / v) in terms of minimizing the use of additives. More preferably, it is contained in an amount of. Further, trometamol is preferably not contained or contained in an amount of less than 0.1% (w / v) from the viewpoint of minimizing the use of the additive.
本発明の水性医薬組成物に用いることができる粘稠剤の例としては、メチルセルロース、エチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシエチルメチルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、ヒドロキシプロピルメチルセルロースアセテートサクシネート、ヒドロキシプロピルメチルセルロースフタレート、カルボキシメチルエチルセルロース、酢酸フタル酸セルロース、ポリビニルピロリドン、ポリビニルアルコール、カルボキシビニルポリマー、ポリエチレングリコール、ヒアルロン酸ナトリウム等が挙げられ、ヒドロキシエチルセルロースが好ましい。 Examples of thickening agents that can be used in the aqueous pharmaceutical composition of the present invention include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxy Examples thereof include propylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, sodium hyaluronate, and the like, with hydroxyethylcellulose being preferred.
本発明の水性医薬組成物に粘稠剤を配合する場合の粘稠剤の含有量は、粘稠剤の種類などにより適宜調整することができるが、０．００１〜５％（ｗ／ｖ）が好ましく、０．０１％〜３％（ｗ／ｖ）がより好ましく、０．１〜２％（ｗ／ｖ）がさらに好ましく、０．２〜１％（ｗ／ｖ）が最も好ましい。ただし、粘稠剤は、添加剤使用の最小化の観点では、含まれない又は上記量未満で含まれてもよい。 The content of the thickener when blending the thickener in the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the thickener, etc., but is 0.001 to 5% (w / v). Is preferable, 0.01% to 3% (w / v) is more preferable, 0.1 to 2% (w / v) is more preferable, and 0.2 to 1% (w / v) is most preferable. However, the thickener is not included or may be included in less than the above amount from the viewpoint of minimizing the use of the additive.
本発明の水性医薬組成物に用いることができる界面活性化剤の例としては、カチオン性界面活性化剤、アニオン性界面活性化剤、非イオン性界面活性化剤等が挙げられる。カチオン性界面活性化剤としては、アルキルアミン塩、アルキルアミンポリオキシエチレン付加物、脂肪酸トリエタノールアミンモノエステル塩、アシルアミノエチルジエチルアミン塩、脂肪酸ポリアミン縮合物、アルキルイミダゾリン、１−アシルアミノエチル−２−アルキルイミダゾリン、１−ヒドロキシルエチル−２−アルキルイミダゾリン等が挙げられる。アニオン性界面活性化剤としては、レシチン等のリン酸脂質等が挙げられる。非イオン性界面活性化剤の例としては、ステアリン酸ポリオキシル４０等のポリオキシエチレン脂肪酸エステル；ポリソルベート８０、ポリソルベート６０、ポリソルベート４０、ポリオキシエチレンソルビタンモノラウレート、ポリオキシエチレンソルビタントリオレート、ポリソルベート６５等のポリオキシエチレンソルビタン脂肪酸エステル；ポリオキシエチレン硬化ヒマシ油１０、ポリオキシエチレン硬化ヒマシ油４０、ポリオキシエチレン硬化ヒマシ油５０、ポリオキシエチレン硬化ヒマシ油６０等のポリオキシエチレン硬化ヒマシ油；ポリオキシル５ヒマシ油、ポリオキシル９ヒマシ油、ポリオキシル１５ヒマシ油、ポリオキシル３５ヒマシ油、ポリオキシル４０ヒマシ油等のポリオキシルヒマシ油；ポリオキシエチレン（１６０）ポリオキシプロピレン（３０）グリコール、ポリオキシエチレン（４２）ポリオキシプロピレン（６７）グリコール、ポリオキシエチレン（５４）ポリオキシプロピレン（３９）グリコール、ポリオキシエチレン（１９６）ポリオキシプロピレン（６７）グリコール、ポリオキシエチレン（２０）ポリオキシプロピレン（２０）グリコール等のポリオキシエチレンポリオキシプロピレングリコール；ショ糖ステアリン酸エステル等のショ糖脂肪酸エステル；トコフェロールポリエチレングリコール１０００コハク酸エステル（ビタミンＥ ＴＰＧＳ）等が挙げられる。ポリオキシエチレンソルビタン脂肪酸エステルが好ましく、ポリソルベート８０が特に好ましい。 Examples of surfactants that can be used in the aqueous pharmaceutical composition of the present invention include cationic surfactants, anionic surfactants, nonionic surfactants, and the like. Examples of cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkylimidazolines, 1-acylaminoethyl-2 -Alkyl imidazoline, 1-hydroxylethyl-2-alkyl imidazoline, etc. are mentioned. Examples of the anionic surfactant include phospholipids such as lecithin. Examples of nonionic surfactants include polyoxyethylene fatty acid esters such as polyoxyl 40 stearate; polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, polysorbate 65 Polyoxyethylene sorbitan fatty acid esters such as: polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, etc .; polyoxyl Polyoxyl castor oil such as 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 castor oil; polyoxyethylene (16 ) Polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol Polyoxyethylene polyoxypropylene glycol such as polyoxyethylene (20) polyoxypropylene (20) glycol; sucrose fatty acid ester such as sucrose stearate; tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS) and the like Can be mentioned. Polyoxyethylene sorbitan fatty acid esters are preferred, and polysorbate 80 is particularly preferred.
