CN101039668A - 包含抗菌素、三唑和皮质类固醇的药物制剂 - Google Patents
包含抗菌素、三唑和皮质类固醇的药物制剂 Download PDFInfo
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- CN101039668A CN101039668A CNA2005800351223A CN200580035122A CN101039668A CN 101039668 A CN101039668 A CN 101039668A CN A2005800351223 A CNA2005800351223 A CN A2005800351223A CN 200580035122 A CN200580035122 A CN 200580035122A CN 101039668 A CN101039668 A CN 101039668A
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- sodium
- pharmaceutically acceptable
- antibiotics
- acid
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- 239000003246 corticosteroid Substances 0.000 title claims abstract description 11
- 239000003242 anti bacterial agent Substances 0.000 title claims description 23
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 11
- 150000003852 triazoles Chemical class 0.000 title abstract description 6
- 230000003115 biocidal effect Effects 0.000 title description 3
- 239000000203 mixture Substances 0.000 claims abstract description 44
- 230000000843 anti-fungal effect Effects 0.000 claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 241001465754 Metazoa Species 0.000 claims abstract description 14
- 208000015181 infectious disease Diseases 0.000 claims abstract description 7
- -1 triazole compounds Chemical class 0.000 claims description 79
- 229940088710 antibiotic agent Drugs 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 22
- 229940121375 antifungal agent Drugs 0.000 claims description 19
- QIPQASLPWJVQMH-DTORHVGOSA-N Orbifloxacin Chemical compound C1[C@@H](C)N[C@@H](C)CN1C1=C(F)C(F)=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1F QIPQASLPWJVQMH-DTORHVGOSA-N 0.000 claims description 16
- 229960004780 orbifloxacin Drugs 0.000 claims description 16
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 14
- 229930195733 hydrocarbon Natural products 0.000 claims description 11
- 239000002689 soil Substances 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 claims description 6
- 229910052805 deuterium Inorganic materials 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 229940056360 penicillin g Drugs 0.000 claims description 6
- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 claims description 6
- 229960001589 posaconazole Drugs 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 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 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Substances [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 5
- 229960000223 tilmicosin Drugs 0.000 claims description 5
- JTSDBFGMPLKDCD-XVFHVFLVSA-N tilmicosin Chemical compound O([C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CCN1C[C@H](C)C[C@H](C)C1)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@@H]1O[C@H](C)[C@@H](O)[C@H](N(C)C)[C@H]1O JTSDBFGMPLKDCD-XVFHVFLVSA-N 0.000 claims description 5
- GNWUOVJNSFPWDD-XMZRARIVSA-M Cefoxitin sodium Chemical compound [Na+].N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)CC1=CC=CS1 GNWUOVJNSFPWDD-XMZRARIVSA-M 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 claims description 4
- 229960002537 betamethasone Drugs 0.000 claims description 4
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 claims description 4
- NBFNMSULHIODTC-CYJZLJNKSA-N cefadroxil monohydrate Chemical compound O.C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=C(O)C=C1 NBFNMSULHIODTC-CYJZLJNKSA-N 0.000 claims description 4
- FLKYBGKDCCEQQM-WYUVZMMLSA-M cefazolin sodium Chemical compound [Na+].S1C(C)=NN=C1SCC1=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 FLKYBGKDCCEQQM-WYUVZMMLSA-M 0.000 claims description 4
- 229960003408 cefazolin sodium Drugs 0.000 claims description 4
- ZINFAXPQMLDEEJ-GFVOIPPFSA-N cefoselis Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CN1C=CC(=N)N1CCO ZINFAXPQMLDEEJ-GFVOIPPFSA-N 0.000 claims description 4
- 229950001580 cefoselis Drugs 0.000 claims description 4
- 229960004261 cefotaxime Drugs 0.000 claims description 4
- VUFGUVLLDPOSBC-XRZFDKQNSA-M cephalothin sodium Chemical compound [Na+].N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C([O-])=O)C(=O)CC1=CC=CS1 VUFGUVLLDPOSBC-XRZFDKQNSA-M 0.000 claims description 4
- VGEOUKPOQQEQSX-OALZAMAHSA-M cephapirin sodium Chemical compound [Na+].N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C([O-])=O)C(=O)CSC1=CC=NC=C1 VGEOUKPOQQEQSX-OALZAMAHSA-M 0.000 claims description 4
- 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 4
- 229960003276 erythromycin Drugs 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 235000019371 penicillin G benzathine Nutrition 0.000 claims description 4
- 229940081561 rocephin Drugs 0.000 claims description 4
- 108090000204 Dipeptidase 1 Proteins 0.000 claims description 3
- 102000006635 beta-lactamase Human genes 0.000 claims description 3
- OLVCFLKTBJRLHI-AXAPSJFSSA-N cefamandole Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](O)C=3C=CC=CC=3)[C@H]2SC1 OLVCFLKTBJRLHI-AXAPSJFSSA-N 0.000 claims description 3
- 229960003012 cefamandole Drugs 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 239000000837 restrainer Substances 0.000 claims description 3
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 3
- AYIRNRDRBQJXIF-NXEZZACHSA-N (-)-Florfenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)C=C1 AYIRNRDRBQJXIF-NXEZZACHSA-N 0.000 claims description 2
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 claims description 2
- JETQIUPBHQNHNZ-NJBDSQKTSA-N (2s,5r,6r)-3,3-dimethyl-7-oxo-6-[[(2r)-2-phenyl-2-sulfoacetyl]amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound C1([C@H](C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)S(O)(=O)=O)=CC=CC=C1 JETQIUPBHQNHNZ-NJBDSQKTSA-N 0.000 claims description 2
- ALYUMNAHLSSTOU-CIRGZYLNSA-N (6r,7r)-7-[[(2r)-2-amino-2-(4-hydroxyphenyl)acetyl]amino]-8-oxo-3-[(e)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;hydrate Chemical compound O.C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)/C=C/C)C(O)=O)=CC=C(O)C=C1 ALYUMNAHLSSTOU-CIRGZYLNSA-N 0.000 claims description 2
- WKJGTOYAEQDNIA-IOOZKYRYSA-N (6r,7r)-7-[[(2r)-2-amino-2-phenylacetyl]amino]-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;hydrate Chemical compound O.C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 WKJGTOYAEQDNIA-IOOZKYRYSA-N 0.000 claims description 2
- MMRINLZOZVAPDZ-LSGRDSQZSA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(1-methylpyrrolidin-1-ium-1-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;chloride Chemical compound Cl.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 MMRINLZOZVAPDZ-LSGRDSQZSA-N 0.000 claims description 2
- GPYKKBAAPVOCIW-HSASPSRMSA-N (6r,7s)-7-[[(2r)-2-amino-2-phenylacetyl]amino]-3-chloro-8-oxo-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;hydrate Chemical compound O.C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CC[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 GPYKKBAAPVOCIW-HSASPSRMSA-N 0.000 claims description 2
- MCKJPJYRCPANCC-XLXYOEISSA-N (8s,9s,10r,11s,13s,14s,17r)-11,17-dihydroxy-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthrene-17-carboxylic acid Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(O)=O)[C@@H]4[C@@H]3CCC2=C1 MCKJPJYRCPANCC-XLXYOEISSA-N 0.000 claims description 2
- 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 2
- AFNXATANNDIXLG-SFHVURJKSA-N 1-[(2r)-2-[(4-chlorophenyl)methylsulfanyl]-2-(2,4-dichlorophenyl)ethyl]imidazole Chemical compound C1=CC(Cl)=CC=C1CS[C@H](C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 AFNXATANNDIXLG-SFHVURJKSA-N 0.000 claims description 2
- NNGQLSIGRSTLLU-UHFFFAOYSA-N 1-[2-(2,4-dichlorophenyl)-2-[(2,6-dichlorophenyl)methoxy]ethyl]imidazole;nitric acid Chemical compound O[N+]([O-])=O.ClC1=CC(Cl)=CC=C1C(OCC=1C(=CC=CC=1Cl)Cl)CN1C=NC=C1 NNGQLSIGRSTLLU-UHFFFAOYSA-N 0.000 claims description 2
- QXHHHPZILQDDPS-UHFFFAOYSA-N 1-{2-[(2-chloro-3-thienyl)methoxy]-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound S1C=CC(COC(CN2C=NC=C2)C=2C(=CC(Cl)=CC=2)Cl)=C1Cl QXHHHPZILQDDPS-UHFFFAOYSA-N 0.000 claims description 2
- KGWHMDCQVDMTNZ-UHFFFAOYSA-N 2-(butylcarbamoylamino)acetic acid Chemical compound CCCCNC(=O)NCC(O)=O KGWHMDCQVDMTNZ-UHFFFAOYSA-N 0.000 claims description 2
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 claims description 2
- YDCXJAACEIUSDW-UHFFFAOYSA-N 2-chloro-n-(2,2,2-trichloro-1-hydroxyethyl)acetamide Chemical compound ClC(Cl)(Cl)C(O)NC(=O)CCl YDCXJAACEIUSDW-UHFFFAOYSA-N 0.000 claims description 2
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 claims description 2
- UBGCCYGMLOBJOJ-UHFFFAOYSA-N 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-1-ethyl-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCN2CCC1CC2 UBGCCYGMLOBJOJ-UHFFFAOYSA-N 0.000 claims description 2
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 claims description 2
- BHELIUBJHYAEDK-OAIUPTLZSA-N Aspoxicillin Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3[C@H](C(C)(C)S[C@@H]32)C(O)=O)=O)NC(=O)[C@H](N)CC(=O)NC)=CC=C(O)C=C1 BHELIUBJHYAEDK-OAIUPTLZSA-N 0.000 claims description 2
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 claims description 2
- WNJOIIXGSLBJAS-FDVIUCIPSA-M Cefbuperazone sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H]([C@H](C)O)C(=O)N[C@]1(OC)C(=O)N2C(C([O-])=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 WNJOIIXGSLBJAS-FDVIUCIPSA-M 0.000 claims description 2
- NCFTXMQPRQZFMZ-WERGMSTESA-M Cefoperazone sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C([O-])=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 NCFTXMQPRQZFMZ-WERGMSTESA-M 0.000 claims description 2
- QYQDKDWGWDOFFU-IUODEOHRSA-N Cefotiam Chemical compound CN(C)CCN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CC=3N=C(N)SC=3)[C@H]2SC1 QYQDKDWGWDOFFU-IUODEOHRSA-N 0.000 claims description 2
- REACMANCWHKJSM-DWBVFMGKSA-M Cefsulodin sodium Chemical compound [Na+].C1=CC(C(=O)N)=CC=[N+]1CC1=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)[C@@H](C=3C=CC=CC=3)S([O-])(=O)=O)[C@H]2SC1 REACMANCWHKJSM-DWBVFMGKSA-M 0.000 claims description 2
- 229930186147 Cephalosporin Natural products 0.000 claims description 2
- LUKZNWIVRBCLON-GXOBDPJESA-N Ciclesonide Chemical compound C1([C@H]2O[C@@]3([C@H](O2)C[C@@H]2[C@@]3(C[C@H](O)[C@@H]3[C@@]4(C)C=CC(=O)C=C4CC[C@H]32)C)C(=O)COC(=O)C(C)C)CCCCC1 LUKZNWIVRBCLON-GXOBDPJESA-N 0.000 claims description 2
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 claims description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 2
- UIOFUWFRIANQPC-JKIFEVAISA-N Floxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl UIOFUWFRIANQPC-JKIFEVAISA-N 0.000 claims description 2
- WJOHZNCJWYWUJD-IUGZLZTKSA-N Fluocinonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)COC(=O)C)[C@@]2(C)C[C@@H]1O WJOHZNCJWYWUJD-IUGZLZTKSA-N 0.000 claims description 2
- BPFYOAJNDMUVBL-UHFFFAOYSA-N LSM-5799 Chemical compound C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3N(C)COC1=C32 BPFYOAJNDMUVBL-UHFFFAOYSA-N 0.000 claims description 2
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 claims description 2
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 claims description 2
- RRJHESVQVSRQEX-SUYBPPKGSA-N O-formylcefamandole Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](OC=O)C=3C=CC=CC=3)[C@H]2SC1 RRJHESVQVSRQEX-SUYBPPKGSA-N 0.000 claims description 2
- 229930182555 Penicillin Natural products 0.000 claims description 2
- 239000004107 Penicillin G sodium Substances 0.000 claims description 2
- 229930195708 Penicillin V Natural products 0.000 claims description 2
- NJCJBUHJQLFDSW-UHFFFAOYSA-N Rufloxacin Chemical compound C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3CCSC1=C32 NJCJBUHJQLFDSW-UHFFFAOYSA-N 0.000 claims description 2
- FSXPZSJEXMUNIU-UHFFFAOYSA-N [S].C=1C=CNC=1 Chemical compound [S].C=1C=CNC=1 FSXPZSJEXMUNIU-UHFFFAOYSA-N 0.000 claims description 2
- 230000001154 acute effect Effects 0.000 claims description 2
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Abstract
本发明公开了用于治疗动物耳感染的新的制剂,其包含三唑抗真菌化合物、喹诺酮抗菌素和比如莫美他松糠酸酯一水合物的皮质类固醇。
Description
背景技术
所有在此引用的参考文献的全部内容都在此引入本文作为参考。Otomax耳混悬剂含有庆大霉素硫酸盐,USP,倍他米松戊酸盐,USP,和克霉唑,USP。Mometamax耳混悬剂含有庆大霉素硫酸盐,USP,克霉唑,USP,和莫美他松糠酸酯一水合物。
这些产品的问题在于,由于在这些产品中通常使用的氨基糖苷类,因此它们可能存在耳毒性。据此,需要用于治疗动物感染的新组合产品,使动物不遭受这些弱点。
发明概述
据此,在此公开了用于治疗动物感染的药物组合物,其包含奥比沙星或者一种其药学上可接受的盐;抗真菌有效量的化学结构式I所表示的化合物,包含:
莫美他松糠酸酯一水合物和至少一种药学上可接受的载体,其中所述组合物为混悬剂。
在此还公开了用于治疗动物感染的药物组合物,其包含奥比沙星或者一种其药学上可接受的盐;抗真菌有效量的药学上可接受的三唑化合物;莫美他松糠酸酯一水合物和至少一种药学上可接受的载体,其中所述组合物为混悬剂。
发明详述
本发明涉及用于治疗动物感染的药物组合物,其包含奥比沙星或者一种其药学上可接受的盐;抗真菌有效量的化学结构式I所表示的化合物,包含:
莫美他松糠酸酯一水合物和药学上可接受的载体,其中所述组合物为混悬剂。
莫美他松糠酸酯一水合物是糖肾上腺皮质激素家族中的一种合成甾类激素。糖肾上腺皮质激素是有效的抗炎剂。它还表现出了止痒和血管收缩作用。它用于局部治疗皮质类固醇-响应的皮肤病,比如牛皮癣和特异性皮炎。莫美他松糠酸酯,ELOCON洗剂、乳膏剂和膏剂的活性组分,是化学名称为9,21-二氯-11(β),17-二羟基-16(α)-甲基孕-1,4-二烯-3,20-二酮17-(2-糠酸酯)的抗炎皮质类固醇。它实际上不溶于水;微溶于甲醇、乙醇和异丙醇;溶于丙酮和氯仿;和易溶于四氢呋喃。它在辛醇和水之间的分配系数大于5000。莫美他松可以以多种水合物、晶体和对映异构形式存在,比如,作为一水合物存在。该产品得自于Schering-Plough Corporation,Kenilworth,New Jersey。莫美他松糠酸酯一水合物可以以约0.01~约1%的量存在,优选约0.1%。其它用于本发明的皮质类固醇包括倍他米松、Butoxicart、罗氟奈德、布地缩松、地夫可特、环索奈德、氟替卡松、Beclomethasone、倍他米松、肤轻松、泼尼松、泼尼松龙、氯替泼诺或者曲安奈德。
此外,本发明还涉及含有抗真菌有效量的微粒化(micronized)的化学结构式I所表示的化合物的稳定制剂:
美国专利No.5,661,151公开了式I化合物以及它对抗宽范围真菌的有效抗真菌活性,所述真菌比如曲霉菌、念珠菌、隐球菌、镰刀菌和其它机会真菌。美国专利Nos.5,834,472和5,846,971公开了与粘结剂一起涂覆在惰性珠粒上的结构式I化合物的口服药物胶囊组合物。该产品得自于Schering-Plough Corporation,Kenilworth,New Jersey。泊沙康唑可以以约0.01%~约1%的量存在,优选约0.11%。
其它用于本发明的三唑抗真菌化合物包括伏立康唑、酮康唑、氟康唑、伊曲康唑、沙柏康唑、奈康唑、奥昔康唑、硝酸异康唑、硫康唑、Tercanazole、噻康唑和/或其药学上可接受的盐。
奥比沙星是一种归类为喹诺酮羧酸衍生物的有效合成广谱抗菌剂。它可以安全和有效地处理与对奥比沙星敏感的细菌有关的狗和猫疾病。可以用于本发明实践中的喹诺酮类及其衍生物包括但不限于奥比沙星、环丙沙星、丹诺沙星、依诺沙星、格里沙星、左旋氧氟沙星、洛美沙星、萘啶酮酸、诺氟沙星、氧氟沙星、司帕沙星、麻保沙星、恩诺沙星、依巴沙星、佳诺沙星、T-3811M1、T-3811M4、T3811M6、加替沙星、吉米沙星、莫西沙星、二氟沙星、芦氟沙星、宾氟沙星(Pradofloxacin)和曲氟沙星甲磺酸盐和/或其代谢产物。其它可用于本发明实践的喹诺酮类描述于以下文献中:1996年5月30日公开的WO 96/16055;1992年4月14日公布的美国专利No.5,104,868;1996年3月5日公布的美国专利No.5,496,947;1996年3月12日公布的美国专利No.5,498,615;1998年6月23日公布的美国专利No.5,770,597;1998年11月24日公布的美国专利No.5,840,333;1997年9月30日公布的美国专利No.5,672,600;1996年2月13日公布的美国专利No.5,491,139;1996年6月25日公布的美国专利No.5,530,116;和1997年7月8日公布的美国专利No.5,646,163,它们都在此引入本文作为参考。
基于本发明药物组合物的重量,可用于本发明实践的喹诺酮化合物占按重量计约0.01%~约30%。优选基于本发明药物组合物的重量,可用于本发明实践的喹诺酮化合物占按重量计约0.1%~约10%。更优选基于本发明药物组合物的重量,可用于本发明实践中的喹诺酮化合物占按重量计约0.5%~5%。
奥比沙星可以以约0.1%~约10%的量存在,优选约1%。
已经表明,抗菌素氯霉素和甲砜霉素的含氟类似物对于对氯霉素和甲砜霉素敏感和具有抗性的有机体均具有抗菌活性。参见SchaferT.W.等人,“Novel Fluorine-Containing Analogs of Chloramphenicoland Thiamphenicol:Antibacterial and Biological Properties”,于CURRENT CHEMOTHERAPY AND INFECTIOUS DISEASEPROCEEDINGS OF THE 11TH ICC AND THE 19TH ICAACAMERICAN SOCIETY OF MICROBIOLOGY 1980,444-446。上述化合物以及它们的制造方法的实施例描述和保护于美国专利No.4,235,892中。当将用于治疗人类的抗菌素给药至家畜时,医疗专业愈加地关注对于人的细菌抗药性转移。这是因为抗菌素中的氯霉素组现在很少用于治疗人类,但是它的衍生物特别适合于兽医学应用。尤其是令人感兴趣的是其3-氟、3-脱氧衍生物。
式I
其中R为选自以下的基团:甲基或者乙基或者其卤代衍生物、二卤代氘代甲基、1-卤代-1-氘代乙基、1,2-二卤代-1-氘代乙基、叠氮甲基和甲基磺酰基甲基;
X和X′各自是独立地选自以下的基团:NO2、SO2R1、SOR1、SR1、SONH2、SO2NH2、SONHR1、SO2NHR1、COR1、OR1、R1、CN、卤素、氢、苯基和被卤素、NO2、R1、OR1、PO2R1、CONHR1、NHR1、NR1R2、CONR1R2或者OCOR1取代的苯基,其中R1和R2各自是独立地选自甲基、乙基、正丙基、异丙基、丁基、叔丁基、异丁基和苯基的基团;
和Z为氢或者具有最高达16个碳原子的烃类羧酸(优选烃类二羧酸)的酰基或者具有最高达12个碳原子的氨基-烃类羧酸的酰基;和所述酰基的药学上可接受的盐。
预期式I中的部分(moiety)R的卤代基团包括单、二和三氟甲基、单、二和三氯甲基、单和二溴甲基以及碘代甲基,以及单和二氟乙基、单和二氯乙基、单和二溴乙基以及碘代乙基,其中优选卤素取代基位于羰基官能团的α碳原子上。还包括混合的二卤代烷基,其中优选两个卤素键接至羰基的α碳原子上,例如,所述基团比如为氟氯代-、氟溴代-以及氯溴代-甲基和-乙基,以及三卤代甲基,比如二氯氟代甲基和二氟氯代甲基。
式I化合物还包括其酯衍生物,例如,式I的1-烃类羧酸酯,其中Z为具有最高达16个碳原子的烃类羧酸的酰基,所述烃类羧酸可以为饱和、不饱和、直链或者支链、脂族、环状、环状-脂族、芳香、芳基-脂族或者烷基-芳香烃类羧酸并且可以被羟基、含有1~5个碳原子的烷氧基、羧基、NO2、NHR1、NR1R2、SR1、SOR1或者卤素取代,其中R1和R2如上所定义。
其它抗菌活性的式I的酯衍生物为以下化合物,其中Z为含有最高达12个碳原子的氨基酸的酰基,所述氨基酸可以为饱和、不饱和、直链、支链或者环状氨基酸,其可以含有芳香基团并且可以被羟基取代。
优选酯衍生物包括提供水溶性的由二元烃类羧酸酯(例如,1-琥珀酸酯和1-棕榈酸酯)衍生得到的衍生物、药学上可接受的阳离子盐(例如钠盐或者钾盐)以及与胺(例如三甲胺)形成的盐。还优选提供水溶性的氨基酸的酯衍生物、与无机酸或者有机酸形成的药学上可接受的酸加成盐(例如氢氯酸加成盐或者硫酸加成盐或者琥珀酸加成盐)。
由此,在此所使用的术语“药学上可接受的盐”包括其中将本发明二元烃类羧酸酯中的酸性氢替换为阳离子的盐(例如,D-(苏)-1-p-硝基苯基-2-二氯乙酰氨基-3-氟-1-丙基半琥珀酸酯钠盐)以及其中酸性氢与胺形成酸加成盐的盐(例如,D-(苏)-1-p-硝基苯基-2-二氯乙酰氨基-3-氟-1-丙基半琥珀酸酯N-三甲胺盐)。还包括由无机酸或者有机酸与式I化合物的氨基酸酯中的胺之间形成的酸加成盐(例如,D-(苏)-1-p-硝基苯基-2-二氯乙酰氨基-3-氟-1-丙基甘氨酸酯盐酸盐)。
包括在式I中的二元烃类羧酸酯的药学上可接受的阳离子盐为碱金属和碱土金属盐(例如,钠、钾、钙、铝盐)和与胺形成的盐,所述胺比如三烷基胺、普鲁卡因、二苄基胺、N-苄基-β-苯乙胺、N,N′-二苄基乙二胺、N-(低级)烷基哌啶类化合物(例如N-乙基哌啶)和N-甲基葡糖胺。
优选R为甲基或者乙基的卤代衍生物,Z为氢,X为苯基、COR1或者SO2R1,R1为甲基和X′为氢。最优选R为CHCl2或者CHF2。
优选抗菌素化合物为氟苯尼考(D-(苏)-1-p-甲磺酰基苯基-2-二氯乙酰氨基-3-氟-1-丙醇)。另外优选的抗菌素化合物为D-(苏)-1-p-甲磺酰基苯基-2-二氟乙酰氨基-3-氟-1-丙醇。制备这些优选抗菌素化合物的方法和用于上述方法中的中间体描述于美国专利Nos.4,311,857;4,582,918;4,973,750;4,876,352;5,227,494;4,743,700;5,567,844;5,105,009;5,382,673;5,352,832;和5,663,361中。
还优选抗菌素为四环素类化合物。特别优选为氯四环素和土霉素。
还可以用于本发明中的化合物为以下化合物,比如为阿莫西林、氨必西林、氨必西林三水合物、氨苄青霉素钠、阿帕西林、阿扑西林、阿洛西林、氨下青霉素酞酯、羧苄青霉素、羧苄青霉素钠、卡非西林、卡茚西林、环己西林、氯苯唑青霉素钠、氯唑西林本乍生、双氯西林、双氯西林钠、氟氯西林、海他西林、仑氨西林、甲亚胺青霉素、美坦西林、甲氧西林、美洛西林、萘夫西林、萘夫西林钠、恶洒西林、青霉酸、青霉素G、青霉素G本乍生、青霉素G钾、青霉素G钠、青霉素V、苯氧乙基青霉素、苯氧乙基青霉素钾、哌拉西林、哌拉西林钠、匹氨西林、磺苄西林、舒他西林、酞氨苄西林、替卡西林、头孢克罗、头孢羟氨苄、头孢羟氨苄一水合物、头孢孟多、头孢孟多锂、头孢孟多酯钠(Cefamandole Nanfate)、头孢孟多钠、头孢曲秦、头孢西酮、头孢唑啉、头孢唑啉钠、头孢林定(Cefclidine)、头孢地尼、头孢吡肟、头孢他美、头孢克肟、头孢瑞南、头孢甲肟、头孢甲肟钠、头孢地嗪、头孢尼西、头孢哌酮、头孢哌酮钠、头孢雷特、头孢噻利、头孢噻肟、头孢噻肟钠、头孢替安、头孢唑兰、头孢咪坐、头孢咪坐钠、头孢匹胺、头孢匹罗、头孢泊肟、头孢丙烯、头孢喹咪、头孢沙定、头孢磺吡下、头孢磺啶钠水合物、头孢噻甲羧肟、头孢噻甲羧肟五水合物、头孢替唑、头孢布烯、头孢噻利、头孢噻肟、头孢三嗪、头孢三嗪二钠盐、头孢三嗪钠、头孢呋新、头孢唑南、塞发先令、头孢氨下、头孢利定、头孢菌素C、头孢金素、头孢金素钠、头孢吡硫、头孢吡硫钠、塞发莱定、氯碳头孢、头孢布宗、头孢西丁、头孢西丁钠、头孢米诺、头孢美唑、头孢替坦,它们单独使用或者协同β内酰胺酶抑制剂(比如克拉布兰酸、克拉布兰酸钾、舒巴坦Lodopenicillanic acid、6-溴青霉烷酸、Olivanic acid和他巴克坦)使用。
还可以用于本发明中的为大环内酯抗菌素,比如阿奇霉素、布雷菲德菌素、克拉霉素、红霉素、无味红霉素、琥乙红霉素、硬脂酸红霉素、交沙霉素、北里霉素和土拉霉素。
另一种优选的抗菌素化合物为替米考星。替米考星是一种化学定义为20-二氢-20-脱氧-20-(顺式-3,5-二甲基哌啶-1-基)-脱碳霉糖泰乐菌素的大环内酯抗菌素,据报道其公开于美国专利No.4,820,695中。在美国专利No.4,820,695中还公开了包含50%(按体积计)丙二醇、4%(按体积计)苄醇和50~500mg/ml活性成分的可注射含水制剂。替米考星可以以碱或者磷酸盐的形式存在。已经发现,替米考星可以用于治疗呼吸道感染,特别是当注射给药4天疗程时,可以用于治疗牛巴斯德氏菌属溶血杆菌感染。
另一种适用于本发明的抗菌素为土拉霉素。土拉霉素具有以下化学结构:
土拉霉素可以命名为1-氧杂-6氮杂环十五烷-15-酮,13-[[2,6-双脱氧-3-C-甲基-3-O-甲基-4-C-[(丙氨基)甲基]-α-L-核糖-吡喃己糖基]氧基]-2-乙基-3,4,10-三羟基-3,5,8,10,12,14-六甲基-11-[[3,4,6-三脱氧-3-(二甲基氨基)-β-D -木-吡喃己糖基]氧基]-((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)。土拉霉素可以根据美国出版物No.2003/0064939 A1中所述的步骤进行制备,其全文在此引入本文作为参考。土拉霉素可以以按重量计约5.0%~约70%的浓度水平存在于可注射剂型中。土拉霉素的最期望的给药剂量范围为约0.2mg/kg体重/天(mg/kg/day)~约200mg/kg/天,单一或者分次剂量给药(即,每天给药1~4剂量),并且更优选1.25、2.5或者5mg/kg,每周给药一次或者两次,不过需要取决于进行治疗的受试者的物种、重量和状况而变化。土拉霉素可以以按重量计约5.0%~约70%的浓度水平存在于可注射剂型中。
有五个理由证明设计用于宠物(companion animal)中的该耳产品为新产品。先前,氟喹诺酮抗菌素(奥比沙星)先前没有用于该类产品中(虽然在成员国中可以以片剂形式获得用于治疗狗尿路感染)。此外,通常用于此类药品中的抗菌素为庆大霉素(或者其它氨基糖苷类),它们与升高的耳聋发生率相关,特别是在狗中。因此,可以预期该产品具有更好的安全性分布。
优选抗炎药物为莫美他松。它是皮质类固醇类型中的首选。由此,预期该产品比其它当前用于兽医学药物中的局部皮质类固醇制剂更为安全。
优选抗真菌药物为泊沙康唑,该药物的抗真菌活性是用于兽医学药物中的常规抗真菌化合物(比如克霉唑、咪康唑、制霉菌素)的抗真菌活性的10~400x。在兽医学药物中,这将是首次应用三唑抗真菌药物。由此,所建议的耳用产品的组合为新的。该产品每天仅仅需要应用一次。概括地说,使用集中化处理的合理性为:
●用于耳制剂中的新颖抗菌素,其均不具有通常用于所述产品中的氨基糖苷类的耳毒性;
●当同其它用于耳用制剂中的皮质类固醇相比时,所述新颖的皮质类固醇具有更好的安全性分布;
●有效的三唑抗真菌药物;
○如上所述三种药物的新颖组合;
○每日使用一次。
如果期望,可以将其它惰性成分加入到本发明组合物中。所述成分包括防腐剂、螯合剂、抗氧化剂和稳定剂。例证性的防腐剂包括对羟基苯甲酸甲酯(methylparaben)和对羟基苯甲酸丙酯(propylparaben)。例证性的螯合剂包括乙二胺四乙酸钠。例证性的抗氧化剂包括丁基羟基苯甲醚和单硫代甘油钠。
为了制备本发明混悬剂组合物,将赋形剂(们)或者部分赋形剂(们)加入到化合容器中,随后将剩余的赋形剂和活性物质加入其中。还可以将添加剂(比如,如上所列的那些添加剂)并入到容器中并混合成制剂(加入顺序并非至关重要的)。
所述组合物可以每日给药一次或者可以分为多个剂量给药。通常仅一个剂量将足以治疗感染。在某些情况中,治疗动物将需要在一剂量给药48小时后给药第二剂量。另外,所述药物可以每日给药一次,持续长达7天时间。本领域普通技术人员应当理解,准确的剂量将取决于感染的阶段和严重程度、感染有机体对组合物的敏感性和进行治疗的动物物种的个体特定。
如上文所述,药学上可接受的赋形剂包括但不限于树脂、填料、粘合剂、润滑剂、溶剂、助流剂、崩解剂、共溶剂、表面活性剂、防腐剂、缓冲体系、药物级染料或者颜料和粘度增强剂。
优选缓冲体系包括但不限于NaOH、乙酸、硼酸、碳酸、磷酸、琥珀酸、马来酸、酒石酸、柠檬酸、苯甲酸、乳酸、甘油酸(glyceric acid)、葡糖酸、戊二酸和谷氨酸以及它们的钠盐、钾盐和铵盐。本发明的药物组合物通常含有0.1%~20%的缓冲体系。
优选表面活性剂包括但不限于聚氧乙烯脱水山梨糖醇脂肪酸酯、聚氧乙烯单烷基醚、蔗糖单酯以及羊毛脂酯和醚、烷基硫酸酯盐、脂肪酸的钠盐、钾盐和铵盐。
优选防腐剂包括但不限于苯酚、对羟基苯甲酸烷基酯、山梨酸和对羟基苯甲酸甲酯、邻苯基苯酚苯甲酸及其盐、氯代丁醇、苄醇、乙基汞硫代水杨酸钠、乙酸苯汞酯和硝酸苯汞酯、硝基汞甲酚、苯扎氯铵、氯化十六烷基吡啶、对羟苯甲酸甲酯和对羟苯甲酸丙酯。特别优选山梨酸。本发明组合物通常包括0.01%~5%的防腐剂。
优选粘度增强剂包括但不限于甲基纤维素、羧甲基纤维素钠、羟丙基-甲基纤维素、羟丙基纤维素、海藻酸钠、卡波姆、聚乙烯吡咯烷酮、阿拉伯胶、瓜耳豆胶、黄原胶和西黄蓍胶。特别优选为甲基纤维素、卡波姆、黄原胶、瓜耳豆胶、聚乙烯吡咯烷酮、羧甲基纤维素钠和硅酸镁铝。本发明组合物包括0.1%~5%的粘度增强剂。
特别优选增稠剂为Plastibase 50W:其得自于Bristol-MyersSquibb Plastibase50W,在95%矿物油中含有5%聚乙烯。聚乙烯是一种具有高分子量和高熔点的惰性烃。可以将其用作增稠剂以增加矿物油的粘度。其它优选的增稠剂包括羧乙烯基聚合物、角叉菜胶、羟乙基纤维素、合成锂皂石和纤维素醚的水溶性盐类(比如羧甲基纤维素钠和羧甲基羟乙基纤维素钠)。也可以使用天然树胶,比如刺梧桐树胶、黄原胶、阿拉伯树胶和黄蓍树胶。可以将胶状硅酸镁铝或者精细分散的二氧化硅用作部分增稠剂以进一步改良纹理。
液体药物组合物通常包括液体载体,比如水、石油、动物或者植物油、矿物油或者合成油。其中可以含有生理盐水溶液或者二醇(比如乙二醇、丙二醇或者聚乙二醇)。所述组合物和制剂通常含有至少0.1wt%的化合物。
一类优选的增稠剂或者胶凝剂或者悬浮剂包括一类丙烯酸与季戊四醇烷基醚或者蔗糖烷基醚或者卡波姆交联的均聚物。卡波姆可以由B.F.Gooddrich市场购买到,为Carbopol系列。特别优选的Carbopols包括Carbopol 934、940、941、956及其混合物。丙交酯和乙交酯单体的共聚物,该共聚物的分子量为约1,000~约120,000(数均分子量),可以用于递送活性物质。这些聚合物描述于Damani的公布于1993年3月30日的美国专利No.5,198,220和公布于1993年9月7日的美国专利No.5,242,910以及Mattei的公布于1984年4月17日的美国专利No.4,443,430中。
基于总组合物的重量,增稠剂可以使用的量为约0.1%~约15%,优选约2%~约10%,更优选约4%~约8%。对于小袋、非研磨凝胶剂和龈下凝胶剂,可以使用更高的浓度。
本发明组合物可以任选含有乳糖、甘露醇、山梨醇、三元磷酸钙、二元磷酸钙、浓蔗糖、淀粉、硫酸钙、右旋和微晶纤维素、硬脂酸镁、硬脂酸、滑石、胶体二氧化硅、淀粉、羟基乙酸淀粉钠、聚乙烯聚吡咯烷酮、交联羧甲纤维素钠,和微晶纤维素、阿拉伯胶、西黄蓍胶、羟基丙基纤维素、预糊化淀粉、凝胶、聚乙烯吡咯烷酮、乙基纤维素、羟基丙基纤维素、羟基丙基甲基纤维素和甲基纤维素。
本发明更特别描述于以下实施例中,这些实施例仅仅是例证性的实施例,因为对于本领域技术人员很显然的是其中可存在多种变型和变体。
具体实施方式
实施例1
成分 | mg/g |
微粒化的奥比沙星 | 10.0* |
微粒化的莫美他松糠酸酯一水合物 | 1.0** |
微粒化的泊沙康唑 | 1.0*** |
矿物油USP(40厘沲) | 685.0 |
增塑的烃类凝胶-软膏基质(Plastibase 50W) | 适量至1.0g**** |
奥比沙星的实际量基于要进行应用的批量的分析和湿度含量进行确定。莫美他松糠酸酯一水合物的实际量基于要进行应用的批量的分析和湿度含量进行确定。泊沙康唑的实际量基于要进行应用的批量的分析和湿度含量进行确定。该制剂可以如本领域普通技术人员所熟知的方式进行制备。
虽然当前在此已经描述了本发明的某些优选实施方案,但是对于本领域熟练技术人员很明显的是,可以对在此所述的实施方案进行从属于本发明的变体和变型,这并不背离本发明的精神和范围。据此,本发明仅仅限于所附权利要求书和可适用法规所要求的程度。
Claims (24)
1、一种用于治疗动物耳感染的药物组合物,其包含奥比沙星或者一种其药学上可接受的盐;抗真菌有效量的药学上可接受的三唑化合物;莫美他松糠酸酯一水合物和至少一种药学上可接受的载体,其中所述组合物为混悬剂。
2、根据权利要求1的组合物,其中所述莫美他松糠酸酯一水合物以至少约0.01%的量存在。
3、根据权利要求1的组合物,其中所述奥比沙星以至少约0.1%的量存在。
4、根据权利要求1的组合物,其中所述抗真菌有效量的药学上可接受的三唑化合物以至少约0.01%的量存在。
5、根据权利要求4的组合物,其中所述抗真菌有效量的药学上可接受的三唑化合物为泊沙康唑。
7、根据权利要求6的组合物,其中所述莫美他松糠酸酯一水合物以至少约0.01%的量存在。
8、根据权利要求6的组合物,其中所述奥比沙星以至少约0.1%的量存在。
9、根据权利要求6的组合物,其中所述抗真菌有效量的药学上可接受的三唑化合物以至少约0.01%的量存在。
10、一种用于治疗动物感染的药物组合物,其包含抗菌素或者一种其药学上可接受的盐;抗真菌有效量的药学上可接受的三唑化合物;皮质类固醇和至少一种药学上可接受的载体,其中所述组合物为混悬剂。
11、根据权利要求10的组合物,其中所述皮质类固醇选自莫美他松、莫美他松糠酸酯、莫美他松糠酸酯一水合物、倍他米松、Butoxicart、罗氟奈德、布地缩松、地夫可特、环索奈德、氟替卡松、Beclomethasone、氯替泼诺、曲安西龙倍他米松、肤轻松、泼尼松、泼尼松龙和/或其药学上可接受的盐。
12、根据权利要求10的组合物,其中所述皮质类固醇为莫美他松糠酸酯一水合物,并且其中莫美他松糠酸酯一水合物以至少约0.01%的量存在。
13、根据权利要求10的组合物,其中所述抗菌素为喹诺酮抗菌素,并且其中喹诺酮抗菌素以至少约0.1%的量存在。
14、根据权利要求10的组合物,其中所述喹诺酮抗菌素选自奥比沙星、环丙沙星、丹诺沙星、依诺沙星、格里沙星、左旋氧氟沙星、洛美沙星、萘啶酮酸、诺氟沙星、氧氟沙星、司帕沙星、麻保沙星、依巴沙星、佳诺沙星、T-3811M1、T-3811M4、T3811M6、加替沙星、吉米沙星、莫西沙星、二氟沙星、芦氟沙星、宾氟沙星和曲氟沙星甲磺酸盐和/或其代谢产物。
15、根据权利要求14的组合物,其中所述喹诺酮抗菌素为奥比沙星。
16、根据权利要求10的组合物,其中所述抗真菌有效量的药学上可接受的三唑化合物以至少约0.01%的量存在。
17、根据权利要求10的组合物,其中所述抗真菌有效量的药学上可接受的三唑化合物选自伏立康唑、酮康唑、氟康唑、伊曲康唑、沙柏康唑、奈康唑、奥昔康唑、硝酸异康唑、硫康唑、噻康唑和/或其药学上可接受的盐。
18、根据权利要求17的组合物,其中所述抗真菌有效量的药学上可接受的三唑化合物为泊沙康唑。
19、根据权利要求10的组合物,其中所述抗菌素选自阿莫西林、氨必西林、氨必西林三水合物、氨苄青霉素钠、阿帕西林、阿扑西林、阿洛西林、氨下青霉素酞酯、羧苄青霉素、羧苄青霉素钠、卡非西林、卡茚西林、环己西林、氯苯唑青霉素钠、氯唑西林本乍生、双氯西林、双氯西林钠、氟氯西林、海他西林、仑氨西林、甲亚胺青霉素、美坦西林、甲氧西林、美洛西林、萘夫西林、萘夫西林钠、恶洒西林、青霉酸、青霉素G、青霉素G本乍生、青霉素G钾、青霉素G钠、青霉素V、苯氧乙基青霉素、苯氧乙基青霉素钾、哌拉西林、哌拉西林钠、匹氨西林、磺苄西林、舒他西林、酞氨苄西林、替卡西林、头孢克罗、头孢羟氨苄、头孢羟氨苄一水合物、头孢孟多、头孢孟多锂、头孢孟多酯钠、头孢孟多钠、头孢曲秦、头孢西酮、头孢唑啉、头孢唑啉钠、头孢林定、头孢地尼、头孢吡肟、头孢他美、头孢克肟、头孢瑞南、头孢甲肟、头孢甲肟钠、头孢地嗪、头孢尼西、头孢哌酮、头孢哌酮钠、头孢雷特、头孢噻利、头孢噻肟、头孢噻肟钠、头孢替安、头孢唑兰、头孢咪坐、头孢咪坐钠、头孢匹胺、头孢匹罗、头孢泊肟、头孢丙烯、头孢喹咪、头孢沙定、头孢磺吡下、头孢磺啶钠水合物、头孢噻甲羧肟、头孢噻甲羧肟五水合物、头孢替唑、头孢布烯、头孢噻利、头孢噻肟、头孢三嗪、头孢三嗪二钠盐、头孢三嗪钠、头孢呋新、头孢唑南、塞发先令、头孢氨下、头孢利定、头孢菌素C、头孢金素、头孢金素钠、头孢吡硫、头孢吡硫钠、塞发莱定、氯碳头孢、头孢布宗、头孢西丁、头孢西丁钠、头孢米诺、头孢美唑、头孢替坦,它们单独使用或者协同β内酰胺酶抑制剂使用,所述β内酰胺酶抑制剂比如克拉布兰酸、克拉布兰酸钾、舒巴坦Lodopenicillanic acid、6-溴青霉烷酸、Olivanic acids和他巴克坦。
20、根据权利要求10的组合物,其中所述抗菌素选自比如阿奇霉素、布雷菲德菌素、克拉霉素、红霉素、无味红霉素、琥乙红霉素、硬脂酸红霉素、交沙霉素、北里霉素和土拉霉素的抗菌素。
21、根据权利要求10的组合物,其中所述抗菌素选自3-氟,3-脱氧衍生物,
式I
其中R为选自以下的基团:甲基或者乙基或者其卤代衍生物、二卤代氘代甲基、1-卤代-1-氘代乙基、1,2-二卤代-1-氘代乙基、叠氮甲基和甲基磺酰基甲基;
X和X′各自为独立地选自以下的基团:NO2、SO2R1、SOR1、SR1、SONH2、SO2NH2、SONHR1、SO2NHR1、COR1、OR1、R1、CN、卤素、氢、苯基和被卤素、NO2、R1、OR1、PO2R1、CONHR1、NHR1、NR1R2、CONR1R2或者OCOR1取代的苯基,其中R1和R2各自是独立地选自甲基、乙基、正丙基、异丙基、丁基、叔丁基、异丁基和苯基的基团;
和Z为氢或者具有最高达16个碳原子的烃类羧酸(优选烃类二羧酸)的酰基或者具有最高达12个碳原子的氨基-烃类羧酸的酰基;和所述酰基的药学上可接受的盐。
22、根据权利要求21的组合物,其中所述抗菌素为氟苯尼考。
23、根据权利要求10的组合物,其中所述抗菌素为土拉霉素。
24、根据权利要求10的组合物,其中所述抗菌素为替米考星。
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