CN101573118B - 包含加替沙星的含水液体制剂 - Google Patents
包含加替沙星的含水液体制剂 Download PDFInfo
- Publication number
- CN101573118B CN101573118B CN2007800376785A CN200780037678A CN101573118B CN 101573118 B CN101573118 B CN 101573118B CN 2007800376785 A CN2007800376785 A CN 2007800376785A CN 200780037678 A CN200780037678 A CN 200780037678A CN 101573118 B CN101573118 B CN 101573118B
- Authority
- CN
- China
- Prior art keywords
- gatifloxacin
- liquid preparation
- aqueous liquid
- acid
- concentration
- 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.)
- Expired - Fee Related
Links
- 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 title claims abstract description 57
- 229960003923 gatifloxacin Drugs 0.000 title claims abstract description 57
- 238000002360 preparation method Methods 0.000 title claims abstract description 49
- 239000007788 liquid Substances 0.000 title claims abstract description 37
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 150000005846 sugar alcohols Polymers 0.000 claims abstract description 16
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (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-carboxylic acid Chemical compound 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 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims abstract description 13
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 13
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 13
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol group Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 41
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 14
- 229930195725 Mannitol Natural products 0.000 claims description 5
- 239000000594 mannitol Substances 0.000 claims description 5
- 235000010355 mannitol Nutrition 0.000 claims description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
- 210000001742 aqueous humor Anatomy 0.000 abstract description 12
- 210000000795 conjunctiva Anatomy 0.000 abstract description 10
- 239000012530 fluid Substances 0.000 abstract description 2
- 230000014759 maintenance of location Effects 0.000 abstract description 2
- 230000035515 penetration Effects 0.000 abstract 1
- 239000003889 eye drop Substances 0.000 description 13
- 235000011187 glycerol Nutrition 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 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 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 230000035699 permeability Effects 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000012488 sample solution Substances 0.000 description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 235000013772 propylene glycol Nutrition 0.000 description 4