本発明の水性医薬組成物に界面活性化剤を配合する場合の界面活性化剤の含有量は、界面活性化剤の種類などにより適宜調整することができるが、０．０１〜１％（ｗ／ｖ）が好ましく、０．０５〜０．５％（ｗ／ｖ）がより好ましく、０．０５％〜０．２％（ｗ／ｖ）が特に好ましい。ただし、界面活性化剤は、添加剤使用の最小化の観点では、含まれない又は上記量未満で含まれてもよい。 The content of the surfactant when the surfactant is added to the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the surfactant, etc., but is 0.01 to 1% (w / V) is preferable, 0.05 to 0.5% (w / v) is more preferable, and 0.05% to 0.2% (w / v) is particularly preferable. However, the surfactant is not included or may be included in less than the above amount from the viewpoint of minimizing the use of the additive.
本発明の水性医薬組成物に用いることができる等張化剤の例としては、イオン性等張化剤や非イオン性等張化剤等が挙げられる。イオン性等張化剤としては、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム等が挙げられ、塩化ナトリウムが好ましい。非イオン性等張化剤としては、グリセリン、プロピレングリコール、ソルビトール、マンニトール、キシリトール等の糖アルコールが挙げられ、マンニトールが好ましい。 Examples of isotonic agents that can be used in the aqueous pharmaceutical composition of the present invention include ionic tonicity agents and nonionic tonicity agents. Examples of the ionic tonicity agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and sodium chloride is preferable. Examples of nonionic tonicity agents include sugar alcohols such as glycerin, propylene glycol, sorbitol, mannitol, xylitol, and mannitol is preferred.
本発明の水性医薬組成物に等張化剤を配合する場合の等張化剤の含有量は、等張化剤の種類などにより適宜調整することができるが、０．０１〜１０％（ｗ／ｖ）が好ましく、０．０２％〜７％（ｗ／ｖ）がより好ましく、０．１〜５％（ｗ／ｖ）がさらに好ましく、０．５〜４％（ｗ／ｖ）が特に好ましく、０．８〜３％（ｗ／ｖ）が最も好ましい。ただし、等張化剤は、添加剤使用の最小化の観点では、例えばイオン性等張化剤の場合は、含まれない又は上記量未満で含まれてもよく、糖アルコールの場合は含まれない又は０．１％（ｗ／ｖ）未満の量で含まれることが好ましい。 The content of the tonicity agent when the isotonic agent is added to the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the tonicity agent and the like, but is 0.01 to 10% (w / V) is preferable, 0.02% to 7% (w / v) is more preferable, 0.1 to 5% (w / v) is more preferable, and 0.5 to 4% (w / v) is particularly preferable 0.8 to 3% (w / v) is most preferable. However, from the viewpoint of minimizing the use of additives, the tonicity agent is not included in the case of, for example, an ionic tonicity agent, or may be included in less than the above amount, and is included in the case of a sugar alcohol. Preferably, it is included in an amount of less than 0.1% (w / v).
本発明の水性医薬組成物に用いることができる抗酸化剤の例としては、アスコルビン酸、トコフェロール、ジブチルヒドロキシトルエン、ブチルヒドロキシアニソール、エリソルビン酸ナトリウム、没食子酸プロピル、亜硫酸ナトリウム等が挙げられる。 Examples of antioxidants that can be used in the aqueous pharmaceutical composition of the present invention include ascorbic acid, tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite and the like.
