CN101400351A - 含氟喹诺酮类化合物的药物制剂 - Google Patents
含氟喹诺酮类化合物的药物制剂 Download PDFInfo
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- CN101400351A CN101400351A CNA2007800082264A CN200780008226A CN101400351A CN 101400351 A CN101400351 A CN 101400351A CN A2007800082264 A CNA2007800082264 A CN A2007800082264A CN 200780008226 A CN200780008226 A CN 200780008226A CN 101400351 A CN101400351 A CN 101400351A
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- Prior art keywords
- sodium
- pharmaceutical preparation
- acid
- medicine
- injection
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- 229940124307 fluoroquinolone Drugs 0.000 title claims abstract description 24
- 239000003814 drug Substances 0.000 title claims abstract description 15
- 239000000203 mixture Substances 0.000 title abstract description 15
- 238000009472 formulation Methods 0.000 title abstract 3
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 11
- 239000007788 liquid Substances 0.000 claims abstract description 9
- -1 sulphur compound Chemical class 0.000 claims description 32
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 30
- 235000010265 sodium sulphite Nutrition 0.000 claims description 15
- 239000007924 injection Substances 0.000 claims description 13
- 238000002347 injection Methods 0.000 claims description 13
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 13
- 239000005864 Sulphur Substances 0.000 claims description 8
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 claims description 7
- SPFYMRJSYKOXGV-UHFFFAOYSA-N Baytril Chemical compound C1CN(CC)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1CC1 SPFYMRJSYKOXGV-UHFFFAOYSA-N 0.000 claims description 6
- 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 6
- 229960000740 enrofloxacin Drugs 0.000 claims description 6
- PMNLUUOXGOOLSP-UHFFFAOYSA-N 2-mercaptopropanoic acid Chemical compound CC(S)C(O)=O PMNLUUOXGOOLSP-UHFFFAOYSA-N 0.000 claims description 4
- MTIKNVGQQLJIQZ-UHFFFAOYSA-N CC([Na])=O.OS(O)=O Chemical compound CC([Na])=O.OS(O)=O MTIKNVGQQLJIQZ-UHFFFAOYSA-N 0.000 claims description 4
- 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 4
- 229960002531 marbofloxacin Drugs 0.000 claims description 4
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical class OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 3
- 230000000996 additive effect Effects 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 229960003405 ciprofloxacin Drugs 0.000 claims description 3
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 3
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 claims description 2
- DYIOSHGVFJTOAR-JGWLITMVSA-N (2r,3r,4s,5r)-6-sulfanylhexane-1,2,3,4,5-pentol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CS DYIOSHGVFJTOAR-JGWLITMVSA-N 0.000 claims description 2
- LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical compound OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 0.000 claims description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 2
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 claims description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 2
- 229960004308 acetylcysteine Drugs 0.000 claims description 2
- 229960002433 cysteine Drugs 0.000 claims description 2
- 235000018417 cysteine Nutrition 0.000 claims description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 2
- 229960001305 cysteine hydrochloride Drugs 0.000 claims description 2
- 229960003067 cystine Drugs 0.000 claims description 2
- FGRVOLIFQGXPCT-UHFFFAOYSA-L dipotassium;dioxido-oxo-sulfanylidene-$l^{6}-sulfane Chemical compound [K+].[K+].[O-]S([O-])(=O)=S FGRVOLIFQGXPCT-UHFFFAOYSA-L 0.000 claims description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims description 2
- 235000003969 glutathione Nutrition 0.000 claims description 2
- 229960003180 glutathione Drugs 0.000 claims description 2
- 229930182817 methionine Natural products 0.000 claims description 2
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 claims description 2
- 150000002898 organic sulfur compounds Chemical class 0.000 claims description 2
- DJEHXEMURTVAOE-UHFFFAOYSA-M potassium bisulfite Chemical compound [K+].OS([O-])=O DJEHXEMURTVAOE-UHFFFAOYSA-M 0.000 claims description 2
- RWPGFSMJFRPDDP-UHFFFAOYSA-L potassium metabisulfite Chemical compound [K+].[K+].[O-]S(=O)S([O-])(=O)=O RWPGFSMJFRPDDP-UHFFFAOYSA-L 0.000 claims description 2
- BHZRJJOHZFYXTO-UHFFFAOYSA-L potassium sulfite Chemical compound [K+].[K+].[O-]S([O-])=O BHZRJJOHZFYXTO-UHFFFAOYSA-L 0.000 claims description 2
- 235000019252 potassium sulphite Nutrition 0.000 claims description 2
- VYGBQXDNOUHIBZ-UHFFFAOYSA-L sodium formaldehyde sulphoxylate Chemical compound [Na+].[Na+].O=C.[O-]S[O-] VYGBQXDNOUHIBZ-UHFFFAOYSA-L 0.000 claims description 2
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 2
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 claims description 2
- 229940035024 thioglycerol Drugs 0.000 claims description 2
- 208000035143 Bacterial infection Diseases 0.000 claims 2
- 208000022362 bacterial infectious disease Diseases 0.000 claims 2
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 claims 1
- 229960003151 mercaptamine Drugs 0.000 claims 1
- 229960004452 methionine Drugs 0.000 claims 1
- 229940043349 potassium metabisulfite Drugs 0.000 claims 1
- 235000010263 potassium metabisulphite Nutrition 0.000 claims 1
- 239000003963 antioxidant agent Substances 0.000 abstract description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical class [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 42
- 238000002360 preparation method Methods 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 241001465754 Metazoa Species 0.000 description 22
- 239000008215 water for injection Substances 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 229910052739 hydrogen Inorganic materials 0.000 description 17
- 239000001257 hydrogen Substances 0.000 description 17
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 13
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 11
- 239000000463 material Substances 0.000 description 11
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- 150000003839 salts Chemical class 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 239000006184 cosolvent Substances 0.000 description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 241000282472 Canis lupus familiaris Species 0.000 description 8
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 8
- 239000002202 Polyethylene glycol Substances 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 229920001223 polyethylene glycol Polymers 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 125000000217 alkyl group Chemical group 0.000 description 6
- 150000004684 trihydrates Chemical class 0.000 description 6
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 5
- 241000282326 Felis catus Species 0.000 description 5
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- LISFMEBWQUVKPJ-UHFFFAOYSA-N carbostyril Natural products C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 5
- 150000002431 hydrogen Chemical group 0.000 description 5
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- KMZHZAAOEWVPSE-UHFFFAOYSA-N 2,3-dihydroxypropyl acetate Chemical compound CC(=O)OCC(O)CO KMZHZAAOEWVPSE-UHFFFAOYSA-N 0.000 description 4
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- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
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- LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 description 4
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Abstract
本发明涉及含氟喹诺酮类化合物和抗氧化的硫化合物的液体形式的药物制剂。该制剂特别适合肠胃外给药，尤其显著的是其具有很好的耐受性。
Description
本发明涉及含氟喹诺酮类化合物和抗氧化硫化合物的液体形式的药物制剂。该制剂特别适合肠胃外给药，尤其显著的是其具有很好的耐受性。
溶液的化学稳定性可例如通过使用抗氧剂来增强。因此可阻止内含物的氧化分解。这在注射液中也是普遍的，注射液特别属于这种情况。这里通常使用的抗氧剂尤其是亚硫酸盐。DE-A-19500784，EP-A-0187315或EP-A-1121933描述了含亚硫酸盐的注射液。如EP-A-0804267所述，当滴眼液作为溶液存在时，其可含亚硫酸盐。DE-A-2364470描述了亚硫酸盐用于防止制剂脱色的用途。迄今尚未有这样的亚硫酸盐用于增强注射液的局部耐受性的用途的描述。耐受性不好的溶液在实践中必须例如以输液形式静脉给药。然而，该操作的实践特别当治疗动物时是有问题的。为了增强耐受性已进行了大量的尝试，例如通过描述于WO 98/33482中的配制为脂质体。为了提高制剂的溶解性或耐受性，也经常研究被作为可能方案的环糊精，参见EP-A-0209768。如果一点也不能提高制剂的耐受性，应用该制剂时，则可能需要使用局部麻醉剂，如在GB-A-1143330中所描述的；或者如EP-A-1121933描述的使用油状制剂替代。
用于动物肠胃外给药的溶液具有如下特点，也即其必须根据动物种类以不同的方法和方式施加。例如，在欧洲一般对猪皮下和对狗或猫肌内给药注射液。不仅动物物种而且不同的给药方式都导致应该满足提高耐受性的要求(EP-A-1121933)。例如牛耐受的事实不能必然得到例如猫或狗耐受的结论(WO 01/81358)。因此为了保证广泛的适用性，提高注射液的局部耐受性以甚至在敏感的动物物种仍可使用是有意义的。
因为大多数含氟喹诺酮类化合物的注射液尤其本身不具有好的耐受性，因此这些注射剂不适用于狗或猫也不令人感到惊奇。
为了保证该溶液尽可能地具有好的耐受性，建议其pH尽可能保持中性(大约7.4)，然而该pH与氟喹诺酮类化合物的溶解度背道而驰(widersprechen)。同样，在该pH范围可经常观察到氟喹诺酮类化合物的甜菜碱形式的颗粒形成，这就是当溶液具有耐受性时，其就具有短暂的贮藏期且有颗粒形成的原因。这可例如通过替代选择冻干产品来避免。但是，冻干产品在实践中难以处理，其重构溶液(rekonstituierten
)经常开始(Anbruch)后仅有最多4周的贮藏期，或者由于颗粒形成的可能性必须直接丢弃。因此，备用的溶液(也被称为备用制剂)作为注射剂是有利的。
另外，如WO 99/29322中所述，要求给药后氟喹诺酮以合适的量进入血清。而且，这与可注射的氟喹诺酮制剂不相关联，而可同样取决于各种动物物种。
已经发现直接可用(备用)的含氟喹诺酮类化合物的可注射制剂，其包含足够浓度的氟喹诺酮，在贮藏期内在制药条件下该制剂是稳定的且无颗粒形成，并且尤其狗对其有很好的耐受性，同时其具有有利的血清动力学。
因此，本发明涉及：
液体形式的药物制剂，包括：
(a)氟喹诺酮，
(b)抗氧化的硫化合物
(c)视需要的另外的药用辅助剂和/或添加剂
氟喹诺酮类化合物尤其是如在以下文献中公开的那些化合物：US4670444(Bayer AG)、US 4472405(Riker Labs)、US 4730000(Abbott)、US 4861779(Pfizer)、US 4382892(Daiichi)、US 4704459(Toyama)，以下为所提到的具体例子：培诺沙星(Benofloxacin)、宾氟沙星、西诺沙星、环丙沙星、单诺沙星、二氟沙星、依诺沙星、恩诺沙星、氟罗沙星、依巴沙星、左氧氟沙星、洛美沙星、马波沙星、莫西沙星、诺氟沙星、氧氟沙星、奥比沙星、培氟沙星、吡哌酸、替马沙星、托氟沙星、沙拉沙星、司巴沙星。
氟喹诺酮类的优选组是如式(I)或(II)表示的那些：
其中
X代表氢、卤素、C1-4烷基、C1-4烷氧基、NH2，
Y代表下面结构的基团
其中
R4 代表任选的经羟基或甲氧基取代的直链或支链的C1-C4烷基、环丙基，具有1-3个C原子的酰基，
R5 代表氢、甲基、苯基、噻吩基或吡啶基，
R6 代表氢或C1-4烷基，
R7 代表氢或C1-4烷基，
R8 代表氢或C1-4烷基，
和
R1 代表具有1-3个碳原子的烷基基团、环丙基、2-氟乙基、甲氧基、4-氟苯基、2，4-二氟苯基或甲氨基，
R2 代表氢或任选的经甲氧基或2-甲氧基乙氧基取代的具有1-6个碳原子的烷基和环己基、苄基、2-氧代丙基(2-Oxopropyl)、苯酰基、乙氧羰甲基、特戊酰氧基甲基，
R3 代表氢、甲基或乙基，和
A代表氮、＝CH-，＝C(卤素)-，＝C(OCH3)-，＝C(CH3)-或＝C(CN)，
B代表氧、任选的经甲基或苯基取代的＝NH或＝CH2，
Z代表＝CH-或＝N-，
和它们在药学上可用的盐和水合物。
式(I)优选的化合物是那些
其中
A 代表＝CH-或者＝C-CN，
R1 代表任选的经卤素取代的C1-C3的烷基或环丙基，
R2 代表氢或C1-4的烷基，
Y 代表下面结构的基团
其中
R4 代表任选经羟基取代的直链或支链C1-C3烷基、具有1-4个碳原子的氧杂烷基，
R5 代表氢、甲基或苯基，
R6 代表氢，
R7 代表氢或甲基，
R8 代表氢，
和它们在药学上可用的水合物和盐。
式(I)特别优选的化合物是：
其中
A 代表＝CH-或＝C-CN，
R1 代表环丙基，
R2 代表氢、甲基或乙基，
Y代表下面结构的基团
其中
R4 代表甲基、任选经羟基取代的乙基
R5 代表氢或甲基，
R6 代表氢，
R7 代表氢或甲基，
R8 代表氢，
和它们在药学上可用的盐和水合物。
作为式(II)的氟喹诺酮的优选例子提到马波沙星：
作为特别优选的氟喹诺酮类提到在WO 97/31001中所述的化合物，特别优选8-氰基-1-环丙基-7-((1S，6S)-2，8-二氮杂二环[4.3.0]壬-8-基)-6-氟-1，4-二氢-4-氧代-3-喹啉甲酸(普多沙星)，其具有下式
恩诺沙星也是特别优选应用的：1-环丙烷基-7-(4-乙基-1-哌嗪基)-6-氟-1，4-二氢-4-氧代-3-喹啉甲酸
使用在人类药品中通常使用的活性物质环丙沙星也是可行的。
光学活性的氟喹诺酮类化合物可以它们的外消旋化合物或以对映体的形式存在。根据本发明，既可以使用纯的对映体也可以使用它们的混合物。
合适的盐是药学上可用的酸加成盐和碱性盐。
作为药学上可用的盐意指，例如，盐酸、硫酸、乙酸、羟乙酸、乳酸、琥珀酸、柠檬酸、酒石酸、甲烷磺酸、4-甲基苯磺酸、半乳糖醛酸、葡萄糖酸、双羟萘酸、谷氨酸或门冬氨酸的盐。另外，根据本发明的化合物可结合在酸性或碱性离子交换剂上。可能提及的药学上可用的碱性盐是碱金属盐例如钠盐或钾盐，碱土金属例如镁盐或钙盐；锌盐、银盐和胍鎓盐。
水合物既指氟喹诺酮类化合物本身的水合物，也指它们的盐的水合物。例如，可能提及的一个例子是普多沙星，它形成稳定的三水合物(参见WO 2005/097789)。
在一定的环境下，固体的氟喹诺酮类化合物可形成不同的晶体变体。对本发明的药物有利的是那些有合适溶解度性质的变体。
给体重达到大约80kg的动物有代表性地使用0.1-15％，优选0.5-15％和特别优选1-15％量的氟喹诺酮。在动物体重超过大约80kg的情况下，有代表性使用1-30％，优选3-25％和特别优选4-20％量的氟喹诺酮。每种情况下以重量/体积给出百分比的数据。
抗氧化硫化合物的例子如下：亚硫酸盐(亚硫酸钠、亚硫酸钾)、亚硫酸氢盐(Bisulfit)(例如偏亚硫酸氢钠，偏亚硫酸氢钾、焦亚硫酸(pyrosulphite)钾、焦亚硫酸(pyrosulphite)钠、偏亚硫酸氢乙酰钠(Acetonatriummetabisulfit)、亚硫酸氢乙酰钠(Acetonatriumbisulfit))、硫代硫酸盐(例如硫代硫酸钾、硫代硫酸钠)和有机硫化合物(例如甲醛合次硫酸氢钠、硫脲、硫代山梨糖醇、盐酸半胱氨酸、胱氨酸、半胱氨酸、乙酰半胱氨酸、谷胱甘肽、巯乙酸、蛋氨酸、硫代甘油、巯基乙酸、硫代乳酸)。
通常使用0.05-10％，优选0.1-8％和特别优选0.5-5％浓度的抗氧化硫化合物。每种情况下以重量/体积给出百分比的数据。
该液体制剂可包含能提高在给药时的局部耐受性的其它物质。可提及的例子是：自由基清除剂或抗氧剂，例如维生素E、水溶性的维生素E酯或维生素C、丁基羟基茴香醚或丁基羟甲苯。络合物形成剂例如EDTA(乙二胺四乙酸)-钠、聚乙烯基吡咯烷酮或环糊精，其特别优选如下，羟丙基-β-环糊精或硫代丁基醚(Sulfobutylether)-β-环糊精，右泛醇，脂肪酸盐如辛酸钠，多价阳离子的盐(例如碱土金属Me2+或Me3+)的和这里特别优选的镁盐、氨基酸和这里特别优选的精氨酸或赖氨酸，泊洛沙姆、泊洛沙胺(Poloxamine)，助溶剂例如正丁醇、甘油、聚乙二醇、丙二醇、或二甲基乙酰胺、葡聚糖、酸(例如葡萄糖酸半乳糖酸(Gluconolactonsaure)、乳酸、双羟萘酸、柠檬酸、酒石酸、粘酸或透明质酸、卵磷脂(从大豆或小鸡蛋白中得到的含70-100％磷酸卵磷脂)或肌酸酐。
提高耐受性的物质通常以0.05-10％，优选0.1-8％和特别优选0.5-5％的浓度存在。每种情况下以重量/体积给出百分比的数据。
能避免颗粒形成的物质例如是泊洛沙姆、卵磷脂、聚乙烯基吡咯烷酮、助溶剂、抗氧剂、络合物形成剂或者季铵化合物例如苄索氯铵或苯扎氯铵。
能提高稳定性和避免例如颗粒形成的物质通常以0.001-10％，优选0.005-6％和特别优选0.001-3％的浓度使用。每种情况下以重量/体积给出百分比的数据。
液体制剂可包含作为溶剂的水或可与水共混的物质。可提及的例子是甘油、丙二醇、聚乙二醇、耐受的醇类(例如乙醇、苯甲醇或正丁醇)、乳酸乙酯、醋酸乙酯、甘油醋酸酯、N-甲基吡咯烷酮、碳酸亚丙酯、丙二醇、四氢呋喃聚乙二醇醚(Glycofurol)、二甲乙酰胺、2-吡咯烷酮、异亚丙基丙三醇(Isopropylidenglycerol)或缩甲醛甘油(Glycerinformal)。也可以使用不同溶剂的混合物。优选以水为基础的制剂，其中当然也可包括其它溶剂和助溶剂。
除水或可与水共混的物质之外，液体制剂也可以包含乳剂形式的油作为溶剂。其中，可提及的物质是植物油、动物油和合成油，例如棉籽油、麻油、大豆油、具有C12-C18链长度的中链甘油三酸酯、辛酸丙二醇酯/癸酸丙二醇酯或石蜡。
通常溶剂的浓度分别为99.8-72％或98.9-55％，优选99.4-81％或96.9-67％，且特别优选98.8-87％或94.5-77％。每种情况下以重量/体积给出百分比的数据。
液体制剂的pH通常为2-11，优选3-8和特别优选4-8。
所述药物也可包含助溶剂，特别在制剂含水的情况下优选包含助溶剂。通常使用量为1-10重量％，优选3-8重量％。可提及的助溶剂的例子是：药学上耐受的醇、二甲亚砜、乳酸乙酯、酸酸乙酯、甘油醋酸酯、N-甲基吡咯烷酮、碳酸亚丙酯、丙二醇、四氢呋喃聚乙二醇醚(Glycofurol)、二甲基乙酰胺、2-吡咯烷酮、异亚丙基丙三醇(Isopropylidenglycerol)、缩甲醛甘油(Glycerinformal)、甘油和聚乙二醇。特别适合作为助溶剂的物质是药学上可接受的醇，例如乙醇、苯甲醇或正丁醇。上述溶剂的混合物也可用作助溶剂。
液体制剂也包含防腐剂，例如，如苯甲醇、乙醇、正丁醇、苯酚、甲酚、氯代丁醇、对羟基苯甲酸酯(特别是甲基或丙基酯)的脂肪醇，如山梨酸、苯甲酸、乳酸或丙酸的羧酸的游离酸或盐，苯扎氯铵、苄索氯铵或氯化十六烷基吡啶鎓。
本发明的药物根据其制剂类型和给药方式，可包含其它常用的药学上可接受的添加剂和辅助剂。可提及的例子是：
·抗氧剂例如苯酚类(生育酚类、以及维生素E、维生素E-TPGS(d-α-生育酚基聚乙二醇1000琥珀酸酯))、丁基羟基茴香醚、丁基羟甲苯、没食子酸辛酯和没食子酸十二烷基酯，有机酸(抗坏血酸、柠檬酸、酒石酸、乳酸)及它们的盐和酯。
·湿润剂例如脂肪酸盐或脂肪烷基硫酸盐，脂肪烷基磺酸盐、线型的烷基苯磺酸盐、脂肪烷基聚乙二醇醚硫酸盐、脂肪烷基聚乙二醇醚、烷基苯酚聚乙二醇醚、烷基多苷(Alkylpolyglycoside)、脂肪酸N-甲基葡糖酰胺、聚山梨酯、山梨糖醇酐脂肪酸酯和泊洛沙姆。
·等渗物质例如氯化钠、葡萄糖或甘油。
·药学上可接受的着色剂例如氧化铁、胡萝卜素类等。
除了氟喹诺酮类化合物，本发明的制剂还可包括其它药学上的活性成分。例如，止痛药、特别是称作NSAID(非类固醇类的抗炎药类物质)可与氟喹诺酮类联合使用。这样的NSAID可以是例如美洛昔康、氟胺烟酸、酮基布洛芬、卡布洛芬、安乃近或(乙酰基)水杨酸。
通过将氟喹诺酮在抗氧化的硫化合物之后分散在溶剂中，并向其中添加用来提高耐受性和视需要用来避免颗粒形成的其它物质，即可制备得到本发明的药物。助溶剂和例如防腐剂的其它内含物可事先加入该溶剂中或稍后混合。
或者，也可首先将助溶剂、防腐剂、影响耐受性或颗粒形成的物质溶解在溶剂中，然后，才向该混合物中加入氟喹诺酮。抗氧化的硫化合物也可随之同时分散在其中或在氟喹诺酮之后分散在其中。
一般而言，根据本发明的药物制剂适用于人类和动物。优选适用于在家畜、种畜、动物园动物、实验室动物、试验动物及宠物的动物饲育和动物繁殖。
家畜和种畜包括例如牛、马、绵羊、猪、山羊、骆驼、水牛、驴、兔子、小鹿、驯鹿的动物，如水貂、灰鼠、浣熊的皮毛动物，和如鸡、鹅、火鸡、鸭、鸽子的禽类及在家庭和在公园饲育的鸟类物种。
实验室动物和试验动物包括小鼠、大鼠、豚鼠、金仓鼠、狗和猫。
宠物包括兔子、仓鼠、豚鼠、小鼠、马、爬行类动物、合适的鸟类物种、狗和猫。
也可提及鱼，尤其是生活在淡水和海水中所有年龄的有用鱼类、饲育鱼类、水族馆鱼类和观赏鱼。
根据本发明的制剂优选对例如马、猫和狗的宠物适用。其特别适合猫和狗。
优选的有用动物的例子是牛、绵羊、猪、山羊和鸡。特别优选的有用动物是牛和猪。
给药既可以预防实施也可以治疗实施。
这里所述的药物制剂可通过不同的途径对目标机体(人或动物)给药。例如，其可通过特别是通过注射的形式(例如皮下地、肌内地、静脉地、乳房内地(intramammar)、腹腔内地)肠胃外地、皮肤地、口腔地、经直肠地、经阴道地或经鼻腔地给药，特别优选以注射方式肠胃外给药。
优选地，所述制剂作为溶液、悬浮液或乳液给药。
根据本发明的药物活性成份的特点在于好的稳定性和好的溶解性。而且，特别肠胃外给药时，其在动物体内具有好的耐受性和适宜的血清动力学。
实施例
以下实施例的制剂可通过将规定的配料混合或溶解在注射用水中而制备。通过加入酸或碱来调节溶液的pH。所述溶液经过滤灭菌，并转移到适宜的容器中。普多沙星可以其无水物(Anhydrat)或三水合物的形式使用；在每种情况下的数值均以无水物计算。
(重量百分比以成品制剂的总体积为基础，[W/V])
实施例1
3.0％ 普多沙星
0.1％ 泊洛沙姆F68
0.2％ 亚硫酸氢钠(Natriumdisulfit)
3％ 正丁醇
1.6％ 氢氧化钠(1N)
2.7％ 氯化钠
补充注射用水至100％
将3.0g普多沙星、0.1g泊洛沙姆、0.2g亚硫酸氢钠、3g正丁醇、2.7g氯化钠溶解在大约80g的注射用水中，检查其pH值，视需要可用1.6g1N的氢氧化钠调节pH至7.4。然后，加入剩余的注射用水将最终体积(Endgewicht)调节至100ml。
实施例2
3％普多沙星
0.1％泊洛沙姆F68
0.5％ 亚硫酸氢钠
3％ 正丁醇
2.4％ 氯化钠
4.6％ 1N氢氧化钠
补充注射用水至100％
将3.0g普多沙星、0.1g泊洛沙姆、0.5g亚硫酸氢钠、3g正丁醇、2.4g氯化钠溶解在大约80g的注射用水中，检查其pH值，并用4.6g的氢氧化钠调节pH至7.4。然后，加入剩余的注射用水将最终体积调节至100ml。
实施例3
3％ 普多沙星
0.2％ 亚硫酸氢钠
3％ 正丁醇
20％ N-甲基吡咯烷酮
补充注射用水至100％
将70g注射用水与3g正丁醇和20g N-甲基吡咯烷酮相混合。将0.2％的亚硫酸氢钠和然后将3g普多沙星溶解在其中。加入剩余的3.8g的注射用水将最终体积调节至100ml。
实施例4
1％恩氟沙星
0.5％ 亚硫酸氢钠
1.4％ 苯甲醇
1.4g 1N KOH
3％ 氯化镁六水合物
补充注射用水至 100％
将70g注射用水与1.4g苯甲醇和3g氯化镁六水合物相混合。并将0.5％的亚硫酸氢钠与1.4g 1N KOH溶解在混合物中，随后将1g恩氟沙星溶解在其中。然后加入剩余的22.7g的注射用水调节至最后体积。
实施例5
5％ 普多沙星(三水合物)
0.1％ 泊洛沙姆F68
3％ 正丁醇
0.5％ 亚硫酸氢钠
9％ 1N 盐酸
补充注射用水至100％
将80g注射用水与0.5g亚硫酸氢钠、3g正丁醇和0.1g泊洛沙姆相混合。将5g普多沙星(三水合物、以纯普多沙星计算)溶解在该混合物中。如果需要，用大约9g的酸将混合液的pH调节为5，同时用剩余的注射用水将最后体积调节到100ml。
实施例6
2％ 普多沙星(三水合物)
0.1％ 泊洛沙姆F68
3％ 正丁醇
0.5％ 亚硫酸氢钠
2.6％ 氯化钠
9％ 1N 氢氧化钠
补充注射用水至100％
将80g注射用水与0.5g亚硫酸氢钠、3g正丁醇、2.6g氯化钠和0.1g泊洛沙姆相混合。将2普多沙星(三水合物、以纯普多沙星计算)溶解在该混合物中。如果需要，用大约2.4g氢氧化钠将混合物的pH调节为7.4，并用剩余的注射用水使其最后体积达到100ml。
活体耐受性
在临床试验中，这里所述的制剂与其它制剂相对比增强了其局部耐受性。因活性物质引起的组织刺激和注射位置肿胀的程度取决于使用的制剂。选择的实施例在下面表1所示。
表1：
SC＝皮下的，IM＝肌内的
血清药物代谢动力学曲线
制剂影响血清药物代谢动力学(PK)曲线。不同的制剂的血清浓度——时间曲线明显不同。对于喹诺酮类化合物，优选快速吸收、高的浓度峰和长的消除阶段的曲线。这里下面表2列出了各种制剂和它们对PK曲线的影响。
表2
SC＝皮下的，IM＝肌内的
Claims (10)
1.液体形式的药物制剂，包括：
(a)氟喹诺酮
(b)抗氧化的硫化合物
(c)视需要的其它药用辅助剂和/或添加剂。
2.根据权利要求1的药物制剂，包括作为抗氧化的硫化合物的亚硫酸盐，特别是亚硫酸钠、亚硫酸钾；亚硫酸氢盐，特别是偏亚硫酸氢钠、偏亚硫酸氢钾、焦亚硫酸钾、焦亚硫酸钠、偏亚硫酸氢乙酰钠、亚硫酸氢乙酰钠；硫代硫酸盐，特别是硫代硫酸钾、硫代硫酸钠；或者有机硫化合物，特别是甲醛合次硫酸氢钠、硫脲、硫代山梨糖醇、盐酸半胱氨酸、胱氨酸、半胱氨酸、乙酰半胱氨酸、谷胱甘肽、半胱胺、蛋氨酸、硫代甘油、巯基乙酸、硫代乳酸。
3.根据上述权利要求任一项的药物制剂，包括亚硫酸氢钠。
4.根据上述权利要求任一项的药物制剂，包括环丙沙星、恩氟沙星、普多沙星或马波沙星作为氟喹诺酮。
5.根据权利要求4的药物制剂，包括普多沙星。
6.根据权利要求4的药物制剂，包括恩氟沙星。
7.根据权利要求4的药物制剂，包括马波沙星。
8.根据上述权利要求任一项的药物制剂用于制备用以治疗细菌性疾病的药物的用途。
9.根据权利要求8的用于制备用以治疗细菌性疾病的药物的用途，所述药物适合注射。
10.根据权利要求8或9的用于制备药物的用途，所述药物具有更好的耐受性。
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| DE3517709A1 (de) * | 1985-01-05 | 1986-07-10 | Bayer Ag | Basische zubereitungen von chinoloncarbonsaeuren |
| AT392789B (de) * | 1985-01-23 | 1991-06-10 | Toyama Chemical Co Ltd | Verfahren zur herstellung von 1-substituierten aryl-1,4-dihydro-4-oxonaphthyridinderivaten |
| US4614572A (en) * | 1985-07-08 | 1986-09-30 | The Dow Chemical Company | Liquid phase chlorination of chlorinated methanes |
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| DE19500784A1 (de) * | 1995-01-13 | 1996-07-18 | Bayer Ag | Enrofloxacin-Injektions- oder Infusionslösungen |
| JP3416145B2 (ja) * | 1995-12-21 | 2003-06-16 | ファイザー インク． | 注射用キノロン製剤 |
| DE19729879C2 (de) * | 1997-07-11 | 1999-07-08 | Mann Gerhard Chem Pharm Fab | Lagerstabile ophthalmische Zusammensetzungen, umfassend Diclofenac und Ofloxacin |
| US6482799B1 (en) * | 1999-05-25 | 2002-11-19 | The Regents Of The University Of California | Self-preserving multipurpose ophthalmic solutions incorporating a polypeptide antimicrobial |
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| IL152421A0 (en) * | 2000-04-27 | 2003-05-29 | Pfizer Prod Inc | The use of azalide antibiotic compositions for treating or preventing a bacterial or protozoal infection in mammals |
| US7083802B2 (en) * | 2003-07-31 | 2006-08-01 | Advanced Ocular Systems Limited | Treatment of ocular disease |
| DE102004015981A1 (de) * | 2004-04-01 | 2005-10-20 | Bayer Healthcare Ag | Neue kirstalline Form von 8-Cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure |
| CA2576589C (en) * | 2004-08-13 | 2013-11-12 | Schering-Plough Ltd. | Pharmaceutical formulation comprising an antibiotic, a triazole and a corticosteroid |
| DE102006010643A1 (de) * | 2006-03-08 | 2007-09-13 | Bayer Healthcare Aktiengesellschaft | Arzneimittel enthaltend Fluorchinolone |
-
2006
- 2006-03-08 DE DE102006010642A patent/DE102006010642A1/de not_active Withdrawn
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2007
- 2007-02-23 BR BRPI0708692-0A patent/BRPI0708692A2/pt not_active IP Right Cessation
- 2007-02-23 KR KR1020087023898A patent/KR20080110599A/ko not_active Application Discontinuation
- 2007-02-23 NZ NZ571047A patent/NZ571047A/en not_active IP Right Cessation
- 2007-02-23 EP EP07711642A patent/EP1993549A1/de not_active Withdrawn
- 2007-02-23 CN CNA2007800082264A patent/CN101400351A/zh active Pending
- 2007-02-23 MX MX2008011489A patent/MX2008011489A/es not_active Application Discontinuation
- 2007-02-23 JP JP2008557621A patent/JP2009529014A/ja not_active Withdrawn
- 2007-02-23 RU RU2008139633/15A patent/RU2008139633A/ru not_active Application Discontinuation
- 2007-02-23 WO PCT/EP2007/001568 patent/WO2007101560A1/de active Application Filing
- 2007-02-23 CA CA2644981A patent/CA2644981C/en not_active Expired - Fee Related
- 2007-02-23 AU AU2007222676A patent/AU2007222676A1/en not_active Abandoned
- 2007-02-23 US US12/280,996 patent/US20090163484A1/en not_active Abandoned
-
2008
- 2008-09-01 ZA ZA200807486A patent/ZA200807486B/xx unknown
- 2008-09-05 CR CR10274A patent/CR10274A/es not_active Application Discontinuation
- 2008-09-05 SV SV2008003018A patent/SV2008003018A/es not_active Application Discontinuation
- 2008-09-08 EC EC2008008722A patent/ECSP088722A/es unknown
-
2014
- 2014-11-21 US US14/550,877 patent/US20150080387A1/en not_active Abandoned
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011147280A1 (zh) * | 2010-05-22 | 2011-12-01 | 鼎正动物药业（天津）有限公司 | 一种恩诺沙星注射液及其制备方法 |
| CN110248643A (zh) * | 2017-02-13 | 2019-09-17 | 拜耳动物保健有限责任公司 | 含普拉沙星的液体组合物 |
| CN110248643B (zh) * | 2017-02-13 | 2023-11-24 | 拜耳动物保健有限责任公司 | 含普拉沙星的液体组合物 |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2009529014A (ja) | 2009-08-13 |
| KR20080110599A (ko) | 2008-12-18 |
| BRPI0708692A2 (pt) | 2011-06-14 |
| CR10274A (es) | 2009-03-18 |
| AU2007222676A1 (en) | 2007-09-13 |
| WO2007101560A1 (de) | 2007-09-13 |
| DE102006010642A1 (de) | 2007-09-27 |
| SV2008003018A (es) | 2009-11-26 |
| NZ571047A (en) | 2012-03-30 |
| US20150080387A1 (en) | 2015-03-19 |
| EP1993549A1 (de) | 2008-11-26 |
| ECSP088722A (es) | 2008-11-27 |
| MX2008011489A (es) | 2008-11-14 |
| ZA200807486B (en) | 2009-11-25 |
| CA2644981A1 (en) | 2007-09-13 |
| CA2644981C (en) | 2015-04-28 |
| US20090163484A1 (en) | 2009-06-25 |
| RU2008139633A (ru) | 2010-04-20 |
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