- -1 salt salt Chemical class 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- XOQQVKDBGLYPGH-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carboxylic acid Chemical class C1=CC=C2NC(=O)C(C(=O)O)=CC2=C1 XOQQVKDBGLYPGH-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229960000686 benzalkonium chloride Drugs 0.000 description 3
- 239000004327 boric acid Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 235000008504 concentrate Nutrition 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 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 description 3
- 229960002422 lomefloxacin Drugs 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- 206010010741 Conjunctivitis Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241000283977 Oryctolagus Species 0.000 description 2
- 206010033078 Otitis media Diseases 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229960001950 benzethonium chloride Drugs 0.000 description 2
- 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 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 231100000478 corneal permeability Toxicity 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- BEGBSFPALGFMJI-UHFFFAOYSA-N ethene;sodium Chemical group [Na].C=C BEGBSFPALGFMJI-UHFFFAOYSA-N 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 208000008025 hordeolum Diseases 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N methyl pentane Natural products CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 206010033072 otitis externa Diseases 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 2
- 201000009890 sinusitis Diseases 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229910052684 Cerium Inorganic materials 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 206010011841 Dacryoadenitis acquired Diseases 0.000 description 1
- 208000003870 Drug Overdose Diseases 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
- 206010015548 Euthanasia Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010027137 Meibomianitis Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 206010033296 Overdoses Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
- 206010067268 Post procedural infection Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 239000004288 Sodium dehydroacetate Substances 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 206010064996 Ulcerative keratitis Diseases 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
- 239000008351 acetate buffer Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 229960002684 aminocaproic acid Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 208000010217 blepharitis Diseases 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- ZMIGMASIKSOYAM-UHFFFAOYSA-N cerium Chemical compound [Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce] ZMIGMASIKSOYAM-UHFFFAOYSA-N 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 201000007717 corneal ulcer Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 