CN102335117A - 具有改进的药物性质的含有调味剂的药物制剂 - Google Patents
具有改进的药物性质的含有调味剂的药物制剂 Download PDFInfo
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- CN102335117A CN102335117A CN2011102916216A CN201110291621A CN102335117A CN 102335117 A CN102335117 A CN 102335117A CN 2011102916216 A CN2011102916216 A CN 2011102916216A CN 201110291621 A CN201110291621 A CN 201110291621A CN 102335117 A CN102335117 A CN 102335117A
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Abstract
本发明涉及具有改进的药物性质的含有调味剂的药物制剂以及其制备的方法。
Description
本申请是申请号为200480032577.5、申请日为2004年10月30日的发明专利申请的分案申请。
技术领域
本发明涉及具有改进的药物性质的含有调味剂的药物制剂，以及其制备方法。
背景技术
芳香物质(Aromastoffen)在药物制剂中的应用在兽医学领域中正变得日益重要。芳香物质应是用来帮助动物，例如狗或猫服用固体形式的药品。市场上可用的芳香物质，如Trigarol Bayopal(Haarmann und Reimer GmbH，Holzminden，D)或Artificial BeefFlavor(Pharma Chemie，Syracuse，Nebraska，USA)对于药片的药物性质有不利的影响。因而，比如，片剂硬度(片剂硬度的测定如Bauer，Kurt H.；
Karl-Heinz；Führer，Claus：Lehrbuch derPharmazeutischen Technologie，6th revised and corrected edition，1999中所述)会降低或者药片的稳定性由于在释放中或片剂硬度的衰退而受到不利影响。这些变化造成药物产品的质量的缺点。
Botzolakis，Harris和Nesbitt在Pharm.Res.(5，No.10，Suppl.S253，1988)和EP-A-0345787或US 04910023中公开了具有令人不愉快的味道的活性成分的制剂和其制备方法。既然这样，令人不愉快的味道，吸湿的活性成分悬浮在水中，并用高分散二氧化硅一起干燥。这产生令人愉快的味道，较少吸湿的片剂。
适于动物应用的固体药物制剂所应满足的要求是各种各样的：
-良好的动物可接受性，在最好的情况下随意摄入，
-良好的存储稳定性，特别是较低的吸收水分的倾向，
-良好的机械性能，特别是片剂硬度，
-良好的崩解和释放特性。
通过加入芳香物质或调味剂实现提高了的可接受性。到此为止，该问题在于这些芳香物质导致相应的固体制剂的药物特性的衰退。
发明内容
现已惊人的发现，可以通过加入比较大量的高分散二氧化硅降低或完全弥补调味剂或芳香物质的不利影响，并且所得的固体药物制剂在所有上述提到的标准上都有良好或非常良好的特性。因此值得注意的是高分散二氧化硅几乎不影响调味或芳香物质的作用，尽管在该现有技术中它是用来遮蔽味道。
因此本发明涉及一种固体药物制剂，其含有药物活性成分、调味剂和按所得的制剂的总重量为基准计，至少1.5重量％的高分散二氧化硅。
本发明的药物制剂通常含有的药物活性成分的量为0.001-90重量％。
适用的药物活性成分通常是所有兽药中的常规药物活性成分。可以提及的实例为：喹诺酮-抗生素和治疗癌症的试剂，特别是MMP抑制剂。
喹诺酮-抗生素特别公开在下列文献中：US4670444(Bayer AG)，US4472405(Riker Labs)，US 4730000(Abbott)、US4861779(Pfizer)，US4382892(Daiichi)，US4704459(Toyama)，需要提及的喹诺酮抗生素的具体实例为：环丙沙星(ciprofloxacin)、恩氟沙星(enrofloxacin)、依巴沙星(ibafloxacin)、沙氟沙星(sarafloxacin)、双氟哌酸(difloxacin)、宾氟沙星(binfloxacin)、达氟沙星(danofloxacin)、马波沙星(marbofloxacin)、benofloxacin、氧氟沙星(ofloxacin)、奥比沙星(orbifloxacin)、托舒沙星(tosufloxacin)、替马氟沙星(temafloxacin)、pipemidic acid(吡哌酸)、诺氟沙星(norfloxacin)、培氟沙星(pefloxacin)、ofloxacin、氟罗沙星(fleroxacin)。此外作为更合适的喹诺酮抗生素可以提及的是公开在WO97/31001中的化合物，特别是，下式的pradofloxacin(8-氰基-1-环丙基-7-((1S，6S)-2，8-二氮杂双环[4.3.0]壬-8-基)-6-氟-1，4-二氢-4-氧代-3-喹啉甲酸)。
优选的喹诺酮-抗生素如通式(I)和(Ⅱ)一般性所示：
其中
A为氮或＝C-R4，
R4为氢、氟、氯、氰基、硝基或甲基，
B为
和
R5为氢、带支链或不带支链的含有1-4个碳原子的烷基基团，其可任选的被羟基或甲氧基基团所取代，
R6为氢、甲基或苯基，
R7为氢或甲基，
R8为氨基、在烷基基团中含有1或2个碳原子的烷基氨基或二烷基氨基、氨甲基、在烷基基团中含有1或2个碳原子的烷基氨基甲基或二烷基氨基甲基，
R1为含有1-3个碳原子的烷基、环丙基、2-氟代乙基、乙烯基、甲氧基、4-氟代苯基或甲氨基，
R2为氢、含有1-6个碳原子的烷基以及环己基、苯甲基、2-氧代丙基、苯甲酰甲基和乙氧羰基甲基，
R3为氢、甲基或乙基，
Z为氧、被甲基或苯基取代的氮和-CH2-，
以及它们的可药用盐。
优选的活性成分是如式(Ia)所示的喹诺酮羧酸和它们的衍生物，
其中
B为
且A，R2，R5，R6和R7的定义如上所述。
更优选的活性成分是如式(Ia)所示的喹诺酮羧酸和它们的衍生物，
其中
R2为氢、含有1-4个碳原子的烷基以及苯甲基、2-氧代丙基、苯甲酰甲基和乙氧羰基甲基，
B为
R5为氢、甲基或乙基，
R6为氢或甲基，
R7为氢或甲基，且
A的定义如上所述。
特别作为活性成分可提及的是由下述喹诺酮羧酸及它们的衍生物：
1-环丙基-6-氟-1，4-二氢-4-氧代-7-(1-哌嗪基)喹啉-3-羧酸(卷须霉素)、1-环丙基-6-氟-1，4-二氢-4-氧代-7-(4-甲基-1-哌嗪基)喹啉-3-羧酸、1-环丙基-6-氟-1，4-二氢-4-氧代-7-(4-乙基-1-哌嗪基)喹啉-3-羧酸(恩氟沙星)、1-乙基-6-氟-1，4-二氢-4-氧代-7-(4-甲基-1-哌嗪基)喹啉-3-羧酸、1-乙基-6-氟-1，4-二氢-4-氧代-7-(1-哌嗪基)喹啉-3-羧酸、1-乙基-6-氟-1，4-二氢-4-氧代-7-(1-哌嗪基)-1，8-
啶-3-羧酸、9-氟-3-甲基-10-(4-甲基-1-哌嗪基)-7-氧代-2，3-二氢-7，H-吡啶并-[1，2，3-de]-1，4-苯并
嗪-6-羧酸以及它们的可药用盐，和这些化合物的甲基和乙基酯。
恩氟沙星和pradofloxacin和它们的可药用盐是非常特别优选使用的。
需要提及的可药用盐是生理学上可接受的酸加成盐和与碱形成的盐。这些盐是已知的或可以通过类似于已知方法的方法来制备。
需要提及的酸的实例为：盐酸、硫酸、磷酸、有机酸例如甲酸、乙酸、乳酸、苹果酸、富马酸、柠檬酸、抗坏血酸、丁二酸、酒石酸、丙二酸、马来酸、扑酸(embonic acid)。
作为优选，可被提到的是盐酸、乙酸、乳酸、扑酸。
与碱形成的盐的实例是基础羧酸的碱金属、碱土金属、银和
盐。可提及的合适的碱的实例为无机碱例如NaOH、KOH、Ca(OH)2、氨，有机碱例如胺如单-、二-、三烷基胺、取代胺例如乙醇胺、环胺例如吗啉、哌嗪、碱性氨基酸例如精氨酸、赖氨酸、胆碱、N-甲基葡糖胺。
优选以下碱：NaOH、KOH、乙醇胺、赖氨酸、N-甲基葡糖胺。
更优选以下碱：NaOH、KOH。
同样可以使用活性成分或盐的药学上可接受的溶剂化物，特别是水合物。
活性成分是已知的或可以通过类似于已知方法的方法来制备。
适用的MMP抑制剂详细的公开在WO96/15096中，特别援引该参考文献。在那里公开的化合物中，优选具有联苯基结构的；需要提及的更优选的例子是化合物tanomastat：
在药学上可接受的盐，水合物等可同样地被使用。
本发明所用的调味剂或芳香物质涉及通过特别加工得到的蛋白质、脂肪和碳水化合物的混合物。特别提及的是Haarmann & Reimer公司的Trigarol Bayopal
和Pharma Chemie公司(Syracuse，Nebraska，USA)的Artificial Beef
本发明的药物制剂中使用的调味剂或芳香物质，以所得制剂的总重量为基准计，的量为1-40重量％，优选2.5-30重量％，特别是4-20重量％。
高分散二氧化硅如欧洲药典(欧洲药典，二氧化硅，无水胶体)或美国药典(美国药典，胶体二氧化硅)中所述。商业化产品是例如为Aerosil(Degussa)、Dissolvurol或Entero-Teknosal。
本发明的固体药物制剂包含，按所得制剂的总重量为基准计，至少1.5重量％的高分散二氧化硅，按所得制剂的总重量为基准计，优选含有至少2.5重量％，更优选至少4重量％的高分散二氧化硅。通常本发明的固体药物制剂含有不多于15重量％，优选不多于10重量％的高分散二氧化硅。在上示限制范围内，已证明特别有利的是，以高分散二氧化硅与芳香物质的重量比为从1∶4-1∶1来加工高分散二氧化硅。
此外，制备本发明的固体药物制剂的方法也被发现，其中调味剂和高分散二氧化硅以及一种或多种助剂和制药上常用的活性物质被造粒。本发明制备方法可以是下列变体：
-加入调味剂和高分散二氧化硅进行混合(也就是加入到由其它成分构成的颗粒中)，在合适的容器中进行固体成分的混合2-30分钟，作选在筛分后，例如通过筛格尺寸为0.5-2mm的筛子，
-使用由水或水和，例如，淀粉(玉米淀粉、米淀粉、小麦淀粉、马铃薯淀粉)、改性淀粉(预糊化淀粉、羟乙基淀粉)、明胶、黄茋胶、纤维素衍生物(甲基纤维素、羟丙基甲基纤维素、羟丙基纤维素、羧甲基纤维素钠)或聚乙烯吡咯烷酮构成的粘合剂溶液进行调味剂和高分散二氧化硅的含水造粒，加入这些颗粒进行混合(也就是加入到由其它成分构成的颗粒中)或进一步造粒，
-调味剂和高分散二氧化硅的含醇(例如乙醇)造粒，将这些颗粒加入/进入混合，或进一步造粒，
-使用其它粘合剂，使调味剂和高分散二氧化硅造粒，加入这些颗粒进行混合或进一步造粒，
-加入调味剂和高分散二氧化硅到活性成分的造粒中，可能一起加入的其它助剂例如，填料、崩解助剂或粘合剂。
造粒可以通过高速搅拌机作为湿法造粒(abbauende造粒)和之后的干燥例如在流化床或入口空气温度为40-120℃的盘式烘燥器中进行，或者作为aufbauende造粒例如在流化床选粒装置中进行。
本发明的药物制剂适用于兽医，例如，家畜管理和家畜饲养。它们可以用于农业和饲养家畜、动物园、实验室和试验动物和宠物。
农业和饲养家畜包括哺乳动物，例如，牛、马、绵羊、猪、山羊、骆驼、水牛、驴子、兔、扁角鹿、驯鹿，毛皮动物，例如，水貂、南美栗鼠、浣熊，鸟类，例如，鸡、鹅、火鸡、鸭、鸽，以及在家中或动物园饲养的鸟类。生产性和观赏鱼也包括在内。
实验室和试验动物包括小鼠、大鼠、豚鼠、金地鼠、狗和猫。
宠物包括狗和猫。
本发明的固体药物制剂优选为片剂。然而，其它固体配制品也是合适的，如粉剂、预混合料或浓缩物、颗粒剂、丸剂、boli、胶囊剂、气雾剂和吸入剂。
本发明的固体药物制剂可以含有其它制药学上可接受的添加剂和助剂，例如，载体和下文中详述的助剂。
可提及的载体是所有生理学上可接受的固体惰性物质。无机和有机物质都可使用。无机物质的例子是氯化钠、碳酸盐如碳酸钙、碳酸氢盐、氧化铝、二氧化硅、矾土、磷酸盐。
有机物质的例子是蔗糖、乳糖、甘露醇、纤维素、人类或动物的食物例如奶粉、骨粉、磨碎和碾碎的谷物、淀粉。
助剂是抗氧化剂，例如，抗坏血酸、生育酚、色素，其被批准用于动物且可在溶液或悬浮液中使用。
其它适用的助剂为润滑剂和助流剂，例如，硬脂酸镁、硬脂酸、滑石、膨润土，促崩解物质例如淀粉和淀粉衍生物、交联羧甲基纤维素钠或交联聚乙烯吡咯烷酮，粘合剂，例如，淀粉(玉米淀粉、米淀粉、小麦淀粉、马铃薯淀粉)、改性淀粉(预糊化淀粉、羟乙基淀粉)、明胶、黄茋胶、纤维素衍生物(甲基纤维素、羟丙基甲基纤维素、羟丙基纤维素、羧甲基纤维素钠)或聚乙烯吡咯烷酮，和干燥粘合剂如微晶纤维素。
附图说明：
图1表示了实施例1-4与标准相比，破碎耐性[N]与所施加载荷[kN]的依赖性关系曲线。
图2表示了实施例2、5和6以及标准的破碎耐性[N]与所施加载荷[kN]的依赖性关系曲线。
图3表示了实施例7-11的挠曲强度[N]。
图4表示了实施例20-23的7天时间期间的吸水率[％]。
图5表示了实施例20-23在片剂硬度上的减少[％]。
图6表示了实施例20与27-30的破碎耐性[N]与所施加载荷[kN]的依赖性关系曲线。
图7表示了实施例20与27-30的崩解时间[min]与破碎耐性[N]的依赖性关系曲线；已示出可接受的崩解时间的上限。该时间应该远低于由欧洲药典规定的上限15分钟，为了确保所有药片总能遵照所需的限制。由于这个原因，少于10分钟的崩解时间被认为是可接受的。
图8表示了实施例28和30在潮湿环境下储存8周后的药片释放动力学。所释放的活性成分的百分数基于时间标绘。
图9表示了采用不同方法制备的实施例28的组成的药片的破碎耐性[N]与所施加载荷[kN]的依赖性关系曲线。
图10表示了采用不同方法制备的实施例30的组成的药片的破碎耐性[N]与所施加载荷[kN]的依赖性关系曲线。
具体实施方式
实施例
I.恩氟沙星片剂
表1
配方研究：
片剂成分[mg/片]
芳香物质的加入产生具有调味剂含量增加的片剂硬度，如图1所示。
片剂硬度可以通过加入大量高分散二氧化硅(例如Aerosil
)和通过加入其它助剂来改进(图2)。
表2
用mg/片表示成分的用量
Ⅱ.Pradofloxacin片剂
为pradofloxacin(结构式)选择不同的配方，并测试了加入的芳香物质对片剂性质的影响。
表3
甘露糖醇基配方：
用mg/片表示成分用量
片剂规格：椭圆形14×6r5[mm]
Bayopal的加入减小了片剂硬度(表示为硬度产率＝挠曲强度/载荷比)。与无芳香物质的配方相比，椭圆形片剂的挠曲强度减小了。片剂硬度可以通过加入高分散二氧化硅明显提高，这也对生产(运输、包装)和片剂的服用有利。
含高分用二氧化硅的配方的另外的优势体现在潮湿环境中的储存上。在空气湿度＞80％下储存一周后，所有带芳香物质的片剂的挠曲强度都减小了。在使用大量高分散二氧化硅时，这种减小可以被缩小到一个实际可接受的范围，如后面的图3所示。
表4
基于微晶纤维素的配方：
| 实施例12 | 实施例13 | 实施例14 | 实施例15 | 实施例16 | |
| Pradofloxacin | 100 | 100 | 100 | 100 | 100 |
| 微晶纤维素 | 152.8 | 152.8 | 152.8 | 152.8 | 152.8 |
| PVP25 | 30 | 30 | 30 | 30 | 30 |
| 人造牛肉调味剂 | 15 | ||||
| Bayopal | 15 | 15 | 15 | ||
| Croscarmellose Natrium | 15 | 15 | 15 | 15 | 15 |
| 高分散二氧化硅 | 0.9 | 0.9 | 15.9 | 4.65 | 15.9 |
| 硬脂酸镁 | 1.35 | 1.35 | 1.35 | 1.35 | 1.35 |
| 挠曲强度/载荷的比例 | 6.53×10-3 | 4.25×10-3 | 5.29×10-3 | 4.68×10-3 | 6.46×10-3 |
用mg/片表示成分用量
片剂规格：椭圆形14×6r5[mm]
改进片剂硬度的原理，已经叙述过多次的，也被应用在基于微晶纤维素的pradofloxacin配方。这些片剂表明，芳香物质的加入对于这些片剂的硬度有特别不利的影响，但这可以通过加入高分散二氧化硅避免。
带有乳糖和微晶纤维素的pradofloxacin片剂：
下面混合物可以压缩成各种尺寸的片剂：
表5
| Pradofloxacin | 15.0％ |
| 微晶纤维素 | 35.0％ |
| 乳糖 | 24.0％ |
| PVP25 | 5.0％ |
| 人造牛肉调味剂 | 10.0％ |
| Croscarmellose Natrium | 7.5％ |
| 高分散二氧化硅 | 2.5％ |
| 硬脂酸镁 | 1.0％ |
具有下面尺寸和剂量的片剂是可能的，例如：
Pradofloxacin剂量 片剂的形式
实施例17：15mg 8×4r4.5[mm]
实施例18：60mg 14×7r6[mm]
实施例19：120mg 18×8r6[mm]
小的片剂对于湿度特别敏感。实施例17的片剂在没有保护的包装下在室外储存后，它们保留的硬度对与它们的尺寸是足够的，如下所示，而且由前面pradofloxacin片剂实施例的结果确认和补充。
表6
在85％相对湿度下室外储存15天后片剂硬度：
| 载荷[kN] | 室外储存后的片剂硬度[N] |
| 9 | 32 |
| 12 | 34 |
| 13.5 | 36 |
Ⅲ.Tanomastat片剂
tanomastat(结构式)以各种最佳味道片剂的形式被研究。
表7
含人造牛肉调味剂的配方
| 实施例20 | 实施例21 | 实施例22 | 实施例23 | |
| Tanomastat | 200.0 | 200.0 | 200.0 | 200.0 |
| 乳糖 | 121.20 | 121.20 | 121.20 | 121.20 |
| 微晶纤维素 | 60.8 | 60.80 | 60.80 | 60.80 |
| 月桂基硫酸钠 | 2.0 | 2.0 | 2.0 | 2.0 |
| 人造牛肉调味剂 | - | 40.0 | 40.0 | 20.0 |
| Croscarmellose Natrium | 12.0 | 12.0 | 12.0 | 12.0 |
| 高分散二氧化硅 | - | - | 10.0 | 20.0 |
| 硬脂酸镁 | 4.0 | 4.0 | 4.0 | 4.0 |
用mg/片表示成分用量
实施例20是作为对比的不带调味剂的配方。含有调味剂的配方在潮湿条件下储存时，它们吸收水分，如之后对于实施例配方的图4所示。这可以通过大量加入高分散二氧化硅来缩减。
在储存中，片剂另外会损失硬度到一个明显的程度，这可能导致在市场中的问题(消费者的抱怨)。这一问题也可以用本发明的方法减低(见图5)。
对应于实施例23的配方可以压制成多种尺寸的片剂，如下面例子的方法所示：
表8
| 实施例23 | 实施例24 | 实施例25 | 实施例26 | |
| Tanomastat | 200.0 | 50.0 | 300.0 | 400.0 |
| 乳糖 | 121.20 | 30.3 | 181.8 | 242.4 |
| 微晶纤维素 | 60.80 | 15.2 | 91.2 | 121.6 |
| 月桂基硫酸钠 | 2.0 | 0.5 | 3.0 | 4.0 |
| 人造牛肉调味剂 | 20.0 | 5.0 | 30.0 | 40.0 |
| Croscarmellose Natrium | 12.0 | 3.0 | 18.0 | 24.0 |
| 高分散二氧化硅 | 20.0 | 5.0 | 30.0 | 40.0 |
| 硬脂酸镁 | 4.0 | 1.0 | 6.0 | 8.0 |
| 片剂形式 | 16*6r 5 | 9*4r 4.5 | 17*7r 6 | 18*8r 6 |
用mg/片表示成分用量；片剂规格以mm计。
所有这些配方表现了在潮湿条件下储存的上述优势。
表9
含Bayopal的配方
| 实施例20 | 实施例27 | 实施例28 | 实施例29 | 实施例30 | |
| Tanomastat | 200.0 | 200.0 | 200.0 | 200.0 | 200.0 |
| 乳糖 | 121.20 | 121.20 | 121.20 | 121.20 | 121.20 |
| 微晶纤维素 | 60.80 | 60.80 | 60.80 | 60.80 | 60.80 |
| 月桂基硫酸钠 | 2.0 | 2.0 | 2.0 | 2.0 | 2.0 |
| Bayopal | - | 40.0 | 40.0 | 40.0 | 40.0 |
| Croscarmellose Natrium | 12.0 | 12.0 | 12.0 | 12.0 | 12.0 |
| 高分散二氧化硅 | - | - | 40.0 | 20.0 | 10.0 |
| 硬脂酸镁 | 4.0 | 4.0 | 4.0 | 4.0 | 4.0 |
用mg/片表示成分用量
Bayopal的加入使配方损失了硬度。这可以，也如已经在其它活性成分和调味剂描述的，通过加入高分散二氧化硅来避免(见图6)。
除了对于片剂硬度的不利影响，调味剂也会引起崩解和释放性能的变坏。这些不利影响也可通过所述的本发明的措施来减小。
含有高分散二氧化硅的片剂的崩解，不论改进的片剂硬度，都比含有调味剂不含高分散二氧化硅的片剂快(图7)。
如果已加入大量高分散二氧化硅，在潮湿条件储存8周后，如含有50mg类似于实施例28和30的成分的50mg活性成分生产的片剂显示了改进的释放(图8)。
Ⅳ.狗的接受性试验
对应于实施例23和24的配方用于40只狗试验。与EP00345787或US04910023所述的味觉遮蔽相比，被测配方被受调查狗的92.5％自愿吞下，证明加入的芳香物质惊人的并未损失它的功能性。
V.生产工艺的影响
所有所述的配方都可以选择各种生产工艺：
-调味剂和高分散二氧化硅加入混合物中，
-调味剂和高分散二氧化硅的含水造粒，加入这些颗粒进行后混合或进一步造粒，
-调味剂和高分散二氧化硅的含醇(例如乙醇)造粒，加入这些颗粒进行后混合或进一步造粒，
-使用其它粘合剂使调味剂和高分散二氧化硅造粒，加入这些颗粒进行后混合或进一步造粒，
-加入调味剂和高分散二氧化硅进行活性成分的造粒，可能一起加入的其它助剂例如，填料、崩解剂或粘合剂。
这些生产工艺带来了具有同样性质的片剂。图9示出对应于由不同造粒工艺生产的实施例28的组成的片剂的硬度。
根据实施例30为片剂选择不同的生产工艺同样带来具有实际上同样的负载/硬度分布的片剂(图10)。
这些数据证明在含有调味剂的制剂中加入大量高分散二氧化硅导致了片剂在药物性质上的改进的原理，与所选择的造粒或压片工艺无关。
Claims (8)
1.一种固体药物制剂，其含有：
-喹诺酮抗生素作为药物活性成分；
-按最终制剂的总重量为基准计，4-20重量％的调味剂或芳香物质，所述调味剂或芳香物质包含通过特别加工得到的蛋白质、脂肪和碳水化合物的混合物；和
-1.5-15重量％的高分散二氧化硅，按最终制剂的总重量为基准计，所述高分散二氧化硅与调味剂或芳香物质以从1∶4-1∶1的重量比存在。
2.如权利要求1所述的固体药物制剂，其中含有作为药物活性成分的恩氟沙星、恩氟沙星盐或恩氟沙星或其盐的水合物。
3.如权利要求1或2所述的固体药物制剂，其中含有作为药物活性成分的pradofloxacin、pradofloxacin盐或pradofloxacin或其盐的水合物。
4.如权利要求1或2所述的固体药物制剂，其中含有至少4重量％的高分散二氧化硅，按最终制剂的总重量为基准计。
5.如权利要求1或2所述的固体药物制剂，其中含有不多于10重量％的高分散二氧化硅。
6.一种生产如权利要求1所述的固体药物制剂的方法，其中调味剂和高分散二氧化硅以及和一种或多种活性成分及制药学常用的添加剂和/或助剂造粒。
7.权利要求1-5中任一项的固体药物制剂在制备用于兽药中的药物中的用途。
8.权利要求7的用途，其是在制备用于狗或猫的药物中的用途。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10351448.1 | 2003-11-04 | ||
| DE10351448A DE10351448A1 (de) | 2003-11-04 | 2003-11-04 | Geschmackstoffhaltige Arzneimittelformulierungen mit verbesserten pharmazeutischen Eigenschaften |
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| CN2004800325775A Division CN1972687B (zh) | 2003-11-04 | 2004-10-30 | 具有改进的药物性质的含有调味剂的药物制剂 |
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| Publication Number | Publication Date |
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| CN102335117A true CN102335117A (zh) | 2012-02-01 |
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| CN2004800325775A Expired - Lifetime CN1972687B (zh) | 2003-11-04 | 2004-10-30 | 具有改进的药物性质的含有调味剂的药物制剂 |
| CN2011102916216A Pending CN102335117A (zh) | 2003-11-04 | 2004-10-30 | 具有改进的药物性质的含有调味剂的药物制剂 |
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| CN2004800325775A Expired - Lifetime CN1972687B (zh) | 2003-11-04 | 2004-10-30 | 具有改进的药物性质的含有调味剂的药物制剂 |
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| EP (2) | EP2080515A1 (zh) |
| JP (1) | JP4892351B2 (zh) |
| KR (2) | KR101325146B1 (zh) |
| CN (2) | CN1972687B (zh) |
| AR (2) | AR046226A1 (zh) |
| AT (1) | ATE454891T1 (zh) |
| AU (1) | AU2004286785B2 (zh) |
| BR (1) | BRPI0416188A (zh) |
| CA (1) | CA2544344C (zh) |
| CR (1) | CR8371A (zh) |
| CY (2) | CY1110541T1 (zh) |
| DE (2) | DE10351448A1 (zh) |
| DK (1) | DK1682144T3 (zh) |
| ES (1) | ES2337793T3 (zh) |
| HR (1) | HRP20100189T1 (zh) |
| IL (1) | IL175147A (zh) |
| LU (1) | LU91882I2 (zh) |
| MY (1) | MY149864A (zh) |
| NO (1) | NO339326B1 (zh) |
| NZ (1) | NZ546921A (zh) |
| PE (1) | PE20050575A1 (zh) |
| PL (1) | PL1682144T3 (zh) |
| PT (1) | PT1682144E (zh) |
| RU (1) | RU2377018C2 (zh) |
| SI (1) | SI1682144T1 (zh) |
| TW (1) | TWI343819B (zh) |
| UA (1) | UA85691C2 (zh) |
| WO (1) | WO2005044271A1 (zh) |
| ZA (1) | ZA200603451B (zh) |
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| DE10351448A1 (de) * | 2003-11-04 | 2005-06-09 | Bayer Healthcare Ag | Geschmackstoffhaltige Arzneimittelformulierungen mit verbesserten pharmazeutischen Eigenschaften |
| CN100360131C (zh) * | 2006-01-24 | 2008-01-09 | 新昌国邦化学工业有限公司 | 一种掩味恩诺沙星的生产方法 |
| DE102006049520A1 (de) | 2006-10-20 | 2008-04-24 | Bayer Healthcare Ag | Verfahren zur Herstellung von Pradofloxacin |
| DE102007004732A1 (de) * | 2007-01-31 | 2008-08-07 | Bayer Healthcare Ag | Enrofloxacin-Hexahydrat |
| FR2918567B1 (fr) * | 2007-07-11 | 2012-08-03 | Pf Medicament | Composition pharmaceutique stable d'un sel hydrosoluble de vinorelbine. |
| GB0722484D0 (en) * | 2007-11-15 | 2007-12-27 | Ucl Business Plc | Solid compositions |
| DE102008022520A1 (de) * | 2008-05-07 | 2009-11-12 | Bayer Animal Health Gmbh | Feste Arzneimittelformulierung mit verzögerter Freisetzung |
| US20110223297A1 (en) * | 2010-03-12 | 2011-09-15 | Pepsico., Inc. | Anti-Caking Agent for Flavored Products |
| AU2013361760B2 (en) | 2012-12-19 | 2018-07-05 | Elanco Animal Health Gmbh | Tablets with improved acceptance and good storage stability |
| WO2015042596A1 (en) * | 2013-09-23 | 2015-03-26 | Kindred Biosciences, Inc | Treatment of atopic dermatitis in non-human animals |
| JP6600084B2 (ja) * | 2016-04-27 | 2019-10-30 | 富士フイルム富山化学株式会社 | トスフロキサシントシル酸塩、崩壊剤および酸性アミノ酸を含む錠剤 |
| WO2017188361A1 (ja) * | 2016-04-27 | 2017-11-02 | 富山化学工業株式会社 | トスフロキサシントシル酸塩を含む錠剤 |
| CN105997908B (zh) * | 2016-06-03 | 2019-06-21 | 湖北回盛生物科技有限公司 | 一种马波沙星牛肉风味片及其制备方法 |
| AU2019260015C1 (en) | 2018-04-25 | 2024-11-21 | Elanco Animal Health Gmbh | Process for the hydrolysis of quinolone carboxylic esters |
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2003
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2004
- 2004-10-30 WO PCT/EP2004/012327 patent/WO2005044271A1/de not_active Ceased
- 2004-10-30 CN CN2004800325775A patent/CN1972687B/zh not_active Expired - Lifetime
- 2004-10-30 JP JP2006538719A patent/JP4892351B2/ja not_active Expired - Lifetime
- 2004-10-30 PT PT04791080T patent/PT1682144E/pt unknown
- 2004-10-30 HR HR20100189T patent/HRP20100189T1/hr unknown
- 2004-10-30 CA CA2544344A patent/CA2544344C/en not_active Expired - Lifetime
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- 2004-10-30 DK DK04791080.7T patent/DK1682144T3/da active
- 2004-10-30 AT AT04791080T patent/ATE454891T1/de active
- 2004-10-30 KR KR1020067009479A patent/KR101325146B1/ko not_active Expired - Lifetime
- 2004-10-30 ES ES04791080T patent/ES2337793T3/es not_active Expired - Lifetime
- 2004-10-30 NZ NZ546921A patent/NZ546921A/en not_active IP Right Cessation
- 2004-10-30 UA UAA200606220A patent/UA85691C2/ru unknown
- 2004-10-30 DE DE502004010644T patent/DE502004010644D1/de not_active Expired - Lifetime
- 2004-10-30 RU RU2006119294/15A patent/RU2377018C2/ru active
- 2004-10-30 CN CN2011102916216A patent/CN102335117A/zh active Pending
- 2004-10-30 PL PL04791080T patent/PL1682144T3/pl unknown
- 2004-10-30 US US10/576,408 patent/US7858120B2/en active Active
- 2004-10-30 EP EP09006259A patent/EP2080515A1/de not_active Withdrawn
- 2004-10-30 SI SI200431377T patent/SI1682144T1/sl unknown
- 2004-10-30 KR KR1020127012940A patent/KR20120093299A/ko not_active Withdrawn
- 2004-10-30 AU AU2004286785A patent/AU2004286785B2/en not_active Expired
- 2004-10-30 EP EP04791080A patent/EP1682144B1/de not_active Expired - Lifetime
- 2004-10-30 BR BRPI0416188-2A patent/BRPI0416188A/pt not_active Application Discontinuation
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- 2004-11-02 AR ARP040104032A patent/AR046226A1/es not_active Application Discontinuation
- 2004-11-03 PE PE2004001067A patent/PE20050575A1/es not_active Application Discontinuation
- 2004-11-03 TW TW093133413A patent/TWI343819B/zh not_active IP Right Cessation
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- 2010-02-04 CY CY20101100111T patent/CY1110541T1/el unknown
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