CN1477977A - N-(甲基乙基氨基羰基)-4-(3-甲基苯基氨基)-3-吡啶基磺酰胺及环状低聚糖的组合物 - Google Patents
N-(甲基乙基氨基羰基)-4-(3-甲基苯基氨基)-3-吡啶基磺酰胺及环状低聚糖的组合物 Download PDFInfo
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- CN1477977A CN1477977A CNA018198309A CN01819830A CN1477977A CN 1477977 A CN1477977 A CN 1477977A CN A018198309 A CNA018198309 A CN A018198309A CN 01819830 A CN01819830 A CN 01819830A CN 1477977 A CN1477977 A CN 1477977A
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- Prior art keywords
- cyclodextrin
- alkyl
- inclusion complex
- torasemide
- physical mixture
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Abstract
本发明涉及释放得以增加的N－(1－甲基乙基氨基羰基)－4－(3－甲基苯基氨基)－3－吡啶基磺酰胺及环状低聚糖的组合物，本发明还涉及此组合物的制备方法，含有此组合物的药物形式以及其用途。
Description
技术领域
本发明涉及释放性得以增加的N-(1-甲基乙基氨基羰基)-4-(3-甲基苯基氨基)-3-吡啶基磺酰胺(在本文中还按其通用名，称作“托拉塞米”)及环状低聚糖的组合物，本发明还涉及此组合物的制备方法，含有此组合物的药物形式以及其用途。
背景技术
托拉塞米是一种属于所谓“袢利尿剂”类的新的有效利尿剂，其在DE专利2515025的实施例71中有所描述。结构上讲，它全然不同于同类的利尿剂，例如呋塞米、布美他尼和阿佐塞米。除利尿剂特性外，它还具有抗高血压特性。
作为髓袢的利尿剂，其在治疗血栓形成、心绞痛、气喘、高血压、肾病性水肿、肺水肿、原发性和继发性醛固酮增多症、巴特综合征、肿瘤、青光眼、眼内压降低、急性或慢性支气管炎，治疗因创伤、局部缺血、脑震荡、转移或癫痫发作引起的脑水肿和治疗因变应原引起的鼻感染中，作为预防与局部缺血相联的代谢或离子异常所引起的心脏损伤或心组织损伤的药剂是有意义的。
公知的是，托拉塞米可以按四种晶体变体：多晶形I[ActaCryst.B34，(1978)1304-1310]、多晶形II(Acta Cryst.B34，(1978)2659-2662)、多晶形III(PCT/WO 00/20395)和多晶形V(HR专利申请P 20000328A)以及一种无定形变体(HR专利申请P20000162A)的形式存在。
托拉塞米的变体(多晶形I-V)疏水性很强并且事实上不溶于水。托拉塞米的非常差的水溶性和润湿性是在制备具有良好溶解性和均一生物利用率的药物制剂方面存在的问题。
很多领域中都存在增加水溶性差的活性物质的溶解速率的问题，其范围从植物药剂至杀虫剂，总的来说，包括使用生物活性物质的所有领域。
溶解速率由活性物质的物化性质所决定，特别是由其在水中的溶解性所决定。由此，活性物质的溶解速率在物质的吸收过程和治疗活性中是限制性因素。此外，在药物制剂中形成活性物质的崩解产物还会引起不同的负效应。因此，通过制备适宜的制剂来达到溶解性和稳定性的增加，便可以增加活性物质的效力。在制药领域中，溶解性差的活性物质，其溶解速率和稳定性的增加，可通过各种方法来解决，例如通过微粉化；通过制备无定形物、笼形物；通过化学改性；通过pH调节，并且经常是通过制备活性物质与生理学适宜的添加剂的固体组合物，使得可以实现活性物质的合意的物化转变，即改进活性物质的溶解速率和润湿性。作为生理学适宜的添加剂，通常使用例如聚乙烯吡咯烷酮、羧甲基纤维素、羟丙基纤维素和使用得愈来愈多的环糊精，其是可商购获得的由6、7和8个相连的吡喃葡萄糖单元组成的环状低聚糖(α-、β-和γ-环糊精及它们的衍生物)。
固体组合物活性物质/生理学适宜的添加剂可以通过共混、混炼、沉淀、蒸发、冻干、喷雾干燥和熔融来制备。
环糊精的特性是公知的并且在期刊中有详细的描述：[SzejtliJ.，环糊精技术(1988)Kluwer Academic Publishers，Dordrecht；Szejtli J.，药物制剂中的环糊精：第I部分，Pharm.Techn.Int.3(1991)15-22；Szejtli J.，药物制剂中的环糊精：第II部分，Pharm.Tcehn.Int.3(3)(1991)16-24；T.Loftson，β-环糊精的药物应用，Pharm.Techn。Eur.11(1999)20；W.Saenger，研究和工业中的环糊精包含化合物，Angew.Chem.Int.Ed.Engl.19(1980)344]。
环糊精的特征是其分子形状呈圆筒形式。在圆筒内部，是疏水性的分子内空腔，而外侧是亲水性的。分子内空腔的这种疏水特性能够允许其它分子或分子的一部分(称作“客体”分子)进入该主体分子中，形成包合配合物。
包合配合物(inclusion complex)可以通过许多力来稳定，也包括范德华吸引力和氢键。相应“客体”分子被环糊精所包合配合(inclusion complexing)，可以导致“客体”分子的性能发生很多物化变化。熔点被改变，包合配合物的IR光谱和X-射线粉末衍射图相对地不同于纯“客体”分子或者“主体”分子和“客体”分子的简单(没有配合的)混合物。借助于环糊精包合配合物，水不溶性的“客体”分子变得较可溶。在很多情形中，化学不稳定的化合物是通过包合配合技术来稳定化的。由于被环糊精包合配合而使“客体”分子的物化性质发生的所说的变化，证明环糊精包合配合物是固态“客体”分子的独特形式。
虽然通过制备固体组合物活性物质/生理学适宜的添加剂，在许多溶解性差的药物活性物质中发现溶解速率有所增加，但这并不能作为一个规则来接受。即，对每种活性物质和生理学适宜的添加剂来说，必须要建立何种制备方法、生理学适宜的添加剂和活性物质/生理学适宜的添加剂摩尔比、溶剂、时间、制备温度等能够使固体组合物达到合意的活性物质溶解速率。
从专利以及文献中已知有很多环糊精与各种药物活性物质的固体组合物，这里仅提及以下一些实例。
M.I.La Rotonda等比较了非甾族抗炎药物尼美舒利和β-环糊精(摩尔比1∶1)的固体组合物，其通过物理共混、蒸发、冻干、喷雾干燥和捏和来制备，并且报导了溶解速率取决于各固体组合物的物化性质。与单独的尼美舒利相比，固体组合物中的尼美舒利的溶解明显加速并且通过冻干和喷雾干燥获得的固体组合物表现出是尼美舒利溶解的最快形式[S.T.P.Pharma Sci.10(2000)157]。
P.R.Vavia等也比较了尼美舒利与β-环糊精和HP-β-环糊精按摩尔比1∶1的固体组合物(物理混合物和冻干物)。正如作者所陈述的，与物理混合物相比，通过冻干制备的包合配合物可增加尼美舒利的溶解，特别是通过包合配合物尼美舒利/HP-β-环糊精，达到明显较高的溶解[Drug Develop.Ind.Pharm.25(1999)543]。
J.R.Mayano等通过物理混合、喷雾干燥和捏和制备了药物去甲羟安定与β-环糊精按摩尔比1∶1和1∶2的固体组合物，并且与单独的去甲羟安定相比，所有的固体组合物都加速了去甲羟安定的溶解。当是物理混合物的时候，两种摩尔比的去甲羟安定/β-环糊精都对去甲羟安定的溶解显出相同的影响，而通过捏和和喷雾干燥制备的摩尔比1∶2的固体组合物相比于摩尔比1∶1的固体组合物，相当大地加速了去甲羟安定的溶解[Int.J.Pharm.114(1995)95]。
此外，M.Guyot等制备了药物诺氟沙星与β-环糊精和HP-β-环糊精按摩尔比1∶1和1∶2的物理混合物和包合配合物。物理混合物以及包合配合物与单独的诺氟沙星相比都明显增加了溶解性。没有发现摩尔比对溶解性有什么影响[Int.J.Pharm.123(1995)53]。
除此之外，M.Pedersen等陈述了抗菌剂咪康唑和β-环糊精按摩尔比1∶2的物理混合物，相比于与β-环糊精的包合配合物，显出更快的溶解性[Drug Develop.Ind.Pharm.25(1999)1241]。
在US专利5,849,329中，作者保护了一种具有受控溶解性的药物组合物的制备方法，该组合物通过将活性物质、特别是还与α-、β-、γ-和HP-β-环糊精及其衍生物研磨或干混来制备。作为活性物质，可以是萘醌腙、丁苯哌丁醇、卡马西平、格列齐特、格列本脲、联苯苄唑以及硝苯地平、地西泮和酮洛芬。
在US专利5,449,521中，作者保护了药物组合物，其中含有灰黄霉素、吡罗昔康、双醋瑞因、地尔硫卓、醋酸甲地孕酮、硝苯地平、尼麦角林、酮洛芬、萘普生、双氯酚酸钠、布洛芬、劳拉西泮、去甲羟安定作为活性物质，尤其还含有交联聚合的环糊精。所提及的药物组合物通过将活性物质和适宜的添加剂在用溶剂或溶剂混合物的蒸气所饱和的碾磨机中研磨来制备。
另外，在US专利5,010,064中，作者保护了一种双嘧达莫(dipyrimidole)和β-环糊精(摩尔比为1∶1至1∶12)的包合配合物，而在US专利5,019,563中，保护了一种布洛芬钠盐与β-环糊精(摩尔比1∶0.2至1∶0.75)的配合物。
此外，在US专利5,674,854中，作者描述并保护了双氯芬酸的药学适宜的盐和β-环糊精(摩尔比1∶1)的制剂和包合配合物，并且在US专利5,744,165中，作者保护了尼美舒利的碱金属和碱土金属盐与α-、β-和γ-环糊精及其衍生物的包合配合物。
在公开的专利中请WO 93/00097中，作者要求保护一种稳定的药物制剂，其含有托拉塞米或其盐和添加剂，所说的添加剂诸如羟丙基纤维素、聚乙烯吡咯烷酮、交联羧甲基纤维素钠(sodium-croscarmellose)、交聚维酮(cros-povidone)、羧甲基纤维素钙、低级取代的羟丙基纤维素、改性淀粉等。其中没有提及环糊精。
发明内容
在我们对托拉塞米的进一步研究中，意想不到地发现托拉塞米的变体I-V与环糊精或环糊精衍生物的物理混合物具有托拉塞米较快溶解的特点。此外，意想不到地发现，托拉塞米的变体I-V与环糊精或环糊精衍生物的包合配合物具有托拉塞米较快溶解的特点。
首先，本发明涉及托拉塞米的变体I、II、III、IV或V与环糊精或环糊精衍生物或者托拉塞米的变体I、II、III、IV和V的任何混合物与环糊精或环糊精衍生物的生理学适宜的物理混合物。
物理混合物中所含的环糊精是α-、β-和γ-环糊精及它们的衍生物。α-、β-和γ-环糊精的适宜的衍生物是它们的醚和混合醚，其中环糊精的葡糖酐部分(anhydroglucose parts)的一个或多个基团被以下基团所取代：C1-6烷基，优选甲基、乙基或异丙基；羟基C1-6烷基，优选羟乙基或羟丙基或羟丁基；羧基C1-6烷基，优选羧甲基或羧乙基；C1-6烷基羰基，优选乙酰基；C1-6烷氧基羰基C1-6烷基或羧基-C1-6烷氧基-C1-6烷基，优选羧基-甲氧基丙基或羧基-乙氧基丙基；C1-6烷氧基羰基氧基-C1-6烷基，优选2-乙酰氧基丙基。特别重要的环糊精或它们的衍生物是α-、β和γ-环糊精，2-羟丙基-α-环糊精，2-羟丙基-β-环糊精，2-羟丙基-γ-环糊精，2-羟乙基-β-环糊精，2-羟乙基-γ-环糊精，2，6-二甲基-β-环糊精和(2-羧基甲氧基)-丙基-β-环糊精。
总的来说，在本发明的物理混合物中，托拉塞米的变体I-V与环糊精或环糊精衍生物的摩尔比范围可以为1∶0.1至1∶5。
此外，本发明还涉及前述托拉塞米的变体I-V与环糊精或环糊精衍生物的物理混合物的制备方法。在实践中，此方法可以按照以下方法来实施：
将托拉塞米的变体I、II、III、IV或V与环糊精或环糊精衍生物或者将托拉塞米的变体I、II、III、IV和V的任何混合物与环糊精或环糊精衍生物按特定的摩尔比合并，在制药工业中常用的研钵或混合器中，在为获得具有合意托拉塞米溶解速率的混合物所需的温度下和时间内均化。
根据本发明的第一个目的，本发明还涉及托拉塞米的变体I、II、III、IV或V与环糊精或环糊精衍生物或者托拉塞米的变体I、II、III、IV和V的任何混合物与环糊精或环糊精衍生物的生理学适宜的包合配合物。
包合配合物中所含的环糊精是α-、β-和γ-环糊精或它们的衍生物。α-、β-和γ-环糊精的适宜的衍生物是它们的醚和混合醚，其中环糊精的葡糖酐部分的一个或多个基团被以下基团所取代：C1-6烷基，优选甲基、乙基或异丙基；羟基C1-6烷基，优选羟乙基或羟丙基或羟丁基；羧基C1-6烷基，优选羧甲基或羧乙基；C1-6烷基羰基，优选乙酰基；C1-6烷氧基羰基C1-6烷基或羧基-C1-6烷氧基-C1-6烷基，优选羧基-甲氧基丙基或羧基-乙氧基丙基；C1-6烷氧基羰基氧基C1-6烷基，优选2-乙酰氧基丙基。特别重要的环糊精或它们的衍生物是α-、β和γ-环糊精，2-羟丙基-α-环糊精，2-羟丙基-β-环糊精，2-羟丙基-γ-环糊精，2-羟乙基-β-环糊精，2-羟乙基-γ-环糊精，2，6-二甲基-β-环糊精和(2-羧基甲氧基)-丙基-β-环糊精。
总的来说，在本发明的包合配合物中，托拉塞米的变体I-V与环糊精或环糊精衍生物的摩尔比范围可以为1∶0.1至1∶5。
此外，本发明还涉及前述托拉塞米的变体I-V与环糊精或环糊精衍生物的包合配合物的制备方法。在实践中，此方法可以按照以下方法来实施：
将托拉塞米的变体I、II、III、IV或V或者将托拉塞米的变体I、II、III、IV和V的任何混合物添加到环糊精或环糊精衍生物的水溶液中，并且加入或不加入氨水溶液，在为形成包合配合物所需的温度下和时间内搅拌。待包合配合物形成后，通过冻干、喷雾干燥、低温下真空蒸发或者通过药学领域已知的其它方法除去其中的水分。
根据本发明方法制备的托拉塞米的变体I-V与环糊精或环糊精衍生物的物理混合物以及托拉塞米的变体I-V与环糊精或环糊精衍生物的包合配合物，可以作为适宜的托拉塞米形式，用作利尿剂或用作预防与局部缺血相联的代谢或离子异常所引起的心脏损伤或心组织损伤的药剂，用作治疗血栓形成、心绞痛、气喘、高血压、肾病性水肿(nephroedema)、肺水肿、原发性和继发性醛固酮增多症、巴特综合征、肿瘤、青光眼、眼内压降低、急性或慢性支气管炎，治疗因创伤、局部缺血、脑震荡、转移或癫痫发作引起的脑水肿和治疗因变应原引起的鼻感染的药剂。
本发明还涉及药物形式，例如片剂、胶囊剂、注射剂或喷雾剂，其中含有托拉塞米的变体I、II、III、IV或V与环糊精或环糊精衍生物或者托拉塞米的变体I、II、III、IV和V的任何混合物与环糊精或环糊精衍生物的物理混合物或包合配合物作为活性成分，不含任何添加剂或者与一种或多种可药用添加剂相联用，诸如糖、淀粉、淀粉衍生物、纤维素、纤维素衍生物、脱模剂和防粘剂以及可用可不用的调节流动性用试剂。
图1显示了β-环糊精的DSC曲线。
图2显示了托拉塞米的变体I的DSC曲线。
图3显示了托拉塞米的变体I和β-环糊精的物理混合物(摩尔比1∶1)的DSC曲线。
图4显示了托拉塞米的变体I和β-环糊精的包合配合物(摩尔比1∶1)的DSC曲线。
图5显示了用KBr记录的β-环糊精的IR光谱。
图6显示了用KBr记录的托拉塞米的变体I的IR光谱。
图7显示了用KBr记录的托拉塞米的变体I和β-环糊精的物理混合物(摩尔比1∶1)的IR光谱。
图8显示了用KBr记录的托拉塞米的变体I和β-环糊精的包合配合物(摩尔比1∶1)的IR光谱。
图9显示了β-环糊精的X-射线粉末衍射图(X-ray powderpattern)。
图10显示了托拉塞米的变体I的X-射线粉末衍射图。
图11显示了托拉塞米的变体I和β-环糊精的物理混合物(摩尔比1∶1)的X-射线粉末衍射图。
图12显示了托拉塞米的变体I和β-环糊精的包合配合物(摩尔比1∶1)的X-射线粉末衍射图。
本发明将通过以下实施例作非限定性举例说明。
实施例1
将根据PCT/WO 00/20395的托拉塞米的变体I(0.50g)和等摩尔量的β-环糊精在混合器中均化24小时。
图3所示的差示扫描量热法(DSC)曲线中包括有托拉塞米变体I和β-环糊精的放热峰。在Perkin-Elmer DSC7型仪器上以25℃/min的加热速率进行DSC分析。
图7所示的IR光谱中包括有托拉塞米变体I和β-环糊精的特征峰。在Nicolet，Magna 760型IR分光光度计上记录IR光谱，记录范围从4000至600cm-1。
代表性的X-射线粉末衍射图在图11中显示，并且在PHILIPSPW 3710型衍射仪上记录，记录范围2θ＝5-40°，使用CuKα射线＝1.541埃。记录步数为0.029°并且记录时间为1s每步。
实施例2
测试本发明实施例1制备的托拉塞米变体I和β-环糊精的物理混合物的活性物质在37℃(USP 24)水中的释放，并且结果示于下表1中。表1：托拉塞米变体I和β-环糊精(摩尔比1∶1)的物理混合物在水(USP 24)(37℃，50rpm，1000ml)中的托拉塞米的释放
实施例3
| 时间(分钟) | 释放的托拉塞米(％) | |
| 托拉塞米的变体I | 物理混合物 | |
| 0 | 0 | 0 |
| 15 | 0.7 | 32.2 |
| 30 | 20.3 | 57.1 |
| 45 | 38.5 | 70.2 |
| 60 | 51.8 | 80.6 |
| 90 | 68.5 | 89.1 |
| 120 | 78.7 | 93.8 |
将β-环糊精(1.81g)溶解于50ml去离子水中并且加入10滴氨水溶液。随后，将等摩尔量的根据PCT/WO 00/20395制备的托拉塞米的变体I添加到此溶液中，剧烈搅拌24小时，然后过滤并且通过冻干除去水分。
通过差示扫描量热法、IR分析获得的数据和X-射线粉末衍射图证明，形成了托拉塞米和β-环糊精的包合配合物。
图4所示的差示扫描量热(DSC)曲线中不包括有托拉塞米变体I和β-环糊精的强特征峰。
图8所示的IR光谱与图5和图6所示的托拉塞米变体I的IR光谱及β-环糊精的IR光谱完全不同。
图12中所示的X-射线粉末衍射图与图10和11所示的托拉塞米变体I的X-射线粉末衍射图和β-环糊精的X-射线粉末衍射图完全不同。
实施例4
将β-环糊精(0.28g)溶解于50ml去离子水，将溶液在剧烈搅拌条件下加热至80℃，搅拌60分钟，然后用90分钟的时间加入等摩尔量的根据PCT/WO 00/20395制备的托拉塞米的变体I。随后，将此热溶液过滤，冷却至室温，通过冻干来除去水分。
如此所得样品的IR光谱与根据本发明实施例3制备的样品的IR光谱相同。
实施例5
测试本发明实施例3制备的托拉塞米变体I和β-环糊精的包合配合物的活性物质在37℃水(USP 24)中的释放，并且结果示于下表2中。表2：托拉塞米变体I和β-环糊精(摩尔比1∶1)的包合配合物在水(USP 24)(37℃，50rpm，1000ml)中的托拉塞米的释放
| 时间(分钟) | 释放的托拉塞米(％) | |
| 托拉塞米的变体I | 包合配合物 | |
| 0 | 0 | 0 |
| 15 | 0.7 | 95.8 |
| 30 | 20.3 | 98.2 |
| 45 | 38.5 | 97.9 |
| 60 | 51.8 | 98.3 |
| 90 | 68.5 | 98.8 |
| 120 | 78.7 | 98.5 |
Claims (27)
1、物理混合物，其特征在于它们含有托拉塞米和环糊精或环糊精衍生物。
2、权利要求1的物理混合物，其特征在于托拉塞米选自变体I、II、III、IV和V或其任何混合物。
3、权利要求1的物理混合物，其特征在于环糊精选自α-，β-和γ-环糊精。
4、权利要求1的物理混合物，其特征在于环糊精衍生物选自α-、β-和γ-环糊精的醚或混合醚，其中环糊精的葡糖酐部分的一个或多个基团被以下基团所取代：C1-6烷基，优选甲基、乙基或异丙基；羟基C1-6烷基，优选羟乙基或羟丙基或羟丁基；羧基C1-6烷基，优选羧甲基或羧乙基；C1-6烷基羰基，优选乙酰基，C1-6烷氧基羰基C1-6烷基或羧基-C1-6烷氧基-C1-6烷基，优选羧基甲氧基丙基或羧基乙氧基丙基；C1-6烷氧基羰基氧基C1-6烷基，优选2-乙酰氧基丙基。
5、权利要求1的物理混合物，其特征在于环糊精衍生物选自2-羟丙基-α-环糊精，2-羟丙基-β-环糊精，2-羟丙基-γ-环糊精，2-羟乙基-β-环糊精，2-羟乙基-γ-环糊精，2，6-二甲基-β-环糊精和(2-羧基甲氧基)-丙基-β-环糊精。
6、权利要求1的物理混合物，其特征在于托拉塞米和环糊精或环糊精衍生物的摩尔比为1∶0.1至1∶5。
7、制备权利要求1的物理混合物的方法，其特征在于将托拉塞米和环糊精或环糊精衍生物均化。
8、权利要求7的物理混合物的制备方法，其特征在于所说的均化在研钵或在混合器中进行。
9、权利要求7的物理混合物的制备方法，其特征在于所说的混合在10℃至100℃下完成。
10、权利要求7的物理混合物的制备方法，其特征在于所说的混合用0.1小时至24小时完成。
11、权利要求1的物理混合物，其特征在于它们在治疗血栓形成、心绞痛、气喘、高血压、肾病性水肿、肺水肿、原发性和继发性醛固酮增多症、巴特综合征、肿瘤、青光眼、眼内压降低、急性或慢性支气管炎，治疗因创伤、局部缺血、脑震荡、转移或癫痫发作引起的脑水肿和治疗因变应原引起的鼻感染中，用作利尿剂或用作预防与局部缺血相联的代谢或离子异常所引起的心脏损伤或心组织损伤的药剂。
12、一种药物形式，其特征在于其含有权利要求1的物理混合物作为活性物质，并与一种或多种可药用添加剂相联用，其中所说的可药用添加剂诸如糖、淀粉、淀粉衍生物、纤维素、纤维素衍生物、脱模剂和防粘剂以及可用可不用的调节流动性用试剂。
13、权利要求12的药物形式，其特征在于其是片剂、胶囊剂、注射剂或喷雾剂。
14、包合配合物，其特征在于它们含有托拉塞米和环糊精或环糊精衍生物。
15、权利要求14的包合配合物，其特征在于环糊精选自α-，β-和γ-环糊精。
16、权利要求14的包合配合物，其特征在于环糊精衍生物选自α-、β-和γ-环糊精的醚或混合醚，其中环糊精的葡糖酐部分的一个或多个基团被以下基团所取代：C1-6烷基，优选甲基、乙基或异丙基；羟基C1-6烷基，优选羟乙基或羟丙基或羟丁基；羧基C1-6烷基，优选羧甲基或羧乙基；C1-6烷基羰基，优选乙酰基，C1-6烷氧基羰基C1-6烷基或羧基-C1-6烷氧基-C1-6烷基，优选羧基甲氧基丙基或羧基乙氧基丙基；C1-6烷氧基羰基氧基-C1-6烷基，优选2-乙酰氧基丙基。
17、权利要求14的包合配合物，其特征在于环糊精衍生物选自2-羟丙基-α-环糊精，2-羟丙基-β-环糊精，2-羟丙基-γ-环糊精，2-羟乙基-β-环糊精，2-羟乙基-γ-环糊精，2，6-二甲基-β-环糊精和(2-羧基甲氧基)-丙基-β-环糊精。
18、权利要求14的包合配合物，其特征在于托拉塞米和环糊精或环糊精衍生物的摩尔比为1∶0.1至1∶5。
19、制备权利要求14的包合配合物的方法，其特征在于将托拉塞米和环糊精或环糊精衍生物在水中反应，其中所说的水中有或没有碱的水溶液存在。
20、权利要求19的包合配合物的制备方法，其特征在于使用氨水溶液作为碱的水溶液。
21、权利要求19的包合配合物的制备方法，其特征在于此反应在10℃至100℃下完成。
22、权利要求19的包合配合物的制备方法，其特征在于此反应用0.1小时至7天完成。
23、权利要求19的包合配合物的制备方法，其特征在于在形成所说的包合配合物后，通过干燥除去水和碱。
24、权利要求23的包合配合物的制备方法，其特征在于所说的干燥通过冻干、喷雾干燥、真空蒸发或真空干燥来完成。
25、权利要求14的包合配合物，其特征在于它们在治疗血栓形成、心绞痛、气喘、高血压、肾病性水肿、肺水肿、原发性和继发性醛固酮增多症、巴特综合征、肿瘤、青光眼、眼内压降低、急性或慢性支气管炎，治疗因创伤、局部缺血、脑震荡、转移或癫痫发作引起的脑水肿和治疗因变应原引起的鼻感染中，用作利尿剂或用作预防与局部缺血相联的代谢或离子异常所引起的心脏损伤或心组织损伤的药剂。
26、一种药物形式，其特征在于其含有权利要求14的包合配合物作为活性成份，并与一种或多种可药用添加剂相联用，其中所说的可药用添加剂诸如糖、淀粉、淀粉衍生物、纤维素、纤维素衍生物、脱模剂和防粘剂以及可用可不用的调节流动性用试剂。
27、权利要求26的药物形式，其特征在于其是片剂、胶囊剂、注射剂或喷雾剂。
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| EP (1) | EP1347780B1 (zh) |
| JP (1) | JP2004513155A (zh) |
| KR (1) | KR20030060929A (zh) |
| CN (1) | CN1477977A (zh) |
| AR (1) | AR026815A1 (zh) |
| AU (1) | AU2001228721A1 (zh) |
| BG (1) | BG107896A (zh) |
| BR (1) | BR0115281A (zh) |
| CA (1) | CA2428179A1 (zh) |
| CZ (1) | CZ20031490A3 (zh) |
| DE (1) | DE60125828T2 (zh) |
| EA (1) | EA005111B1 (zh) |
| EE (1) | EE200300197A (zh) |
| GE (1) | GEP20043403B (zh) |
| HR (1) | HRP20000765A2 (zh) |
| HU (1) | HUP0400776A2 (zh) |
| IL (1) | IL155818A0 (zh) |
| IS (1) | IS6810A (zh) |
| MX (1) | MXPA03004111A (zh) |
| NO (1) | NO20032091L (zh) |
| PL (1) | PL361667A1 (zh) |
| SK (1) | SK6722003A3 (zh) |
| WO (1) | WO2002038186A1 (zh) |
| YU (1) | YU35303A (zh) |
| ZA (1) | ZA200303601B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100372534C (zh) * | 2006-04-20 | 2008-03-05 | 南京海辰药业有限公司 | 托拉塞米冻干制剂及制备方法 |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SI21703A (en) * | 2004-01-14 | 2005-08-31 | Lek Farmacevtska Druzba Dd | Inclusion complexes of perindopril, procedure of their preparation, pharmaceutical compositions containing these complexes and their application in treatment of hypertensia |
| ATE375977T1 (de) * | 2004-01-22 | 2007-11-15 | Pfizer | Sulfonamidderivate zur behandlung von krankheiten |
| WO2008127682A2 (en) | 2007-04-13 | 2008-10-23 | Millennium Pharmaceuticals, Inc. | Combination anticoagulant therapy with a compound that acts as a factor xa inhibitor |
| BR102012009317B1 (pt) * | 2012-04-20 | 2022-05-31 | Universidade Federal De Minas Gerais - Ufmg | Processo de preparação de compostos de inclusão envolvendo ciclodextrinas e fármacos, usando um sistema de fluxo contínuo |
| WO2020141226A1 (en) * | 2019-01-04 | 2020-07-09 | Sq Innovation Ag | Pharmaceutical compositions of torsemide and uses thereof |
| CN113271923A (zh) | 2019-01-04 | 2021-08-17 | Sq创新股份公司 | 呋塞米的药物组合物及其用途 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US576511A (en) * | 1897-02-02 | Georg steinike and friedrich schmidt | ||
| DE3529529A1 (de) * | 1985-08-17 | 1987-02-19 | Boehringer Mannheim Gmbh | Verfahren zur herstellung einer stabilen modifikation von torasemid |
| EP0807361B1 (en) * | 1995-12-01 | 2005-11-23 | Koninklijke Philips Electronics N.V. | A digital cordless telephony system, a radio base station, and a combination of a radio base station and a cordless handset |
| US6828334B2 (en) * | 2002-05-23 | 2004-12-07 | Usv Limited | Fenofibrate-cyclodextrin inclusion complexes and their pharmaceutical composition |
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2000
- 2000-11-10 HR HR20000765A patent/HRP20000765A2/hr not_active Application Discontinuation
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2001
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- 2001-01-31 MX MXPA03004111A patent/MXPA03004111A/es unknown
- 2001-01-31 YU YU35303A patent/YU35303A/sh unknown
- 2001-01-31 EP EP01993478A patent/EP1347780B1/en not_active Expired - Lifetime
- 2001-01-31 GE GE5156A patent/GEP20043403B/en unknown
- 2001-01-31 PL PL01361667A patent/PL361667A1/xx unknown
- 2001-01-31 SK SK672-2003A patent/SK6722003A3/sk unknown
- 2001-01-31 CZ CZ20031490A patent/CZ20031490A3/cs unknown
- 2001-01-31 AU AU2001228721A patent/AU2001228721A1/en not_active Abandoned
- 2001-01-31 EE EEP200300197A patent/EE200300197A/xx unknown
- 2001-01-31 BR BR0115281-5A patent/BR0115281A/pt not_active IP Right Cessation
- 2001-01-31 IL IL15581801A patent/IL155818A0/xx unknown
- 2001-01-31 DE DE60125828T patent/DE60125828T2/de not_active Expired - Fee Related
- 2001-01-31 KR KR10-2003-7006357A patent/KR20030060929A/ko not_active Application Discontinuation
- 2001-01-31 CN CNA018198309A patent/CN1477977A/zh active Pending
- 2001-01-31 HU HU0400776A patent/HUP0400776A2/hu unknown
- 2001-01-31 CA CA002428179A patent/CA2428179A1/en not_active Abandoned
- 2001-01-31 ZA ZA200303601A patent/ZA200303601B/xx unknown
- 2001-01-31 WO PCT/HR2001/000004 patent/WO2002038186A1/en active IP Right Grant
- 2001-01-31 US US10/416,303 patent/US7037928B2/en not_active Expired - Fee Related
- 2001-01-31 JP JP2002540768A patent/JP2004513155A/ja active Pending
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2003
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100372534C (zh) * | 2006-04-20 | 2008-03-05 | 南京海辰药业有限公司 | 托拉塞米冻干制剂及制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| YU35303A (sh) | 2006-03-03 |
| CA2428179A1 (en) | 2002-05-16 |
| AR026815A1 (es) | 2003-02-26 |
| AU2001228721A1 (en) | 2002-05-21 |
| BG107896A (bg) | 2004-01-30 |
| KR20030060929A (ko) | 2003-07-16 |
| BR0115281A (pt) | 2003-07-29 |
| JP2004513155A (ja) | 2004-04-30 |
| EA005111B1 (ru) | 2004-10-28 |
| IL155818A0 (en) | 2003-12-23 |
| HRP20000765A2 (en) | 2002-06-30 |
| WO2002038186A1 (en) | 2002-05-16 |
| US20040039204A1 (en) | 2004-02-26 |
| DE60125828D1 (de) | 2007-02-15 |
| EP1347780B1 (en) | 2007-01-03 |
| EE200300197A (et) | 2003-08-15 |
| HUP0400776A2 (hu) | 2004-08-30 |
| GEP20043403B (en) | 2004-06-10 |
| DE60125828T2 (de) | 2007-08-16 |
| MXPA03004111A (es) | 2004-05-05 |
| ZA200303601B (en) | 2004-07-19 |
| US7037928B2 (en) | 2006-05-02 |
| PL361667A1 (en) | 2004-10-04 |
| SK6722003A3 (en) | 2003-10-07 |
| IS6810A (is) | 2003-05-08 |
| NO20032091D0 (no) | 2003-05-09 |
| CZ20031490A3 (cs) | 2003-08-13 |
| EA200300556A1 (ru) | 2003-08-28 |
| NO20032091L (no) | 2003-07-02 |
| EP1347780A1 (en) | 2003-10-01 |
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