201000004400 dacryoadenitis Diseases 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 231100000725 drug overdose Toxicity 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 238000000892 gravimetry Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 206010023332 keratitis Diseases 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 210000004086 maxillary sinus Anatomy 0.000 description 1
- 239000012528 membrane Substances 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
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 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
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229930185107 quinolinone Natural products 0.000 description 1
- 238000001073 sample cooling Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019259 sodium dehydroacetate Nutrition 0.000 description 1
- 229940079839 sodium dehydroacetate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- DSOWAKKSGYUMTF-GZOLSCHFSA-M sodium;(1e)-1-(6-methyl-2,4-dioxopyran-3-ylidene)ethanolate Chemical compound [Na+].C\C([O-])=C1/C(=O)OC(C)=CC1=O DSOWAKKSGYUMTF-GZOLSCHFSA-M 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002351 wastewater Substances 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
Images
Classifications
-
- 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Ophthalmology & Optometry (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种含水液体制剂，所述制剂包括(A)加替沙星、加替沙星的药学上可接受的盐或加替沙星的水合物，(B)透明质酸或透明质酸的药学上可接受的盐，以及(C)多元醇。该含水液体制剂是一种加替沙星在泪液中的保留性以及加替沙星在房水和结膜中的渗透性优异的眼用含水液体制剂。
Description
技术领域
本发明涉及含有加替沙星(化学名称：(±)-1-环丙基-6-氟-1，4-二氢-8-甲氧基-7-(3-甲基-1-哌嗪基)-4-氧代-3-喹啉甲酸)的含水液体制剂。更具体地说，本发明涉及具有改进的加替沙星眼内渗透性的眼用含水液体制剂。
背景技术
加替沙星是一种喹诺酮羧酸衍生物，并且是一种新型喹诺酮合成抗菌剂。它不仅对革兰氏阴性细菌而且对革兰氏阳性细菌、厌氧菌和支原体显示了强力的抗菌效力，并且有人提出了应用于眼部区域的传染病如结膜炎、泪腺炎和麦粒肿以及耳部区域的传染病如外耳炎、中耳炎和鼻窦炎(参见专利文献1)。在含抗菌剂的滴眼剂的情况下，扩大药物的角膜渗透性以及增加渗透到房水中的量成为制剂设计的一个指标。
然而，通常，施用于眼睛的药物由于被泪液稀释和角膜的阻隔功能而几乎不渗透到眼内。为此，有必要改进药物的眼内渗透性，以及设计制剂以提高药物的效应。
含有喹诺酮羧酸抗菌剂的眼用液体制剂是普遍已知的，例如专利文献2公开了对全日光(full daylight)稳定的滴眼液，它在pH 6.0到7.0的含喹诺酮羧酸合成抗菌物质的等渗溶液中含有透明质酸或其盐。专利文献3涉及喹诺酮羧酸的水性组合物，并且描述了含有洛美沙星的水性组合物，它通过将多元醇或硼酸加入到洛美沙星中使之等渗并且进一步调节至pH3-6.5来获得。作为多元醇，可以例举甘油。该含水组合物包括滴眼剂，还描述了在使用甘油代替氯化钠时的洛美沙星的溶解度数据。专利文献4涉及含有加替沙星和乙二胺四乙酸钠的眼用含水液体制剂，并且公开了提高加替沙星的角膜渗透性的方法，防止加替沙星的晶体沉积的方法，以及防止加替沙星着色的方法。另外，作为任选的添加剂，例举了透明质酸钠和甘油。
专利文献1：JP 8-9597 B
专利文献2：JP 2002-37746 A
专利文献3：JP 63-174930 A
专利文献4：WO 00/10570 A
发明内容
本发明所要解决的问题
本发明的目的是提供加替沙星的眼内渗透性(即，在泪液(tear fluid)中的保留性以及在房水和结膜中的渗透性)优异的含水液体制剂。
解决问题的方式
为了达到该目的，本发明人已经进行了深入研究，结果发现，通过将透明质酸和多元醇配制到含加替沙星的含水液体制剂中，可以改进加替沙星的眼内渗透性，从而完成了本发明。
也就是说，本发明提供：
(1)含水液体制剂，包括(A)加替沙星，其药学上可接受的盐盐或水合物，(B)透明质酸或其药学上可接受的盐，以及(C)多元醇；
(2)根据以上项(1)所述的含水液体制剂，其中加替沙星的浓度为0.1到1.0w/v％；
(3)根据以上项(1)所述的含水液体制剂，其中加替沙星的浓度为0.2到0.8w/v％；
(4)根据以上项(1)所述的含水液体制剂，其中透明质酸的浓度为0.01到1.0w/v％；
(5)根据以上项(1)所述的含水液体制剂，其中透明质酸的浓度为0.02到0.8w/v％；