本発明の水性医薬組成物に抗酸化剤を配合する場合の抗酸化剤の含有量は、抗酸化剤の種類などにより適宜調整することができるが、０．０００１〜１％（ｗ／ｖ）が好ましく、０．０００５％〜０．１％（ｗ／ｖ）がより好ましく、０．００１〜０．０２％（ｗ／ｖ）がさらに好ましく、０．００５〜０．０１％（ｗ／ｖ）が最も好ましい。ただし、抗酸化剤は、添加剤使用の最小化の観点では、含まれない又は上記量未満で含まれてもよい。 The content of the antioxidant when the antioxidant is mixed with the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the kind of the antioxidant, etc., but is 0.0001 to 1% (w / v) Is preferred, 0.0005% to 0.1% (w / v) is more preferred, 0.001 to 0.02% (w / v) is more preferred, 0.005 to 0.01% (w / v) ) Is most preferred. However, the antioxidant is not included or may be included in less than the above amount from the viewpoint of minimizing the use of the additive.
本発明の水性医薬組成物に用いることができるｐＨ調整化剤の例としては、塩酸、リン酸、クエン酸、酢酸、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸水素ナトリウム等が挙げられる。ただし、ｐＨ調整化剤は、添加剤使用の最小化の観点では、含まれなくてもよい。 Examples of the pH adjusting agent that can be used in the aqueous pharmaceutical composition of the present invention include hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like. However, the pH adjusting agent may not be included from the viewpoint of minimizing the use of the additive.
本発明の水性医薬組成物のｐＨは、４．０〜８．０が好ましく、５．０〜６．０がより好ましく、５．１〜５．８がさらに好ましい。 The pH of the aqueous pharmaceutical composition of the present invention is preferably 4.0 to 8.0, more preferably 5.0 to 6.0, and still more preferably 5.1 to 5.8.
また、本発明の水性医薬組成物では、６０℃での保存による、１４日間平均ｐＨ低下値が０．０４６／日以下であることが好ましい。
６０℃での保存による、１４日間平均ｐＨ低下値は、０．０４６／日以下がより好ましく、０．０４０／日以下がさらに好ましく、０．０３５／日以下、０．０３０／日以下が最も好ましい。ｐＨが５．０以上である場合の１４日間平均ｐＨ低下値の下限は、特に限定されないが、０．００５以上であってよい。
Moreover, in the aqueous | water-based pharmaceutical composition of this invention, it is preferable that the 14-day average pH fall value by storage at 60 degreeC is 0.046 / day or less.
The average pH drop value for 14 days by storage at 60 ° C. is more preferably 0.046 / day or less, further preferably 0.040 / day or less, most preferably 0.035 / day or less, and 0.030 / day or less. preferable. The lower limit of the 14-day average pH lowering value when the pH is 5.0 or more is not particularly limited, but may be 0.005 or more.
保存剤の例としては、塩化ベンザルコニウム、塩化ベンゼトニウム、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、エデト酸ナトリウム、ホウ酸、ソルビン酸等が挙げられる。なお、ホウ酸は、添加剤使用の最小化の観点では、含まれない又は０．１％（ｗ／ｖ）未満の量で含まれることが好ましい。また、保存剤は、添加剤使用の最小化の観点では、含まれなくてもよい。 Examples of preservatives include benzalkonium chloride, benzethonium chloride, methyl paraoxybenzoate, ethyl paraoxybenzoate, sodium edetate, boric acid, sorbic acid, and the like. Note that boric acid is preferably not contained or contained in an amount of less than 0.1% (w / v) from the viewpoint of minimizing the use of additives. Moreover, the preservative may not be included from the viewpoint of minimizing the use of the additive.
本発明の水性医薬組成物におけるドルゾラミド又はその塩は、有効成分（例えば緑内障又は高眼圧の治療剤）として含まれてもよく、クロロブタノールの安定化剤、経時的ｐＨ抑制剤、水性医薬組成物の保存効力向上剤等として含まれてもよい。前者及び後者のいずれにおいても、本発明の水性医薬組成物はドルゾラミド又はその塩とは異なる有効成分を含んでもよい。前者において、本発明の水性医薬組成物は、有効成分としてドルゾラミド又はその塩のみを含んでもよい。 Dorzolamide or a salt thereof in the aqueous pharmaceutical composition of the present invention may be contained as an active ingredient (for example, a therapeutic agent for glaucoma or high intraocular pressure), a chlorobutanol stabilizer, a temporal pH inhibitor, an aqueous pharmaceutical composition It may be contained as an agent for improving the preservation effect of the product. In both the former and the latter, the aqueous pharmaceutical composition of the present invention may contain an active ingredient different from dorzolamide or a salt thereof. In the former, the aqueous pharmaceutical composition of the present invention may contain only dorzolamide or a salt thereof as an active ingredient.
