CN1684642A - 从抗血栓形成的多层涂敷的斯滕特固定模中的药物释放 - Google Patents
从抗血栓形成的多层涂敷的斯滕特固定模中的药物释放 Download PDFInfo
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- CN1684642A CN1684642A CNA038233487A CN03823348A CN1684642A CN 1684642 A CN1684642 A CN 1684642A CN A038233487 A CNA038233487 A CN A038233487A CN 03823348 A CN03823348 A CN 03823348A CN 1684642 A CN1684642 A CN 1684642A
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Abstract
具有多层与表面粘合的涂层的、可以预防植入部位上再狭窄和血栓形成的斯滕特固定模。所述的斯滕特固定模涂层由两层组成。第一层为含有分散在其中的一种或多种生物活性剂聚合物涂层。第二层由疏水肝素化聚合物组成,该层抑制血液凝固并提供用于减少斯滕特固定模与损害部位之间的摩擦的亲水表面。在本发明优选的实施方案中,多层斯滕特固定模有效阻止植入部位上的再狭窄和血栓形成。在这些相同的优选实施方案中,多层斯滕特固定模能够减少生物活性剂从第一层中突然释放并维持这些活性剂的有效量释放相对延长的时间期限。将所述的多层涂层涂布在斯滕特固定模上的方法也是本发明的组成部分。
Description
技术领域
本发明涉及用于携带生物活性剂的涂敷的斯滕特固定模(stent)以提供植入部位上的局部治疗并涉及涂布斯滕特固定模涂层的方法。
本发明特别涉及带有多层涂层的抗血栓形成和抗再狭窄的斯滕特固定模,其中第一层或内层由聚合物和一种或多种生物活性剂形成,而第二层或外层由抗血栓形成的肝素化聚合物形成。本发明还涉及将多层涂层涂布在斯滕特固定模表面上的方法和使用这类涂敷的斯滕特固定模的方法。
发明背景
致动脉粥样化动脉狭窄和血栓形成是两种潜在的致命性相关疾病,美国和全世界的各种卫生组织已经将它们鉴定为主要杀手。狭窄指的是通常因脂肪、胆固醇和其它物质在一段时间内积累所致的血管狭窄或收缩。在严重的情况中,狭窄完全阻塞了血管。血栓形成是在血管或心脏腔内形成或存在血块。这种血块通常因血液因子、主要是血小板和血纤蛋白聚集和细胞成分截留而形成。血栓形成、如狭窄通常在其形成时产生血管阻塞。
清除因狭窄导致的收缩或阻塞的动脉的一种手段为经皮腔内冠状动脉成形术(PTCA)或球囊冠状动脉成形术。在这种操作中,插入球囊导管并使其在血管的收缩部分膨胀以清除阻塞。约三分之一进行PTCA的患者在手术的约6个月内发生再狭窄,即变宽的节段重新狭窄。再狭窄的动脉必须再进行血管成形术。
可以通过由将斯滕特固定模插入动脉的受侵害区组成的常规手术而不是血管成形术或与血管成形术一起抑制再狭窄。斯滕特固定模是由金属或塑料制成的可以带有固体壁或网状壁的管。大部分应用的斯滕特固定模是金属的且可以自我膨胀或球囊膨胀。进行斯滕特固定模插入操作的决定取决于动脉狭窄的某些特征。它们包括动脉的大小和狭窄的位置。斯滕特固定模的功能在于支持近来已经使用血管成形术加宽的动脉,或如果不使用血管成形术,那么将斯滕特固定模用于预防动脉的弹性回缩。一般通过导管植入斯滕特固定模。就可球囊膨胀的斯滕特固定模而言,斯滕特固定模塌陷成小直径并在球囊导管上滑动。然后通过患者的脉管系统将导管移至损害部位或近来加宽的区域。一旦就位,则斯滕特固定模膨胀并适当固定。该斯滕特固定模永久性地停留在动脉内、保持其开放、改善通过动脉的血流并缓解症状(通常为胸痛)。
斯滕特固定模并非在预防植入部位上的再狭窄中100%有效。再狭窄可以在斯滕特固定模长度内和/或越过斯滕特固定模端发生。临床医师近来使用了涂敷聚合物薄膜的新型斯滕特固定模,所述的聚合物薄膜上载有抑制平滑肌细胞增殖的药物。使用本领域技术人员众所周知的方法、诸如溶剂蒸发技术将这种涂层涂布在斯滕特固定模上,此后将其插入动脉。溶剂蒸发技术要求将聚合物和药物在溶剂中混合。然后可以通过浸渍或喷雾将含有聚合物、药物和溶剂的溶液涂布在斯滕特固定模表面上。随后使斯滕特固定模进行干燥过程,在此过程中溶剂被蒸发且聚合物材料与分散在其中的药物在斯滕特固定模上形成薄膜层。
药物从聚合物材料中的释放机理取决于聚合物材料和掺入的药物的性质。药物通过聚合物扩散至聚合物-流体界面且然后进入流体。释放还可以通过聚合物材料的降解而发生。聚合物材料的降解通过水解发生,这种水解腐蚀聚合物使其进入流体且由此也将药物释放入流体。
使用涂敷的斯滕特固定模的一个重要考虑在于药物从涂层中的释放速率。理想的是有效治疗量的药物从斯滕特固定模中尽可能释放最长时间。突然释放、即植入后即刻的高释放速率是不理想的且成为持久性的难题。尽管一般对患者无害,但是通过释放数倍所需有效量,突然释放“浪费”了有限的药物供应且缩短了释放时间期限。已经研发了几种技术来尝试减少突然释放。例如,Yang等的美国专利6,258,121 B1中公开了通过掺合具有不同释放率的两种聚合物并将它们掺入单层而改变释放率的方法。
一般来源于猪肠的肝素是众所周知其抗凝能力的物质。本领域中已知使用溶剂蒸发技术将载有肝素的薄聚合物涂层涂布在斯滕特固定模表面上。例如,Ding等的美国专利5,837,313中描述了制备肝素涂层组合物的方法。
根据上述描述,可以理解研发带有多层涂层的斯滕特固定模是本领域中的重大进展,在所述的带有多层涂层的斯滕特固定模中,一层包括其中分散有生物活性剂的聚合物材料薄膜且第二层排列在第一层上,其中第二层包括疏水肝素化聚合物。还可以理解本发明抑制了再狭窄和血栓形成且可以在相对延长的时间期限内将宽范围的治疗剂有效传递至植入部位。
发明概述
本发明提供了带有多层涂层的斯滕特固定模,所述的多层涂层包括彼此紧密排列的至少两层,它们用于在持续时间期限内通过传递生物活性剂抑制再狭窄和血栓形成。第一层包括其中分散有生物活性剂的聚合物材料且第二层包括具有抗凝特性的疏水肝素化聚合物。本发明还提供了几种用于将涂层的多层内层涂布在斯滕特固定模上的方法,其中将疏水肝素化聚合物涂布为涂层的外层和最后一层。
通过将聚合物材料和生物活性剂与溶剂混合、由此形成均匀溶液制备第一层或下层。该聚合物材料可以选自广泛合成材料,但在一个举例说明的实施方案中,使用聚丙烯酸。根据所需治疗结果的不同选择生物活性剂。例如,可以使用抗癌药和/或抗炎药。作为其它实例,如果需要平滑肌细胞增殖抑制剂,那么可以使用棘霉素或紫杉醇。一旦制备,则可以将该溶液通过浸渍或喷雾工艺涂布在斯滕特固定模上。在干燥过程中,溶剂蒸发且在斯滕特固定模上保持涂敷载有生物活性剂的聚合物材料的薄层。应注意本发明并不限于每层中仅有一层内层或一种生物活性剂。在本发明范围内,可以向每层中加入一种或多种不同的生物活性剂和/或使一层以上内层中载有生物活性剂。
第二层或外层为例如使用浸渍工艺涂布在斯滕特固定模内层上的抗血栓形成的肝素化聚合物。通过使多功能大分子诸如丙烯酸和疏水物质诸如十八胺与肝素结合制备抗血栓形成的肝素化聚合物涂层。然后将斯滕特固定模浸入已经混合了溶剂的疏水肝素化聚合物。干燥后,溶剂蒸发且疏水肝素化聚合物在第一层上形成薄膜。
使用随斯滕特固定模类型改变的适宜操作将涂敷的斯滕特固定模插入受侵害的血管,诸如冠状动脉。一旦就位,则斯滕特固定模结构会保持血管开放。生物活性剂从第一层中释放,由此提供所需的治疗效果,诸如抑制平滑肌细胞增殖。抗血栓形成的肝素化聚合物防止在斯滕特固定模周围发生血液凝固,由此抑制血栓形成和亚急性斯滕特固定模血栓形成。此外,抗血栓形成的肝素化聚合物层减少或防止了生物活性剂从第一层中突然释放,由此使释放在相对延长的时间期限内发生。
因此,本发明的优点在于提供了能够抑制植入部位上再狭窄和血栓形成的斯滕特固定模。
本发明的另一个优点在于提供了带有用于传递抑制平滑肌细胞增殖和血块的生物活性剂的多层涂层的斯滕特固定模。
本发明的另一个优点在于提供了带有多层涂层的斯滕特固定模,所述的多层涂层带有包含抗血栓形成的肝素化聚合物的外层。
本发明的另一个优点在于提供了带有多层涂层的斯滕特固定模,其中所述的多层涂层用于在相对延长的时间期限内传递广泛的治疗剂并减缓生物活性剂从内层或多内层中突然释放。
本发明的还有另一个优点在于提供了用于将多层涂层涂布在斯滕特固定模表面上的方法。
几个附图的简要描述
图1是显示斯滕特固定模涂层的第一层和第二层的斯滕特固定模不完整部分的截面表示。
图2(a)是放大2,000倍的来自未涂布的斯滕特固定模粗表面的扫描电子显微镜(SEM)图像。
图2(b)是放大2,000倍的带有通过浸渍法涂布的第一层涂层的斯滕特固定模平滑表面的SEM图像。
图2(c)是放大2,000倍的多层涂敷的斯滕特固定模平滑表面的SEM图像,其中通过浸渍法涂布第一层和第二层。
图3(a)是放大50倍的通过喷涂法涂敷的斯滕特固定模的SEM图像。
图3(b)是放大2000倍的图3(a)的斯滕特固定模表面的SEM图像。
图4表示进行全血检测后的三种斯滕特固定模表面;斯滕特固定模A是未涂布的斯滕特固定模,斯滕特固定模B是第一层涂敷的斯滕特固定模,且斯滕特固定模C是多层涂敷的斯滕特固定模。
图5(a)是放大3000倍的血小板粘着检测后的未涂布斯滕特固定模表面的SEM图像。
图5(b)是放大3000倍的血小板粘着检测后的第一层涂敷的斯滕特固定模的SEM图像。
图5(c)是放大3000倍的血小板粘着检测后的多层涂敷的斯滕特固定模的SEM图像。
图6(a)表示雄性Sprague-Dawley大鼠体内14天后5个不同涂敷的条,各条显示出不同水平的炎症。
图6(b)表示雄性Sprague-Dawley大鼠体内30天后5个如图6(a)中的不同涂敷的条,各条显示出不同水平的炎症。
图7(a)举例说明在9天期限内单层涂层和多层涂层释放的紫杉醇百分比。
图7(b)举例说明在9天期限内单层涂层和多层涂层每单位面积上释放的紫杉醇的量。
图8(a)举例说明在9天期限内多层涂层释放的棘霉素和地塞米松百分比。
图8(b)举例说明在9天期限内多层涂层每单位面积上释放的棘霉素和地塞米松的量。
图9(a)表示植入了未涂布的斯滕特固定模的血管的截面。
图9(b)表示植入了第一层中0.1%载量的棘霉素的多层涂敷的斯滕特固定模的血管截面。
图9(c)表示植入了第一层中1%载量的棘霉素的多层涂敷的斯滕特固定模的血管截面。
图9(d)表示植入了第一层中5%载量的棘霉素的多层涂敷的斯滕特固定模的血管截面。
图10举例说明通过比较内膜与中层的再狭窄评价(内膜/中层)。
发明详述
在公开和描述本发明带有多层涂层的斯滕特固定模和使用和制备带有多层涂层的斯滕特固定模的方法前,应理解本发明并不限于本文公开的特定构造、工艺步骤和材料,因为这类构造、工艺步骤和材料可以有一定程度的改变。还应理解本文所用的术语仅用于描述特定的实施方案的目的,但并不用来起限定作用,因为本发明的范围仅通过后附权利要求和等同技术方案来限定。
本文涉及的公开文献和其它参考材料描述了本发明的背景技术并提供了有关其实施的其它详细内容,将它们引入本文作为参考。本文所述的参考文献仅用于提供本申请的申请日之前的公开内容。这里不能认为承认本发明人无权通过在前发明居先于这些公开内容。
必须注意除非上下文中有清楚的说明,如本说明书和后附权利要求中所有的单数形式“一种(a)”、“一种(an)”和“所述的(the)”包括复数的指示物。因此,例如,涉及的“生物活性剂”包括两种或多种这类活性剂的混合物,涉及的“抑制剂”包括这类抑制剂中的一种或多种,且涉及的“溶剂”包括涉及的两种或多种溶剂的混合物。
在描述和要求保护的本发明中,按照下列定义使用如下术语。
本文所用的“斯滕特固定模”指的是插入血管或通道以保持腔开放并防止因狭窄或外部挤压导致的闭合的金属或塑料管。
本文所用的“生物活性剂”指的是对活生物体具有治疗价值的药物或其它物质,包括但不限于抗血栓药、抗凝血药、抗血小板药、溶栓药、抗增殖药、抗炎药、抑制再狭窄的药剂、平滑肌细胞抑制剂、抗生素等及其混合物。
举例说明的抗癌药包括阿西维辛、阿柔比星、阿考达唑、山油柑碱、阿多来新、阿拉诺新、阿地白介素、别嘌醇钠、六甲蜜胺、氨鲁米特、氨萘非特、聚肌胞、安吖啶、雄激素、蛇形菌素(anguidine)、氨基乙酸阿非迪霉素、亮氨酸溶肉瘤素(asaley)、天冬酰胺酶、5-阿扎胞苷、硫唑嘌呤、卡介苗(BCG)、三嗪苯酰胺(可溶性)、β-2’-脱氧硫代鸟苷、盐酸比生群、硫酸博来霉素、白消安、buthionine sulfoximine、BWA 773U82、BW502U83×HCl、BW 7U85甲磺酸盐、ceracemide、卡贝替姆、卡铂、卡莫司汀、苯丁酸氮芥、氯喹喔啉-磺酰胺、氯脲菌素、色霉素A3、顺铂、克拉屈滨、皮质类固醇、短小棒状杆菌、CPT-11、克立那托、安西他滨、环磷酰胺、阿糖胞苷、溴茴丙烯酸钠、dabis maleate、达卡巴嗪、放线菌素D、盐酸柔红霉素、deazauridine、右雷佐生、二去水卫矛醇、地吖醌、二溴卫矛醇、didemnin B、二乙基二硫代氨甲酸酯、二甘醇醛、二氢-5-氮杂胞、多柔比星、棘霉素、依达曲沙、依地福新、依氟鸟氨酸、Elliott’s溶液、依沙芦星、表柔比星、依索比星、雌莫司汀磷酸盐、雌激素、依他硝唑、氨磷汀、依托泊苷、法倔唑(fadrazole)、法扎拉滨、芬维A胺、非格司亭、非那雄胺、黄酮乙酸、氟尿苷、磷酸氟达拉滨、5-氟尿嘧啶、Fluosola、氟他胺、硝酸镓、吉西他滨、醋酸戈舍瑞林、hepsulfam、六亚甲基双乙酰胺、高三尖杉酯碱、硫酸肼、4-羟基雄烯二酮、羟基脲(hydrozyurea)、盐酸伊达比星、异环磷酰胺、干扰素α、干扰素β、干扰素γ、白细胞介素-1α和β、白细胞介素-3、白细胞介素-4、白细胞介素-6、4-依波米醇、异丙铂、异维A酸、亚叶酸钙、醋酸亮丙立德、左旋咪唑、柔红霉素脂质体、脂质体包囊的多柔比星、洛莫司汀、氯尼达明、美登素、盐酸氮芥、美法仑、美诺立尔、merbarone、6-巯嘌呤、巯乙磺酸钠、卡介苗的甲醇提取残余物、甲氨蝶呤、N-甲基甲酰胺、米非司酮、米托胍腙、丝裂霉素-C、米托坦、盐酸米托蒽醌、单核细胞/巨噬细胞集落刺激因子、大麻隆、萘福昔定、新制癌菌素、醋酸奥曲肽、奥马铂、奥沙利铂、紫杉醇、pala、喷司他丁、哌嗪二酮、哌泊溴烷、吡柔比星、吡曲克辛、盐酸吡罗蒽醌、PIXY-321、普卡霉素、卟吩姆钠、泼尼莫司汀、丙卡巴肼、孕酮、吡唑呋林、雷佐生、沙格司亭、司莫司汀、锗螺胺、螺莫司汀、链黑霉素、链佐星、磺氯苯脲、舒拉明钠、他莫昔芬、泰索帝、替加氟、替尼泊苷、对苯二脒(terephthalamidine)、替罗昔隆、硫鸟嘌呤、塞替派、胸苷注射剂、噻唑呋林、托泊替康、托瑞米芬、维A酸、盐酸三氟拉嗪、曲氟尿苷、三甲曲沙、肿瘤坏死因子、乌拉莫司汀、硫酸长春碱、硫酸长春新碱、长春地辛、长春瑞滨、长春利定、Yoshi 864、佐柔比星及其混合物。
举例说明的抗炎药包括:传统的非甾类抗炎药(NSAIDS),诸如阿司匹林、双氯芬酸、吲哚美辛、舒林酸、酮洛芬、氟比洛芬、布洛芬、萘普生、吡罗昔康、替诺昔康、托美丁、酮咯酸、噁丙嗪、甲芬那酸、非诺洛芬、nambumetone(瑞力芬)、对乙酰氨基酚(Tylenol)及其混合物;COX-2抑制剂,诸如尼美舒利、NS-398、氟舒胺、L-745337、塞来考昔、罗非考昔、SC-57666、DuP-697、帕瑞考昔钠、JTE-522、伐地考昔、SC-58125、艾托考昔、RS-57067、L-748780、L-761066、APHS、依托度酸、美洛昔康、S-2474及其混合物;糖皮质类固醇:诸如氢化可的松、可的松、泼尼松、泼尼松龙、甲泼尼龙、甲泼尼松、曲安西龙、帕拉米松、氟泼尼龙、倍他米松、地塞米松、氟氢可的松、去氧皮质酮及其混合物;以及上述药物的混合物。
本文所用的“聚合物”指的是由重复单体单元或原体构成的大分子。
本文所用的“大分子”指的是合成的大分子、蛋白质、生物聚合物和其它分子量一般大于1000的分子。
本文所用的“抗血栓形成的肝素化聚合物”、“疏水肝素化聚合物”和类似术语指的是如与本发明共有的国际专利申请PCT/KR00/01255(WO02/34312 A1)所述的疏水性多成分肝素缀合物,将该文献的全部内容引入本文作为参考。这些疏水的肝素化聚合物包括含有肝素的缀合物、大分子成分和疏水性成分。
本文所用的“有效量”指的是药物活性剂的用量,它非毒性,但足以以致力于任何医疗的合理有益性/危害性比提供所需的局部或全身作用和性能。
本发明涉及带有多层涂层的抗血栓形成的斯滕特固定模。在举例说明的实施方案中,第一层包括载有预防平滑肌细胞增殖的生物活性剂、诸如棘霉素的聚合物薄膜。可以用于制备聚合物薄膜的举例说明的聚合物包括聚氨基甲酸酯类、聚对苯二甲酸乙二酯(PET)、PLLA-聚-乙醇酸(PGA)共聚物(PLGA)、聚己内酯(PCL)、聚-(羟基丁酸酯/羟基戊酸酯)共聚物(PHBV)、聚(乙烯基吡咯烷酮)(PVP)、聚四氟乙烯(PTFE,TeflonTM)、聚(2-羟乙基甲基丙烯酸酯)(聚-HEMA)、聚(醚氨酯脲)、硅氧烷类、丙烯酸类、环氧衍生物、聚酯类、尿烷类、parlenes、聚磷腈聚合物、含氟聚合物、聚酰胺类、聚烯烃类及其混合物。第二层包括具有强抗凝特性的疏水肝素化聚合物。疏水的肝素化聚合物的第二层还具有防止分散在第一层中的生物活性剂突然释放(burst release)的作用-产生较长的生物活性剂释放期限。还应理解第一层可以含有一种以上生物活性剂。
斯滕特固定模的类型和组成可以包括任意具有支持患病血管的能力的生物相容性材料。一般来说,优选使用金属斯滕特固定模,诸如由不锈钢、金、钛等制成的那些,但可以使用塑料或其它合适的材料。在一个优选的实施方案中,斯滕特固定模为由Cordis Corp.(Miami,Florida)生产的Palmz-Schatz斯滕特固定模。斯滕特固定模可以自我膨胀或球囊膨胀。优选涂层基本上覆盖整个斯滕特固定模表面,但在本发明范围内的是仅需要使涂层覆盖斯滕特固定模的一部分。还应理解也可以涂敷接触有机流体(organic fluid)等的任何基体(substrate)、医疗装置或其部分。
通过溶剂蒸发法或某些其它已知方法涂布第一层。溶剂蒸发法要求将聚合物材料和生物活性剂与溶剂、诸如四氢呋喃(THF)合并,然后通过搅拌混合成混合物。第一层中的举例说明的聚合物材料包括聚氨基甲酸酯,而举例说明的生物活性剂包括棘霉素。然后通过如下方法将所述混合物涂布在斯滕特固定模表面:(1)将该溶液喷在斯滕特固定模上;或(2)将斯滕特固定模浸入该溶液。在涂布该混合物后,使斯滕特固定模进行干燥过程,在此过程中,溶剂蒸发且聚合物材料和生物活性剂在斯滕特固定模上形成薄膜。在另一个举例说明的实施方案中,可以将一种以上生物活性剂加入到第一层中。
斯滕特固定模涂层的第二层包括抗血栓形成的肝素化聚合物。抗血栓形成的肝素化聚合物仅溶于有机溶剂,但不溶于水。通过使肝素与大分子和疏水物质结合生产抗血栓形成的肝素聚合物。
举例说明的大分子包括合成的大分子、蛋白质、生物聚合物及其混合物。举例说明的合成的大分子包括聚二烯烃类、聚烯烃类、聚乙炔类、聚丙烯酸及其衍生物、聚“-取代的丙烯酸及其衍生物、聚乙烯醚类、聚乙烯醇、聚卤代乙烯类、聚苯乙烯及其衍生物、多氧化物、聚醚类、聚酯类、聚碳酸酯类、聚酰胺类、聚氨基酸、聚脲类、聚氨基甲酸酯类、聚亚胺类、聚硫化物、多磷酸盐、聚硅氧烷类、聚倍半硅氧烷类、聚杂环类、纤维素及其衍生物和多糖类及其共聚物或衍生物。可以用于本发明的举例说明的蛋白质包括鱼精蛋白、聚赖氨酸、聚天冬氨酸、聚谷氨酸及其衍生物和共聚物。可以用于本发明的举例说明的生物聚合物包括多糖类、明胶、胶原蛋白、藻酸盐、透明质酸、藻酸、角叉菜聚糖、软骨素、果胶、脱乙酰壳多糖及其衍生物和共聚物。
在举例说明的实施方案中,通过下列步骤制备抗血栓形成的肝素衍生物。首先,通过使用N,N-二环己基碳化二亚胺盐酸盐(DDC)或4-对叠氮基水杨基酰氨基-丁胺(ASBA)使大分子活化。第二步,使肝素、重组肝素、肝素衍生物或肝素类似物(具有的优选分子量为1,000-1,000,000道尔顿)与大分子结合。尽管可以使用羟基、胺基、硫羟基或叠氮基在肝素与大分子之间形成共价键,但是优选使用胺基。最后,使疏水物质与已经与肝素合并的大分子的官能团结合。尽管应理解可以使用带有官能团的任意疏水物质,但是优选使用十八胺、链烷酸胺、胆汁酸、甾醇类或链烷酸。
一旦制备了疏水的肝素化聚合物,则使用溶剂蒸发法或其它适宜方法将第二层直接涂布在第一层上。备好疏水的肝素化聚合物用于涂布,通过将其与溶剂、诸如环己烷合并来进行,由此形成疏水的肝素化聚合物悬浮于其中的水溶液。然后使用浸渍法将抗血栓形成的肝素化聚合物和溶剂溶液涂布在斯滕特固定模上。在干燥过程中使溶剂从斯滕特固定模上蒸发;使疏水的肝素化聚合物薄膜保留在第一层上。
抗血栓形成的肝素化聚合物层抑制植入部位上的凝固。此外,第二层抑制或防止生物活性剂从第一层中突然释放。第二层还用于延长生物活性剂从第一层中的释放期限,由此延长治疗时间。
实施例
<实施例1>
通过浸渍涂敷法制备斯滕特固定模上的多层涂层
通过合并和搅拌聚合物、生物活性剂和THF至充分混合制备用于第一层的涂敷溶液。选择的聚合物为聚氨基甲酸酯且具有的浓度为3wt%。生物活性剂为紫杉醇且具有的浓度范围为0-20wt%。在涂布第一层前,备好斯滕特固定模表面并通过用甲醇洗涤进行清洁且在真空干燥器中将其干燥约30分钟。一旦干燥,则将清洁的斯滕特固定模完全浸入第一层涂敷溶液并在室温下和THF饱和的烧杯中干燥约5小时。将这种浸渍/干燥过程重复5次。在第5次重复后,在室温下将斯滕特固定模在真空干燥器中干燥约1小时。
通过将疏水的肝素化聚合物.1-20wt%在环己烷中混合制备第二层涂敷溶液。然后将斯滕特固定模浸入肝素化聚合物溶液并在室温下干燥约1小时,随后在室温下的真空干燥器中干燥6小时。作为斯滕特固定模表面上涂布的两层涂层如图1中所阐明。
<实施例2>
通过喷涂法制备斯滕特固定模上的多层涂层
如实施例1中所述制备用于第一层和斯滕特固定模的涂敷溶液。然后将制备的第一层溶液在清洁的斯滕特固定模上喷雾约10分钟并在室温下干燥。将这种浸渍/干燥过程重复10次,此后将斯滕特固定模在真空干燥器中干燥约1小时。如实施例1中所述给第二层涂布疏水的肝素化聚合物溶液。作为斯滕特固定模表面上涂布的两层涂层如图1中所阐明。
<实施例3>
制备载有两种生物活性剂的多层涂敷的斯滕特固定模
通过在THF中合并和搅拌聚氨基甲酸酯、紫杉醇、地塞米松至充分混合制备第一层涂敷溶液。生物活性剂的加载量分别为0-20wt%。如实施例1中所述清洁斯滕特固定模。将制备的溶液在斯滕特固定模上喷雾约10分钟并在室温下干燥。在将喷雾过程重复10次后,将斯滕特固定模在真空中干燥1小时。如实施例1中所述给第二层涂布疏水的肝素化聚合物溶液。
<实施例4>
多层涂敷的斯滕特固定模的形态
用扫描电子显微镜在不同放大倍数下检查未涂敷和涂敷的斯滕特固定模的表面。对未涂敷的金属斯滕特固定模的表面观察到具有如图2(a)中所示的极为粗糙的外观。然后在涂布第一层和第二层后观察斯滕特固定模表面。在两种情况中,观察到涂敷表面相对远比未涂布的斯滕特固定模表面平滑。这一结果保持可靠而与是采用浸渍法还是喷涂法涂布第一层无关。这一结果分别如图2(b)和2(c)以及图3(a)和(b)中所示。
<实施例5>
多层涂敷的斯滕特固定模的血液相容性-全血试验
提供三种不锈钢斯滕特固定模、即斯滕特固定模A、B和C用于本试验。斯滕特固定模A未涂敷且不带有涂布的涂层。斯滕特固定模B带有涂布在斯滕特固定模表面上的聚氨基甲酸酯单层涂层,其中载有紫杉醇。最后,斯滕特固定模C带有如第二种斯滕特固定模上的第一层涂层与疏水的肝素化聚合物上层。将所有三种斯滕特固定模浸入新鲜的家兔血液约3分钟期限。取出后,检验斯滕特固定模以测定斯滕特固定模表面上血栓形成的水平。观察到斯滕特固定模A在其表面上带有相对高水平的血栓形成和血液凝固。当与第一种斯滕特固定模相比时,观察到斯滕特固定模B带有减少量的血栓形成和血液凝固。当与第二种斯滕特固定模相比时,斯滕特固定模C表现出减少量的血栓形成。图4表示所有三种斯滕特固定模和不同程度血栓形成的图像。
<实施例6>
多层涂敷的斯滕特固定模的血液相容性-血小板粘着试验
将新鲜的家兔血液与3.8wt%柠檬酸钠溶液按9∶1比例的浓度混合。然后将血液放入离心机中并在5℃下以2,000rpm旋转10分钟以分离血浆中的血小板。通过加入几乎不含血小板的血浆控制血浆血小板浓度、以4,000RPM旋转至得到3×105/∶1的浓度水平。然后如实施例5中所述制备三种不锈钢斯滕特固定模。将所述的斯滕特固定模在37℃下在制备的血浆中温育约1小时。取出后,用PBS溶液将斯滕特固定模洗涤3次。然后使斯滕特固定模进行血小板固定过程,它由将斯滕特固定模在2.5%戊二醛中温育4小时组成。在血小板固定完成时,用50%、80%和100%乙醇水溶液洗涤斯滕特固定模。在进行第二次洗涤后,将样品冻干6小时。然后用扫描电子显微镜检验斯滕特固定模以测定各斯滕特固定模表面上存在的血小板浓度。未涂布的斯滕特固定模在其表面上显示出如图5(a)中所示的血小板形成的均匀分布。带有单聚氨基甲酸酯层的第二种斯滕特固定模和带有多层涂层的第三种斯滕特固定模在血小板粘着水平上分别显示出80%和90%的减少,如图5(b)和图5(c)中所示。
<实施例7>
多层涂敷的斯滕特固定模的炎症评价
用不同组成的表面涂层制备5种不同类型的大量不锈钢条。正如下表1中所示,A、B、C、D和E型条全部不带有涂层、带有一层涂层或两层涂层。制备条用于植入雄性Sprague-Dawley大鼠。
<表1>
条类型 | 第一层 | 第二层 |
A | 无 | 无 |
B | 载有紫杉醇(20wt%)的聚氨基甲酸酯 | 无 |
C | 载有紫杉醇(20wt%)的聚氨基甲酸酯 | 疏水的肝素化聚合物 |
D | 载有紫杉醇(20wt%)和地塞米松(5wt%)的聚氨基甲酸酯 | 无 |
E | 载有紫杉醇(20wt%)和地塞米松(5wt%)的聚氨基甲酸酯 | 疏水的肝素化聚合物 |
随机选择体重为200-300g的大鼠。首先用二乙醚气体麻醉大鼠并将其固定在手术台上。将5种类型的钢条之一通过用解剖刀造成的切口插入各大鼠的背部。然后在14或30天后回收条。通过再次用乙醚麻醉大鼠且然后经手术取出已经插入条的右下区和看起来已经发生再狭窄的组织区回收条。取出后,用PBS缓冲溶液洗涤条和组织。然后用4%甲醛溶液固定组织。随后通过用眼观察检验各条以确定相对于其它条而言已经发生再狭窄的水平(如果有的话)。
14天后,未涂布的条类型、即A类型条表现出重度再狭窄。对那些在作为主要层涂布的聚氨基甲酸酯中载有紫杉醇的条、即B类型条而言,观察到了相当程度的再狭窄。另一方面,带有疏水的肝素化聚合物的第二涂层的条、即C类型条几乎没有出现再狭窄。此外,当样本接受聚氨基甲酸酯的第一层中载有地塞米松(一种抗炎药)和紫杉醇的条、即D类型条时,样本几乎没有表现出再狭窄。对还带有疏水的肝素化聚合物的第二层的样本、即E类型条而言保持同样的可靠结果。这些结果如图6(a)中所示。
30天后,在未涂敷的条、即A类型条上和在载有紫杉醇的单层条、即B类型条上观察到了重度再狭窄。在载有紫杉醇和地塞米松的条、即D类型条中也观察到了再狭窄。然而,当将疏水的肝素化聚合物涂布为外层时,在C和E类型条中没有观察到再狭窄。这一结果如图6(b)中所示。
<实施例8>
从多层涂敷的薄膜上洗脱紫杉醇
将从不锈钢样品上的单层聚氨基甲酸酯涂层中洗脱的紫杉醇量与多层涂敷的样品比较。将两种样品分别在37℃下在缓冲溶液中温育。通过包括下列步骤的提取法在4、8、12、24、36、48、60、144、216小时时测定洗脱的紫杉醇。首先,通过使用6ml DCM/100ml缓冲溶液经强烈搅拌约15秒提取溶液。接下来分离DCM部分中的溶液并在氮气中干燥。最终将提取的紫杉醇溶于1ml乙腈并通过HPLC测定。
正如图7(a)和7(b)中所示,当与单层涂敷的薄膜相比时,紫杉醇从多层涂敷的表面上的洗脱率显示突然释放减少和更持续的释放模式。
<实施例9>
从多层涂敷的斯滕特固定模上洗脱棘霉素
评价棘霉素从多层涂敷的斯滕特固定模上的洗脱。使用实施例2的方法制备多层涂敷的斯滕特固定模,但将棘霉素加载入第一层而不是紫杉醇。棘霉素的加载量为3wt%并将喷涂过程重复10次。通过用1wt%疏水的肝素化聚合物溶液浸涂形成第二层。正如图8(a)和8(b)中所示,当与单层涂敷的薄膜相比时,紫杉醇从多层涂敷的表面上的洗脱率显示突然释放减少和更持续的释放模式。
<实施例10>
从多层涂敷的斯滕特固定模上洗脱地塞米松
以5wt%将地塞米松加载入涂敷的斯滕特固定模的聚氨基甲酸酯第一层。如实施例1所述通过使用1wt%疏水的肝素化聚合物溶液的浸渍法涂布第二层。然后测定地塞米松从涂敷的斯滕特固定模上的洗脱率。正如图8(a)和8(b)中所示,地塞米松显示出突然释放减少且如实施例9中所示洗脱率高于棘霉素的洗脱率。
<实施例11>
多层涂敷的斯滕特固定模的再狭窄的评价-斯滕特固定模的制备和动物选择
首先制备5组三种斯滕特固定模,各组斯滕特固定模带有相同的涂层(或不带有涂层),和各组带有不同的涂层,在层的数量和药物组成和/或浓度上可变。各组带有如下涂层之一:聚合物对照斯滕特固定模、未涂布的斯滕特固定模和带有疏水的肝素化聚合物外层且加载了0.1%wt、1%wt或5%wt棘霉素的三种多层涂敷的斯滕特固定模。然后选择15头猪并随机分成各包含3头猪的组。猪的平均体重为23kg且在实验前,将猪全部保持在相同条件下并饲喂不含脂类的实验用饲料。还通过饲料对猪给予300mg/天的阿司匹林。
<实施例12>
多层涂敷的斯滕特固定模的再狭窄的评价-实验方法
通过注射氯胺酮(22mg/kg)对每头猪进行全身麻醉并准备用于手术。接下来在暴露颈动脉的中线处颈前部造切口。同时将肝素剂量(300U/kg)注入猪的动脉。然后将8号French动脉导线通过动脉壁上的小切口插入颈动脉。随后插入导管并移至左和右冠状动脉且在其中移动。使用冠状动脉血管成形术选择右侧冠状动脉上的适宜部位。
使合适的斯滕特固定模与带有能够膨胀至大于冠状动脉直径10-20%的球囊的球囊导管连接。将球囊导管移至上述选择的冠状动脉内的部位并使球囊在4-12大气压下膨胀至其最大尺寸30秒以便损害冠状动脉。在给球囊放气后,使斯滕特固定模保留在该部位。应注意,为了阻止血管受损后的冠状动脉痉挛,将硝酸甘油(200Fg)通过导管连续给药入冠状动脉。手术后,进行冠状动脉血管造影术以观察对冠状动脉和血流开放的损害程度。然后取出动脉导线并连接颈动脉中的裂隙。
28天后,再次麻醉猪且如上所述插入导线。通过导线再将肝素剂量(300U/kg)注入动脉。在证实冠状动脉中的血管开放后,通过导管注射致死量的硫喷妥和氯化钾以诱发安乐死。然后通过胸廓取出猪心脏。随后使心脏进行灌注-固定术。在处死动物前,将使用OEC(GE medical,USA)进行的追踪冠状动脉血管造影术用于测定血管大小并评价在血管损害前后拍摄的图像以便确定斯滕特固定模固定的冠状动脉节段的动脉狭窄部位和程度。
<实施例13>
多层涂敷的斯滕特固定模的再狭窄的评价-组织学评价
从心脏中取出受损的动脉部分与另一受损部位周围的2cm区。使用包埋系统(Technovit 7100,Kulzer,Germany)固定含有斯滕特固定模的样本。然后使用安装了钨刀片的切片机将样本切成薄片。用苏木精-曙红和弹性VanGieson对各薄切片染色。
然后用显微镜研究各薄切片。使用Schwartz等级评价薄切片。对薄切片进行定量和形态分析。特别测定腔面积、内部弹性薄片面积和外部弹性面积、内膜面积、中层面积和I/M比。图9(a)-9(d)和10显示结果和I/M比率。结果证实当与其它斯滕特固定模、尤其是未涂布的斯滕特固定模相比时,第一层已经加载1wt%棘霉素的多层斯滕特固定模在28天时表现出显著减小的新内膜组织体积水平。
Claims (28)
1.制品,包含:
斯滕特固定模体;和
包含排列在至少部分斯滕特固定模体上的至少两层的涂层,其中所述至少两层中的至少一层包含分散在其中的生物活性剂。
2.权利要求1所述的制品,其中所述的斯滕特固定模体包含表面且所述的涂层包含排列在斯滕特固定模表面上的第一层和排列在第一层上的第二层,所述的第一层包含聚合物薄膜,其中分散有生物活性剂,且所述的第二层包含抗血栓形成的肝素化聚合物。
3.权利要求2所述的制品,其中所述的聚合物薄膜选自聚氨基甲酸酯类、聚对苯二甲酸乙二酯、PLLA-聚-乙醇酸(PGA)共聚物(PLGA)、聚己内酯、聚-(羟基丁酸酯/羟基戊酸酯)共聚物、聚(乙烯基吡咯烷酮)、聚四氟乙烯、聚(2-羟乙基甲基丙烯酸酯)、聚(醚氨酯脲)、硅氧烷类、丙烯酸类、环氧衍生物、聚酯类、尿烷类、parlenes、聚磷腈聚合物、含氟聚合物、聚酰胺类、聚烯烃类及其混合物。
4.权利要求2所述的制品,其中分散在第一层中的生物活性剂选自抗癌药、抗炎药及其混合物。
5.权利要求4所述的制品,其中所述的抗癌药选自阿西维辛、阿柔比星、阿考达唑、山油柑碱、阿多来新、阿拉诺新、阿地白介素、别嘌醇钠、六甲蜜胺、氨鲁米特、氨萘非特、聚肌胞、安吖啶、雄激素、蛇形菌素、氨基乙酸阿非迪霉素、亮氨酸溶肉瘤素、天冬酰胺酶、5-阿扎胞苷、硫唑嘌呤、卡介苗(BCG)、三嗪苯酰胺(可溶性)、β-2’-脱氧硫代鸟苷、盐酸比生群、硫酸博来霉素、白消安、buthionine sulfoximine、BWA 773U82、BW502U83×HCl、BW 7U85甲磺酸盐、ceracemide、卡贝替姆、卡铂、卡莫司汀、苯丁酸氮芥、氯喹喔啉-磺酰胺、氯脲菌素、色霉素A3、顺铂、克拉屈滨、皮质类固醇、短小棒状杆菌、CPT-11、克立那托、安西他滨、环磷酰胺、阿糖胞苷、溴茴丙烯酸钠、dabis maleate、达卡巴嗪、放线菌素D、盐酸柔红霉素、deazauridine、右雷佐生、二去水卫矛醇、地吖醌、二溴卫矛醇、didemnin B、二乙基二硫代氨甲酸酯、二甘醇醛、二氢-5-氮杂胞、多柔比星、棘霉素、依达曲沙、依地福新、依氟鸟氨酸、Elliott’s溶液、依沙芦星、表柔比星、依索比星、雌莫司汀磷酸盐、雌激素、依他硝唑、氨磷汀、依托泊苷、法倔唑、法扎拉滨、芬维A胺、非格司亭、非那雄胺、黄酮乙酸、氟尿苷、磷酸氟达拉滨、5-氟尿嘧啶、Fluosola、氟他胺、硝酸镓、吉西他滨、醋酸戈舍瑞林、hepsulfam、六亚甲基双乙酰胺、高三尖杉酯碱、硫酸肼、4-羟基雄烯二酮、羟基脲、盐酸伊达比星、异环磷酰胺、干扰素α、干扰素β、干扰素γ、白细胞介素-1α和β、白细胞介素-3、白细胞介素-4、白细胞介素-6、4-依波米醇、异丙铂、异维A酸、亚叶酸钙、醋酸亮丙立德、左旋咪唑、柔红霉素脂质体、脂质体包囊的多柔比星、洛莫司汀、氯尼达明、美登素、盐酸氮芥、美法仑、美诺立尔、merbarone、6-巯嘌呤、巯乙磺酸钠、卡介苗的甲醇提取残余物、甲氨蝶呤、N-甲基甲酰胺、米非司酮、米托胍腙、丝裂霉素-C、米托坦、盐酸米托蒽醌、单核细胞/巨噬细胞集落刺激因子、大麻隆、萘福昔定、新制癌菌素、醋酸奥曲肽、奥马铂、奥沙利铂、紫杉醇、pala、喷司他丁、哌嗪二酮、哌泊溴烷、吡柔比星、吡曲克辛、盐酸吡罗蒽醌、PIXY-321、普卡霉素、卟吩姆钠、泼尼莫司汀、丙卡巴肼、孕酮、吡唑呋林、雷佐生、沙格司亭、司莫司汀、锗螺胺、螺莫司汀、链黑霉素、链佐星、磺氯苯脲、舒拉明钠、他莫昔芬、泰索帝、替加氟、替尼泊苷、对苯二脒、替罗昔隆、硫鸟嘌呤、塞替派、胸苷注射剂、噻唑呋林、托泊替康、托瑞米芬、维A酸、盐酸三氟拉嗪、曲氟尿苷、三甲曲沙、肿瘤坏死因子、乌拉莫司汀、硫酸长春碱、硫酸长春新碱、长春地辛、长春瑞滨、长春利定、Yoshi 864、佐柔比星及其混合物。
6.权利要求4所述的方法,其中所述的抗炎药选自非甾类抗炎药、COX-2抑制剂、糖皮质类固醇及其混合物。
7.权利要求6所述的方法,其中所述的非甾类抗炎药选自阿司匹林、双氯芬酸、吲哚美辛、舒林酸、酮洛芬、氟比洛芬、布洛芬、萘普生、吡罗昔康、替诺昔康、托美丁、酮咯酸、噁丙嗪、甲芬那酸、非诺洛芬、nambumetone、对乙酰氨基酚及其混合物。
8.权利要求6所述的方法,其中所述的COX-2抑制剂选自尼美舒利、NS-398、氟舒胺、L-745337、塞来考昔、罗非考昔、SC-57666、DuP-697、帕瑞考昔钠、JTE-522、伐地考昔、SC-58125、艾托考昔、RS-57067、L-748780、L-761066、APHS、依托度酸、美洛昔康、S-2474及其混合物。
9.权利要求6所述的方法,其中所述的糖皮质类固醇选自:诸如氢化可的松、可的松、泼尼松、泼尼松龙、甲泼尼龙、甲泼尼松、曲安西龙、帕拉米松、氟泼尼龙、倍他米松、地塞米松、氟氢可的松、去氧皮质酮及其混合物。
10.权利要求2所述的制品,其中所述的第一层包含分散在其中的第二种生物活性剂。
11.权利要求2所述的制品,其中所述的抗血栓形成的肝素化聚合物包含大分子、疏水物质和通过共价键结合在一起的肝素。
12.权利要求11所述的制品,其中所述的大分子选自合成的大分子、蛋白质、生物聚合物及其混合物。
13.权利要求12所述的制品,其中所述的合成大分子选自聚二烯烃类、聚烯烃类、聚乙炔类、聚丙烯酸及其衍生物、聚“-取代的丙烯酸及其衍生物、聚乙烯醚类、聚乙烯醇、聚卤代乙烯类、聚苯乙烯及其衍生物、多氧化物、聚醚类、聚酯类、聚碳酸酯类、聚酰胺类、聚氨基酸、聚脲类、聚氨基甲酸酯类、聚亚胺类、聚硫化物、多磷酸盐、聚硅氧烷类、聚倍半硅氧烷类、聚杂环类、纤维素及其衍生物、及其共聚物和混合物。
14.权利要求12所述的制品,其中所述的蛋白质选自鱼精蛋白、聚赖氨酸、聚天冬氨酸、聚谷氨酸、及其衍生物和共聚物。
15.权利要求12所述的制品,其中所述的生物聚合物选自多糖类、明胶、胶原蛋白、藻酸盐、透明质酸、藻酸、角叉菜聚糖、软骨素、果胶、脱乙酰壳多糖、及其衍生物和共聚物。
16.权利要求11所述的制品,其中所述的疏水物质带有一种以上的活性官能团且在与大分子结合后的水溶性低于100mg/ml。
17.权利要求11所述的制品,其中所述的疏水物质选自十八胺、链烷酸胺、胆汁酸、甾醇类、链烷酸及其混合物。
18.权利要求16所述的制品,其中所述的肝素选自重组肝素、肝素衍生物和肝素类似物。
19.制品的制备方法,所述的制品包含斯滕特固定模和其上排列的涂层,该涂层包含第一层和第二层,第一层包含其中分散有生物活性剂的聚合物薄膜且第二层包含抗血栓形成的肝素化聚合物,所述的方法包含下列步骤:
用洗涤剂清洁斯滕特固定模;
通过用溶剂将聚合物与生物活性剂合并、由此形成聚合物和生物活性剂混合物并将该混合物涂布在斯滕特固定模上制备第一层;
通过将疏水肝素化聚合物与溶剂合并制备第二层并通过将斯滕特固定模浸入疏水肝素化聚合物和溶剂溶液且然后干燥斯滕特固定模涂布第二层。
20.权利要求19所述的方法,进一步包含将第二种生物活性剂加入到聚合物与生物活性剂的混合物中。
21.权利要求19所述的方法,其中涂布第一层涂层包含将斯滕特固定模浸入聚合物与生物活性剂的混合物。
22.权利要求19所述的方法,其中涂布第一层涂层包含将聚合物与生物活性剂混合物喷雾在斯滕特固定模上。
23.防止分散在斯滕特固定模上薄膜聚合物层中的生物活性剂突然释放的方法,包含将第二层涂布在第一层上的步骤;所述的第二层由疏水的肝素化聚合物组成。
24.涂敷的抗血栓形成的斯滕特固定模,包含:
斯滕特固定模体;和
排列在至少部分斯滕特固定模体上的涂层,所述的涂层包含抗血栓形成的肝素化聚合物。
25.抑制带有与有机流体接触表面的医疗装置中血栓形成的方法,包含用抗血栓形成的肝素化聚合物层涂敷所述医疗装置的表面。
26.权利要求25所述的方法,进一步包含涂布最下层涂层的步骤,所述的最下层涂层排列在疏水肝素化聚合物层下且包含其中分散有生物活性剂的聚合物。
27.带有多层涂层的抗血栓形成的斯滕特固定模,包含:
带有排列在其上的多层涂层的斯滕特固定模体,所述的多层涂层带有内层,所述的内层中分散有生物活性剂;和
用于防止生物活性剂从第一层中突然释放的部件。
28.制品,包含:
包含表面的斯滕特固定模体;和
包含排列在至少部分斯滕特固定模体上的至少两层的涂层,其中所述至少两层中的至少一层包含分散在其中的生物活性剂且所述至少两层中的至少一层包含抗血栓形成的肝素化聚合物。
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US10/262,432 US6702850B1 (en) | 2002-09-30 | 2002-09-30 | Multi-coated drug-eluting stent for antithrombosis and antirestenosis |
US10/262,432 | 2002-09-30 | ||
PCT/KR2003/000058 WO2004028406A1 (en) | 2002-09-30 | 2003-01-11 | Drug release from antithrombogenic multi-layer coated stent |
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Also Published As
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AU2003208018A1 (en) | 2004-04-19 |
KR20040028486A (ko) | 2004-04-03 |
KR100661396B1 (ko) | 2006-12-27 |
US7638158B2 (en) | 2009-12-29 |
EP1549247A4 (en) | 2007-10-31 |
WO2004028406A1 (en) | 2004-04-08 |
EP1549247A1 (en) | 2005-07-06 |
US6702850B1 (en) | 2004-03-09 |
JP2006500987A (ja) | 2006-01-12 |
US20040254638A1 (en) | 2004-12-16 |
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