(6)根据以上项(1)所述的含水液体制剂，其中透明质酸的浓度为0.05到0.5w/v％；
(7)根据以上项(1)所述的含水液体制剂，其中该多元醇的浓度为0.1到10w/v％；
(8)根据以上项(1)所述的含水液体制剂，其中该多元醇的浓度为1.0到5.0w/v％；
(9)根据以上项(1)所述的含水液体制剂，其中该多元醇是至少一种选自甘油、丙二醇和甘露醇中的化合物；
(10)根据以上项(1)所述的含水液体制剂，它是眼用的；
(11)根据以上项(1)所述的含水液体制剂，它是滴眼剂；
(12)一种改善加替沙星的眼内渗透性的方法，所述方法包括将透明质酸或其药学上可接受的盐和多元醇引入到加替沙星、加替沙星的药学上可接受的盐或加替沙星的水合物中；
(13)透明质酸或透明质酸的药学上可接受的盐和多元醇在制备含有加替沙星、其药学上可接受的盐或水合物的具有加替沙星眼内渗透性的眼用含水液体制剂中的用途；等等。
本发明的效果
根据本发明，加替沙星的眼内渗透性通过将透明质酸或透明质酸的药学上可接受的盐和多元醇加入到含有加替沙星、加替沙星的药学上可接受的盐或加替沙星的水合物的含水液体制剂中来改善。
附图说明
图1所示为试验例1中的泪液中的加替沙星浓度的测量结果图。
图2所示为试验例2中的房水中的加替沙星浓度的测量结果图。
图3所示为试验例2中的结膜中的加替沙星浓度的测量结果图。
具体实施方式
在本说明书中，眼内渗透性的改进表示药物渗透到泪液、房水或结膜中的量的改进。
本发明使用加替沙星，它的药学上可接受的盐或它的水合物作为活性成分。加替沙星药学上可接受的盐的实例包括它与无机酸如盐酸、硫酸和磷酸的盐，它与有机酸比如甲磺酸、乳酸、草酸和乙酸的盐，以及钠、钾、镁、钙、铝、铈、铬、钴、铜、铁、锌、铂、银等的盐。水合物的实例包括2/5、1/2、3/2和5水合物。引入到本发明的含水液体制剂中的加替沙星、它的药学上可接受的盐或它的水合物的量根据所遭受的感染的程度而改变，但通常是0.1到1.0w/v％，优选0.2到0.8w/v％，按基于含水液体制剂总量的游离加替沙星计。
在本发明中，透明质酸的药学上可接受的盐的例子包括钠盐、钾盐、钙盐、镁盐和碱性氨基酸盐。
用于本发明的透明质酸的平均分子量通常是300000到8000000，优选500000到3000000。
透明质酸或它的药学上可接受的盐的量通常是0.01到1.0w/v％，优选0.02到0.8w/v％，并且进一步优选0.05到0.5w/v％，按基于含水液体制剂总量的透明质酸计。
该多元醇的实例包括甘油、丙二醇、甘露醇、聚乙二醇、木糖醇和聚乙烯醇，优选甘油、丙二醇和甘露醇，可以使用它们的一种或多种。特别优选的是甘油。
所引入的多元醇的量通常是0.1到10w/v％，优选1.0到5.0w/v％，以含水液体制剂的总量为基准计。
本发明的含水液体制剂可以口服或肠道外给药。剂型的实例包括口服剂型如糖浆剂，以及肠道外剂型如溶液状可注射的制剂，外用制剂如滴眼剂等，该含水液体制剂优选以眼睛局部给药的形式，尤其优选滴眼剂的形式使用。
本发明的含水液体制剂的pH通常是5到8，优选5.5到7.5，进一步优选5.8到7.2，并且特别优选6到7。
如果需要，该含水液体制剂可以适当地进一步含有等渗性剂(isotonicities)(例如氯化钠，氯化钾，硼酸，葡萄糖等)，缓冲剂(例如磷酸盐缓冲液，乙酸盐缓冲剂，硼酸盐缓冲剂，柠檬酸盐缓冲剂，谷氨酸，ε-氨基己酸等)，防腐剂(苯扎氯铵(benzalkonium chloride)，苄索氯铵(benzethonium chloride)，双氯苯双胍已烷葡糖酸盐，氯丁醇，苄醇，脱氢醋酸钠，对羟基苯甲酸酯(paraoxybenzoic acid esters)等)，增稠剂(甲基纤维素，羟基乙基纤维素，羟丙基甲基纤维素，羧甲基纤维素，羧乙烯聚合物，聚乙烯醇，聚乙烯吡咯烷酮，聚乙二醇，等等)，pH调节剂(盐酸，氢氧化钠，乙酸，磷酸等)，稳定剂(乙二胺四乙酸钠，柠檬酸等)以及其它等等。
本发明的含水液体制剂可以通过本身已知的方法来制备，并且例如可以通过在日本药典(Japanese Pharmacopoeia)第15次再版的“制剂一般规则、滴眼剂或液体制剂”中所述的方法来制备。
本发明的含水液体制剂如滴眼剂具有抗菌活性，并且可以在每一只眼睛中施用一滴，每天1-3次，用于预防或治疗睑炎，麦粒肿，泪囊炎(dacryocytitis)，结膜炎，睑板腺炎，角膜炎，角膜溃疡，术后感染性疾病等。对于外耳炎和中耳炎，该制剂通常可以每只耳朵施用6到10滴，每天1-2次。另外，对于鼻窦炎，通常，该制剂可以每隔一天喷雾 吸入2-4ml，每周三次，或者该制剂可以按1ml/周的量注入到上颌窦。在这方面，施用的次数可以根据特定症状的程度来适当增加或减少。
实施例
以下实施例和试验例进一步详细说明本发明，然而本发明不限于这些实施例。
实施例1和对比例1-3
试验例1
透明质酸和甘油对加替沙星在泪液中的浓度的效应
1.实验材料
根据表1中所示的配方，通过常规方法制备含加替沙星的滴眼剂。
表1
| 成分 | 实施例1 | 对比例1 | 对比例2 | 对比例3 |
| 加替沙星3/2水合物 | 0.32g | 0.32g | 0.32g | 0.32g |
| 透明质酸钠 | 0.125g | - | 0.125g | - |
| 氯化钠 | - | 0.9g | 0.9g | - |
| 浓缩甘油 | 2.5g | - | - | 2.5g |
| 盐酸/氢氧化钠 | 足量 | 足量 | 足量 | 足量 |
| 蒸馏水 | 足量 | 足量 | 足量 | 足量 |
| 总量 | 100mL | 100mL | 100mL | 100mL |
| pH | 7.0 | 7.0 | 7.0 | 7.0 |
使用由Seikagaku Corporation制造的平均分子量为120万的透明质酸钠。
2.实验方法
将表1的各50μL的加替沙星滴眼剂施加于体重约2kg的雄性日本白色家兔的眼睛。在施用于眼睛5、15、30和60分钟之后，使用毛细管收集泪液(2μL)。测定所收集的泪液的重量，用300μL的稀释剂稀释(1％磷酸水溶液和乙腈的混合溶液(4∶1))，其用作样品溶液。通过HPLC方法测定20μL样品溶液的加替沙星浓度。
HPLC条件
检测器：紫外分光光度计(测量波长：280nm)
柱：Inertsil ODS-II(由GL Sciences Inc.制造)
柱温度：40℃
流动相：将磷酸加入到乙腈、水和三乙胺的混合溶液中(18∶81∶1)，以便将pH调节至4.5。
注射量：20μL
流速：0.8mL/min
3.结果
结果在表2和图1中示出。
表2
泪液中的加替沙星浓度
| 时间 | 实施例1 (n＝6) | 对比例1 (n＝6) | 对比例2 (n＝6) | 对比例3 (n＝6) |
| 在5min后 | 516.41±270.27 | 81.15±83.30 | 237.09±353.43 | 180±177 |
| 在15min后 | 264.39±348.38 | 20.30±14.70 | 62.63±49.63 | 32±45 |
| 在30min后 | 147.50±207.66 | 8.99±8.96 | 42.13±75.00 | 23±37 |
| 在60min后 | 5.62±4.04 | 8.66±5.71 | 53.87±96.61 | 4±6 |
每一个值表示平均值±标准偏差(μg/mL)。
从这些结果可以发现，在含有透明质酸钠和甘油的本发明的实施例1中，与含有透明质酸钠的对比例2和含有甘油的对比例3相比，加替沙星在泪液中的渗透性得到协同地改进。
实施例2和对比例4
试验例2
透明质酸对加替沙星在房水和结膜中的浓度的效应
1.试验方法
根据表3的配方，制备加替沙星滴眼剂，将各50μL的滴眼剂施用于体重约2.5kg的雄性日本白色家兔的眼睛。在施用于眼睛后1小时，给药过量的5％戊巴比妥钠，使动物安乐死。在用生理盐水洗涤眼睛前 部(anterior eye)之后，采集房水和结膜。用具有27G注射针头的注射器采集房水以及用剪刀直接切取结膜。用0.22μm过滤膜过滤房水，该房水用作样品溶液。在测定重量之后，通过添加5mL乙腈，随后振荡(200rpm×20min)和离心(2000rpm×10min)将结膜切细。取4ml的该上清液，在减压下蒸发至干燥，然后溶于0.5mL的HPLC用流动相中，用过滤器(0.22μm)过滤，这用作样品溶液。通过HPLC方法测定50μL的各样品溶液的加替沙星的浓度。
表3
| 成分 | 实施例2 | 对比例4 |
| 加替沙星3/2水合物 | 0.32g | 0.32g |
| 透明质酸钠 | 0.2g | - |
| 浓缩甘油 | 2.5g | - |
| 氯化钠 | - | 0.86g |
| 盐酸 | 足量 | 足量 |
| 净化水 | 足量 | 足量 |
| 总量 | 100mL | 100ml |
| pH | 6.0 | 6.0 |
使用由Seikagaku Corporation制造的平均分子量为120万的透明质酸钠。
HPLC条件
HPLC分析条件
检测器：紫外可见光分光光度计(测量波长：280nm)
柱：Inertsil ODS-3 4.6mmφ×150mm，5μm(GL Sciences Inc.)
保护柱：Inertsil ODS-3 4.6mmφ×5mm(GL Sciences Inc.)
柱温：40℃
移动相：将磷酸加入到乙腈，蒸馏水和三乙胺(18∶81∶1)的混合溶液中，以调节pH至4.5。
流速：0.8mL/min
注射量：50μL
样品冷却器的调定温度：4℃
3.结果
结果在表4、图2和图3中示出。
表4
在施用于眼睛之后1小时加替沙星在房水和结膜中的浓度
| 加替沙星在房水中的 浓度(μg/mL) | 加替沙星在结膜中的 浓度(μg/g) | |
| 实施例2(n＝3) | 1.545±0.659 | 4.570±5.166 |
| 对比例4(n＝3) | 0.574±0.049 | 0.538±0.156 |
各值表示平均值±标准偏差。
实施例3-8
根据表5的配方，通过常规方法制备含加替沙星的滴眼剂。
表5
| 配方(g/100mL) | 实施例 3 | 实施例 4 | 实施例 5 | 实施例 6 | 实施例 7 | 实施例 8 |
| 加替沙星3/2水合物 | 0.2 | 0.3 | 0.3 | 0.5 | 0.5 | 0.8 |
| 透明质酸钠 | 0.1 | 0.1 | 0.2 | 0.2 | 0.3 | 0.2 |
| 浓缩甘油 | - | 2.5 | - | - | 2.5 | - |
| 丙二醇 | - | - | 2.0 | - | - | - |
| 甘露醇 | 2.5 | - | - | 5.0 | - | 5.0 |
| 乙二胺四乙酸二钠 | - | 0.02 | - | - | 0.02 | - |
| 磷酸二氢钠 | - | - | 0.1 | - | - | - |
| 苯扎氯铵 | - | 0.005 | - | - | - | 0.005 |
| 对羟基苯甲酸甲酯 | - | - | - | 0.026 | - | - |
| 对羟基苯甲酸丙酯 | - | - | - | 0.014 | - | - |
| 硼酸 | 0.8 | - | - | - | - | - |
| 盐酸/氢氧化钠 | 足量 | 足量 | 足量 | 足量 | 足量 | 足量 |
| 灭菌蒸馏水 | 足量 | 足量 | 足量 | 足量 | 足量 | 足量 |
| 总量 | 100mL | 100ml | 100mL | 100ml | 100mL | 100ml |
| pH | 7.0 | 6.5 | 6.0 | 6.0 | 6.0 | 6.0 |
使用由Seikagaku Corporation制造的平均分子量为120万的透明质酸钠。
工业实用性
如上所述，根据本发明，通过掺入透明质酸和多元醇可以提供具有改进的加替沙星的眼内渗透性的含加替沙星的眼用含水液体制剂。
Claims (5)
1.透明质酸或透明质酸的药学上可接受的盐和选自甘油、丙二醇和甘露醇的至少一种多元醇在制备含有加替沙星、其药学上可接受的盐或水合物的具有改善的加替沙星眼内渗透性的眼用含水液体制剂中的用途。
2.根据权利要求1所述的用途，其中所述加替沙星的浓度为0.1到1.0w/v％。
3.根据权利要求1所述的用途，其中所述透明质酸的浓度为0.01到1.0w/v％。
4.根据权利要求1所述的用途，其中所述透明质酸的浓度为0.05到0.5w/v％。
5.根据权利要求1所述的用途，其中所述多元醇的浓度为0.1到10w/v％。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP279009/2006 | 2006-10-12 | ||
| JP2006279009 | 2006-10-12 | ||
| PCT/JP2007/069847 WO2008044734A1 (fr) | 2006-10-12 | 2007-10-11 | Préparation liquide aqueuse comprenant de la gatifloxacine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101573118A CN101573118A (zh) | 2009-11-04 |
| CN101573118B true CN101573118B (zh) | 2011-09-07 |
Family
ID=39282924
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2007800376785A Expired - Fee Related CN101573118B (zh) | 2006-10-12 | 2007-10-11 | 包含加替沙星的含水液体制剂 |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US20100041623A1 (zh) |
| EP (1) | EP2078527A4 (zh) |
| JP (1) | JPWO2008044734A1 (zh) |
| KR (1) | KR20090064572A (zh) |
| CN (1) | CN101573118B (zh) |
| BR (1) | BRPI0719514A2 (zh) |
| CA (1) | CA2666058A1 (zh) |
| MX (1) | MX2009003878A (zh) |
| WO (1) | WO2008044734A1 (zh) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5535900B2 (ja) * | 2008-03-31 | 2014-07-02 | 杏林製薬株式会社 | ガチフロキサシン含有水性液剤、その製造方法、および、該水性液剤の低温保存および凍結融解時の沈殿生成を抑制する方法 |
| TWI544934B (zh) | 2008-06-09 | 2016-08-11 | 愛爾康研究有限公司 | 含有氟喹諾酮抗生素藥物之經改良藥學組成物 |
| TW201038295A (en) | 2009-04-17 | 2010-11-01 | Alcon Res Ltd | Aqueous ophthalmic compositions containing anionic therapeutic agents |
| UA92423C2 (ru) * | 2009-07-24 | 2010-10-25 | Анатолій Альбертович Кузьмін | Антибактериальная композиция |
| CN102078284B (zh) * | 2009-11-27 | 2013-06-12 | 沈阳兴齐眼药股份有限公司 | 一种含加替沙星的眼用凝胶剂及其制备方法 |
| IL212725A (en) | 2011-05-05 | 2016-06-30 | Resdevco Res And Dev Co | Glycerol Preparation for Non-surgical Conjunctivochalysis |
| SG10201605080VA (en) * | 2011-06-23 | 2016-08-30 | Santen Pharmaceutical Co Ltd | Ophthalmic solution containing hyaluronic acid or salt thereof and propylene glycol |
| GR1008168B (el) * | 2013-03-14 | 2014-04-08 | "Φαρματεν Α.Β.Ε.Ε.", | Παρεντερικο σκευασμα αντιβακτηριακου παραγοντα φθοριοκινολονης και μεθοδος για την παρασκευη αυτου |
| US20170014339A1 (en) * | 2015-07-17 | 2017-01-19 | i.com medical GmbH | Tear Substitute, Fluid for Being Used as a Tear Substitute, and Method for Producing a Tear Substitute |
| CN105168119A (zh) * | 2015-10-28 | 2015-12-23 | 周胜光 | 一种治疗鼻炎的复方滴鼻用凝胶制剂 |
| CN112569211A (zh) * | 2019-09-27 | 2021-03-30 | 盈科瑞（天津）创新医药研究有限公司 | 一种吸入用加替沙星溶液及其制备方法 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1488404A (zh) * | 2003-06-19 | 2004-04-14 | 刘继东 | 眼用制剂中玻璃酸钠的复合应用 |
| CN1839840A (zh) * | 2006-01-12 | 2006-10-04 | 张宏业 | 一种新的加替沙星滴眼液及其制备方法 |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH089597B2 (ja) | 1986-01-21 | 1996-01-31 | 杏林製薬株式会社 | 選択毒性に優れた８‐アルコキシキノロンカルボン酸およびその塩並びにその製造方法 |
| JPH0696533B2 (ja) | 1987-01-14 | 1994-11-30 | 北陸製薬株式会社 | キノロンカルボン酸の水性組成物 |
| EP1025846B1 (en) | 1998-08-21 | 2006-07-12 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid preparations |
| JP2002037746A (ja) | 2000-07-24 | 2002-02-06 | Fuji Yakuhin:Kk | キノロンカルボン酸系抗菌剤を含有する液剤 |
| US20050222769A1 (en) * | 2003-06-26 | 2005-10-06 | Jefferey Simon | Modular sensor system |
| WO2005000307A1 (en) * | 2003-06-26 | 2005-01-06 | Santen Pharmaceutical Co., Ltd. | Ophthalmic composition containing quinolones and method of use |
| US20050009836A1 (en) * | 2003-06-26 | 2005-01-13 | Laskar Paul A. | Ophthalmic composition containing quinolones and method of use |
| CN100427091C (zh) * | 2004-04-20 | 2008-10-22 | 沈阳药科大学 | 以hpmc为基质的加替沙星眼用凝胶剂及其制备方法 |
-
2007
- 2007-10-11 EP EP07829585A patent/EP2078527A4/en not_active Withdrawn
- 2007-10-11 BR BRPI0719514-1A2A patent/BRPI0719514A2/pt not_active IP Right Cessation
- 2007-10-11 US US12/311,728 patent/US20100041623A1/en not_active Abandoned
- 2007-10-11 CN CN2007800376785A patent/CN101573118B/zh not_active Expired - Fee Related
- 2007-10-11 JP JP2008538754A patent/JPWO2008044734A1/ja not_active Withdrawn
- 2007-10-11 MX MX2009003878A patent/MX2009003878A/es not_active Application Discontinuation
- 2007-10-11 KR KR1020097007402A patent/KR20090064572A/ko not_active Application Discontinuation
- 2007-10-11 CA CA002666058A patent/CA2666058A1/en not_active Abandoned
- 2007-10-11 WO PCT/JP2007/069847 patent/WO2008044734A1/ja active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1488404A (zh) * | 2003-06-19 | 2004-04-14 | 刘继东 | 眼用制剂中玻璃酸钠的复合应用 |
| CN1839840A (zh) * | 2006-01-12 | 2006-10-04 | 张宏业 | 一种新的加替沙星滴眼液及其制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2666058A1 (en) | 2008-04-17 |
| EP2078527A4 (en) | 2011-12-21 |
| JPWO2008044734A1 (ja) | 2010-02-18 |
| KR20090064572A (ko) | 2009-06-19 |
| EP2078527A1 (en) | 2009-07-15 |
| MX2009003878A (es) | 2009-09-15 |
| WO2008044734A1 (fr) | 2008-04-17 |
| CN101573118A (zh) | 2009-11-04 |
| BRPI0719514A2 (pt) | 2014-10-07 |
| US20100041623A1 (en) | 2010-02-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101573118B (zh) | 包含加替沙星的含水液体制剂 | |
| AU761040B2 (en) | Aqueous liquid preparations | |
| EP2526923B1 (en) | Ophthalmic gel of gatifloxacin and preparation method thereof | |
| AU2017268575A1 (en) | Otic compositions useful for the treatment of infections of the internal and external ear in mammals | |
| CN101547695B (zh) | 具有改进的加替沙星眼内渗透性的含水液体制剂 | |
| US9114168B2 (en) | Pharmaceutical compositions containing a fluoroquinolone antibiotic drug | |
| JP2010037327A (ja) | ブリンゾラミド水性組成物 | |
| WO2016072440A1 (ja) | 眼科用水性組成物 | |
| CN101669901A (zh) | 用于眼部给药的液体制剂及其制备方法 | |
| CN102046173B (zh) | 含加替沙星的水性液体、其制备和防止形成沉淀的方法 | |
| JPWO2002040028A1 (ja) | 抗菌ゲル化点眼剤 | |
| CN102083434A (zh) | 含加替沙星的水性液体 | |
| CA2900671A1 (en) | Alpha-2 adrenergic agonist for treating intraocular pressure and ocular diseases through intravitreal and intracameral routes | |
| CA2853233A1 (en) | Ophthalmological aqueous composition | |
| MXPA00003859A (en) | Aqueous liquid preparations |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110907 Termination date: 20181011 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |