CN1615133A - 卡维地洛的结晶固体及其制备方法 - Google Patents
卡维地洛的结晶固体及其制备方法 Download PDFInfo
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- CN1615133A CN1615133A CNA038022109A CN03802210A CN1615133A CN 1615133 A CN1615133 A CN 1615133A CN A038022109 A CNA038022109 A CN A038022109A CN 03802210 A CN03802210 A CN 03802210A CN 1615133 A CN1615133 A CN 1615133A
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- Prior art keywords
- carvedilol
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Abstract
本发明涉及一种新的卡维地洛结晶固体或其溶剂化物、其制备方法、含有其的组合物,以及其在药物中的应用。本发明还涉及一种制备II型卡维地洛的结晶固体的新方法。
Description
相关申请的交叉参考
本申请要求享有2002年1月15日提交的序号为60/349310的美国临时申请的权益,在此引用该临时申请作为参考。
发明领域
本发明涉及一种新的卡维地洛结晶固体或其溶剂化物、其制备方法、含有其的组合物,以及其在药物中的应用。本发明还涉及一种制备II型卡维地洛晶体的新方法。
发明背景
卡维地洛,即(±)-1-(咔唑-4-基氧基)-3-[[2-(邻甲氧基苯氧基)乙基]氨基]-2-丙醇,是一种具有α1-阻断活性的非选择性β-肾上腺素能阻断剂。卡维地洛是一种具有下列结构式的外消旋混合物:
卡维地洛(I)
卡维地洛是表明用于治疗充血性心力衰竭以及治疗高血压的药物COREG的活性成分。由于卡维地洛是一种具有多重作用的药物,它的β-阻断活性影响对部分身体中的某些神经冲动的反应。结果,β-阻断剂通过减小心脏的工作负荷降低了心脏对血液和氧的需求。卡维地洛还已知是一种主要源自α-肾上腺素受体阻断的血管扩张剂。卡维地洛的多重作用使该药具有抗高血压的功效,以及具有治疗充血性心力衰竭的效力。
国际申请No.WO99/05105(‘105申请)公开了根据制备方法不同可将卡维地洛分离为两种多晶型物。据报道,这两种被称为I型和II型的多晶型物是单向转变的,并且可根据它们的红外、拉曼及粉末X射线衍射(PXRD)光谱来区分。在文献中没有发现存在卡维地洛溶剂化物形式的证据。
在‘105申请的实施例1中,I型卡维地洛是通过如下方式制备的:将卡维地洛粗品溶解于甲醇中,加热该溶液,冷却并搅拌该溶液足够的时间以生成I型卡维地洛。II型卡维地洛是通过在2-丙醇中重结晶I型卡维地洛而制得的。
本发明涉及卡维地洛的固态物理学特性。可通过控制制备卡维地洛固体形式的条件来影响这些特性。例如,固态物理学特性包括经研磨的固体的流动性。流动性影响在加工成药物产品的过程中对原料进行处理的难易程度。当粉状化合物的颗粒不能在彼此间容易地穿行流动时,制剂专家必须在开发那些可能需要采用诸如胶体二氧化硅、滑石、淀粉或者正磷酸钙之类助流剂的片剂或胶囊剂时考虑到该实际情况。
药物化合物的另一个重要的固态特性是其在水成流体中的溶解速率。活性成分在患者胃液中的溶解速率可具有治疗意义,因为它为口服活性成分可以到达患者血流的速率设置了上限。在配制糖浆、酏剂以及其它液体药物时也应考虑溶解速率。化合物的固态形式还可影响到其压制时的性能及其储藏稳定性。
这些实际的物理学特性受限定物质特定多晶型物的晶胞中分子构象和取向的影响。所述多晶型物可引起不同于非晶态物质或另一多晶型物的热性能。热性能可在实验室通过如毛细管熔点法、热重分析法(TGA)和差示扫描量热法(DSC)之类的技术来测定,并且能够用于将一些多晶型物从其它的多晶型物中区分出来。一种特定的多晶型物还可以引起独特的、可通过粉末X射线晶体学、固态13C NMR光谱测定法和红外光谱测定法来检测的光谱特性。
本发明还涉及卡维地洛的溶剂化物。当一物质从溶液中结晶出时,它可在晶格中以规则的间隔捕捉溶剂分子。溶剂化还影响固态的实用物理学特征,如流动性及溶解速率。
能够形成多晶型物或溶剂化物的药物化合物的最重要的物理特性之一是其在水溶液中的溶解度,尤其是在患者胃液中的溶解度。其它的重要特性涉及将该形式加工成药剂时的简易性,例如粉状或粒状形式的流动趋势和决定该形式的晶体在压制成片时是否彼此粘附的表面特性。
药用化合物的新的多晶型物和溶剂化物的发现提供了一个改善药物产品性能特征的新的机会。它扩大了制剂学家的可用于设计例如具有目标释放特性或者其它所期望特性的药物剂型的材料库。卡维地洛的新的多晶型物和溶剂化物已被发现。
发明概述
一方面,本发明提供了一种卡维地洛结晶固体或其溶剂化物,其特征在于选自于由下列图谱组成的组的数据:在约6.5,7.3,16.0和30.5±0.2度2θ处具有峰的PXRD图谱;在约5.8,10.7,11.1,11.5,13.1,13.7,16.8,17.7,18.5和23.0±0.2度2θ处具有峰的PXRD图谱;在约74℃和112℃处具有吸热峰的DSC热分析图;以及在约613,740,994,1125,1228,1257,1441,1508,1737,2840,3281,3389和3470cm-1处具有峰的FTIR光谱。所述的固体结晶形式称为VI型。
另一方面,本发明提供了一种制备具有VI型的至少一种特征(如这里公开的PXRD峰和/或FTIR峰,和/或DSC峰)的卡维地洛结晶固体或其溶剂化物的方法。根据该方法,将卡维地洛与醋酸乙酯接触以形成溶液。冷却该溶液并任选地用II型卡维地洛作为晶种来接种该溶液。可在高速搅拌下搅拌该溶液以形成悬液,然后可在高速搅拌下冷却该悬液。
再一方面,本发明提供了一种制备II型卡维地洛的结晶固体的方法,包括以下步骤:加热具有VI型的至少一种特征的结晶卡维地洛直到该结晶卡维地洛干燥为止;将II型卡维地洛与该干燥的结晶卡维地洛混合;以及将该混合物存储一段足以使该干燥的结晶卡维地洛转变为II型卡维地洛的时间。
附图说明
图1是VI型卡维地洛的PXRD图谱。
图2是VI型卡维地洛的FTIR光谱。
图3是VI型卡维地洛的DSC热分析图。
图4是VI型卡维地洛的DTG热分析图。
发明详述
一方面,本发明提供了一种新的卡维地洛结晶固体或其溶剂化物,称为VI型。VI型卡维地洛溶剂化物是由在大约6.5,7.3,16.0以及30.5±0.2度2θ处具有峰的PXRD图谱(图1)来表征的。在大约5.8,10.7,11.1,11.5,13.1,13.7,16.8,17.7,18.5以及23.0±0.2度2θ处可观察到更多的PXRD峰。
VI型卡维地洛溶剂化物产生了在大约613,740,994,1125,1228,1257,1441,1508,1737,2840,3281,3389以及3470cm-1处具有特征吸收带的FTIR光谱(图2)。在大约720,1100,1286,1454,1589,2911,以及2935cm-1处可观察到更多的FTIR峰。
VI型卡维地洛溶剂化物产生了显示出两个吸热峰的DSC热分析图(图3):主吸热峰在大约74℃处被观察到,而次吸热峰(dH=0.7J/g)在112℃处被观察到。
VI型卡维地洛溶剂产生了在35-104℃的温度范围内显示出约为13%的重量损失阶梯的差示热重分析法(DTG)热分析图(图4)。该值与相应于每三分子卡维地洛含有两分子醋酸乙酯的预期值相等。
通过Karl-Fisher滴定法测定了VI型卡维地洛溶剂化物的水含量,该方法显示其不含水。
另一方面,本发明提供了一种制备卡维地洛的结晶固体或其溶剂化物的新方法,该方法包括将卡维地洛与醋酸乙酯接触以形成溶液和冷却该溶液、任选地在搅拌下进行该冷却的步骤。优选地,初始卡维地洛是干燥的。可任选地用II型卡维地洛作为晶种来接种该溶液。可在高速搅拌下搅拌该溶液以形成悬液,然后可在高速搅拌下冷却该悬液。通过该方法得到的产品具有VI型卡维地洛的至少一个特征,并可通过常规方法如过滤从醋酸乙酯中分离。所述产品还可被干燥。
优选地,将醋酸乙酯和干燥卡维地洛的混合物加热到在约65℃-约80℃范围内的温度,更优选在约70℃-约77℃范围内,以形成溶液。然后,优选地,将该溶液的温度降低到在约40℃-约55℃之间,更优选在约46℃-约50℃之间。
当用II型卡维地洛晶种来接种该溶液时,在大约46℃-大约50℃的范围内的温度下搅拌已接种的该溶液一段足以沉淀VI型卡维地洛的时间。在高速搅拌下(至少260rpm)约30分钟的一段时间一般是足够的。然后,在高速搅拌下经过一段时间,优选约3小时,将该悬液的温度优选冷却到大约10℃。应将冷却的悬液搅拌约30分钟。
另一方面,本发明提供了制备II型卡维地洛的结晶固体的方法,该方法包括以下步骤:加热具有VI型的至少一个特征的结晶卡维地洛直到该结晶卡维地洛干燥为止;将II型卡维地洛与该干燥的结晶卡维地洛混合;以及将该混合物存放一段足以使该干燥的结晶卡维地洛转变为II型卡维地洛的时间。
优选地,将具有VI型的至少一个特征的结晶卡维地洛加热到在约50-约60℃范围内的温度,并最优选加热到约55℃。该加热步骤可在大气压下或在减压下进行。优选地,压力为大约60mmHg,更优选大约30mmHg。在加热约16小时后,具有VI型的至少一个特征的结晶卡维地洛典型地是干燥的。
将干燥的、具有VI型的至少一个特征的结晶卡维地洛与II型卡维地洛混合,并存放一段足以使该干燥的结晶卡维地洛转变为II型卡维地洛的时间。从约1周-约2周的一段时间一般是足够的。还可出现I型卡维地洛。
VI型卡维地洛可被研磨成粉末并用于药物产品,或者被物理修饰,如通过造粒来生产VI型卡维地洛的较大颗粒。如在下面更为详细地描述的,VI型卡维地洛还可通过将其溶解或分散于液体介质如水、甘油、植物油等中用于制备液体药物产品。
VI型卡维地洛对治疗充血性心力衰竭及高血压患者,以及在包括人类患者在内的哺乳动物中产生降压效果是有用的。VI型卡维地洛可被制成用于对人类和哺乳动物给药的各种组合物。
本发明的药物组合物含有VI型卡维地洛,任选性地与其它的结晶形式和/或其它活性成分如氢氯噻嗪混合。除一种或多种活性成分外,本发明的药物组合物还可含有一种或多种赋形剂。基于多种目的将赋形剂添加到所述组合物中。
稀释剂增加了固体药物组合物的体积,并可使患者和护理者更容易运用含有该组合物的药物剂型。用于固体组合物的稀释剂包括,例如,微晶纤维素(如Avicel)、微细纤维素、乳糖、淀粉、预胶凝淀粉、碳酸钙、硫酸钙、糖、葡萄糖结合剂(dextrates)、糊精、葡萄糖、磷酸氢钙二水合物、正磷酸钙、高岭土、碳酸镁、氧化镁、麦芽糖糊精、甘露醇、聚甲基丙烯酸酯(如Eudragit)、氯化钾、粉状纤维素、氯化钠、山梨醇以及滑石。
被压制成如片剂之类的剂型的固体药物组合物可包含赋形剂,所述赋形剂的功能包括在压缩后帮助将活性成分和其它赋形剂结合到一起。固体药物组合物的粘合剂包括阿拉伯树胶、海藻酸、卡波姆(如卡波浦尔(carbopol))、羧甲基纤维素钠、糊精、乙基纤维素、明胶、瓜尔胶、氢化植物油、羟乙基纤维素、羟丙基纤维素(如Klucel)、羟丙基甲基纤维素(如Methocel)、液体葡萄糖、硅酸镁铝、麦芽糖糊精、甲基纤维素、聚甲基丙烯酸酯、聚维酮(如Kollidon,Plasdone),预胶凝淀粉、海藻酸钠和淀粉。
通过向组合物中添加崩解剂可提高压制的固体药物组合物在患者胃中的溶解速率。崩解剂包括海藻酸、羧甲基纤维素钙、羧甲基纤维素钠(如Ac-Di-Sol,Primellose)、胶体二氧化硅、交联羧甲基纤维素钠、交聚维酮(如Kollidon,Polyplasdone)、瓜尔胶、硅酸镁铝、甲基纤维素、微晶纤维素、polacnilin potassium、粉状纤维素、预胶凝淀粉、海藻酸钠、羟乙酸淀粉钠(如Explotab)和淀粉。
可添加助流剂来改善非压制的固体组合物的流动性并提高给药的精确性。能够起到助流剂作用的赋形剂包括胶体二氧化硅、三硅酸镁、粉状纤维素、淀粉、滑石及正磷酸钙。
当通过压制粉状组合物来制备如片剂之类的剂型时,组合物经受来自冲压机和染料的压力。一些赋形剂和活性成分具有粘附于冲压机和染料的倾向,这会导致产品具有点蚀或其它表面不规则状态。可向组合物中添加润滑剂来减少粘附并使产品易于从染料释放。润滑剂包括硬脂酸镁、硬脂酸钙、单硬脂酸甘油酯、棕榈酰硬脂酸甘油酯、氢化蓖麻油、氢化植物油、矿物油、聚乙二醇、苯甲酸钠、十二烷基硫酸钠、十八烷基富马酸钠、硬脂酸、滑石以及硬脂酸锌。
调味剂和风味增强剂使该剂型对患者更为可口。可包括在本发明组合物中的常用的药物产品用调味剂和风味增强剂包括麦芽醇、香草醛、乙基香草醛、薄荷醇、柠檬酸、富马酸、乙基麦芽醇,以及酒石酸。
固体和液体组合物也可用任何药学上可接受的着色剂进行染色,以改善它们外观和/或便于患者识别该产品和单位剂量水平。
在本发明的液体药物组合物中,将VI型卡维地洛和任何其它固体赋形剂溶解或悬浮在液体载体如水、植物油、酒精、聚乙二醇、丙二醇或甘油中。
液体药物组合物可含有乳化剂,以使活性成分或其它不溶于液体载体的赋形剂在组合物中均匀地分散。可用于本发明的液体组合物的乳化剂包括,例如,明胶、蛋黄、酪蛋白、胆固醇、阿拉伯胶、黄蓍胶、角叉菜、果胶、甲基纤维素、卡波姆、十六醇十八醇混合物以及鲸蜡醇。
本发明的液体药物组合物还可含有增粘剂以改善产品的口感和/或包被胃肠道内层。这样的增粘剂包括阿拉伯胶、海藻酸、膨润土、卡波姆、羧甲基纤维素钙或钠、十六醇十八醇混合物、甲基纤维素、乙基纤维素、明胶、瓜尔胶、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、麦芽糊精、聚乙烯醇、聚维酮、碳酸丙烯、丙二醇海藻酸酯、海藻酸钠、羟乙酸淀粉钠、淀粉、黄蓍胶以及黄原胶。
可添加甜味剂如山梨醇、糖精、糖精钠、蔗糖、阿斯巴甜、果糖、甘露醇以及转化糖以改善口味。
可添加安全摄入水平的防腐剂和螯合剂如乙醇、苯甲酸钠、丁基化羟基甲苯、丁基化羟基苯甲醚和乙二胺四乙酸以改善储藏稳定性。
本发明的液体组合物还可含有缓冲剂,如葡萄糖酸、乳酸、柠檬酸、醋酸、葡萄糖酸钠、乳酸钠、柠檬酸钠或醋酸钠。
制剂学家基于经验和对标准程序的考虑以及本领域的参考文献,可容易地确定赋形剂的选择及其用量。
本发明的固体组合物包括粉剂、颗粒、聚集体以及压制组合物。
VI型卡维地洛可通过将一种或多种活性成分传送到β-阻断活性对患者施加治疗作用的身体部位的任何方式给药,用于治疗充血性心力衰竭和高血压。例如,可通过口服、口腔、胃肠外(包括皮下、肌肉、以及静脉注射)、直肠、吸入以及眼给药。尽管在任何给定情况下最合适的途径将依赖于受治疾病的性质及严重程度,但是本发明最优选的途径是口服。VI型卡维地洛可很方便地以口服单位剂型对患者给药,并可通过制药领域中的任何公知的方法来制备。剂型包括固体剂型,如片剂、粉剂、胶囊剂、袋剂、含片剂(troches)和锭剂,以及液体糖浆,悬液和酏剂。
按照本领域的公知技术,可将一种或多种活性成分和赋形剂制成组合物和剂型。
用于制片或填充胶囊的组合物可通过湿式制粒法来制备。在湿式制粒中,将处于粉末状态的活性成分和赋形剂的一部分或全部混合起来,并在一种使粉末聚结成为颗粒的液体(典型地为水)的存在下进一步混合。将颗粒筛分和/或研磨,干燥,然后再筛分和/或研磨成为需要的颗粒大小。接着可将颗粒制片,或在制片之前可添加其它赋形剂,如助流剂或润滑剂。
制片组合物通常可通过干式混合法来制备。例如,可将混合的活性成分和赋形剂组合物压制成小块或薄片,然后粉碎成压缩颗粒。随后可将该压缩颗粒压制成片剂。
作为干式制粒的替代,可以用直接压缩技术将经混合的组合物直接压成压缩剂型。直接压缩产生更为均匀的无颗粒片剂。尤其适合于直接压缩制片的赋形剂包括微晶纤维素、喷雾干燥的乳糖、磷酸二钙二水合物以及胶体二氧化硅。在直接压缩制片中正确应用这些和其它赋形剂,对本领域尤其是对直接压缩制片的制剂工作有经验和技术的人员来说是公知的。
本发明的胶囊填充物可包括前面提到的、关于制片时所描述的混合物和颗粒,只是它们不经过最终的制片步骤。
更特别地是,片剂可以例如通过混合并在制片机中直接压缩该组合物来制备。
胶囊剂可以例如通过用上述片剂组合物填充明胶胶囊的一半,并用该明胶胶囊的另一半封盖它来制备。
简单的肠胃外注射液可以例如通过将VI型卡维地洛、无菌丙二醇和无菌水混合并在无菌条件下密封该组合物于无菌瓶中来制备。
胶囊剂、片剂和锭剂以及其它单位剂型优选含有约1mg至约100mg VI型卡维地洛的剂量水平。
下列实施例是用来说明本发明的,不应理解为限定本发明的范围或精神。
实施例
一般方法
粉末X射线衍射图谱是通过本领域公知的方法、采用一种带有固态探测器的SCINTAG粉末X射线衍射仪X’TRA型(可变测角仪)来获得的。采用λ=1.5418的铜辐射。扫描参数包括:测量范围:2-40度2θ;连续扫描;速率:3度/分钟。
热重分析曲线是通过本领域公知的方法、采用Mettler Toledo DSC821°获得的。样品的重量为约3-5mg。温度范围为从约30℃到至少250℃,以10℃/分钟的速率进行。
热重分析曲线也可通过本领域公知的方法、采用Shimadzu DTG-50来获得。温度范围是从约30℃到至少250℃,以10℃/分钟的速率进行。样品用氮气以20ml/min的流速进行净化。
可通过本领域公知的方法,如漫反射系数法,采用Perkin-Elmer,SpectrumOne FTIR分光光度计来获得FTIR光谱。扫描参数如下:范围:4000-400cm-1,扫描16次,分辨率:4.0cm-1。
实施例1:VI型卡维地洛
将干燥卡维地洛(7kg)加入乙酸乙酯(70L)中并在搅拌下加热到70-77℃。在完全溶解后,将溶液在搅拌下冷却到约46-50℃。然后以II型卡维地洛作为晶种接种该溶液,并在约46-50℃在高速搅拌(至少260rpm)下搅拌约30分钟。在高速搅拌下,经过3小时将得到的悬液冷却至约为10℃的温度。将悬液再搅拌30分钟然后过滤,得到VI型卡维地洛。
实施例2:II型卡维地洛
将装有VI型卡维地洛的三个托盘(每盘1kg)插入真空炉中,在30mmHg的真空下加热到约55℃并干燥约16小时。干燥后立即得到的干燥样品的多晶型内含物是VI型卡维地洛和II型卡维地洛的混合物。在室温下储存大约4周后,得到I型、II型和VI型卡维地洛的混合物。
Claims (27)
1.一种卡维地洛结晶固体或其溶剂化物,其特征在于选自于由下列图谱组成的组的数据;在约6.5,7.3,16.0和30.5±0.2度2θ处具有峰的PXRD图谱;在约74℃和112℃处具有吸热峰的DSC热分析图;以及在约613,740,994,1125,1228,1257,1441,1508,1737,2840,3281,3389和3470cm-1处具有峰的FTIR光谱。
2.如权利要求1所述的卡维地洛,其特征在于在约6.5,7.3,16.0和30.5±0.2度20处的PXRD峰。
3.如权利要求2所述的卡维地洛,其进一涉特征在于在约5.8,10.7,11.1,11.5,13.1,13.7,16.8,17.7,18.5和23.0±0.2度2θ处的PXRD峰。
4.如权利要求3所述的卡维地洛,其特征在于基本上如图1中所示的PXRD图谱。
5.如权利要求1所述的卡维地洛,其特征在于在约74℃和112℃处的DSC峰。
6.如权利要求5所述的卡维地洛,其特征在于基本上如图3中所示的DSC热分析图。
7.如权利要求6所述的卡维地洛,其特征在于在约613,740,994,1125,1228,1257,1441,1508,1737,2840,3281,3389和3470cm-1的FTIR峰。
8.如权利要求7所述的卡维地洛,其进一步特征在于在约720,1100,1286,1454,1589,2911和2935cm-1的FTIR峰。
9.如权利要求8所述的卡维地洛,其特征在于基本上如图2中所示的FTIR光谱。
10.VI型结晶卡维地洛。
11.一种制备权利要求1所述的卡维地洛结晶固体或其溶剂化物的方法,该方法包括如下步骤:
将卡维地洛与乙酸乙酯接触以形成溶液,和
冷却该溶液从而形成沉淀。
12.如权利要求11所述的方法,其中所述的冷却步骤是在搅拌下进行的。
13.如权利要求11所述的方法,其中所述溶液的温度被降低到约40℃至约55℃。
14.如权利要求11所述的方法,该方法进一步包括如下步骤:
用II型卡维地洛作为晶种来接种所述溶液以形成悬液,和
冷却该悬液从而形成沉淀。
15.如权利要求14所述的方法,其中所述悬液的温度被降低到大约10℃。
16.如权利要求15所述的方法,其中所述冷却步骤是在搅拌下进行的。
17.通过权利要求11所述的方法制备的卡维地洛结晶固体或其溶剂化物。
18.一种药物组合物,其含有有效量的权利要求1所述的卡维地洛结晶固体或其溶剂化物和至少一种药学上可接受的赋形剂。
19.一种含有权利要求18所述的药物组合物的药物剂型。
20.如权利要求19所述的药物剂型,其中所述剂型是一种口服剂型。
21.如权利要求20所述的药物剂型,其中所述口服剂型是胶囊或片剂。
22.一种通过将权利要求19所述的剂型对患者给药来治疗患高血压患者的高血压的方法。
23.一种通过将权利要求19所述的剂型对患者给药来治疗患充血性心力衰竭患者的充血性心力衰竭的方法。
24.一种制备II型卡维地洛结晶固体的方法,该方法包括如下步骤:
加热权利要求1所述的结晶卡维地洛直到所述结晶卡维地洛干燥为止,
将II型卡维地洛与所述干燥的结晶卡维地洛混合,和
将该混合物存储一段足以使干燥的结晶卡维地洛转变为II型卡维地洛的时间。
25.如权利要求24所述的方法,其中所述结晶卡维地洛被加热至约50℃到约60℃的温度。
26.如权利要求25所述的方法,其中所述加热步骤是在减压下进行的。
27.如权利要求26所述的方法,其中所述压力为约30mmHg。
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US60/349,310 | 2002-01-15 |
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EP (1) | EP1474133A4 (zh) |
JP (1) | JP2005515226A (zh) |
KR (1) | KR20040077872A (zh) |
CN (1) | CN1298322C (zh) |
AU (1) | AU2003205146A1 (zh) |
CA (1) | CA2472377A1 (zh) |
HR (1) | HRP20040673A2 (zh) |
IS (1) | IS7351A (zh) |
MX (1) | MXPA04006909A (zh) |
NO (1) | NO20043383L (zh) |
PL (1) | PL371409A1 (zh) |
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- 2003-01-15 WO PCT/US2003/001137 patent/WO2003059807A2/en active Application Filing
- 2003-01-15 CN CNB038022109A patent/CN1298322C/zh not_active Expired - Fee Related
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IS7351A (is) | 2004-07-13 |
US7598396B2 (en) | 2009-10-06 |
JP2005515226A (ja) | 2005-05-26 |
US20090163721A1 (en) | 2009-06-25 |
US20030166702A1 (en) | 2003-09-04 |
EP1474133A2 (en) | 2004-11-10 |
US20040171665A1 (en) | 2004-09-02 |
CN1298322C (zh) | 2007-02-07 |
US7514467B2 (en) | 2009-04-07 |
EP1474133A4 (en) | 2006-02-01 |
HRP20040673A2 (en) | 2005-06-30 |
AU2003205146A1 (en) | 2003-07-30 |
MXPA04006909A (es) | 2005-04-19 |
WO2003059807A2 (en) | 2003-07-24 |
CA2472377A1 (en) | 2003-07-24 |
PL371409A1 (en) | 2005-06-13 |
WO2003059807A3 (en) | 2003-12-04 |
ZA200405443B (en) | 2005-07-08 |
NO20043383L (no) | 2004-08-13 |
US6710184B2 (en) | 2004-03-23 |
KR20040077872A (ko) | 2004-09-07 |
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