具体的に、本発明の水性医薬組成物は、さらに別の緑内障又は高眼圧症の治療剤を治療上有効な量で、本発明の効果を損なわない範囲で配合することができる。なお、本発明の水性医薬組成物は、使用成分の最小化の観点で、フマル酸ケトチフェン、マレイン酸クロルフェニラミン、アミノカプロン酸のいずれをも含まなくてもよく、具体的には有効成分として緑内障又は高眼圧症の治療剤のみを含んでもよい。 Specifically, the aqueous pharmaceutical composition of the present invention can further contain another therapeutic agent for glaucoma or ocular hypertension in a therapeutically effective amount within a range that does not impair the effects of the present invention. The aqueous pharmaceutical composition of the present invention may not contain any of ketotifen fumarate, chlorpheniramine maleate, and aminocaproic acid from the viewpoint of minimizing the components used, and specifically, glaucoma as an active ingredient. Or it may contain only the therapeutic agent for ocular hypertension.
本発明の水性医薬組成物に含有することができる別の緑内障治療剤の例としては、プロスタグランジン製剤、α遮断薬、β遮断薬、副交感神経作動薬等が挙げられる。特に、チモロール又はその塩、カルテオロール又はその塩、ベタキソロール又はその塩、ニプラジロール又はその塩等のβ遮断薬が好ましく、チモロール又はその塩がより好ましく、チモロールマレイン酸塩が特に好ましい。具体的に、本発明の水性医薬組成物に含まれる有効成分は、ドルゾラミド又はその塩と、チモロール又はその塩とのみからなってもよい。 Examples of other glaucoma therapeutic agents that can be contained in the aqueous pharmaceutical composition of the present invention include prostaglandin preparations, α blockers, β blockers, parasympathomimetic agents and the like. In particular, β-blockers such as timolol or a salt thereof, carteolol or a salt thereof, betaxolol or a salt thereof, nipradilol or a salt thereof are preferable, timolol or a salt thereof is more preferable, and timolol maleate is particularly preferable. Specifically, the active ingredient contained in the aqueous pharmaceutical composition of the present invention may consist only of dorzolamide or a salt thereof and timolol or a salt thereof.
本発明の水性医薬組成物は、緑内障又は高眼圧症の治療剤として有用である。慢性疾患の原因は多岐であり、その治療が長期にわたることから、作用機序の異なる多数の緑内障治療薬を併用することが多く、そのため有効成分以外の添加剤の累積による毒性を考慮する必要がある。しかし、本発明の水性医薬組成物は、前述のように最小限の添加剤でも十分な保存効力を付与し得るので、上記問題を抑制することができる。 The aqueous pharmaceutical composition of the present invention is useful as a therapeutic agent for glaucoma or ocular hypertension. Because the causes of chronic diseases are diverse and the treatment is long-lasting, many drugs for glaucoma with different mechanisms of action are often used in combination, so it is necessary to consider the toxicity of cumulative additives other than the active ingredient. is there. However, since the aqueous pharmaceutical composition of the present invention can impart sufficient storage efficacy even with a minimum of additives as described above, the above problem can be suppressed.
本発明の水性医薬組成物を投与する場合、所望の薬効を奏するのに十分であれば用法用量に特に制限はないが、１回１〜３滴、１日１〜３回点眼するのが好ましく、１回１〜２滴、１日１〜２回点眼するのがより好ましく、１回１滴、１日２回点眼するのが最も好ましい。
前述のように、本発明の水性医薬組成物は、クロロブタノールの分解抑制、経時的ｐＨ低下の抑制、保存効力の向上に優れるので、遮光性の容器が好ましいが、非遮光性の容器に収容することもできる。非遮光性は、透明に限らず、光透過可能な限りにおいて不透明も包含する。点眼容器としては、例えば、ポリエチレン容器、ポリプロピレン容器、ポリエチレンテレフタレート容器等が挙げられる。
When the aqueous pharmaceutical composition of the present invention is administered, there is no particular limitation on the dosage as long as it is sufficient to achieve a desired drug effect, but it is preferable to instill 1 to 3 drops once to 1 to 3 times a day. It is more preferable to apply 1 to 2 drops once or 1 to 2 times a day, and most preferable to apply 1 drop once or twice a day.
As described above, the aqueous pharmaceutical composition of the present invention is excellent in suppressing degradation of chlorobutanol, suppressing pH decrease over time, and improving storage efficiency. Therefore, a light-shielding container is preferable, but it is housed in a non-light-shielding container. You can also The non-light-shielding property includes not only transparent but also opaque as long as light can be transmitted. As an eye drop container, a polyethylene container, a polypropylene container, a polyethylene terephthalate container etc. are mentioned, for example.
同様の理由により、本発明の水性医薬組成物は、冷所に限られず、室温で保管されてもよい。なお、室温とは、例えば１〜３０℃を指し、１５℃超３０℃以下であってもよい。 For the same reason, the aqueous pharmaceutical composition of the present invention is not limited to a cold place and may be stored at room temperature. In addition, room temperature refers to 1-30 degreeC, for example, 15 degreeC or more and 30 degrees C or less may be sufficient.
本発明の水性医薬組成物は、マルチドーズ型容器、１回使い切りのユニットドーズ容器またはＰＦＭＤ（Ｐｒｅｓｅｒｖａｔｉｖｅ Ｆｒｅｅ Ｍｕｌｔｉ Ｄｏｓｅ）容器のいずれに収容されていてもよい。 The aqueous pharmaceutical composition of the present invention may be contained in any of a multi-dose container, a single-use unit dose container, or a PFMD (Preservative Free Multi Dose) container.
本発明の水性医薬組成物の剤形は、医薬品として使用可能なものであれば特に制限されないが、特に点眼剤が好ましく、当該技術分野における通常の方法に従って製造することができる。 The dosage form of the aqueous pharmaceutical composition of the present invention is not particularly limited as long as it can be used as a pharmaceutical product, but an eye drop is particularly preferable and can be produced according to a usual method in the art.
以下に製剤例及び保存効力試験の結果を示すが、これらは本発明をより良く理解するためのものであり、本発明の範囲を限定するものではない。 Although the example of a formulation and the result of a storage efficacy test are shown below, these are for understanding this invention better, and do not limit the scope of the present invention.
製剤例
以下に本発明の代表的な製剤例を示す。なお、下記製剤例において各成分の配合量は製剤１ｍＬ中の含量である。
Formulation Example A typical formulation example of the present invention is shown below. In the following formulation examples, the amount of each component is the content in 1 mL of the formulation.
製剤例１
ドルゾラミド塩酸塩 １１．１ｍｇ
クロロブタノール ４．０ｍｇ
クエン酸ナトリウム ３．０ｍｇ
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
クロロブタノールに対するドルゾラミドの質量比は、２．５である。
Formulation Example 1
Dorzolamide hydrochloride 11.1mg
Chlorobutanol 4.0mg
Sodium citrate 3.0mg
Dilute hydrochloric acid appropriate amount Sodium hydroxide appropriate amount Purified water appropriate amount The mass ratio of dorzolamide to chlorobutanol is 2.5.
製剤例２
ドルゾラミド塩酸塩 ２２．３ｍｇ
クロロブタノール ４．０ｍｇ
チモロールマレイン酸塩 ６．８ｍｇ
クエン酸ナトリウム ３．０ｍｇ
希塩酸 適量
水酸化ナトリウム 適量
精製水 適量
クロロブタノールに対するドルゾラミドの質量比は、５．０である。
Formulation Example 2
Dorzolamide hydrochloride 22.3mg
Chlorobutanol 4.0mg
Timolol maleate 6.8mg
Sodium citrate 3.0mg
Dilute hydrochloric acid appropriate amount Sodium hydroxide appropriate amount Purified water appropriate amount The mass ratio of dorzolamide to chlorobutanol is 5.0.
なお、前記製剤例１及び２における、ドルゾラミド、クロロブタノール及び添加剤の種類や配合量を適宜調整し所望の組成物を得ることができる。 In addition, the kind and compounding quantity of a dorzolamide, chlorobutanol, and an additive in the said formulation examples 1 and 2 can be adjusted suitably, and a desired composition can be obtained.
１．安定性試験
（１）被験製剤の調製
ドルゾラミド塩酸塩（１１．１３ｍｇ）、クロロブタノール（４．００ｍｇ）、クエン酸ナトリウム水和物（３．００ｍｇ）を水に溶解し、希塩酸及び水酸化ナトリウムを用いてｐＨ５．６５とした後、水を加えて全量を１ｍＬとすることにより、実施例１の製剤を調製した。
1. Stability test (1) Preparation of test preparation Dorzolamide hydrochloride (11.13 mg), chlorobutanol (4.00 mg) and sodium citrate hydrate (3.00 mg) were dissolved in water, and diluted hydrochloric acid and sodium hydroxide were added. After using to pH 5.65, the formulation of Example 1 was prepared by adding water to bring the total volume to 1 mL.
実施例１（１ｍＬ中）
ドルゾラミド塩酸塩 １１．１３ｍｇ
クロロブタノール ４．００ｍｇ
クエン酸ナトリウム水和物 ３．００ｍｇ
希塩酸 適量
水酸化ナトリウム 適量
注射用水 適量
ｐＨ ５．６５
クロロブタノールに対するドルゾラミドの質量比は、２．５である。
Example 1 (in 1 mL)
Dorzolamide hydrochloride 11.13mg
Chlorobutanol 4.00mg
Sodium citrate hydrate 3.00mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Water for injection Appropriate amount pH 5.65
The mass ratio of dorzolamide to chlorobutanol is 2.5.
実施例１の調製方法と同様の方法にて、実施例２、実施例３、比較例１、及び比較例２の製剤を調製した。 The preparations of Example 2, Example 3, Comparative Example 1, and Comparative Example 2 were prepared in the same manner as the preparation method of Example 1.
実施例２（１ｍＬ中）
ドルゾラミド塩酸塩 １１．１３ｍｇ
チモロールマレイン酸塩 ６．８３ｍｇ
クロロブタノール ４．００ｍｇ
クエン酸ナトリウム水和物 ３．００ｍｇ
希塩酸 適量
水酸化ナトリウム 適量
注射用水 適量
ｐＨ ５．６４
クロロブタノールに対するドルゾラミドの質量比は、２．５である。
Example 2 (in 1 mL)
Dorzolamide hydrochloride 11.13mg
Timolol maleate 6.83mg
Chlorobutanol 4.00mg
Sodium citrate hydrate 3.00mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Water for injection Appropriate amount pH 5.64
The mass ratio of dorzolamide to chlorobutanol is 2.5.
実施例３（１ｍＬ中）
ドルゾラミド塩酸塩 １１．１３ｍｇ
チモロールマレイン酸塩 ６．８３ｍｇ
クロロブタノール ４．００ｍｇ
希塩酸 適量
水酸化ナトリウム 適量
注射用水 適量
ｐＨ ５．６８
クロロブタノールに対するドルゾラミドの質量比は、２．５である。
Example 3 (in 1 mL)
Dorzolamide hydrochloride 11.13mg
Timolol maleate 6.83mg
Chlorobutanol 4.00mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Water for injection Appropriate amount pH 5.68
The mass ratio of dorzolamide to chlorobutanol is 2.5.
比較例１（１ｍＬ中）
チモロールマレイン酸塩 ６．８３ｍｇ
クロロブタノール ４．００ｍｇ
クエン酸ナトリウム水和物 ３．００ｍｇ
希塩酸 適量
水酸化ナトリウム 適量
注射用水 適量
ｐＨ ５．６５
Comparative Example 1 (in 1 mL)
Timolol maleate 6.83mg
Chlorobutanol 4.00mg
Sodium citrate hydrate 3.00mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Water for injection Appropriate amount pH 5.65
比較例２（１ｍＬ中）
クロロブタノール ４．００ｍｇ
クエン酸ナトリウム水和物 ３．００ｍｇ
希塩酸 適量
水酸化ナトリウム 適量
注射用水 適量
ｐＨ ５．６５
Comparative Example 2 (in 1 mL)
Chlorobutanol 4.00mg
Sodium citrate hydrate 3.00mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Water for injection Appropriate amount pH 5.65
（２）試験方法
実施例１、実施例２、実施例３、比較例１及び比較例２をガラスアンプルに充填して遮光下において６０℃で２週間保存した。保存中、製剤調製直後（０日）及び調製１４日後に、それぞれのサンプルのｐＨを測定した。
(2) Test method Example 1, Example 2, Example 3, Comparative Example 1 and Comparative Example 2 were filled in a glass ampule and stored at 60 ° C. for 2 weeks in the dark. During storage, the pH of each sample was measured immediately after preparation preparation (day 0) and 14 days after preparation.
（３）試験結果及び考察
試験結果を表１に示す。表１の試験結果は、各測定ポイントでのｐＨ値を示す。０日は製剤調製直後の値である。表１の、０−１４日変化、及び１日当たり変化（０−１４日）（１４日間平均ｐＨ低下値とも表す）は、それぞれ以下の通り算出される。
０−１４日変化 ＝ （０日のｐＨ）−（１４日後のｐＨ）
１日当たり変化（０−１４日） ＝ （０−１４日変化）／１４（日間）
(3) Test results and discussion Table 1 shows the test results. The test result of Table 1 shows the pH value at each measurement point. Day 0 is the value immediately after preparation preparation. The 0-14 day change and the change per day (0-14 day) (also expressed as the 14-day average pH drop value) in Table 1 are calculated as follows.
0-14 days change = (pH of day 0)-(pH after 14 days)
Change per day (0-14 days) = (0-14 days change) / 14 (days)
表１に示されるように、ドルゾラミド又はその塩を含まない比較例１及び比較例２のｐＨは、いずれも経時的に低下を示したのに対し、ドルゾラミド又はその塩及びクロロブタノールを含有する実施例１の製剤は、経時的なｐＨの低下を抑制した。さらには、ドルゾラミド又はその塩及びクロロブタノールにチモロールを含有する実施例２の製剤は、経時的なｐＨの低下をより抑制した。これにより、本発明の水性医薬組成物は、ｐＨ低下を抑制する水性医薬組成物であることが示唆された。また、クエン酸又はその塩を含む実施例２と、クエン酸又はその塩を含まない実施例３との対比により、クエン酸又はその塩は、経時的ｐＨ低下抑制に寄与するものの、必須ではないことが示唆された。 As shown in Table 1, the pH values of Comparative Example 1 and Comparative Example 2 not containing dorzolamide or a salt thereof both decreased over time, whereas those containing dorzolamide or a salt thereof and chlorobutanol were reduced. The formulation of Example 1 suppressed the decrease in pH over time. Furthermore, the preparation of Example 2 containing timolol in dorzolamide or a salt thereof and chlorobutanol further suppressed the decrease in pH over time. Thereby, it was suggested that the aqueous | water-based pharmaceutical composition of this invention is an aqueous | water-based pharmaceutical composition which suppresses pH fall. Further, by comparing Example 2 containing citric acid or a salt thereof with Example 3 not containing citric acid or a salt thereof, citric acid or a salt thereof is not essential, although it contributes to suppression of pH decrease over time. It has been suggested.
Claims (16)
An aqueous eye drop containing dorzolamide or a salt thereof and chlorobutanol and having an average pH drop of 14 days or less upon storage at 60 ° C. of 0.046 / day or less (provided that the eye drop does not contain ripaspil) .
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2015189118A JP6050454B1 (en) | 2015-09-28 | 2015-09-28 | Aqueous pharmaceutical composition |
| PCT/JP2016/078578 WO2017057434A1 (en) | 2015-09-28 | 2016-09-28 | Aqueous pharmaceutical composition |
| JP2016189378A JP2017066138A (en) | 2015-09-28 | 2016-09-28 | Aqueous pharmaceutical composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2015189118A JP6050454B1 (en) | 2015-09-28 | 2015-09-28 | Aqueous pharmaceutical composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP6050454B1 true JP6050454B1 (en) | 2016-12-21 |
Family
ID=57572401
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2015189118A Active JP6050454B1 (en) | 2015-09-28 | 2015-09-28 | Aqueous pharmaceutical composition |
| JP2016189378A Pending JP2017066138A (en) | 2015-09-28 | 2016-09-28 | Aqueous pharmaceutical composition |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2016189378A Pending JP2017066138A (en) | 2015-09-28 | 2016-09-28 | Aqueous pharmaceutical composition |
Country Status (2)
| Country | Link |
|---|---|
| JP (2) | JP6050454B1 (en) |
| WO (1) | WO2017057434A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP6628924B2 (en) * | 2018-06-05 | 2020-01-15 | 千寿製薬株式会社 | Aqueous liquid |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003192583A (en) * | 2001-12-25 | 2003-07-09 | Taisho Pharm Ind Ltd | Antiinflammatory eye drop |
| JP2004256519A (en) * | 2003-02-07 | 2004-09-16 | Senju Pharmaceut Co Ltd | Chlorobutanol-containing artificial tear liquid |
| JP2005187383A (en) * | 2003-12-25 | 2005-07-14 | Lion Corp | Ophthalmic composition |
| WO2011013794A1 (en) * | 2009-07-30 | 2011-02-03 | わかもと製薬株式会社 | Water-based composition for eye drop |
| JP2011516537A (en) * | 2008-04-07 | 2011-05-26 | テクノファーマ ソシエテ アノニム | Stable ophthalmic formulation |
| JP2011105706A (en) * | 2009-10-21 | 2011-06-02 | Taisho Pharmaceutical Co Ltd | Ophthalmic agent |
| JP2013528589A (en) * | 2010-05-05 | 2013-07-11 | センジュ ユーエスエー、インコーポレイテッド | Ophthalmic composition |
| JP2016166198A (en) * | 2015-03-06 | 2016-09-15 | 興和株式会社 | Aqueous composition |
-
2015
- 2015-09-28 JP JP2015189118A patent/JP6050454B1/en active Active
-
2016
- 2016-09-28 WO PCT/JP2016/078578 patent/WO2017057434A1/en active Application Filing
- 2016-09-28 JP JP2016189378A patent/JP2017066138A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003192583A (en) * | 2001-12-25 | 2003-07-09 | Taisho Pharm Ind Ltd | Antiinflammatory eye drop |
| JP2004256519A (en) * | 2003-02-07 | 2004-09-16 | Senju Pharmaceut Co Ltd | Chlorobutanol-containing artificial tear liquid |
| JP2005187383A (en) * | 2003-12-25 | 2005-07-14 | Lion Corp | Ophthalmic composition |
| JP2011516537A (en) * | 2008-04-07 | 2011-05-26 | テクノファーマ ソシエテ アノニム | Stable ophthalmic formulation |
| WO2011013794A1 (en) * | 2009-07-30 | 2011-02-03 | わかもと製薬株式会社 | Water-based composition for eye drop |
| JP2011105706A (en) * | 2009-10-21 | 2011-06-02 | Taisho Pharmaceutical Co Ltd | Ophthalmic agent |
| JP2013528589A (en) * | 2010-05-05 | 2013-07-11 | センジュ ユーエスエー、インコーポレイテッド | Ophthalmic composition |
| JP2016166198A (en) * | 2015-03-06 | 2016-09-15 | 興和株式会社 | Aqueous composition |
Non-Patent Citations (1)
| Title |
|---|
| JPN6016038030; 日本薬局方解説書編集委員会編: 第十四改正 日本薬局方解説書 , 2001, Ｆ-１３１〜１３８ * |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2017066138A (en) | 2017-04-06 |
| WO2017057434A1 (en) | 2017-04-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6785330B2 (en) | Pharmaceutical formulation containing pyridylaminoacetic acid compound | |
| JP6441087B2 (en) | Pharmaceutical composition containing pyridylaminoacetic acid compound | |
| JP6886878B2 (en) | Pharmaceutical composition containing dorzolamide, timolol and surfactant | |
| JP6903448B2 (en) | Pharmaceutical composition containing dorzolamide and brimonidine | |
| JP6683622B2 (en) | Ophthalmic aqueous composition | |
| JP2019178083A (en) | Aqueous solution for eye drops | |
| JP2017066033A (en) | Aqueous pharmaceutical composition | |
| JP2018048134A (en) | Eye drop containing JAK inhibitor | |
| JP6050454B1 (en) | Aqueous pharmaceutical composition | |
| JP2011246383A (en) | Ophthalmologic formulation for alleviation of tired eyes of contact lens wearer | |
| JP7247278B2 (en) | Aqueous pharmaceutical composition | |
| JP6132968B1 (en) | Pharmaceutical composition containing dorzolamide, polymer and boric acid | |
| KR20230145458A (en) | Aqueous pharmaceutical composition containing ursodeoxycholic acid or its salt | |
| CN109641059B (en) | Ophthalmic pharmaceutical composition with improved preservative efficacy or photostability | |
| JP2018048133A (en) | Agent for the treatment and/or prevention of inflammatory eye disease | |
| JP6877613B2 (en) | Combination of preservative medicines | |
| JP2022123792A (en) | Aqueous pharmaceutical composition | |
| WO2016136651A1 (en) | Preservative containing dorzolamide | |
| JP2015044751A (en) | Eye drop which contains latanoprost and timolol maleate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20150928 |
|
| A871 | Explanation of circumstances concerning accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A871 Effective date: 20150928 |
|
| A975 | Report on accelerated examination |
Free format text: JAPANESE INTERMEDIATE CODE: A971005 Effective date: 20151022 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20161004 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20161024 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20161115 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20161124 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 6050454 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |