CN1886120B - 用于制备可口腔给药的固态药物组合物的方法 - Google Patents

用于制备可口腔给药的固态药物组合物的方法 Download PDF

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CN1886120B
CN1886120B CN200480035106XA CN200480035106A CN1886120B CN 1886120 B CN1886120 B CN 1886120B CN 200480035106X A CN200480035106X A CN 200480035106XA CN 200480035106 A CN200480035106 A CN 200480035106A CN 1886120 B CN1886120 B CN 1886120B
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K·本克
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Abstract

本发明涉及用于制备可口腔给药的固态药物组合物的方法及其用于预防和/或治疗疾病的用途，所述组合物包含亲水形式的5-氯-N-({(5S)-2-氧-3-[4-(3-氧-4-吗啉基)-苯基]-1，3-噁唑烷-5-基}-甲基)-2-噻吩羧酰胺。

Description

用于制备可口腔给药的固态药物组合物的方法
本发明涉及用于制备可口腔给药的固态药物组合物的方法及其用于预防和/或治疗疾病的用途，所述组合物包含亲水形式的5-氯-N-({(5S)-2-氧-3-[4-(3-氧-4-吗啉基)-苯基]-1，3-噁唑烷-5-基}-甲基)-2-噻吩羧酰胺。
5-氯-N-({(5S)-2-氧-3-[4-(3-氧-4-吗啉基)-苯基]-1，3-噁唑烷-5-基}-甲基)-2-噻吩羧酰胺(I)是凝血因子Xa的可口腔给药的低分子量抑制剂，其可以用于预防和/或治疗各种血栓栓塞疾病(例如参见WO-A01/47919、其公开文本通过引入作为参考)。如果下文中谈论到活性物质(I)，那么其中包括5-氯-N-({(5S)-2-氧-3-[4-(3-氧-4-吗啉基)-苯基]-1，3-噁唑烷-5-基}-甲基)-2-噻吩羧酰胺(I)的所有变体和各种水合物。
所述活性物质(I)具有较差的水溶性(约7mg/L)。因此导致难于口服生物利用和提高的吸收率的生物变化性。
为了提高口腔生物利用率在过去记载有各种构思：
通常使用了活性物质的溶液，所述溶液例如可以填充到柔软的明胶胶囊中。由于活性物质(I)难以溶解在用于该目的合适的溶剂中，这种选择在该情况下不可行，因为其中必需的剂量浓度将导致不再可吞咽的胶囊尺寸。
一种可供替换的方法提出使活性物质无定形化。在此，这种解决方法也被证实是有问题的，因为活性物质(I)在药物可接受的溶剂例如乙醇或者丙酮中也是难溶的。而且因为高的活性物质熔点(约230℃)，通过熔融方法使该活性物质无定形化也是不利的，因为在制备中产生了不理想的高分解组分含量。
此外，以环己烯巴比妥和苯妥英为例记载了使疏水性活性物质亲水化的方法(Lerk，Lagas，Fell，Nauta，Journal of PharmaceuticalSciences第67卷，第7期，1978年7月，第935-939页：“Effect ofHydrophilization of Hydrophobic Drugs on Release Rate fromCapsules”；Lerk，Lagas，Lie-A-Huen，Broersma，Zuurman，Journalof Pharmaceutical Sciences第68卷，第7期，1979年5月，第634-638页：“In Vitro and In Vivo Availability of Hydrophilized Phenytoinfrom Capsules”)。在此，这种活性物质微粒在基本上免去附聚步骤的条件下在混合器中与甲基纤维素或者羟乙基纤维素溶液混合并随后干燥。随后无需进一步处理，将由此得到的活性物质填充到硬明胶胶囊中。
令人惊讶的是，现已发现，在湿法造粒阶段特殊处理活性物质(I)的表面起到了改善吸收性能的作用。在制备可口腔给药的固态药物组合物中使用亲水形式的活性物质(I)导致由此得到的制剂的显著提高的生物利用率。
本发明的主题在于用于制备含亲水形式的5-氯-N-({(5S)-2-氧-3-[4-(3-氧-4-吗啉基)-苯基]-1，3-噁唑烷-5-基}-甲基)-2-噻吩羧酰胺的可口腔给药的固态药物组合物的方法，其中，
(a)首先通过湿法造粒制备含有亲水形式的活性物质(I)的颗粒，
(b)然后视需要在添加对药物合适的添加剂的情况下将该颗粒转移到药物组合物中。
在方法步骤(a)中的湿法造粒可以在混合器(＝混合造粒)或者在流化床(＝流化层造粒)中进行，优选流化床造粒。
在湿法造粒时，活性物质(I)可以作为固体物质添加到预混物(储备液)中或者悬浮在造粒液体中。优选将悬浮在造粒液体中的活性物质(I)引入到湿法造粒中(悬浮方法)。
在本发明的一个优选实施方案中，所述活性物质(I)以结晶形式使用。
在本发明的一个特别优选的实施方案中，所述结晶活性物质(I)以微粉化形式使用。其中活性物质(I)优选具有低于10μm、尤其优选1-8μm的平均粒度X50和低于20μm、尤其低于15μm的X90(90％的比例)。
本发明所用的造粒液体含有溶剂、亲水粘合剂和视需要的湿润剂。其中亲水粘合剂分散或者优选溶解在造粒液体中。
作为造粒液体的溶剂可以使用有机溶剂，例如乙醇或者丙酮，或水或者它们的混合物。优选使用水作为溶剂。
作为造粒液体的亲水性粘合剂使用对药物合适的亲水添加剂，优选本身溶于造粒液体的溶剂中的添加剂。
优选地，其中使用亲水性聚合物例如羟丙基甲基纤维素(HPMC)、羧甲基纤维素(钠盐和钙盐)、乙基纤维素、甲基纤维素、羟乙基纤维素、乙基羟乙基纤维素、羟丙基纤维素(HPC)、L-HPC(低取代的HPC)、聚乙烯基吡咯烷酮、聚乙烯醇、丙烯酸的聚合物及其盐、乙烯基吡咯烷酮-乙酸乙烯酯共聚物(例如VA64，BASF)、明胶、瓜耳胶、部分水解的淀粉、藻酸盐或者黄原胶。尤其优选使用HPMC作为亲水性粘合剂。
其中亲水性粘合剂的浓度(以药物组合物的总质量计)可以为1-15％、优选1-8％。
作为视需要存在的造粒液体的湿润剂可以使用对药物合适的湿润剂(表面活性剂)。可以示例性提及：
硫酸脂肪醇酯的钠盐例如月桂基硫酸钠，磺基琥珀酸盐例如二辛基磺基琥珀酸钠，多元醇的脂肪酸偏酯例如甘油单硬脂酸酯，脱水山梨糖醇的脂肪酸偏酯例如脱水山梨糖醇单月桂酸酯，多羟基亚乙基脱水山梨糖醇的脂肪酸偏酯例如多乙二醇-脱水山梨糖醇单月桂酸酯、聚乙二醇-脱水山梨糖醇单硬脂酸酯或者聚乙二醇-脱水山梨糖醇单油酸酯，多羟基亚乙基脂肪醇醚，多羟基亚乙基脂肪酸酯，环氧乙烷-环氧丙烷嵌段共聚物()或者乙氧基化的甘油三酯。优选使用月桂基硫酸钠作为湿润剂。
所述湿润剂视需要以0.1-5％、优选0.1-2％的浓度(以药物组合物的总质量计)使用。
在湿法造粒的预混物(储备液)中含有其他对药物合适的添加剂。可以示例性提及：
-填料和干粘合剂例如纤维素粉末、微晶纤维素、硅化的微晶纤维素、磷酸二钙、磷酸三钙、三硅酸镁、甘露糖醇、麦芽糖醇、山梨糖醇、木糖醇、乳糖(无水或者作为水合物，例如一水合物)、右旋葡萄糖、麦芽糖、蔗糖、葡萄糖、果糖或者麦芽糖糊精。
-崩解促进剂(崩解剂)如羧甲基纤维素、交联羧甲基纤维素(交联的羧甲基纤维素)、交聚维酮(交联的聚乙烯基吡咯烷酮)、L-HPC(低取代的羟丙基纤维素)、羧甲基淀粉钠、土豆淀粉的羟乙酸钠、部分水解淀粉、小麦淀粉、玉米淀粉、大米淀粉或者土豆淀粉。
