CN101405032B - 含有吡啶并(3,2,1-ij)苯并噁二嗪型化合物的抗感染溶液 - Google Patents
含有吡啶并(3,2,1-ij)苯并噁二嗪型化合物的抗感染溶液 Download PDFInfo
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- CN101405032B CN101405032B CN2007800033484A CN200780003348A CN101405032B CN 101405032 B CN101405032 B CN 101405032B CN 2007800033484 A CN2007800033484 A CN 2007800033484A CN 200780003348 A CN200780003348 A CN 200780003348A CN 101405032 B CN101405032 B CN 101405032B
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Abstract
本发明涉及一种抗菌溶液,其在药学上可接受的载体中,其中含有至少一种如下式(I)所示的吡啶并(3r,2,1-ij)苯并噁二嗪型化合物或者至少一种该物质的药学上可接受的盐,以及至少一种增溶剂。
Description
技术领域
本发明的技术领域涉及一种用于治疗动物的抗感染溶液。
本发明更具体而言涉及一种含有至少一种吡啶并(3,2,1-ij)苯并噁二嗪化合物的抗感染溶液,特别是一种浓缩溶液。
背景技术
为诸如牛、猪、山羊、羊、家禽和/或马的牲畜以及宠物给药、特别是通过注射给药用于治疗、预防或准预防目的的抗感染产品是非常常见的。
非胃肠道给药的产品的量以及注射位点的数量是选择产品制剂时的重要考虑因素。制得浓缩型制剂的目的在于减少给药量和/或次数,尤其是对于牲畜而言,要减少屠宰时不能进行加工的肌肉区域。在制备浓缩型制剂时需要考虑的另一因素是注射位点的局部耐受力,尤其是在减少屠宰损失的情况下。
然而,某些抗感染产品,例如马波沙星,呈现出低水溶性。这将导致需要采用提高其溶解性的工艺,例如成盐作用、利用比该分子本身更易溶的络合物(例如与环糊精配合)、利用pH调节剂、利用分散体系(乳液、脂质体、载体体系)、或者加入诸如有机溶剂、共溶剂或表面活性剂的佐剂。
然而,上述提及的工艺对于某些具体化合物会呈现出截然相反的效果。
在市售溶液中,可列举出马波沙星含量高达10%的稳定溶液。然而,对于治疗、预防或准预防某些适应症,尤其是用于牲畜时,治疗剂量呈现增长。实际应用的市售溶液也同样需要很高的注射给药量,尤其是大于等于40ml,且分散在多个注射位点上。这种情况将导致出现耐受力的问题。
文献EP 0 868 183描写了含有金属盐的达氟沙星浓缩药物水溶液,以改善注射位点的耐受力。
然而,这种之前被设计用于四环素的制剂类型,被证明有可能不适用于或者无法对全部分子类型发挥足够的作用,尤其是在涉及某些喹诺酮的情况中。
然而,出于各种因素,包括善待动物,节省时间,和/或提高肉的产量,希望降低通过非胃肠道途径给药的产品的量、注射位点的数量和/或提高耐受力。
因而,对于抗感染化合物、尤其是喹诺酮型化合物的浓缩型制剂,总是存在减少给药量、给药次数和/或呈现出改善的耐受力的需要,由此对于牲畜可要减少不具有经济价值的肌肉区域。
发明内容
根据本发明的一方面,本发明的目的在于提供一种溶液,其在药学上可接受的载体中,基于溶液总量计,含有10-30重量%的至少一种吡啶并(3,2,1-ij)苯并噁二嗪型化合物或至少一种该物质的药学上可接受的盐,以及至少一种增溶剂。
“吡啶并(3,2,1-ij)苯并噁二嗪型化合物”指对应下式(I)的化合物:
式(I)
其中:
X表示氢原子、卤素原子或羟基,特别是氟原子,
R1表示:
-1-哌嗪基,其4位可被甲基、乙酰基或4-氨基苄基取代;
-吗啉代基;
-1-吡咯烷基,其3位被氯原子或氨基、氨甲基、(甲氨基)甲基、(乙氨基)甲基或甲氧基取代;
-1-咪唑基,其4位可被甲基取代,或者
-1-哌啶基,其4位被羟基或甲氧基取代,以及
R2表示具有1-10个碳原子的直链、支链或环状烷基,尤其是甲基,以及上述化合物的药学上可接受的盐。
更特别地,吡啶并(3,2,1-ij)苯并噁二嗪型化合物所对应的式(I)化合物中,R1表示4位上被甲基取代的1-哌嗪基,R2表示甲基,以及X表示氟原子。该化合物可特别通过文献EP 0 259 804中所述的方法制得。该化合物尤其对应国际通用命名为马波沙星的化合物。
基于溶液的总量计,该溶液可含有10-30重量%,尤其是11-28重量%,特别是12-27重量%,更特别是13-25重量%,以及更特别的是14-23重量%,甚至达到15-20重量%的吡啶并(3,2,1-ij)苯并噁二嗪型化合物。
该溶液含有至少一种增溶剂。该增溶剂可与吡啶并(3,2,1-ij)苯并噁二嗪型化合物形成复合物。特别是当该增溶剂为酸时,其可与吡啶并(3,2,1-ij)苯并噁二嗪型化合物形成盐。
这些复合物制剂能够改善吡啶并(3,2,1-ij)苯并噁二嗪型化合物在溶液中的溶解性,尤其是在水溶液中的溶解性。
关于增溶剂,可列举:
-无机酸,尤其是盐酸、氢溴酸、硫酸、磷酸和硝酸,以及
-有机酸,例如羧酸、磺酸和膦酸;尤其是甲酸、乙酸、丙酸、丁二酸、乙醇酸、乳酸或聚乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、马来酸、羟基马来酸、苯乙酸、苯甲酸、4-氨基苯甲酸、邻氨基苯甲酸、4-羟基苯甲酸、水杨酸、氨基水杨酸、烟酸、甲磺酸、乙磺酸、羟基乙磺酸、苯磺酸、对甲苯磺酸;多羧基的羧酸,例如葡糖酸、葡糖醛酸、半乳糖醛酸、间苯二甲酸和乳糖酸;氨基酸,例如天冬氨酸和谷氨酸、蛋氨酸、色氨酸、赖氨酸和精氨酸;这些酸的酯,其中可列举葡糖酸内酯;以及这些酸的盐,以及
-这些物质的混合物。
在吡啶并(3,2,1-ij)苯并噁二嗪型化合物、尤其是马波沙星的增溶剂中,特别优选的是乳酸、葡糖酸和葡糖酸内酯。
基于溶液的总量计,溶液中增溶剂的含量可为4-58重量%,尤其是5-35重量%,特别是6-25重量%,甚至达到7-20重量%。
特别地,本发明的溶液中增溶剂与吡啶并(3,2,1-ij)苯并噁二嗪型化合物的摩尔比为0.9-4,尤其是1-3,特别是1.1-2.4。
所述溶液中增溶剂的含量使溶液的pH为2-7,尤其是2.8-5。
如上所述的溶液可能表现出有限的稳定性,尤其是当其中含有高浓度的吡啶并(3,2,1-ij)苯并噁二嗪型化合物和低浓度的增溶剂时。
本发明者已发现可以通过添加至少一种增溶剂和/或稳定剂来改善某些浓缩溶液的可行性和/或它们的稳定性。
稳定剂可选自醇、丙二醇、聚乙二醇、丙三醇。更具体而言,该稳定剂为一种醇,尤其是芳香醇、烷醇、芳烷醇或烷芳醇,特别是具有5-15个碳原子,更特别是为苄醇及其衍生物。
“苄醇的衍生物”在本发明中指对应式(II)的化合物:
式(II)
其中R3、R4、R5、R6、R7、R8和R9各自独立地表示氢原子,卤素原子,任选被取代的醇、醚、胺官能团,任选被取代的硫醚、酯、酰胺,或者烷基,芳烷基,烷芳基。
具体而言,基于溶液的总量计,该溶液所含稳定剂的量为0.2-20重量%,尤其是0.3-10重量%,特别是0.4-5重量%,更特别是0.5-3重量%。
另外,所述溶液中稳定剂与吡啶并(3,2,1-ij)苯并噁二嗪型化合物的摩尔比可为0.02-7,尤其是0.05-5,特别是0.1-1.5,甚至为0.2-1。
特别地,所述溶液中增溶剂与稳定剂的摩尔比可为1-15,尤其是1.5-10,特别是2-8,甚至为2.5-7。
本发明的溶液还可另外含有至少一种添加剂,尤其是选自物质的添加剂:-溶剂,例如选自可通过非胃肠道途径利用的非水性溶剂,即与水不混溶的溶剂,例如植物油、油酸乙酯,或者可与水混溶的溶剂,尤其是醇,如乙醇;酰胺,如N,N-二甲基乙酰胺;多元醇酯,如聚葡糖甘油酯;醚,如二甲基-1,3-二氧戊环-4-甲醇、二甘醇单***、甘油缩甲醛、聚乙二醇,尤其是PEG 300和PEG400;多元醇,如甘油、丙二醇;二甲基亚砜;2-吡咯烷酮;或上述物质的混合物,
-表面活性剂,例如非离子、阴离子、阳离子表面活性剂,或者表面活性剂的混合物,以及特别是非离子表面活性剂,
-螯合剂,例如EDTA
-防腐剂,尤其是抗氧剂,或
-抗菌剂,以及
-上述物质的混合物。
所述溶液可特别为水溶液。
所述溶液的pH值为2-7,尤其为2.8-5。
本发明的溶液特别为可注射溶液的形式,更具体而言可通过肌肉注射、皮下注射、腹膜内注射和/或静脉注射途径进行注射。所述溶液还可为输注液或灌注液。该溶液可用于治疗牲畜,如羊、牛、猪、山羊、马和/或家禽,和/或宠物,如狗和猫。
特别地,所述溶液在20℃呈现出的黏性为10-4—10-2Pa.s,更特别是10-3—5×10-3Pa.s。
该溶液可为透明的,特别是不含有悬浮颗粒。
根据本发明的另一方面,本发明的目的在于至少一种如上所述的吡啶并(3r,2,1-ij)苯并噁二嗪型化合物在制造用于治疗或预防感染、特别是动物感染的溶液中的应用,基于该溶液的总量计,所述吡啶并(3,2,1-ij)苯并噁二嗪型化合物的含量为10-30重量%,尤其是11-28重量%,甚至于为12-27重量%,特别是为13-25重量%,更特别是为14-23重量%,甚至于为15-20重量%。
根据本发明的另一方面,本发明的目的在于本发明的溶液在制备用于治疗或预防感染、特别是动物感染的药物中应用。
关于可治疗的感染,可列举呼吸***感染、生殖***感染、泌尿***感染、消化***感染、运动***感染、心血管感染、皮肤型感染、中耳炎、眼炎,尤其是动物体中的这些感染。
根据本发明的另一方面,本发明的目的在于提供一种用于治疗、预防和准预防动物感染的方法。所述治疗方法包括向每kg需治疗的动物注射0.01—0.5ml浓缩溶液,尤其是注射0.01—0.1ml的浓缩溶液。特别地,所述治疗包括在一个位点只进行一次注射。
例如,对于重300kg的动物,用“麻佛微素(MARBOCYL S)”治疗呼吸***感染需要24ml的给药量,并需要在2个注射点上给药,而使用本发明的溶液,只需要在1个位点上注射15ml的药量。
在本发明中,“治疗”是指治疗本身,但也包括预防和准预防。
根据本发明的另一方面,本发明的目的在于至少一种选自醇、丙二醇、聚乙二醇、丙三醇中的化合物作为式(I)化合物溶液的稳定剂的应用。更特别地,所述稳定剂为醇,尤其是芳香醇、烷醇、芳烷醇或烷芳醇,特别是具有5-15个碳原子,更特别是苄醇及其衍生物,作为包含至少一种式(I)化合物以及任选增溶剂的溶液的稳定剂,特别地,所述式(I)化合物是高浓度的,基于溶液的总量计,尤其是具有大于10重量%的浓度。
本发明还涉及至少一种如下列举的化合物作为含有式(I)化合物和任选还含有一种稳定剂的溶液的增溶剂的应用:
-无机酸,尤其是盐酸、氢溴酸、硫酸、磷酸和硝酸,以及
-有机酸,例如羧酸、磺酸和膦酸;尤其是甲酸、乙酸、丙酸、丁二酸、乙醇酸、乳酸或聚乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、马来酸、羟基马来酸、苯乙酸、苯甲酸、4-氨基苯甲酸、邻氨基苯甲酸、4-羟基苯甲酸、水杨酸、氨基水杨酸、烟酸、甲磺酸、乙磺酸、羟基乙磺酸、苯磺酸、对甲苯磺酸;多羧基的羧酸,例如葡糖酸、葡糖醛酸、半乳糖醛酸、间苯二甲酸和乳糖酸;氨基酸,例如天冬氨酸和谷氨酸、蛋氨酸、色氨酸、赖氨酸和精氨酸;这些酸的酯,其中可列举葡糖酸内酯;以及这些酸的盐,以及
-这些物质的混合物,
特别地,所述式(I)化合物是高浓度的,基于溶液的总量计,尤其是具有大于10重量%的浓度。
另外,稳定剂的使用,特别是苄醇的使用,可使含有式(I)化合物(尤其是马波沙星)和含有至少一种增溶剂(尤其是葡糖酸内酯)的浓缩溶液相对于含有相同浓度式(I)化合物和任选含有增溶剂的溶液,呈现出更低的pH值和/或渗透性。这特别是可以使含有至少一种式(I)化合物、增溶剂和稳定剂的浓缩溶液的pH值和/或同渗浓度接近于较低浓度的组合物,尤其是接近于含有较低浓度式(I)化合物和/或较低浓度增溶剂的组合物。这是由于稳定剂的存在使得容许使用较少的增溶剂。
另外,稳定剂的添加同样使制造适于注射的非常高浓度的式(I)化合物的某些溶液成为可能,如果不加入该试剂,则不可能制造该产品,或者制造该产品将非常困难。实际上,稳定剂的作用随稳定剂含量而提高。
特别地,本发明的目的在于使用苄醇作为一部分与乳酸、葡糖酸或葡糖酸内酯作为另外一部分结合作为含有式(I)化合物的溶液的增溶剂和稳定剂,基于溶液的总量计,所述式(I)化合物的浓度特别是大于10重量%,尤其是大于11重量%,更特别是大于12重量%,以及更特别是大于13重量%,或者甚至于大于14重量%。
具体实施方式
提供下述实施例的目的在于描述本发明,在任何情况下,其不能够用于限制本发明范围。
实施例
实施例1
制得下表1中所述的溶液:
第1份 | 对比例 | |
马波沙星(单位g) | 15.00 | 10.00 |
葡糖酸内酯(单位g) | 8.11 | 8.00 |
脱矿物质水qsp | 100ml | 100ml |
70-80kg重量的猪接受肌肉内注射,注射液为单一的右列对比例溶液或左列第1份溶液,剂量为8ml/kg。给药1周后,检查局部耐受力(损伤情况)。
注射第1份溶液呈现出的损伤体积约为9cm3,而注射对比例的溶液呈现出高达32cm3的损伤体积。
该结果表明,相对于对比例溶液,马波沙星的浓缩溶液表现出了更好的局部耐受力。
实施例2
制得以下各份溶液:
第1份 | 第2份 | 第3份 | 第4份 | |
马波沙星 | 20.00g | 20.00g | 20.00g | 20.00g |
葡糖酸内酯 | 19.00g | 19.00g | 17.00g | 17.00g |
苄醇 | - | 2.00g | - | 2.00g |
脱矿物质水 | qsp100ml | qsp100ml | qsp100ml | qsp100ml |
低温下的稳定性 | 24小时 | >7天* | 24小时 | >7天* |
*7天之后,没有发现任何沉淀。
“低温下的稳定性”指各份溶液在+4至+8℃下静置直至沉淀形成的时间。
上述数据清楚地显示本发明的溶液具有改善的稳定性。
Claims (10)
1.一种抗感染溶液,其在药学上可接受的载体中,含有:
(i)基于溶液的总量计,10-30重量%的至少一种对应下式(I)的化合物:
式(I)
其中
X表示氢原子、卤素原子或羟基,
R1表示:
-1-哌嗪基,其4位可被甲基、乙酰基或4-氨基苄基取代;
-吗啉代基;
-1-吡咯烷基,其3位被氯原子或氨基、氨甲基、(甲氨基)甲基、(乙氨基)甲基或甲氧基取代;
-1-咪唑基,其4位可被甲基取代,或者
-1-哌啶基,其4位被羟基或甲氧基取代,以及
R2表示具有1-10个碳原子的直链、支链或环状烷基,或者
至少一种上述化合物的药学上可接受的盐,
(ii)作为稳定剂的苄醇,基于溶液的总量计,该稳定剂的含量为0.2-20重量%,以及
(iii)至少一种选自羧酸及其酯的增溶剂,基于溶液的总量计,该增溶剂的含量为4-58重量%。
2.根据权利要求1所述的溶液,其中,式(I)化合物中的R1表示4位上被甲基取代的1-哌嗪基,R2表示甲基,以及X表示氟原子。
3.根据权利要求1所述的溶液,其中,基于溶液的总量计,该溶液含有11-28重量%的式(I)化合物。
4.根据权利要求1-3任一项所述的溶液,其中,所述增溶剂选自乳酸、葡糖酸和葡糖酸内酯。
5.根据权利要求1-3任一项所述的溶液,其中,所述增溶剂与式(I)化合物的摩尔比为0.9-4。
6.根据权利要求1-3任一项所述的溶液,其中,所述增溶剂的含量使溶液的pH为2-7。
7.根据权利要求1-3任一项所述的溶液,其中,所述稳定剂与式(I)化合物的摩尔比为0.02-7。
8.根据权利要求1-3任一项所述的溶液,其pH为2-7。
9.根据权利要求1-3任一项所述的溶液,其是用作抗感染药物。
10.权利要求1-9任一项所述的溶液在制备用于治疗或预防动物感染的药物中的应用。
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FR0650246 | 2006-01-24 | ||
FR0650246A FR2896416B1 (fr) | 2006-01-24 | 2006-01-24 | Composition anti-infectieuse comprenant un compose de type pyrido (3,2,1-ij)-benzoxadiazine |
PCT/FR2007/050682 WO2007085760A2 (fr) | 2006-01-24 | 2007-01-24 | Solution anti-infectieuse comprenant un compose de type pyrido(3,2,1-ij)-benzoxadiazine |
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EP2145891A1 (en) | 2008-07-09 | 2010-01-20 | Vetoquinol S.A. | 9-substituted-5-carboxy-oxadiazino-quinolone derivatives, their preparation and their application as anti-bacterials |
EP2332916A3 (en) | 2009-11-19 | 2011-08-03 | Krka Tovarna Zdravil, D.D., Novo Mesto | A process for a preparation of marbofloxacin and intermediate thereof |
CN103271875A (zh) * | 2013-07-01 | 2013-09-04 | 浙江华尔成生物药业股份有限公司 | 一种注射用麻保沙星冻干粉及其制备方法与应用 |
US10519409B2 (en) * | 2014-12-31 | 2019-12-31 | Ge Healthcare Bio-Sciences Corp. | Shaft-mounted fluid transfer assembly for a disposable bioreactor |
US10440147B2 (en) | 2015-11-24 | 2019-10-08 | William Edward Woodcock, IV | Quality-of-service management for domain name service |
US20170239250A1 (en) | 2016-02-19 | 2017-08-24 | Eagle Pharmaceuticals, Inc. | Pemetrexed formulations |
CN107445977B (zh) * | 2017-07-13 | 2019-08-09 | 江西傲新生物科技有限公司 | 一种水溶性马波沙星及其制备方法与应用 |
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CN1177300A (zh) * | 1995-01-13 | 1998-03-25 | 拜尔公司 | 恩氟沙星注射液或输液 |
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