WO2004103373A1 - キノロン系抗菌化合物を含有する点眼液 - Google Patents
キノロン系抗菌化合物を含有する点眼液 Download PDFInfo
- Publication number
- WO2004103373A1 WO2004103373A1 PCT/JP2004/007312 JP2004007312W WO2004103373A1 WO 2004103373 A1 WO2004103373 A1 WO 2004103373A1 JP 2004007312 W JP2004007312 W JP 2004007312W WO 2004103373 A1 WO2004103373 A1 WO 2004103373A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ophthalmic solution
- water
- soluble
- compound
- salt
- Prior art date
Links
- 239000002997 ophthalmic solution Substances 0.000 title claims abstract description 46
- 229940054534 ophthalmic solution Drugs 0.000 title claims abstract description 44
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 title abstract description 9
- 239000004599 antimicrobial Substances 0.000 title abstract 3
- 229920002554 vinyl polymer Polymers 0.000 claims abstract description 15
- 229920002678 cellulose Polymers 0.000 claims abstract description 12
- 239000001913 cellulose Substances 0.000 claims abstract description 12
- 239000004480 active ingredient Substances 0.000 claims abstract description 7
- 238000001556 precipitation Methods 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 43
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical group 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 claims description 40
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 27
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 27
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 26
- 229940072132 quinolone antibacterials Drugs 0.000 claims description 21
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 claims description 19
- 230000000844 anti-bacterial effect Effects 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 15
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 13
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 13
- 229960003405 ciprofloxacin Drugs 0.000 claims description 9
- -1 sihufloxacin Chemical compound 0.000 claims description 9
- 229960001180 norfloxacin Drugs 0.000 claims description 6
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 claims description 6
- 229960002422 lomefloxacin Drugs 0.000 claims description 5
- ZEKZLJVOYLTDKK-UHFFFAOYSA-N lomefloxacin Chemical compound FC1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNC(C)C1 ZEKZLJVOYLTDKK-UHFFFAOYSA-N 0.000 claims description 5
- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 claims description 3
- 229960003923 gatifloxacin Drugs 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 13
- 230000000052 comparative effect Effects 0.000 description 12
- 239000003889 eye drop Substances 0.000 description 12
- 235000002639 sodium chloride Nutrition 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 229940012356 eye drops Drugs 0.000 description 10
- 239000002504 physiological saline solution Substances 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000000607 artificial tear Substances 0.000 description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 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
- 235000011187 glycerol Nutrition 0.000 description 3
- QKDHBVNJCZBTMR-LLVKDONJSA-N (R)-temafloxacin Chemical compound C1CN[C@H](C)CN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1=CC=C(F)C=C1F QKDHBVNJCZBTMR-LLVKDONJSA-N 0.000 description 2
- RUXPNBWPIRDVTH-UHFFFAOYSA-N Amifloxacin Chemical compound C1=C2N(NC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCN(C)CC1 RUXPNBWPIRDVTH-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 229950009484 amifloxacin Drugs 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- NOCJXYPHIIZEHN-UHFFFAOYSA-N difloxacin Chemical compound C1CN(C)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1=CC=C(F)C=C1 NOCJXYPHIIZEHN-UHFFFAOYSA-N 0.000 description 2
- 229950001733 difloxacin Drugs 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229960002549 enoxacin Drugs 0.000 description 2
- IDYZIJYBMGIQMJ-UHFFFAOYSA-N enoxacin Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 IDYZIJYBMGIQMJ-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 229960004576 temafloxacin Drugs 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 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-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 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
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 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
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002125 Sokalan® Polymers 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
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 1
- 229960004150 aciclovir Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229960002684 aminocaproic acid Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000003560 epithelium corneal Anatomy 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229960003306 fleroxacin Drugs 0.000 description 1
- XBJBPGROQZJDOJ-UHFFFAOYSA-N fleroxacin Chemical compound C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(CCF)C2=C1F XBJBPGROQZJDOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 150000002605 large molecules Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 239000002245 particle Substances 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
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- 239000004328 sodium tetraborate Substances 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- the present invention provides a method of contacting tear fluid by adding at least one selected from a water-soluble vinyl polymer compound and a water-soluble cellulose derivative to an ophthalmic solution containing a quinoline antibacterial compound or a salt thereof as an active ingredient.
- the present invention relates to an ophthalmic solution in which the precipitation of a quinolone antibacterial compound or a salt thereof is suppressed.
- Quinolone-based antibacterial compounds exhibit strong antibacterial properties, are highly safe, and are excellent antibacterial agents, and are widely used in eye drops. Although some of these quinolone antibacterial compounds are water-soluble, those having both an acidic group (such as a carboxylic acid group) and a basic group (such as an amino group) as a substituent are particularly effective in the neutral region. It tends to be insoluble in water due to its in-structure.
- an acidic group such as a carboxylic acid group
- a basic group such as an amino group
- Examples of such a quinolone antibacterial conjugate include ciprofloxacin, lotafloxacin, norfloxacin, lomefloxacin, tosfloxacin, gatifloxacin, amifloxacin, fleloxacin, enoxacin, difloxacin, temafloxacin, and the like (Patent No. 2714) No. 597, Japanese Patent No. 2121924, Japanese Patent Application Laid-Open No. Sho 53-128, Japanese Patent Application Laid-Open No. 57-77683, etc.).
- water-soluble cellulose derivatives such as polyvinyl alcohol, polyvinylpyrrolidone and other water-soluble high molecular weight compounds such as hydroxypropylmethylcellulose are used as thickeners or dispersants in the field of eye drops.
- the pamphlet can be mixed with acyclovir, which is active against herpes virus, with carboxymethylcellulose, etc., to obtain an aqueous suspension with a uniform particle size. It is described. In J. Ocul. Pharm col. Ther., 11, 555-563 (2001), adding hydroxypropylmethylcellulose to eye drops containing a quinolone-based antibacterial compound provides a sustained release of the quinolone-based antibacterial compound. It is described that it can be converted.
- the present inventors have conducted intensive studies on ophthalmic solutions containing a quinolone antibacterial compound. However, if a water-soluble vinyl polymer compound or a water-soluble cell mouth derivative is blended, the quinoline antibacterial compound can be prevented from being precipitated even when the ophthalmic solution is in contact with the tear. I found that I could.
- the present invention relates to an ophthalmic solution containing a quinolone antibacterial compound or a salt thereof as an active ingredient, and comprising at least one selected from a water-soluble vinyl polymer compound and a water-soluble cellulose derivative, It is an ophthalmic solution in which the quinolone antibacterial conjugate or its salt is prevented from precipitating when contacted with the liquid.
- an ophthalmic solution containing a quinolone antibacterial conjugate or a salt thereof as an active ingredient at least one selected from a water-soluble vinyl polymer compound and a water-soluble cellulose derivative is blended. This is a method of suppressing the precipitation of the quinolone antibacterial compound later.
- the quinoquinone-based antibacterial compound of the present invention or a salt thereof is not particularly limited as long as it is an antibacterial quinoquinone compound or a salt thereof which may be precipitated on the eye surface when it comes into contact with tears.
- ciprofloxacin sihufloxacin, norfloxacin, lomefloxacin, tosfloxacin, gatifloxacin, amifloxacin, fleroxacin, enoxacin, difloxacin, temafloxacin and the like.
- concentration of the quinolone antibacterial compound or a salt thereof in the ophthalmic solution of the present invention is not particularly limited since it can be appropriately selected in accordance with their medicinal effects.
- the water-soluble vinyl polymer compound in the present invention is not particularly limited as long as it is a water-soluble vinyl polymer.
- polyvinyl alcohol polyvinylpyrrolidone (polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, polyvinyl Pyrrolidone K90), carboxyvinyl polymer and the like. More preferably, it is polyvinyl alcohol or polyvinyl pyrrolidone.
- the water-soluble cellulose derivative in the present invention may be a water-soluble cellulose derivative.
- examples thereof include hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, and more preferably, hydroxypropylmethylcellulose.
- the ophthalmic solution may contain at least one selected from a water-soluble vinyl polymer compound and a water-soluble cellulose derivative. It is preferable to combine them so that at least one selected concentration is 0.01 to 5% (w / v).
- the ophthalmic solution of the present invention may appropriately contain, as other additives, isotonic agents, buffers, pH adjusters, solubilizers, stabilizers, preservatives, and the like.
- Examples of the tonicity agent include glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol and the like.
- Examples of the buffer include phosphoric acid, phosphate, citric acid, acetic acid, £ -aminocaproic acid, trometamol, and the like.
- pH adjuster examples include hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, boric acid, borax, sodium carbonate, sodium hydrogen carbonate and the like.
- solubilizing agent examples include polysorbate 80, polyoxyethylene hydrogenated castor oil 60, macrogol 400, and the like.
- Examples of the stabilizer include edetic acid, sodium edetate, and the like.
- preservatives general-purpose sorbic acid, potassium sorbate, benzalkonium chloride, penzetonium chloride, and no. Examples thereof include methyl laoxybenzoate, propyl paraoxybenzoate, and chlorobutanol, and these preservatives can be used in combination.
- the pH of the eye drop of the present invention is desirably set to 4.5 to 8.5, and the osmotic pressure ratio is desirably set to around 1.0.
- the dose of the ophthalmic solution of the present invention can be appropriately selected depending on symptoms, age, etc., but may be instilled once or several times a day.
- hydroxypropyl methylcellulose 2910
- cioxafloxacin aqueous sodium hydroxide solution and dilute hydrochloric acid
- the pH was adjusted to 5.1 with aqueous sodium hydroxide solution and dilute hydrochloric acid, and then adjusted to 10 OmL with physiological saline, and filtered through a 0.22 ⁇ m membrane filter to obtain eye drops. .
- An ophthalmic solution was obtained by performing the same operation as in Example 1 except that 0.3 g of hydroxypropylmethylcellulose (2910) was used.
- Example 4 An ophthalmic solution was obtained in the same manner as in Example 1 except that 3.0 g of polyvinylpyrrolidone was used instead of 0.1 g of hydroxypropylmethylcellulose (2910).
- Example 4
- An ophthalmic solution was obtained in the same manner as in Example 1 except that 1.0 g of polyvinyl alcohol was used instead of 0.1 g of hydroxypropylmethylcellulose (2910).
- Hydroxypropylmethylcellulose (2910) (0.3 g) was added to physiological saline (90 mL), and ciprofloxacin (0.3 g) was added thereto.] Then, an appropriate amount of diluted hydrochloric acid was added to dissolve the ciprofloxacin. After adjusting the pH to 4.5 using an aqueous sodium hydroxide solution and dilute hydrochloric acid, physiological saline was added to adjust the pH to 10 OmL, and the mixture was filtered through a 0.22 ⁇ m membrane filter to obtain eye drops.
- Comparative ophthalmic solution was obtained by performing the same operation as in Example 5 except that 0.3 g of hydroxypropylmethylcellulose (2910) was not used.
- Hydroxypropylmethylcellulose (2910) (0.3 g) was added to physiological saline (90 mL), norfloxacin (0.3 g) was added, and dilute hydrochloric acid was added in an appropriate amount to dissolve norfloxacin.
- the pH was adjusted to 6.4 using aqueous sodium hydroxide solution and dilute hydrochloric acid, and then adjusted to 10 OmL with physiological saline, and filtered through 0.22 ⁇ m membrane filter to obtain eye drops. .
- An ophthalmic solution was obtained in the same manner as in Example 9 except that 1.0 g of polyvinyl alcohol was used instead of 0.3 g of hydroxypropyl methylcellulose (2910).
- Comparative ophthalmic solution was obtained by performing the same operation as in Example 10 except that 0.3 g of hydroxypropyl methylcellulose (2910) was not used.
- Hydroxypropylmethylcellulose (2910) 1. Og was added to 9 OmL of a 2.5% concentrated glycerin solution, then 1.2 g of lomefloxacin was added, and an appropriate amount of dilute hydrochloric acid was added to dissolve lomefloxacin. After adjusting the pH to 6.3 with aqueous sodium hydroxide and dilute hydrochloric acid, add 2.5% concentrated glycerin solution to make 10 OmL, filter it with a 0.22 ⁇ m membrane filter, and apply it to eye drops. Was obtained.
- Comparative ophthalmic solution was obtained in the same manner as in Example 11, except that 1.0 g of hydroxypropyl methylcellulose (2910) was not used.
- Hydroxypropyl methylcellulose (2910) (0.3 g) was added to physiological saline (90 mL), and then tosfloxacin (0.0Olg) was added, and an appropriate amount of an aqueous sodium hydroxide solution was added to dissolve tosfloxacin. After adjusting the pH to 5.2 using dilute hydrochloric acid and sodium hydroxide, physiological saline was added to adjust the pH to 10 OmL, and the mixture was filtered through a 0.22 m membrane filter to obtain eye drops.
- An ophthalmic solution was obtained in the same manner as in Example 13, except that 1.0 g of polyvinyl alcohol was used instead of 0.3 g of hydroxypropylmethylcellulose (2910).
- Comparative ophthalmic solution was obtained by performing the same operation as in Example 13 except that 0.3 g of hydroxypropylmethylcellulose (2910) was not used.
- Examples 1 to 14 and Comparative Example 15 mL of each ophthalmic solution of No. 5 to 5 was placed in a 20 mL glass beaker and stirred with a magnetic mixer. Next, 3 mL of artificial tears (isotonic phosphate buffer: PH7.5) was added to each eye drop and stirred. Immediately after injection, 5 minutes and 10 minutes later, 2 mL of each ophthalmic solution was sampled and filtered using a 0.22 ⁇ m membrane filter. The concentration of the quinolone antibacterial compound in each filtrate was determined by high performance liquid chromatography, and after a certain period of time from the quinoline concentration immediately after the addition of artificial tears. The quinolone concentration ratio was calculated as the dissolution rate (%). The results of these tests are
- quinolone antibacterial compounds such as cilufloxacin, ciprofloxacin, norfloxacin, and water-soluble vinyl polymer compounds such as polyvinyl alcohol and hydroxypropyl methylcellulose or water-soluble cell ports
- water-soluble vinyl polymer compounds such as polyvinyl alcohol and hydroxypropyl methylcellulose or water-soluble cell ports
- the ophthalmic solution containing a quinolone-based antibacterial compound or a salt thereof as an active ingredient contains a water-soluble vinyl polymer compound and a water-soluble cellulose derivative. If at least one selected is added, the precipitation of the quinolone antibacterial compound or its salt can be suppressed even when the ophthalmic solution is brought into contact with tears.
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Description
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Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
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EP04734397A EP1627637A1 (en) | 2003-05-23 | 2004-05-21 | Ophthalmic solution containing quinolone antimicrobial compound |
US11/283,674 US20060074053A1 (en) | 2003-05-23 | 2005-11-22 | Ophthalmic solution containing quinolone antimicrobial compound |
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JP2003146621 | 2003-05-23 | ||
JP2003-146621 | 2003-05-23 |
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US11/283,674 Continuation US20060074053A1 (en) | 2003-05-23 | 2005-11-22 | Ophthalmic solution containing quinolone antimicrobial compound |
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WO2004103373A1 true WO2004103373A1 (ja) | 2004-12-02 |
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PCT/JP2004/007312 WO2004103373A1 (ja) | 2003-05-23 | 2004-05-21 | キノロン系抗菌化合物を含有する点眼液 |
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US (1) | US20060074053A1 (ja) |
EP (1) | EP1627637A1 (ja) |
WO (1) | WO2004103373A1 (ja) |
Families Citing this family (8)
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US6716830B2 (en) * | 1998-09-30 | 2004-04-06 | Alcon, Inc. | Ophthalmic antibiotic compositions containing moxifloxacin |
CA2666440A1 (en) | 2006-10-12 | 2008-04-17 | Kyorin Pharmaceutical Co., Ltd. | Aqueous liquid preparation having improved intraocular gatifloxacin penetration |
TWI415629B (zh) | 2006-10-26 | 2013-11-21 | Otsuka Pharma Co Ltd | 含有瑞巴匹特之水性醫藥懸浮物及其製造方法 |
KR20100133980A (ko) * | 2008-03-07 | 2010-12-22 | 썬 파마 어드밴스트 리서치 컴패니 리미티드 | 안약 조성물 |
CA2718641A1 (en) * | 2008-03-31 | 2009-10-08 | Kyorin Pharmaceutical Co., Ltd. | Gatifloxacin-containing aqueous liquid preparation, its production and method for suppressing formation of precipitate during storage at lower temperature and at the time of freezing and thawing of the aqueous liquid preparation |
BRPI0909366A2 (pt) * | 2008-03-31 | 2017-06-13 | Kyorin Seiyaku Kk | preparação líquida aquosa contendo gatifloxacina |
CN101690712B (zh) * | 2009-08-25 | 2011-06-15 | 武汉武药科技有限公司 | 一种西他沙星滴眼剂及其制备方法 |
RU2563985C2 (ru) * | 2011-03-23 | 2015-09-27 | Тояма Кемикал Ко., Лтд. | Фармацевтическая композиция, содержащая тосуфлоксацин или его соль |
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JP2001509476A (ja) * | 1997-07-11 | 2001-07-24 | ドクトル ゲルハルト マン ケム−ファルム. ファブリック ゲゼルシャフト ミット ベシュレンクテル ハフツンク | ジクロフェナクおよびオフロキサシンを含む貯蔵安定な眼科用組成物 |
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US4670444B1 (en) * | 1980-09-03 | 1999-02-09 | Bayer Ag | and-naphthyridine-3-carboxylic acids and antibacte7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-rial agents containing these compounds |
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2004
- 2004-05-21 EP EP04734397A patent/EP1627637A1/en not_active Withdrawn
- 2004-05-21 WO PCT/JP2004/007312 patent/WO2004103373A1/ja active Application Filing
-
2005
- 2005-11-22 US US11/283,674 patent/US20060074053A1/en not_active Abandoned
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JP2001509476A (ja) * | 1997-07-11 | 2001-07-24 | ドクトル ゲルハルト マン ケム−ファルム. ファブリック ゲゼルシャフト ミット ベシュレンクテル ハフツンク | ジクロフェナクおよびオフロキサシンを含む貯蔵安定な眼科用組成物 |
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EP1627637A1 (en) | 2006-02-22 |
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