在具有改性(延迟的)活性物质释放的片剂制剂情况下，可以不含崩解促进剂(崩解剂)而含有影响释放速率的物质。可示例性提及：羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素、乙基纤维素、羧甲基纤维素、半乳甘露聚糖、黄原胶、甘油酯、蜡、丙烯酸酯和/或甲基丙烯酸酯与甲基丙烯酸三甲基铵的共聚物、二甲基氨基甲基丙烯酸和中性甲基丙烯酸酯的共聚物、甲基丙烯酸或甲基丙烯酸酯的聚合物、丙烯酸乙酯-甲基丙烯酸甲酯共聚物或者甲基丙烯酸-丙烯酸甲酯共聚物。
在方法步骤(a)中得到的颗粒随后在方法步骤(b)中转移到根据本发明的药物组合物中。
方法步骤(b)包括例如压片、填入胶囊(优选硬明胶胶囊)或者作为囊剂填充，这些步骤均根据本领域技术人员熟悉的常规方法，视需要在添加其他对药物合适的添加剂的情况下进行。
作为对药物合适的添加剂可以示例性提及：
-润滑剂、滑动剂、流动调节剂，例如富马酸、硬脂酸、硬脂酸镁、硬脂酸钙、硬脂基富马酸钠、高分子量脂肪醇、聚乙二醇、淀粉(小麦淀粉、大米淀粉、玉米淀粉或者土豆淀粉)、滑石粉、高分散性(胶体)二氧化硅、氧化镁、碳酸镁或者硅酸钙
-崩解促进剂(崩解剂)，例如羧甲基纤维素、交联羧甲基纤维素(交联的羧甲基纤维素)、交聚维酮(交联的聚乙烯基吡咯烷酮)、L-HPC(低取代的羟丙基纤维素)、羧甲基淀粉钠、部分水解淀粉、小麦淀粉、玉米淀粉、大米淀粉或者土豆淀粉
本发明的另一主题是包含亲水形式的5-氯-N-({(5S)-2-氧-3-[4-(3-氧-4-吗啉基)-苯基]-1，3-噁唑烷-5-基}-甲基)-2-噻吩羧酰胺(I)可口腔给药的固态药物组合物。
根据本发明的可口腔给药的固态药物组合物示例性地和优选地包括：颗粒剂、用颗粒填充的硬明胶胶囊剂或者囊剂以及快速或者经改变(延缓)释放活性物质(I)的片剂。片剂、尤其是快速释放活性物质(I)的片剂是优选的。在本发明范围内，快速释放的片剂尤其是根据USP释放方法用例如在5.2.2章的实验部分中所记载的设备2(桨)具有75％的Q值(30分钟)的那些片剂。
本发明的药物组合物中活性物质(I)可以0.1-60％、优选1-40％的浓度存在，以制剂的总质量计。在此活性物质(I)的剂量优选为1-100mg。
根据本发明的颗粒剂或者片剂视需要在本领域技术人员熟悉的常规条件下在另一步骤中经涂覆。所述涂覆在添加本领域技术人员熟悉的常规涂覆介质和成膜剂的条件下进行，这些涂覆介质和成膜剂例如是羟丙基纤维素、羟丙基甲基纤维素、乙基纤维素、聚乙烯基吡咯烷酮、乙烯基吡咯烷酮-乙酸乙烯酯共聚物(例如VA64，BASF)、虫胶、丙烯酸酯和/或甲基丙烯酸酯和甲基丙烯酸三甲基铵的共聚物、二甲基氨基甲基丙烯酸和中性甲基丙烯酸酯的共聚物、甲基丙烯酸或甲基丙烯酸酯的聚合物、丙烯酸乙酯-甲基丙烯酸甲酯共聚物、甲基丙烯酸-丙烯酸甲酯共聚物、丙二醇、聚乙二醇、三乙酸甘油酯、柠檬酸三乙酯和/或染料添加剂/颜料例如二氧化钛、氧化铁、靛蓝或者合适的色淀。
本发明的另一主题是根据本发明的药物组合物用于预防和/或治疗疾病的用途，所述疾病尤其是血栓栓塞疾病例如心肌梗塞、心绞痛(包括不规则绞痛)、在血管成形术或者主动脉冠状动脉分流术之后的再阻塞和再狭窄、大脑梗塞、暂时性局部缺血发作、外周动脉闭合症、肺栓塞或者深度静脉血栓。
下文中本发明通过优选的实施例进一步进行阐述，但是本发明并不限于这些实施例。除非另行给出，下面的所有给出量为重量百分比。
实验部分
1.使用含有亲水形式的活性成分(I)的颗粒制备片剂/流动床造 粒方法
1.1片剂组成(mg/片)
活性成分(I)，微粉化                             20.0mg
微晶纤维素                                      35.0mg
乳糖一水合物                                    22.9mg
交联羧甲基纤维素(FMC)              3.0mg
羟丙基甲基纤维素，5cp                           3.0mg
月桂基硫酸钠                                    0.5mg
硬脂酸镁                                        0.6mg
羟丙基甲基纤维素，15cp                          1.5mg
聚乙二醇3.350  0.5mg
二氧化钛       0.5mg
               87.5mg
1.2制备
将羟丙基甲基纤维素(5cp)和月桂基硫酸钠溶于水中。将微粉化的活性物质(I)悬浮到该溶液中。由此制备的悬浮液在流动床造粒阶段作为颗粒化液体喷雾到由微晶纤维素、乳糖一水合物和交联羧甲基纤维素组成的储备液上。在干燥和过筛(0.8mm网眼宽度)所得的颗粒后添加和混合硬脂酸镁。由此得到的即可压制的混合物被压制成6mm直径和50-100N断裂强度的片剂。随后用二氧化钛涂覆片剂，二氧化钛悬浮在由羟丙基甲基纤维素(15cp)和聚乙二醇组成的水溶液中。
2.使用含亲水形式的活性成分(I)的颗粒制备片剂/快速混合器 造粒方法
2.1片剂组成(mg/片)
活性成分(I)，微粉化                             5.0mg
微晶纤维素                                      40.0mg
乳糖一水合物                                    33.9mg
交联羧甲基纤维素(
Figure S04835106X20060609D000061
FMC)              3.0mg
羟丙基甲基纤维素，3cp                           2.0mg
月桂基硫酸钠                                    0.5mg
硬脂酸镁                                        0.6mg
羟丙基甲基纤维素，15cp                          1.5mg
聚乙二醇400                                     0.5mg
氧化铁黄                                        0.1mg
二氧化钛                                        0.4mg
                                                87.5mg
2.2制备
在快速混合器中混合配料微晶纤维素、乳糖一水合物和交联羧甲基纤维素(造粒储备液)。将羟丙基甲基纤维素(3cp)和月桂基硫酸钠溶于水中。在该溶液中悬浮微粉化的活性成分(I)。由此制备的悬浮液作为造粒液体添加到造粒储备液中并借助快速旋转的搅拌工具与颗粒储备液均匀混合。在所进行的均匀混合后将湿的颗粒过筛(4mm网眼宽度)和在流动床中干燥。在筛分经干燥的颗粒(0.8mm网眼宽度)后添加并混合硬脂酸镁。由此得到的即可压制的混合物被压制成6mm直径和50-100N断裂强度的片剂。随后的片剂涂覆用二氧化钛和氧化铁黄进行，其中所述颜料预先被悬浮在由羟丙基甲基纤维素(15cp)和聚乙二醇组成的水溶液中。
3.制备含有亲水形式的活性物质(I)的颗粒并作为囊剂填充
3.1颗粒组成(mg/药囊) 
活性成分(I)，微粉化                         50.0mg
甘露糖醇                                    662.0mg
交联羧甲基纤维素(FMC)          15.0mg
羟丙基甲基纤维素，5cp                       15.0mg
月桂基硫酸钠                                1.0mg
高分散性二氧化硅(
Figure S04835106X20060609D000072
Degussa)     2.0mg
草莓香料，经喷雾干燥                         5.0mg
                                            750.0mg
3.2制备
将羟丙基甲基纤维素(5cp)和月桂基硫酸钠溶于水中。在该溶液中悬浮微粉化的活性物质(I)。在流化床造粒阶段使由此制备的悬浮液作为颗粒液体喷雾到由甘露糖醇和交联羧甲基纤维素组成的储备液上。在干燥和筛分(0.8mm网眼宽度)所得的颗粒后添加并混合高分散性二氧化硅
Figure S04835106X20060609D000073
和草莓香料。由此得到的混合物借助药囊填充机以每份775.0mg填充到药囊袋中。
4.制备含有亲水形式的活性物质(I)的颗粒并填充到硬明胶胶 囊中
4.1颗粒组成(mg/胶囊)
活性成分(I)，微粉化                           20.0mg
微晶纤维素                                    30.0mg
乳糖一水合物                                  79.5mg
玉米淀粉                                      25.0mg
羟丙基甲基纤维素，5cp                         4.5mg
月桂基硫酸钠                                  0.5mg
高分散性二氧化硅(
Figure S04835106X20060609D000081
Degussa)       0.5mg
                                             160.0mg
4.2制备
将羟丙基甲基纤维素(5cp)和月桂基硫酸钠溶于水中。在该溶液中悬浮微粉化的活性物质(I)。在流化床造粒阶段使由此制备的悬浮液作为颗粒液体喷雾到由微晶纤维素、乳糖一水合物和玉米淀粉组成的储备液上。在干燥和筛分(0.8mm网眼宽度)所得的颗粒后添加并混合高分散性二氧化硅
Figure S04835106X20060609D000082
将由此得到的混合物以每份160mg填充到2号大小胶囊的硬明胶胶囊中。
5.含和不含经亲水化的活性物质(I)的片剂的对比
5.1片剂组成，片剂制备
为了研究具有亲水的活性物质(I)的制剂的片剂性质和经改善的生物利用率，制备具有下列组成(mg/片)的含10mg活性物质含量(I)的未经涂覆的片剂：
活性成分(I)，微粉化                    10.0mg
微晶纤维素                             40.0mg
乳糖一水合物                           27.9mg
交联羧甲基纤维素(
Figure S04835106X20060609D000083
FMC)     3.0mg
羟丙基甲基纤维素，5cp                  3.0mg
月桂基硫酸钠                           0.5mg
硬脂酸镁                               0.6mg
                                       85.0mg
片剂A：未经造粒直接由压片制备
片剂B：由1.2描述的流化床造粒/悬浮方法制备
用于片剂A的混合物和用于片B的颗粒均被压制成6mm直径和约70-80N断裂强度的片剂。
5.2片剂性质
5.2.1在水中的崩解时间(USP崩解测试器，Erweka)：
片剂A：约1.5分钟
片剂B：约6.5分钟
5.2.2体外释放
在下表1中给出了以所公布的片剂总含量计的释放出的活性物质量：
表1：体外释放
  15分钟   30分钟   45分钟   60分钟
 片剂A   87％   92％   93％   94％
 片剂B   94％   95％   96％   96％
(USP桨、900ml乙酸盐缓冲液pH 4.5+0.5％月桂基硫酸钠，75转每分)
5.2.3生物利用率
为了研究生物利用率，对三只狗以交叉形式给药三片片剂A或者三片片剂B。在下表2中列出了在口服给药3mg活性成分(I)/kg后相应的药物动力学参数：
表2：活性物质(I)的药物动力学参数
Figure S04835106X20060609D000101
结果：尽管更慢的崩解(参见5.2.1)和非常相似的体外释放(参见5.2.2)，片剂B与片剂A相比在吸收方面具有显著的优势和因而提高了约35％的生物利用率。同时证实了变化性的显著降低。片剂A和片剂B的唯一区别在于在片剂B的情况下在湿法造粒阶段借助悬浮方法使物质(I)亲水化。

Claims (19)

1.用于制备含亲水形式的5-氯-N-({(5S)-2-氧-3-[4-(3-氧-4-吗啉基)-苯基]-1，3-噁唑烷-5-基}-甲基)-2-噻吩羧酰胺(I)的可口腔给药的固态药物组合物的方法，其特征在于，
(a)首先通过湿法造粒制备含有活性物质(I)的颗粒，其中活性物质(I)用含溶剂、亲水粘合剂和任选湿润剂的造粒液体处理，
(b)然后在有或没有添加对药物合适的添加剂的情况下将该颗粒转换为药物组合物。
2.权利要求1的方法，其特征在于，采用流化床造粒作为湿法造粒方法。
3.权利要求1或2的方法，其特征在于，使用结晶形式的活性物质(I)。
4.权利要求3的方法，其特征在于，使用微粉化形式的活性物质(I)。
5.权利要求1的方法，其特征在于，将悬浮在造粒液体中的活性物质(I)引入到湿法造粒过程中。
6.权利要求1的方法，其特征在于，所述药物组合物是快速释放活性物质(I)的片剂。
7.通过权利要求1的方法制备的可口腔给药的固态药物组合物。
8.含有5-氯-N-({(5S)-2-氧-3-[4-(3-氧-4-吗啉基)-苯基]-1，3-噁唑烷-5-基}-甲基)-2-噻吩羧酰胺(I)的可口腔给药的固态药物组合物，其中该活性化合物(I)用含溶剂、亲水粘合剂和任选湿润剂的造粒液体处理。
9.权利要求8的药物组合物，含有结晶形式的活性物质(I)。
10.权利要求9的药物组合物，含有微粉化形式的活性物质(I)。
11.权利要求7-10中任一项的药物组合物，其特征在于，所述活性成分(I)以1-60％的量存在，以制剂的总质量计。
12.权利要求7的药物组合物，含有作为湿润剂的月桂基硫酸钠。
13.权利要求12的药物组合物，含有0.1-5％量的月桂基硫酸钠，以总质量计。
14.权利要求7的药物组合物，含有羟丙基甲基纤维素作为亲水粘合剂。
15.权利要求14的药物组合物，含有1-15％量的羟丙基甲基纤维素，以总质量计。
16.权利要求7的药物组合物，其为片剂形式。
17.权利要求16的药物组合物，其为快速释放的片剂形式。
18.权利要求16或17的药物组合物，其特征在于，用涂层覆盖所述片剂。
19.5-氯-N-({(5S)-2-氧-3-[4-(3-氧-4-吗啉基)-苯基]-1，3-噁唑烷-5-基}-甲基)-2-噻吩羧酰胺(I)在制备用于预防和/或治疗血栓栓塞疾病的药物中的用途，其中该活性化合物(I)用含溶剂、亲水粘合剂和任选湿润剂的造粒液体处理。
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19962924A1 (de) 1999-12-24 2001-07-05 Bayer Ag Substituierte Oxazolidinone und ihre Verwendung
DE10129725A1 (de) * 2001-06-20 2003-01-02 Bayer Ag Kombinationstherapie substituierter Oxazolidinone
DE10300111A1 (de) * 2003-01-07 2004-07-15 Bayer Healthcare Ag Verfahren zur Herstellung von 5-Chlor-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophencarboxamid
DE10355461A1 (de) 2003-11-27 2005-06-23 Bayer Healthcare Ag Verfahren zur Herstellung einer festen, oral applizierbaren pharmazeutischen Zusammensetzung
DE102004062475A1 (de) * 2004-12-24 2006-07-06 Bayer Healthcare Ag Feste, oral applizierbare pharmazeutische Darreichungsformen mit modifizierter Freisetzung
EP1685841A1 (en) 2005-01-31 2006-08-02 Bayer Health Care Aktiengesellschaft Prevention and treatment of thromboembolic disorders
DE102005045518A1 (de) 2005-09-23 2007-03-29 Bayer Healthcare Ag 2-Aminoethoxyessigsäure-Derivate und ihre Verwendung
DE102005047561A1 (de) * 2005-10-04 2007-04-05 Bayer Healthcare Ag Feste, oral applizierbare pharmazeutische Darreichungsformen mit schneller Wirkstofffreisetzung
EP1934208B1 (de) 2005-10-04 2011-03-23 Bayer Schering Pharma Aktiengesellschaft Neue polymorphe form von 5-chlor-n-({ ( 5s )-2-0x0-3-[4-( 3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl} -methyl)-2-thiophencarboxamid
DE102005047558A1 (de) * 2005-10-04 2008-02-07 Bayer Healthcare Ag Kombinationstherapie substituierter Oxazolidinone zur Prophylaxe und Behandlung von cerebralen Durchblutungsstörungen
DE102006007146A1 (de) 2006-02-16 2007-08-23 Bayer Healthcare Ag Aminoacyl-Prodrugs
TWI351399B (en) * 2006-06-12 2011-11-01 Schering Corp Pharmaceutical formulations and compositions of a
DE102006039589A1 (de) * 2006-08-24 2008-03-06 Bayer Healthcare Ag Aminoacyl-Prodrugs II
DE102006051625A1 (de) * 2006-11-02 2008-05-08 Bayer Materialscience Ag Kombinationstherapie substituierter Oxazolidinone
EP2090300A4 (en) * 2006-11-30 2010-02-10 Takeda Pharmaceutical PREPARATION WITH EXTENDED RELEASE
EP2120879A2 (en) * 2006-12-22 2009-11-25 Schering Corporation Disintegration promoters in solid dose wet granulation formulations
TW200835527A (en) * 2006-12-26 2008-09-01 Shionogi & Co Orally disintegrating tablet and bitter taste-masked formulation comprising risperidone
CA2680039C (en) 2007-03-29 2015-05-26 Daiichi Sankyo Company, Limited Pharmaceutical composition comprising edoxaban, an anticoagulant
DE102007028319A1 (de) * 2007-06-20 2008-12-24 Bayer Healthcare Ag Substituierte Oxazolidinone und ihre Verwendung
DE102007028407A1 (de) * 2007-06-20 2008-12-24 Bayer Healthcare Ag Substituierte Oxazolidinone und ihre Verwendung
RU2457000C1 (ru) * 2008-06-05 2012-07-27 Брейн Бейс Корпорейшн Костно-протезный материал и способ его изготовления
CN102105138A (zh) 2008-07-08 2011-06-22 德国通益药业有限公司 包含5-氯-n-({(5s)-2-氧代-3-[4-(3-氧代-4-吗啉基)-苯基]-1,3-噁唑烷-5-基}-甲基)-2-噻吩羧酰胺的药物组合物
CA2733611A1 (en) * 2008-08-11 2010-02-18 Ratiopharm Gmbh Pharmaceutical compositions with modified release properties comprising 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophencarboxamid
US7816355B1 (en) * 2009-04-28 2010-10-19 Apotex Pharmachem Inc Processes for the preparation of rivaroxaban and intermediates thereof
US20100287817A1 (en) * 2009-05-14 2010-11-18 Fmc Corporation Method for Ant Control
EP2266541A1 (en) 2009-06-18 2010-12-29 Krka Tovarna Zdravil, D.D., Novo Mesto Solid pharmaceutical composition comprising rivaroxaban
WO2010146179A2 (en) 2009-06-18 2010-12-23 Krka, Tovarna Zdravil, D.D., Novo Mesto Solid pharmaceutical composition comprising rivaroxaban
US20120231076A1 (en) * 2009-10-06 2012-09-13 Ratiopharm Gmbh Pharmaceutical compositions comprising rivaroxaban
EP2308472A1 (en) * 2009-10-06 2011-04-13 ratiopharm GmbH Pharmaceutical compositions comprising rivaroxaban
EP3662899A1 (en) * 2010-02-25 2020-06-10 Bristol-Myers Squibb Holdings Ireland Unlimited Company Apixaban formulations
DE102010028362A1 (de) 2010-04-29 2011-11-03 Bayer Schering Pharma Aktiengesellschaft Herstellverfahren
EP2404920A1 (en) 2010-07-06 2012-01-11 Sandoz AG Crystalline form of Rivaroxaban dihydrate
EP2608773A4 (en) * 2010-08-24 2014-03-05 Univ Rutgers FORMULATION AND MANUFACTURE OF PHARMACEUTICAL PRODUCTS BY IMPREGNATING ON POROUS SUBSTRATES
DE102010063127A1 (de) 2010-12-15 2012-06-21 Bayer Schering Pharma Aktiengesellschaft Flüssige, oral applizierbare pharmazeutische Zusammensetzungen enthaltend 5-Chlor-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophencarboxamid
WO2013022924A1 (en) 2011-08-08 2013-02-14 Teva Pharmaceutical Industries Ltd. Pharmaceutical formulations
UY34856A (es) * 2012-07-03 2013-12-31 Bayer Pharma AG Formas de presentación farmacéuticas que contienen 5-cloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4- morfolinil)-fenil]-1,3-oxazolidin-5-il}-metil)-2-tiofencarboxamida
EP2808011A1 (en) * 2013-05-29 2014-12-03 Sandoz Ag Process for the preparation of a pharmaceutical composition comprising Rivaroxaban
CN104337787B (zh) * 2013-08-06 2018-09-07 江苏豪森药业集团有限公司 含有利伐沙班的药物制剂
CN103550165B (zh) * 2013-10-19 2019-07-16 浙江华海药业股份有限公司 一种含有利伐沙班的药物组合物及其制备方法
CN104721156B (zh) * 2013-12-18 2020-05-01 山东新时代药业有限公司 一种含利伐沙班的片剂
WO2015124995A1 (en) 2014-02-19 2015-08-27 Aurobindo Pharma Ltd Solid dosage forms of rivaroxaban
CN104887633B (zh) * 2014-03-04 2019-01-29 山东新时代药业有限公司 一种利伐沙班片剂及其制备方法
CN105078997A (zh) * 2014-05-19 2015-11-25 广东东阳光药业有限公司 一种利伐沙班药用组合物及其制备方法
CN104173313B (zh) * 2014-08-25 2017-05-17 杭州朱养心药业有限公司 利伐沙班片剂药物组合物
KR102271862B1 (ko) 2014-12-31 2021-07-01 한미약품 주식회사 리바록사반 함유 경구용 고형제제
JP2018511158A (ja) * 2015-03-11 2018-04-19 プラスモロジー４，インコーポレイティド 容器処理システム
CN105078915A (zh) * 2015-08-27 2015-11-25 江苏中邦制药有限公司 一种利伐沙班片及其制备方法
CN105287414A (zh) * 2015-10-21 2016-02-03 南京百迪尔生物医药有限公司 一种含有利伐沙班的固体药物组合物及其制备方法
CN105267169B (zh) * 2015-12-07 2018-03-30 石家庄康贺威药业有限公司 一种利伐沙班片剂及其制备方法
US11883404B2 (en) 2016-03-04 2024-01-30 Taiho Pharmaceuticals Co., Ltd. Preparation and composition for treatment of malignant tumors
MA43807A (fr) 2016-03-04 2018-11-28 Taiho Pharmaceutical Co Ltd Préparation et composition de traitement de tumeurs malignes
WO2018007945A1 (en) * 2016-07-05 2018-01-11 Alphamed Formulations Pvt. Ltd Solid composition containing oral anticoagulant
CN106109434B (zh) * 2016-08-26 2019-04-05 乐普药业股份有限公司 一种利伐沙班片剂及其制备方法
JP6574041B2 (ja) * 2017-12-15 2019-09-11 エルメッド株式会社 リバーロキサバン含有医薬組成物
EP4257136A3 (en) 2017-12-31 2023-11-29 Abdi Ibrahim Ilac Sanayi ve Ticaret A.S. Preparation of a solid pharmaceutical composition comprising rivaroxaban and production thereof
US10828310B2 (en) 2018-02-02 2020-11-10 Bayer Pharma Aktiengesellschaft Reducing the risk of cardiovascular events
EP3769765B1 (en) * 2018-03-19 2024-04-17 Taiho Pharmaceutical Co., Ltd. Pharmaceutical composition including sodium alkyl sulfate
CN108864069B (zh) * 2018-05-03 2021-04-20 华东理工大学 一种利伐沙班微粒及其制备方法与应用
GR1009619B (el) * 2018-05-09 2019-10-23 Φαρμαζακ Α.Φ.Ε.Β.Ε. Φαρμακευτικη συνθεση που περιεχει ριβαροξαβανη και μεθοδος για την παρασκευη αυτης
JP2020029455A (ja) * 2018-08-20 2020-02-27 大原薬品工業株式会社 微粉砕されたリバーロキサバンを含有してなる固形製剤
JP7305527B2 (ja) * 2018-11-30 2023-07-10 大原薬品工業株式会社 リバーロキサバンと嬌味剤を含有する固形製剤
CN112675136B (zh) * 2019-10-18 2023-05-16 苏州特瑞药业股份有限公司 降低利伐沙班出血风险的组合物及其制备方法
KR102290670B1 (ko) 2019-12-30 2021-08-18 단국대학교 천안캠퍼스 산학협력단 자가나노유화 약물전달시스템을 이용한 리바록사반의 경구용 고형제 조성물 및 이의 제조방법
US20210267908A1 (en) * 2020-03-02 2021-09-02 Mankind Pharma Ltd. Pharmaceutical compositions of rivaroxaban
EP4208462A1 (en) * 2020-09-05 2023-07-12 Inventia Healthcare Limited Rivaroxaban compositions
GR1010231B (el) 2021-03-24 2022-05-10 Φαρματεν Α.Β.Ε.Ε., Φαρμακευτικο σκευασμα που περιλαμβανει ριβαροξαμπανη και μεθοδος παρασκευης αυτου
CN113425729B (zh) * 2021-06-24 2022-11-15 上海奥全生物医药科技有限公司 一种含有利伐沙班的药物组合物及其应用
WO2023067620A1 (en) * 2021-10-18 2023-04-27 Unison Pharmaceuticals Pvt. Ltd. Orally disintegrating pharmaceutical compositions of rivaroxaban
WO2023194885A1 (en) 2022-04-08 2023-10-12 Intas Pharmaceuticals Ltd. An orodispersible tablet of rivaroxaban
CN116869952A (zh) * 2022-06-16 2023-10-13 北京四环制药有限公司 一种高稳定性的利伐沙班药物组合物及其制备方法
CN115590856A (zh) * 2022-10-31 2023-01-13 南京海纳医药科技股份有限公司（Cn） 一种含有利伐沙班的药物组合物及其制备方法

Family Cites Families (90)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2811555A (en) 1955-05-02 1957-10-29 Eastman Kodak Co Reduction of 2-nitroso-5-diethylaminotoluene
US3279880A (en) 1965-07-12 1966-10-18 Eastman Kodak Co Polyester textile material dyed with 1-hydroxy-4-n-p-(2'-pyrrolidonyl-1-) phenyl-amino anthraquinones
LU80081A1 (fr) 1977-08-26 1979-05-15 Delalande Sa Nouvelles hydroxymethyl-5 oxazolidinones-2,leur procede de preparation et leur application therapeutique
US4128654A (en) 1978-02-10 1978-12-05 E. I. Du Pont De Nemours And Company 5-Halomethyl-3-phenyl-2-oxazolidinones
US4500519A (en) 1978-11-06 1985-02-19 Choay S.A. Mucopolysaccharides having biological properties, preparation and method of use
US4344934A (en) * 1978-11-20 1982-08-17 American Home Products Corporation Therapeutic compositions with enhanced bioavailability
JPS5611061A (en) 1979-07-07 1981-02-04 Seikichi Nakajima Water circulation electrolytic device
US4327725A (en) 1980-11-25 1982-05-04 Alza Corporation Osmotic device with hydrogel driving member
HU190072B (en) 1983-03-11 1986-08-28 Biogal Gyogyszergyar,Hu Process for production of medical preparatives with sinergetic influence
NZ206600A (en) 1983-05-11 1987-01-23 Alza Corp Osmotic drug delivery device
US4765989A (en) 1983-05-11 1988-08-23 Alza Corporation Osmotic device for administering certain drugs
ES8506659A1 (es) 1983-06-07 1985-08-01 Du Pont Un procedimiento para la preparacion de nuevos derivados del amino-metil-oxooxazolidinil-benzeno.
DE3433239A1 (de) * 1984-09-11 1986-03-20 Bayer Ag, 5090 Leverkusen Feste arzneizubereitung enthaltend nitrendipin und verfahren zu ihrer herstellung
CA1317594C (en) 1987-10-21 1993-05-11 Chung-Ho Park Aminomethyloxooxazolidinyl ethenylbenzene derivatives useful as antibacterial agents
US4977173A (en) 1987-10-21 1990-12-11 E. I. Du Pont De Nemours And Company Aminomethyl oxooxazolidinyl ethenylbenzene derivatives useful as antibacterial agents
DE3822650A1 (de) 1988-07-05 1990-02-01 Boehringer Mannheim Gmbh Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel
US4948801A (en) 1988-07-29 1990-08-14 E. I. Du Pont De Nemours And Company Aminomethyloxooxazolidinyl arylbenzene derivatives useful as antibacterial agents
US5254577A (en) 1988-07-29 1993-10-19 The Du Pont Merck Pharmaceutical Company Aminomethyloxooxazolidinyl arylbenzene derivatives useful as antibacterial agents
TW212139B (zh) 1991-04-15 1993-09-01 Yamanouchi Pharma Co Ltd
EP0610265B1 (en) 1991-11-01 1996-12-27 PHARMACIA & UPJOHN COMPANY Substituted aryl- and heteroarylphenyloxazolidinones useful as antibacterial agents
SK283420B6 (sk) 1992-05-08 2003-07-01 Pharmacia & Upjohn Company Antimikrobiálne oxazolidinóny obsahujúce substituované diazínové skupiny
US5349045A (en) 1993-01-26 1994-09-20 United States Surgical Corporation Polymer derived from cyclic amide and medical devices manufactured therefrom
ATE181735T1 (de) 1993-05-01 1999-07-15 Merck Patent Gmbh Substituierte 1-phenyl-oxazolidin-2-on derivate, deren herstellung und deren verwendung als adhäsionsrezeptor-antagonisten
US5688792A (en) 1994-08-16 1997-11-18 Pharmacia & Upjohn Company Substituted oxazine and thiazine oxazolidinone antimicrobials
DE4332384A1 (de) 1993-09-23 1995-03-30 Merck Patent Gmbh Adhäsionsrezeptor-Antagonisten III
JPH10513446A (ja) 1995-02-03 1998-12-22 ファルマシア・アンド・アップジョン・カンパニー ヘテロ芳香族環置換フェニルオキサゾリジノン抗微生物剤
HRP960159A2 (en) 1995-04-21 1997-08-31 Bayer Ag Benzocyclopentane oxazolidinones containing heteroatoms
RU2158607C2 (ru) 1995-07-03 2000-11-10 Санкио Компани Лимитед Лечение артериосклероза и ксантомы
DE19524765A1 (de) 1995-07-07 1997-01-09 Boehringer Mannheim Gmbh Neue Oxazolidinonderivate, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel
ATE207487T1 (de) 1995-09-01 2001-11-15 Upjohn Co Phenyloxazolidinone mit einer c-c-bindung zu 4-8 gliedrigen heterocyclen
PT1019385E (pt) 1995-09-15 2004-06-30 Upjohn Co N-oxidos de aminoaril-oxazolidinona
DE19601264A1 (de) 1996-01-16 1997-07-17 Bayer Ag Pyrido-annellierte Thienyl- und Furanyl-Oxazolidinone
DE19604223A1 (de) 1996-02-06 1997-08-07 Bayer Ag Neue substituierte Oxazolidinone
HRP970049A2 (en) 1996-02-06 1998-04-30 Bayer Ag New heteroaryl oxazolidinones
PL190796B1 (pl) * 1996-05-01 2006-01-31 Ortho Mcneil Pharm Inc Karboksyamidowe pochodne piperydyny do leczenia zaburzeń zakrzepicowych
TR199802718T2 (xx) 1996-06-28 1999-03-22 Schering Corporation Bir triazol mantara kar�� bile�i�ini i�eren a��zdan al�nan bile�im.
GB9614238D0 (en) 1996-07-06 1996-09-04 Zeneca Ltd Chemical compounds
HU225415B1 (en) 1996-07-15 2006-11-28 Sankyo Co Medicinal compositions comprising cs-866 and insulin resistance improving agents and their use for the treatment of arteriosclerosis and xanthoma
FR2758459B1 (fr) * 1997-01-17 1999-05-07 Pharma Pass Composition pharmaceutique de fenofibrate presentant une biodisponibilite elevee et son procede de preparation
FR2759585B1 (fr) * 1997-02-17 1999-06-11 Sanofi Sa Formulations pharmaceutiques presentees sous forme seche pour l'administration orale d'un compose ammonium quaternaire cyclique
US5935724A (en) 1997-04-04 1999-08-10 Wilson Greatbatch Ltd. Electrochemical cell having multiplate electrodes with differing discharge rate regions
US6273913B1 (en) 1997-04-18 2001-08-14 Cordis Corporation Modified stent useful for delivery of drugs along stent strut
ATE293609T1 (de) 1997-05-30 2005-05-15 Upjohn Co Antibakteriell wirksam oxazolidinone mit einer thiocarbonylfunktionalität
AU729745B2 (en) 1997-07-11 2001-02-08 Pharmacia & Upjohn Company Thiadiazolyl and oxadiazolyl phenyl oxazolidinone antibacterial agents
DE19730847A1 (de) 1997-07-18 1999-01-28 Bayer Ag Tricyclisch substituierte Oxazolidinone
DE19747261A1 (de) 1997-10-25 1999-04-29 Bayer Ag Osmotisches Arzneimittelfreisetzungssystem
EP1030852B1 (en) 1997-11-12 2003-09-17 PHARMACIA & UPJOHN COMPANY Oxazolidinone derivatives and pharmaceutical compositions
US6083967A (en) 1997-12-05 2000-07-04 Pharmacia & Upjohn Company S-oxide and S,S-dioxide tetrahydrothiopyran phenyloxazolidinones
DE19755268A1 (de) 1997-12-12 1999-06-17 Merck Patent Gmbh Benzamidinderivate
DE19802239A1 (de) 1998-01-22 1999-07-29 Bayer Ag Neue mit Bicyclen substituierte Oxazolidinone
WO1999037630A1 (en) 1998-01-23 1999-07-29 Versicor, Inc. Oxazolidinone combinatorial libraries, compositions and methods of preparation
SK11082000A3 (sk) 1998-01-27 2001-01-18 Aventis Pharmaceuticals Products Inc. Substituované oxoazaheterocyklické inhibítory faktora xa, farmaceutický prostriedok s ich obsahom a ich použitie
DE19805117A1 (de) 1998-02-09 1999-08-12 Bayer Ag Neue Oxazolidinone mit azolhaltigen Tricyclen
US20010029351A1 (en) 1998-04-16 2001-10-11 Robert Falotico Drug combinations and delivery devices for the prevention and treatment of vascular disease
NZ508256A (en) 1998-05-18 2003-08-29 Upjohn Co Enhancement of oxazolidinone antibacterial agents activity by using arginine derivatives
DE19842753A1 (de) 1998-09-18 2000-03-23 Bayer Ag Agitationsunabhängige pharmazeutische Retardzubereitungen und Verfahren zu ihrer Herstellung
SA99191255B1 (ar) 1998-11-30 2006-11-25 جي دي سيرل اند كو مركبات سيليكوكسيب celecoxib
US6413981B1 (en) 1999-08-12 2002-07-02 Ortho-Mcneil Pharamceutical, Inc. Bicyclic heterocyclic substituted phenyl oxazolidinone antibacterials, and related compositions and methods
PE20010851A1 (es) 1999-12-14 2001-08-17 Upjohn Co Esteres del acido benzoico de oxazolidinonas que tienen un substituyente hidroxiacetilpiperazina
JP2003518117A (ja) 1999-12-21 2003-06-03 ファルマシア・アンド・アップジョン・カンパニー スルホキシミン官能基を有するオキサゾリジノンおよび抗微生物剤としてのその使用
DE19962924A1 (de) * 1999-12-24 2001-07-05 Bayer Ag Substituierte Oxazolidinone und ihre Verwendung
CN1413218A (zh) 1999-12-28 2003-04-23 味之素株式会社 天冬甜素衍生物的结晶
US6514529B2 (en) * 2000-03-22 2003-02-04 Pharmacia & Upjohn Company Oxazolidinone tablet formulation
PE20020300A1 (es) 2000-08-22 2002-05-10 Pharmacia Corp Composicion de solucion de un farmaco antibiotico a base de oxazolidinona con mejoramiento de la carga de farmaco
KR100415318B1 (ko) 2000-09-23 2004-01-16 탁승호 레이저를 이용한 수평 및 수직선 지시계
AU2002212102A1 (en) 2000-11-08 2002-05-21 Aeromatic-Fielder Ag A process for production of particles for pharmaceutical compositions having increased bioavailability
WO2002060448A1 (fr) 2001-01-30 2002-08-08 Teijin Limited Composition medicinale
DE10105989A1 (de) 2001-02-09 2002-08-14 Bayer Ag Substituierte Oxazolidinone und ihre Verwendung
DE10110438A1 (de) 2001-03-05 2002-09-19 Bayer Ag Substituierte 2-Oxy-3,5-dicyano-4-aryl-6-aminopyridine und ihre Verwendung
DE10110747A1 (de) 2001-03-07 2002-09-12 Bayer Ag Substituierte 2,6-Diamino-3,5-dicyano-4-aryl-pyridine und ihre Verwendung
DE10110754A1 (de) 2001-03-07 2002-09-19 Bayer Ag Substituierte 2-Thio-3,5-dicyano-4-aryl-6-aminopyridine und ihre Verwendung
DE10115945A1 (de) 2001-03-30 2002-10-02 Bayer Ag Substituierte 2-Carba-3,5-dicyano-4-aryl-6-aminopyridine und ihre Verwendung
DE10115922A1 (de) 2001-03-30 2002-10-10 Bayer Ag Cyclisch substituierte 2-Thio-3,5-dicyano-4-aryl-6-aminopyridine und ihre Verwendung
DE10129725A1 (de) 2001-06-20 2003-01-02 Bayer Ag Kombinationstherapie substituierter Oxazolidinone
DE10134481A1 (de) 2001-07-16 2003-01-30 Bayer Ag Substituierte 2-Thio-3,5-dicyano-4-phenyl-6-aminopyridine und ihre Verwendung
DE10152460A1 (de) 2001-10-24 2003-05-08 Bayer Ag Stents
DE10238113A1 (de) 2001-12-11 2003-06-18 Bayer Ag Substituierte 2-Thio-3,5-dicyano-4-phenyl-6-aminopyridine und ihre Verwendung
US20030161882A1 (en) 2002-02-01 2003-08-28 Waterman Kenneth C. Osmotic delivery system
DE10300111A1 (de) 2003-01-07 2004-07-15 Bayer Healthcare Ag Verfahren zur Herstellung von 5-Chlor-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophencarboxamid
DE10355461A1 (de) 2003-11-27 2005-06-23 Bayer Healthcare Ag Verfahren zur Herstellung einer festen, oral applizierbaren pharmazeutischen Zusammensetzung
DE102004002044A1 (de) 2004-01-15 2005-08-04 Bayer Healthcare Ag Herstellverfahren
DE102004062475A1 (de) 2004-12-24 2006-07-06 Bayer Healthcare Ag Feste, oral applizierbare pharmazeutische Darreichungsformen mit modifizierter Freisetzung
EP1685841A1 (en) 2005-01-31 2006-08-02 Bayer Health Care Aktiengesellschaft Prevention and treatment of thromboembolic disorders
DE102005045518A1 (de) 2005-09-23 2007-03-29 Bayer Healthcare Ag 2-Aminoethoxyessigsäure-Derivate und ihre Verwendung
EP1934208B1 (de) 2005-10-04 2011-03-23 Bayer Schering Pharma Aktiengesellschaft Neue polymorphe form von 5-chlor-n-({ ( 5s )-2-0x0-3-[4-( 3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl} -methyl)-2-thiophencarboxamid
DE102005047561A1 (de) 2005-10-04 2007-04-05 Bayer Healthcare Ag Feste, oral applizierbare pharmazeutische Darreichungsformen mit schneller Wirkstofffreisetzung
DE102005047558A1 (de) 2005-10-04 2008-02-07 Bayer Healthcare Ag Kombinationstherapie substituierter Oxazolidinone zur Prophylaxe und Behandlung von cerebralen Durchblutungsstörungen
DE102005048824A1 (de) 2005-10-10 2007-04-12 Bayer Healthcare Ag Behandlung und Prophylaxe von Mikroangiopathien
DE102006034916A1 (de) 2006-07-28 2008-01-31 Bayer Healthcare Ag Beschichtung künstlicher Oberflächen von medizinischen Hilfsmitteln und Geräten sowie Reinigung und/oder Vorbehandlung von Kathetern und anderen medizinischen Hilfsmitteln und Geräten
DE102006051625A1 (de) 2006-11-02 2008-05-08 Bayer Materialscience Ag Kombinationstherapie substituierter Oxazolidinone

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BRPI0416404B8 (pt) 2021-05-25
CN1886120A (zh) 2006-12-27
JP4852423B2 (ja) 2012-01-11
EP1689370A2 (de) 2006-08-16
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HN2004000490A (es) 2008-06-24
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