CN101862233B - 药物释放型血管内支架和治疗再狭窄的方法 - Google Patents
药物释放型血管内支架和治疗再狭窄的方法 Download PDFInfo
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Abstract
本发明涉及药物释放型血管内支架和治疗再狭窄的方法。所述支架具有一个可扩张的、相互连接的细丝体和在支架体细丝上形成的可释放药物的涂层,当支架被放入血管损伤部位时,支架扩张,使支架涂层与血管损伤部位相接触。涂层可释放抑制再狭窄量的大环三烯化合物,该化合物在碳位40有一个烷基取代基。当该支架用于治疗血管损伤时,可以很好的防止临床再狭窄,即使血管损伤程度涉及血管过度拉伸在直径上超过30%也可以做到。本发明还公开了具有药物释放涂层的支架,所述涂层由(i)10-60%(重量比)的聚-dl-丙交酯聚合物底材和(ii)40-90%(重量比)的抗再狭窄化合物组成;该支架还具有厚度为1-5微米的聚合物底层。
Description
本申请为2003年4月24日提交的申请号为PCT/US2003/012750、发明名称为“药物释放型血管内支架和治疗再狭窄的方法”的国际申请的分案申请,该申请于2004年10月25日进入中国国家阶段,申请号为03809311.1。
发明领域:
本发明涉及药物释放型血管内支架和治疗再狭窄的方法。
发明背景
支架是一种血管内植入物,通常为管状,一般具有网状、相互连接的金属丝管状结构,其可以扩张,可以永久地置入血管中以对血管提供机械支撑并在血管成形术过程中或术后保持或重建血流通道。支架的支撑结构被设计为能防止由血管成形术导致的变弱和损伤的血管的早期塌陷。已证实支架的置入可在受损血管壁愈合过程的数月期间内防止血管的负性重构和痉挛。
在愈合的过程中,由血管成形术和支架置入损伤所引起的炎症经常导致平滑肌细胞在支架内增殖和再生长,因而使部分血流通道闭塞,由此降低或消除了血管成形术/支架手术的有益效果。这个过程被称为再狭窄。由于支架表面有形成血栓的特性,即使用生物相容性材料制成的支架,在新置入的支架内也可产生血凝块。
由于目前的做法是在血管成形术过程中在血液循环中注入强抗血小板药,所以在手术期间和手术之后短期内不会有大的血凝块形成,但总会有一些血栓存在,至少可以在显微镜下在支架表面观察到,有人认为它通过在支架表面建立生物相容性基质而在再狭窄的早期起重要作用,平滑肌细胞随后在其上附着并增殖。
含有生物活性剂的支架涂层是已知的,它被设计用来减少或消除血栓形成或再狭窄。在支架置入前,所述生物活性剂分散或溶解在附着于支架丝表面的生物耐久性或可生物降解的聚合物基质中。支架置入后,生物活性剂从聚合物基质向外扩散,优选扩散进入周围组织,扩散至少维持4周,在有些情况下可以长达一年或更长,理想的是与再狭窄、平滑肌细胞增殖、血栓形成或这几种情况的组合的时间进程相匹配。
若聚合物是可生物降解的,除通过扩散过程释放药物外,生物活性剂还可以在聚合物被降解或溶解时释放,使周围组织更易得到该生物活性剂。其外表面或甚至整个聚合材料都是多孔的可生物降解的支架和生物耐久性支架是已知的。例如,PCT公布号WO99/07308(与本申请属于同一申请人)公开了这种支架,该专利申请引入本文作为参考。当可生物降解聚合物被用作递送药物的涂层时,许多专利描述了多孔性可帮助组织向内生长,使聚合物的降解更可预见,或调控或提高药物释放速率,例如US专利:6,099,562、5,873,904、5,342,348、5,873,904、5,707,385、5,824,048、5,527,337、5,306,286和6,013,853中所述。
肝素及其它抗血小板或抗血栓溶解表面涂层是已知的,它们化学结合在支架的表面以减少血栓形成。已知肝素化的表面可以干扰人的凝血级联反应,防止血小板(凝血酶的前体)在支架表面的附着。表面含肝素并且涂层内储有活性剂的支架已有记载(参见例如US专利6,231,600和5,288,711)。
有许多活性剂可以抑制平滑肌细胞的增殖,从而抑制再狭窄,已有人提出将这些活性剂用于从血管内支架释放。例如,美国专利6,159,488描述了使用喹唑啉酮衍生物;美国专利6,171,609描述了使用Taxol;美国专利5,176,98描述了使用紫杉醇,它是一种被认为是药物Taxol中的活性成分的细胞毒性剂。在美国专利5,873,904中提到了金属银。在美国专利5,733,327中公开了曲尼司特,它是一种被认为具有抗炎特性的膜稳定剂。
最近,雷帕霉素,一种据报道可以抑制平滑肌细胞和内皮细胞生长的免疫抑制剂,当从支架上的聚合物涂层给药时,被证实具有改善的抗再狭窄的效力。参见例如美国专利5,288,711和6,153,252。此外,PCT公布号WO97/35575中提出了用大环三烯免疫抑制化合物依维莫司(everolimus)和相关化合物通过全身给药来治疗再狭窄。
理想的是,被选择用来通过从支架上释放药物来抑制再狭窄的化合物应具有以下三方面特性:
1、由于支架的轮廓要小,即聚合物基质薄,要求从薄的聚合物涂层释放出的化合物有足够的活性以产生持续治疗剂量最少4-8周。
2、化合物在低剂量的条件下能有效抑制平滑肌细胞增殖。
3、血管腔内表面的内皮细胞在血管成形术和/或置入支架过程中一般会被损伤,化合物应允许内皮细胞在血管腔内再生长,提供血管内环境稳定的回归,促进血管壁和通过血管的血流的正常和重要的相互作用。
发明概述
一方面,本发明包括一种用于置入血管损伤部位以抑制此部位再狭窄的血管内支架。支架由一个或多个细丝所形成的结构件或结构体构成,并且在支架体细丝上带有厚度为3-15微米的可生物降解的药物释放涂层,所述涂层由(i)20-60%(重量比)的聚-dl-丙交酯聚合物底材和40-80%(重量比)的抗再狭窄化合物组成。聚合物底层厚度为1-5微米,位于支架体细丝和涂层之间,起稳定支架细丝上的涂层的作用。支架可以从收缩状态扩张,在收缩状态下,可以将支架通过导管传送到血管损伤部位,在扩张状态时,支架涂层与血管的损伤部位相接触。支架被放入血管损伤部位后,支架涂层能够在至少4周的时间内有效释放再狭窄抑制量的化合物。
在各种示例性的实施方案中,抗再狭窄化合物是一种大环三烯免疫抑制化合物,支架体是金属丝结构,紧附金属丝的底层由聚对亚苯基二甲基聚合物形成,其厚度为0.5-5微米;涂层的厚度为2-10微米。化合物在涂层中的含量可以为50-75%(重量比)。
示例性的大环三烯免疫抑制化合物有以下结构:
其中,(i)当R’是H(R’替代了28位O上的H)时,R是H或CH2-X-OH,并且X是直链或支链的含1-7个碳原子的烷基,或者(ii)R’和R中至少有一个为以下形式:
m是1-3的整数,R1和R2分别是氢或具有1-3个碳原子的烷基,或者R1和R2与它们所连接的氮原子一起形成具有4个碳原子的饱和杂环。在一个示例性的化合物依维莫司中,R’是H,X是-CH2。
根据本发明的另一方面,上述支架被用于抑制血管损伤部位再狭窄的方法中。在该方法中,支架被导入血管损伤部位,然后扩张使支架涂层与血管损伤部位相接触。涂层可在至少4周的时间内有效地释放再狭窄抑制量的化合物。
在另一方面,本发明包括一种血管内支架,该支架用于放入血管损伤部位以抑制该部位的再狭窄。该支架由一个或多个细丝所形成的结构件或结构体构成,并且在支架体细丝上带有厚度为3-25微米的可释放药物的涂层,所述涂层由(i)20-70%重量比的聚合物底材和(ii)30-80%重量比的大环三烯免疫抑制化合物组成,其分子结构如下:
其中R是CH2-X-OH,X是含1-7个碳原子的直链基团。
支架可以从收缩状态扩张,在收缩状态下,可以将支架通过导管传送到血管损伤部位,在扩张状态时,支架涂层与血管的损伤部位相接触。支架被放入血管损伤部位后,支架涂层能够在至少4周的时间内有效释放再狭窄抑制量的化合物。
在多种示例性的实施方案中,R是CH2-X-OH,X是-CH2-,支架体是一个金属丝结构,涂层中的聚合物底材是聚甲基丙烯酸甲酯、乙烯乙烯醇共聚物或聚-dl-丙交酯聚合物。
在一个示例性的实施方案中,涂层中的聚合物底材是由可生物降解的聚-dl-丙交酯形成的,其厚度为3-20微米;涂层中所含化合物的初始浓度为涂层总重量的20-70%。特别是,当涂层中化合物的含量大于40%(重量)时,所述支架还可以在支架体细丝和聚-dl-丙交酯涂层底材之间有一层厚度为1-5微米的聚对亚苯基二甲基聚合物底层。
或者,支架体和涂层底材均可由可生物降解聚合物形成,例如由聚-l-丙交酯或聚-dl-丙交酯形成支架体细丝,由聚-dl-丙交酯形成涂层底材。
当支架被放入指定位置时,在扩张状态下,支架涂层与通过支架的血流相接触。在该实施方案中,涂层可进一步含有生物活性剂如抗血小板剂、纤维蛋白溶解剂或可溶结晶形式的溶栓剂。抗血小板剂、纤维蛋白溶解剂或溶栓剂的实例是肝素、阿司匹林、水蛭素、噻氯匹定、eptifibatide、尿激酶、链激酶、组织纤溶酶原激活物(TPA)或它们的混合物。
再一方面,本发明提供了一种通过放入被设计用来在延长的时间内释放大环三烯免疫抑制化合物的血管内支架来治疗血管损伤部位再狭窄的改进的方法。该改进包括使用大环三烯免疫抑制化合物,化合物的结构式为:
R是CH2-X-OH,X是含1-7个碳原子的直链烷基。在一个示例性的化合物中,X是-CH2-。
支架组成的各种示例性实施方案如上所述。
本发明还公开了一种把含药的聚合物涂层涂到支架体细丝上的新方法。该方法使用自动控制器调整聚合物或含药聚合物溶液流到支架体细丝上,以获得多种支架涂层特性中的一种,包括在支架体细丝一面或多面上的涂层厚度是均匀的;在支架体外(或内)表面的涂层厚度比另一面的厚;内和外涂层含不同的药物;和/或在支架体上涂层厚度有坡度或不连续涂层。
通过以下结合附图对本发明的详细描述,本发明的这些以及其它的目的和特点将更加清楚。
附图概述
图1和图2显示了按照本发明的一个实施方案形成的具有金属丝体的血管内支架,图1是支架的收缩状态;图2是支架的扩张状态。
图3是图1的支架中涂层的金属丝的横断面放大图。
图4是一个带有涂层的可降解聚合物支架的横断面放大图。
图5A和5B是适用于生产本发明的涂层支架的聚合物涂层方法的示意图。
图6是按照本发明构建的可生物降解聚合物支架被安装在用于送至血管部位的导管上的示意图。
图7A和7B是从本发明的支架释放依维莫司的函数图。
图8是本发明支架置入血管部位后的横断面图。
图9A-9C是置入裸金属支架28天后的血管组织学切片。
图10A-10C是置入含聚合物涂层的金属丝支架28天后的血管组织学切片。
图11A-11C和12A-12C是置入含依维莫司的聚合物涂层金属丝支架28天后的血管组织学切片。
图13是一个放大的血管组织学切片,其中可见图11A-11C所用支架的细丝,该细丝上长满新的组织,形成愈合的血管壁。
图14是各种支架、包括按照本发明构建的支架置入后28天时,狭窄的面积与损伤度的函数图。
图15显示一个校正函数图,Y轴为损伤度,X轴为支架置入时B/A(球囊/动脉)的比率。
发明详述
第一部分、血管内支架
图1和图2分别显示了收缩和扩张状态的按照本发明构建的支架20。支架包括一个结构件或结构体22和用来包含和释放抗再狭窄化合物的外涂层,以下将参照图3和图4做进一步描述。
A、支架体
在所示的实施方案中,支架体是由多个通过细丝相连的管状件,如件24和26组成。每个件具有可扩张的Z型锯齿或正弦波结构。各件体通过轴向连接件,例如将相邻部件的波峰和波谷相连的连接件28、30连接。可以理解,此结构使支架可以从收缩状态(如图1所示)扩张到扩张状态(如图2所示),而支架的长度不变或有少许改变。同时,相邻管状件的峰谷之间相对较少的连接使得支架可以弯曲。此特性对于支架在导管中或导管上以收缩状态被导入血管部位特别重要。支架有一个0.5-2mm的典型收缩状态直径(图1),更优选0.71-1.65mm,长度为5-100mm。在支架的扩张状态(见图2),支架的直径至少是它收缩状态的2倍,甚至可达到8-9倍。因此,一个收缩态直径在0.7-1.5mm的支架可放射状地扩张到直径为2-8mm或更大的选定扩张状态。
具有这样的由相连的、可扩张的管状件构成的支架体的支架是已知的,如PCT公布号WO99/07308所述,该专利申请与本申请属于同一申请人,并且引入本文作为参考。其它的例子记载于美国专利6,190,406、6,042,606、5,860,999、6,129,755或5,902,317中,这些专利引入本文作为参考。或者,支架的结构件也可能是连续的螺旋状丝带结构,即,支架体是由单一的连续的丝带样螺旋构成。支架体的基本要求是在放置于血管损伤部位时可以扩张,并且在其外表面能涂覆含药物的涂层,能将涂层中所含的药物输送到血管靶点内层的血管壁(如:组织的中膜、外膜和内皮层)内。优选地,支架体还具有网状或开放结构,允许内皮细胞穿过支架从外向内生长。
B、支架涂层
根据本发明的一个重要特征,支架丝上涂有可释放药物的涂层,该涂层由聚合物基质和分布在基质内的抗再狭窄化合物(活性化合物)组成,用于在至少数周、一般是4-8周,有时持续2-3个月或更长的时期内从支架上释放出药物。
图3以放大的断面图的方式显示了具有涂层32的支架丝24,所述涂层完全覆盖了细丝的所有面,即顶部(形成支架体外表面的细丝侧面)、底部(形成支架体内表面的细丝侧面)和相对的细丝侧面。正如以下将要进一步讨论的,涂层的厚度通常为3-30微米,该厚度取决于构成涂层的聚合物基质材料的性质和聚合物基质与活性化合物的相对量。理想的是,涂层尽可能的薄,如15微米或更小,以使支架在血管损伤部位的轮廓最小。
上(外)表面涂层的厚度也应该相对均匀,以促进释放的药物在靶点的均匀分布。在支架丝上产生相对均匀厚度的涂层的方法将在第二部分讨论。
图3显示了在支架丝和涂层间有一层聚合物底层34。底层的目的是帮助支架体细丝与涂层间的粘合,即稳定细丝上的涂层。以下会看到,此功能在形成涂层的聚合物底材中含有高百分比的抗再狭窄化合物(如:35-80%重量的化合物)时特别有价值。一种底层聚合物的例子是聚对亚苯基二甲基,其用以连接由可生物降解的聚-dl-丙交酯形成的聚合物底材。其它适用的聚合物底层为乙烯乙烯醇共聚物(EVOH)、paryLASTTM、聚对亚苯基二甲基、聚硅氧烷、TEFLONTM和其它含氟聚合物,它们可以通过等离子涂覆、其它涂覆或沉淀工艺沉积在金属支架表面。底层厚度一般为1-5微米。
形成底材的聚合物可以是任何生物相容性聚合物材料,其中所包含的化合物可以通过扩散和/或通过聚合物基质的降解而释放。两种公知的不可降解的用于涂层底材的聚合物是聚甲基丙烯酸甲酯、乙烯乙烯醇共聚物。制备适用于支架体的这些聚合物的方法描述在US2001/0027340A1和WO00/145763中,这两篇申请引入本文作为参考。通常,加入聚合物的药物限量是约20-40%重量。
可生物降解的聚合物,特别是聚-dl-丙交酯,也适合作为涂层底材材料。在本发明中的一个的实施方案中,涂层是可生物降解的聚-dl-丙交酯聚合物底材,即聚-dl-乳酸聚合物,其可容高达80%(干重)的活性化合物分散在聚合物底材内。更一般的,涂层含35-80%干重的活性化合物和20-65%干重的聚合物。示例性的涂层含25-50%干重的聚合物基质和50-75%重量的活性化合物。关于用于沉淀于支架丝上的聚合物和药物的合成的详细说明见第二部分。
有多种抗再狭窄化合物可以用于该实施方案,包括抗增殖剂如TAXOL、反义化合物、阿霉素和最特别的大环三烯免疫抑制化合物,其具有以下所示的通式。后一类化合物和它们的合成记载于在美国专利4,650,803、5,288,711、5,516,781、5,665,772和6,153,252;PCT公布号WO97/35575,美国专利申请号6273913B1、60/176086、20000212/17和2001002935/A1,所有这些专利和专利申请在此引为参考。示例性的大环三烯免疫抑制化合物具有如下结构:
其中(i)当R’是H(R’替代了28位O上的H)时,R是H或CH2-X-OH,并且X是直链或支链的含1-7个碳原子的烷基,或者(ii)R’和R中至少有一个为以下形式:
m是1-3的整数,R1和R2分别是氢或具有1-3个碳原子的烷基,或者R1和R2与它们所连接的氮原子一起形成具有4个碳原子的饱和杂环。在一个示例性的化合物依维莫司中,R’是H,X是-CH2。
一种优选的涂层由25-50%重量的聚-dl-丙交酯聚合物底材和50-75%重量的大环三烯免疫抑制化合物形成,涂层厚度为3-15微米。底层是聚对亚苯基二甲基,厚度为1-5微米。该实施方案中,化合物的含量相当于15μg药物/mm支架长。
在另一个实施方案中,涂层由15-35%重量的可降解或不可降解的聚合物底材和65-85%重量的大环三烯化合物形成。涂层厚度优选为10-30微米,支架还可以含1-5微米的聚合物底层,如聚对亚苯基二甲基底层。在该实施方案中,化合物的含量相当于约15μg药物/mm支架长。活性化合物具有如下结构:
其中R是CH2-X-OH,X是含1-7个碳原子的直链烷基。优选的化合物是依维莫司,其中X=-CH2。X是2、3、4、5、6或7个碳原子的烷基的化合物,无论是单独使用还是以任何组合使用,以及前述化合物、包括依维莫司的乙酸酯的应用,也适用于本发明。
涂层还可以含有第二种可以将血液相关事件例如可能由原血管损伤或支架的存在刺激形成的凝血降至最小或改善血管损伤的愈合的生物活性剂。第二种活性剂的例子包括抗血小板剂、纤维蛋白溶解剂或可溶结晶形式的溶栓剂,或可刺激内皮细胞愈合和控制平滑肌细胞生长的NO供体。抗血小板剂、纤维蛋白溶解剂或溶栓剂的实例是肝素、阿司匹林、水蛭素、噻氯匹定、eptifibatide、尿激酶、链激酶、组织纤溶酶原激活物(TPA)或它们的混合物。第二活性剂在支架涂层中的含量由需要该活性剂提供治疗益处的时期的长短来决定。通常,活性剂在血管损伤和支架置入后的最初几天发挥作用,虽然对于一些活性剂而言,要求更长的释放期。
可以根据已知方法将第二种活性剂包含在涂层配方中涂到支架细丝上。
C、可生物降解支架
在另一个实施方案中,支架体和聚合物涂层均由可生物降解聚合物构成,经一定时间支架被完全吸收。支架优选是一个可扩张的螺旋支架,它具有由螺旋带状细丝形成的支架体(无图示)。在美国专利4,990,155中记载了用于植入血管的自扩张螺旋支架,在此引为参考。
螺旋支架可以用预成形的支架来制备,预成形支架的最终扩张直径略大于拟用此螺旋支架治疗的血管内腔尺寸(对于冠状动脉常见的是3.5mm外径(OD)±1mm)。通常,支架可以通过如下方式制备:铸模扩张状态下的支架,再以支架的长轴为轴拧支架使其处于收缩状态或径向压支架让其处于收缩状态,以便安装在导管尖端上送至血管。支架的总厚度优选为100-1000微米,总长度为0.4-10cm。事实上,该类型可生物降解支架的一个重要的优点是,相对较长的支架、如长度超过3cm的支架,能容易地送入并放置在血管损伤部位。
关于用可生物降解聚合物(如聚-l-丙交酯)的编结丝形成可扩张球囊支架的方法已有报道(美国专利6,080,177)。也有一种形式的装置已被用于释放药物(美国5,733,327)。
一种优选的用于形成支架的聚合物材料是聚-l-或聚-dl-丙交酯(美国专利6,080,177)。如上所述,支架体和涂层可以是一体的,成为一个在整个支架中含有抗再狭窄化合物的可扩张丝支架。或者,可生物降解涂层可以被涂到预制的可生物降解体中,详见以下第二部分的描述。按后者,支架体可以由一种可生物降解聚合物如聚-l-丙交酯形成,涂层由第二种聚合物如聚-dl-丙交酯聚合物形成。涂层如果是被涂到预制支架上的,则涂层具有与以上描述基本相同的组成和厚度特征。
图4显示了一个刚描述的可生物降解支架中的细丝、例如螺旋丝带的横断面图,它具有分别形成的支架体和涂层。图中显示了一个内部的可生物降解的支架细丝36,在其所有侧面均涂有可生物降解的涂层38。一种示例性的涂层是由聚-dl-丙交酯形成的,含有20-40%重量的抗再狭窄药,如大环三烯免疫抑制化合物和60-80%重量的聚合物底材。在另一个实施方案中,涂层含45-75%重量的化合物和25-55%重量的聚合物基质。在以上两种实施方案中均可使用其它类的抗再狭窄化合物,如上面所述的那些。
可生物降解的支架有一个独特的优势,就是用一个装置治疗整个血管,它既可以和球囊成形术结合使用以便在有大的堵塞存在时预扩张血管,也可以作为预防性植入物放入将来可能发生堵塞的高风险患者体内。由于支架是可完全生物降解的,它不会像“全金属衣”、即一串含金属底材的药物洗脱支架那样影响患者以后在血管做非复杂手术的机会。
如以上所说,可以在涂层上掺入第二种活性剂,用于在植入后在希望的一定时间内从涂层中释放。或者,如果使用了第二种活性剂,若涂到支架体的涂层没有覆盖支架体的内表面,则可将第二种活性剂掺入到支架体细丝中。在以下第二部分叙述的关于金属丝支架体的涂层方法也适用于聚合物丝支架体。
第二部分:支架涂层方法
更详细地参考附图,图5A和5B是本发明的支架涂层工艺的示意图。在可相容的溶剂中溶解聚合物得到聚合物溶液40。将至少一种抗再狭窄化合物和,如果需要的话,第二种活性剂,以混悬液或溶液的形式用同种溶剂或不同的溶剂加入聚合物溶液中。将整个混合物置于加压储存器42中。储存器上连有一个液体加压泵44。
加压泵可以采用任何压力来源,只要能把混合溶剂以一个设计的速度推过溶液传输管46。正如精密给料系统领域所公知的,加压泵44由微型控制器(没图示)控制。例如:这样一个微型控制器可以含有4-轴自动给料装置(4-Axis Dispensing Robot,型号为I&J500-R和I&J750-R,可从FairLawn,NJ的I&J Fisnar公司获得,它可通过RS-232C交换界面由个人电脑控制;或精密给料系统如Automove A-400,其来自加拿大卡尔斯拜的Asymtek。一个用于控制RS232C界面的合适的软件程序可从包括Fluidmove系统,其也可由加拿大卡尔斯拜的Asymtek得到。
与储存器42相连的,例如与储存器的底部相连的是溶液导管48,它把溶剂混合物传输到支架的表面。可加压储存器42和导管48被装在一个可移动的支架上(没图示),它可使溶剂导管以微小的步长移动,例如每步0.2mm,或连续地沿支架的长轴方向移动(如图中箭头X1所示)。加压储存器42和导管46的可移动支架也能将导管的尖部(远端)沿Y1所示的方向以微小的步长移向或远离细丝的表面。
未涂层的支架被卡在转动的卡夹上,卡夹至少有一端与支架的内表面相接触。通过步进电机带动卡夹可以使支架以微小的角度沿轴向旋转,如每次0.5度,以使支架结构的最外表面可以被导管涂层,这是本领域公知的。如果需要,支架也可连续转动。精确定位低量液体传导装置的方法在X-Y-Z溶剂给料系统领域是公知的,可以用于本发明。
液体加压泵的活动、液体导管X1和Y1向定位以及支架R1向定位都是由数字控制器和计算机软件来控制,这样定量的溶液被精确地涂到支架表面所需要的地方,然后,溶剂可以被蒸发,支架表面剩下变硬的聚合物和活性剂涂层。溶剂混合物的粘度通常随溶剂的量变化,其范围2-2000厘泊,通常可能为300-700厘泊。或者,可将导管固定在固定的位置,支架除转动外还可沿其长轴方向移动完成涂层工艺。
X-Y-Z定位台和可移动的支架可以从I&J Fisnar采购。溶液导管尺寸最好是18-28计量规格的不锈钢注射管,连有可被锁定的连接器。这种导管可以从RI,East Providence的EFD公司得到。见EFD的特别用途的注射针选择指南。优选的注射针是再订购号从5118-1/4-B到5121-1/4-B的“无泊尔钝化不锈钢针,长度1/4”快速点对点注射充粒子或稠的材料”;再订购号为51150VAL-B的“椭圆的不锈钢针,在平带状沉积物上涂抹稠的浆料、密封剂和环氧物”;再订购号从5121-TLC-B到5125-TLC-B的“抗氰基丙烯酸酯凝结并为低粘度液体提供附加的沉积控制。压纹和衬聚四氟乙烯”。一种可任意使用的加压溶液储存器也可以从EFD得到,库存号1000Y5148到1000Y 5152 F。用于本发明的另一种针头是玻璃毛细管,内径约0.0005-0.002英寸,如约0.001英寸,在VWR目录中可以得到,目录号15401-560“微血球比溶剂管”,长度60mm,内径0.5-0.6mm。
在本生灯下,管子被进一步拉伸,得到用于精确涂层聚合物/药物/溶剂混合物的希望的尺寸。用于操作步进电机的可编程的微控制器和XYZ台可从Asymtek公司获得。本发明还包括使用一个以上的液体给料管共同形成涂层,或在同一涂层工艺中,使用一个以上的装配有不同注射针或含不同粘度的溶液或由多种溶液组成的不同的化学剂的可移动溶液储存器。卡夹和步进电机系统可以从NJ,Barrigton的Edmund Scientific购买。
如上所述,涂层通常被直接涂在支架的外支撑面,可能覆盖或不覆盖支架内表面的全部或一(或多)部分,覆盖的情况取决于如何控制以上所述的本发明的涂层系统,如图5A和5B所示。后图是用涂层材料52涂细丝50的顶部和侧面区域。或者,涂层或涂层混合物也可以直接涂到支架的内表面。一个细的导针可以穿过支架壁的一个或多个缺口处(即:窗户),从而使涂层混合物直接涂到支架内表面希望的位置。用此方法,就可以实现用含不同药物成分的不同涂层材料涂到细丝的内和外面。例如,细丝外表面涂层可含抗再狭窄化合物,细丝的内表面涂层可含有上面所提的第二活性剂之一,如抗血栓或抗凝血化合物。如果支架有足够大的直径,细的“L-型”导针能沿支架的长轴方向插入到支架的开放端以将支架的内表面涂层。
用于本发明的聚合物包括但并不仅限于:聚(d,l-乳酸)、聚(l-乳酸)、聚(d-乳酸)、乙烯乙烯醇共聚物(EVOH)、ε-己内酯、乙基乙烯基羟基化乙酸酯(EVA)、聚乙烯醇(PVA)、聚氧化乙烯(PEO)和其共聚物和混合物,被溶解于氯仿或丙酮或其他适用的溶剂中。所有这些聚合物都有用于系统循环的安全和低炎症史。
一种非聚合物涂层也可用于本发明,如通过离子连接涂到金属支架表面的依维莫司。
使用描述的涂层系统,会发现给支架表面涂层无论上、侧或里面都是可行的。通过仔细选择溶剂和聚合物的合适比率,可以调整溶液的粘度,从而使一些溶液可以沿着支柱的侧面向下移动,并在凝固前占据底部表面,见图5B。通过控制导管接近支架边缘的停留时间,聚合物被涂到支架边缘或底部的量就会被增减。在图3所示的实施方案中,首先将由纯聚合物和溶剂组成的底层34用本发明的涂层系统涂到支架表面24,然后将溶剂蒸发掉。然后涂上含生物活性剂的第二层聚合物涂层32。
如上所述,第二活性剂也可以被加入聚合物的混合物中。如:结晶形式的肝素可以被加入涂层中。将肝素结晶微粒化到粒度约为1-5微米,然后以悬浮液的形式加入聚合物溶液中。当按照本发明的工艺涂层时,肝素的适宜形式是那些在哺乳动物中显示生物活性的结晶态,包括肝素盐(即:肝素钠和低分子量肝素及其盐)。当药物释放型支架被放入血管壁时,如图8所示,靠近凝固的聚合物涂层表面的肝素晶体开始溶解,增加了聚合物的孔。当聚合物慢慢溶解,更多的肝素和生物活性剂以受控的方式被释放。
然而,参见图8,应注意到,并不总是需要在支架内表面涂层。例如,在支架内表面涂层增加了支架起皱的传导轮廓,使在小血管内的可操作性变小。并且,植入血管后内表面直接被通过支架的血流冲洗,导致支架内表面释放的药物流失在系统循环中。所以,在图3和图4所示的实施方案中,凝固的聚合物和活性剂大部分被涂在支架支撑的圆周的外面,其次是在侧面上。在一个优选的实施方案中,仅最小量的聚合物和活性剂被涂在支架的内表面。若需要,也可至少有一部分支架内表面不被涂层或裸露。
此外,图3和图4的涂层也可以有选择地涂到支架丝的表面。涂层的厚度应与用于组织中的生物活性涂层的体积相对应。限制一些范围的涂层是有利的,因为这些范围的涂层会导致放支架时的高损伤。
先在支架的表面均匀地涂上底层,以促进含生物活性剂涂层与支架的粘合,和/或帮助稳定在支架上的聚合物涂层。最初的涂层可以用本领域已知的任何方法涂层,或用本发明的精确给料系统涂层。使用不同的聚合物材料涂最初的涂层也在本发明内,如使用聚对亚苯基二甲基(聚(二氯-对-二甲苯)),或任何其他可以使金属底材和含生物活性剂的涂层能很好粘合的材料。聚对亚苯基二甲基(聚(二氯-对-二甲苯))可以采用等离子沉积或蒸气沉积技术,此技术是本领域公知的(见美国专利6,299,604)。在本发明的一个实施方案中,含肝素的不连续或连续的涂层涂在支架的内表面,而含本发明上述抗增殖药物的涂层涂在支架外表面。
当需要在金属支架底材上形成具有高的药物/聚合物底材比例,如药物含量占涂层重量40-80%的涂层时,最好在支架丝上涂一底层来稳定并牢固地将涂层粘在底材上。在沉积涂层材料前,底层可通过在一种合适的溶剂中溶胀来进一步处理,溶剂可以是例如丙酮、氯仿、二甲苯或它们的混合物。在实施例5中描述了该方法,用于制备具有高的依维莫司/聚-dl-丙交酯比例的支架。
其中,通过等离子沉积法在支架丝上形成聚对亚苯基二甲基底层,然后将该底层在二甲苯中溶胀,最后沉积涂层材料。该方法可用于生产在聚-dl-丙交酯聚合物底材中含50%药物或75%药物的涂层,涂层厚度仅为5-10微米。
如上所述,使用本发明的涂层系统生产完全可生物降解的支架也在本发明的范围内。先用顶部开放的“C-形”螺旋状槽以将要制造的支架形状制一个管状预制件,可以用给料系统向该槽内注入聚合物。预制件的外径是开放的,以便聚合物可被放入预制件中,通常用注射管的一个通道,若需要也可有多个;并同时建立支架均匀一致的边缘,因为聚合物会受预制件的限制。预制件可溶于一种溶剂中,但由此产生的可生物降解支架不溶于此溶剂。在注入聚合物并且聚合物溶液的溶剂已被蒸发后,可将装配组合放入可溶解预制件的溶液中,释放出完整的支架结构。用于制备预制件的有代表性的原料是蔗糖,它可以用标准的注塑技术制成希望的预制件形状。预制件的代表性溶剂是水。
第三部分、使用方法和性能特性
该部分描述了本发明的血管治疗方法和根据本发明所制的支架的性能特性。
A、方法
本发明的方法旨在减小有局部血管损伤或血管闭塞风险的患者再狭窄的危险和/或程度。典型的血管损伤是在血管造影术过程中打开部分闭塞的血管如冠状动脉或外周动脉时造成的。在血管造影术中,球囊导管被放于闭塞处,球囊远端充气和放气一或多次,迫使闭塞的血管打开。这种血管的扩张尤其涉及血管壁的表面创伤,可使其上的斑块移动,经常造成局部创伤,足以使血管随时间的过去而产生细胞增殖和再闭合反应。不奇怪,再狭窄的发生率和严重程度经常与血管造影术中所涉及的血管被牵拉的程度有关。特别是过度拉伸到35%或更高时,再狭窄的发生频率很高并且经常是很严重的,即血管闭塞。
在本发明的实践中,将支架以其收缩状态置于导管的远端,可以在导管腔内,或者以其收缩状态置于球囊的远端。然后将导管远端引导到损伤处或潜在闭合点并从导管上释放支架,例如,如果支架是自扩张型的,用拉发线释放支架到位点,或者,在球囊上通过球囊充气使支架扩张,直到支架与血管壁相接触,从而将支架植入血管壁组织。
图6显示了本发明的一个可完全生物降解的支架和将支架置入心血管系统的血管如冠状动脉内的导管。图中显示了部分放松状态的支架53,称作“药物螺旋支架”。该支架是自扩张的螺旋型支架,由聚乳酸形成并且含有一种或多种本发明的生物活性剂。
该螺旋支架用所述的预制件制成,预制件的最终扩张直径被设定为略大于用此螺旋支架治疗的血管内腔尺寸。除去预制件后,通过将药物螺旋支架的两端向反方向拧使其到较小半径,这样压缩其全长至一个可滑动鞘下,使螺旋的传输直径大约为最终扩张直径的1/3(在体温下)。药物螺旋支架的厚度足够小(约25-125微米),使其易于弯曲到更小的半径,形成与鞘的内径相当的压缩的螺旋。鞘被滑动地放在导管55上,该导管适于将压缩状态的支架导入目标血管。鞘54在其近端有一个把手56,通过它,血管成形术的操作者可以在导管尖端到达血管的适当位置时把鞘向后拉,从而完全释放药物螺旋。
导管55中央有一个直径约为0.014″的内腔,带有柔韧尖端58的导丝57可以在其内滑动。导管还有一个卢尔毂59,用于连接内腔到Y接头和止血阀,这是血管成形术领域公知的。有可滑动鞘的导管的外径范围在2-4F(法国尺寸);若治疗外周动脉会更大。
由于药物螺旋支架是可完全生物降解的,它不影响患者以后接受不复杂血管外科手术的机会,不像全金属衣那样。在某些神经和血管应用领域,裸金属螺旋支架放入血管中经常会产生血栓栓塞,甚至是完全闭塞,而令人惊奇的是,已经发现,已揭示结构中的生物相容性聚合物聚(dl-乳酸)(PDLA)及其混合物,可以提供合适的机械强度以支撑血管成形术后损伤的血管,并且不产生栓塞;因此是用于生产本发明药物螺旋支架的示例性材料。
支架一旦入位即开始释放活性化合物到血管内层的细胞中以抑制细胞增殖。图7A显示依维莫司从两个按照本发明制造的支架释放的动力学,每个支架有大约10微米厚的涂层(涂黑的正方形)。药物释放动力学是通过将支架浸入25%的乙醇溶液中得到的,该溶液可大大加快药物从支架涂层释放的速度。曲线图显示体内可预期的药物释放动力学,但经历的时间要长的多。
图7B显示从金属支架上的本发明涂层释放依维莫司的图形。上面的一组曲线显示直接涂到金属表面的涂层的药物释放。下面一组曲线(显示缓慢释放)是通过在金属支架表面先涂一层聚对亚苯基二甲基底层或初级涂层,然后再涂本发明的涂层系统所获得的。可以看出,涂有底层使涂层与支架表面的机械粘附增加,使可生物降解涂层的分解减慢,药物释放也减慢。当需要强粘附的支架涂层以经得住药物洗脱支架在导管和/或血管内弯曲操作时反复的磨损时;和/或需要支架置入后在置入部位药物释放的速度减慢以延长对动脉粥样硬化过程的治疗时,这样的结构是有用的。
图8显示一个横截面图,图中可以看到已植入一个支架62的血管区域60,所述支架的涂层丝例如丝64带有涂层66。该图显示抗再狭窄化合物从每个丝区域释放到周围的血管壁区域。经过一段时间,形成的血管壁的平滑肌细胞开始在支架内或穿过支架网或螺旋空隙生长,最后形成吞没支架双面的连续的内细胞层。如果支架植入是成功的,以后在支架位置的血管的闭塞程度将小于50%,即在血管内保持血流通道的横截面直径至少是植入时已扩张支架直径的50%。
在如Schwartz等人所述的猪再狭窄动物模型(“球囊血管成形术后再狭窄--一个猪冠状动脉的实用的增殖模型”,Circulation 82:(6)2190-2200,1990年12月)中进行的试验证实了本发明的支架限制再狭窄程度的能力,以及该支架优于现有的和经过测试的支架的优越性,尤其对严重的血管损伤的病例,即血管的拉伸大于35%的病例。研究在实施例4中进行了总结。
简言之,研究比较了几种支架在植入28天后再狭窄的程度,支架包括:裸金属支架、聚合物涂层支架、包含高或低浓度的雷帕霉素和依维莫司的聚合物涂层支架。
实施例4的表1显示雷帕霉素(Rapa-高或Rapa-低)和依维莫司(C-高或C-低)支架大大减少了再狭窄的水平,高剂量依维莫司支架的再狭窄最小。在低损伤动物研究中获得了同样的结果(表2)。
图9A-9C是植入裸金属S-支架(从加洲Bewport Beach的BiosensoresInternational Inc获得)后28天新生内膜的支架横断面图例。图10A-10C是聚合物涂层(无药)S-支架的新内膜形成的例子。图11A-11C和图12A-12C是依维莫司/聚合物涂层支架的新内膜形成。总的来说,依维莫司涂层支架所治疗的血管愈合良好,内皮层建立良好,28天血管完全愈合并达到血管稳态。图13是一个放大91倍的血管横断面,显示支架植入后28天血管腔内愈合和建立的内皮层。
照片显示,在28天消除再狭窄的最佳结合是C-高或C-U高(见实施例4),它们在18.7mm长的支架上分别含325mg和275mg依维莫司。对远系繁殖的幼猪随访28天的数据预测,与目前市场上的裸金属支架(S-支架)相比,再狭窄率减少50%。数据也显示,在同样的支架/聚合物传输平台上,依维莫司优于或至少相当于180mg雷帕霉素。形态度量分析(实施例4)支持这些结果。
图15显示了在动物实验中,血管被球囊过度拉伸(通过球囊/对动脉比率,即(B/A比率)来测量)和血管损伤的关系。该数据显示了用过度扩张的血管成形术球囊造成高度控制的血管损伤是在猪模型中造成可预测和已知的血管损伤的合理的精确方法。
图14显示选择涂到S-支架上的聚合物中的药物剂量的“最佳拟合”线性回归曲线,损伤度与随访时狭窄面积相关。“狭窄面积”是一个由形态度量分析确定的新内膜形成的精确指标。从图上可看出,在测试的样品组中仅高含量的依维莫司涂层支架相对损伤度增加显示负性斜率。此分析提示C-高涂层可能能够在损伤的冠状动脉中控制再狭窄,这实际上与损伤度无关。其它涂层配方均不能显示这一独特特性。
从前述中可以看到,本发明能满足多种目的,并有多种特性。
一方面,发明提供了含高药物/聚合物比率(例如,40-80%重量的药物)的可生物降解的支架涂层。这一特性使从低轮廓的支架可以在较长的时间内连续释放抗再狭窄化合物。同时,聚合物分解的成分例如在生物腐蚀过程中释放的乳酸酯和乳酸的总量相对较少,从而使可能的副反应例如由支架涂层的生物腐蚀引起的刺激减到最小。
另一方面,本发明提供了一种治疗或抑制再狭窄的改良的方法。该方法涉及大环三烯免疫抑制化合物在支架聚合物涂层中的新组合,该方法提供了至少与现有技术中最好的支架相同的抗再狭窄效果,另外还增加了优于现有技术的优点,即该方法的功效似乎与损伤的程度无关,并且该方法可以提供支架血管更大程度的内皮化。
最后,本发明提供了可完全生物降解的支架,该支架具有刚提到的优点,并且比金属支架在设计上更有灵活性,尤其是在支架总长度和已治疗血管的将来手术可能性方面。
以下实施例举例说明了本发明的支架制造和使用的各方面。但本发明不仅限于这些范围。
实施例1
依维莫司及其衍生物的制备
步骤A、2-(叔丁基二甲基硅烷基)氧基乙醇(TBS乙二醇)的合成
将154ml无水THF和1.88g NaH在氮气氛下在带有冷凝器的500ml圆底烧瓶中搅拌。向烧瓶中加入4.4ml无水乙二醇,搅拌45分钟后生成大量沉淀物。向烧瓶中加入11.8g叔丁基二甲基氯硅烷并继续剧烈搅拌45分钟。将形成的混合物倒入950ml乙醚中。用420ml盐水洗乙醚,溶液用硫酸钠干燥。将产物通过真空蒸发乙醚进行浓缩,然后通过快速色谱法用27x5.75cm充硅胶柱进行纯化,用己烷/Et2O(75∶25v/v)溶剂系统洗脱。将产品在0℃保存。
步骤B、2-(叔丁基二甲基硅烷基)氧基乙醇三氟甲磺酸酯(TBS乙二醇Trif)的合成
氮气氛及剧烈搅拌下,将4.22g TBS乙二醇和5.2g 2,6-二甲基吡啶在装有冷凝器的100ml双颈烧瓶中混合。在35-45分钟内缓慢加入10.74g三氟甲磺酸酐,生成黄棕色溶液。然后加入1ml盐水结束反应,溶液用100ml盐水洗5次,最终pH值为6-7。将溶液用硫酸钠干燥,在真空中蒸发二氯甲烷进行浓缩。将产物通过快速色谱法用24x3cm充硅胶柱进行纯化,用己烷/Et2O(85∶15v/v)溶剂系统洗脱,然后在0℃下保存。
步骤C、40-O-[2-(叔丁基二甲基硅烷基)氧基]乙基-雷帕霉素(TBS Rap)的合成
在50ml烧瓶中,将400mg雷帕霉素、10ml甲苯和1.9ml 2,6-二甲基吡啶混合并在55-57℃下搅拌。在另一个3ml的隔膜小瓶中加入1ml甲苯,再加入940μl 2,6-二甲基吡啶,接着加入2.47g的TBS乙二醇Trif。把小瓶内的混合物加到50ml的烧瓶中,反应在搅拌下进行1.5小时。向反应烧瓶中再加入480μL 2,6-二甲基吡啶和另加的1.236g TBS乙二醇Trif,继续搅拌反应1小时。最后再加入480μL 2,6-二甲基吡啶和1.236g TBS乙二醇Trif到混合物中,将混合物再搅拌1-1.5小时。将生成的棕色溶液用真空多孔玻璃过滤器过滤。用甲苯洗涤结晶状的沉淀物直到所有颜色被去掉。然后用60ml饱和NaHCO3溶液洗涤滤液2次,然后再用盐水洗。溶液用硫酸钠干燥,真空浓缩。用少量己烷/EtOAc(40∶60v/v)溶剂溶解产物,用33x2cm快速硅胶色谱柱纯化,用同样的溶剂洗脱。真空除去溶剂,将产物在5℃下存放。
步骤D、40-O-(2-羟基)乙基-雷帕霉素(依维莫司)的合成工艺
向耐热玻璃碟(150x75mm)中加满冰并放置在搅拌盘上。加入少量水。先在一个小的玻璃瓶中用8ml甲醇溶解60-65mg的TBS-雷帕霉素。向小瓶中加入0.8ml 1N的HCl,将溶液搅拌45分钟,然后加3ml饱和NaHCO3水溶液进行中和。向溶液中加入5ml盐水,然后加入20ml EtOAc,产生两相的混合物。混合两相,再用分液漏斗排掉水层。剩下的溶液用盐水洗直到最终pH为6-7,然后用硫酸钠干燥。用多孔玻璃过滤器除去硫酸钠,然后真空蒸除溶剂。将得到的浓缩物溶于EtOAc/甲醇(97∶3)中,然后用23x2cm快速硅胶色谱柱纯化,用同样的溶剂洗脱。真空除去溶剂,将产物在5℃下存放。
实施例2
制备在聚-d,l-丙交酯涂层中含依维莫司的支架
在室温下将100mg的聚-d,l-丙交酯溶于2ml丙酮。将5mg依维莫司放在小瓶中,加入400μL丙交酯溶液。用微处理器控制的注射泵精确给料10μL含药物的丙交酯溶液到支架支柱的顶面。溶剂蒸发后在支架上产生均匀的含药物的单一聚合物层。
以同样的方法将15μL溶液涂到支架支柱的顶面和侧面,产生涂在支架支柱顶部和侧面的单层涂层。
实施例3
在体外从在聚-d,l-丙交酯涂层中含依维莫司的支架上释放药物
将涂层支架放入2ml pH7.4的含25%ETOH的磷酸盐缓冲液中,用0.05%(w/v)叠氮化钠防腐并将温度维持在37℃,构建体外药物释放。定时抽出全部缓冲液进行取样以进行药物测量,同时放入同体积的新的缓冲液(无限沉淀)。图7图示了从2个用此方法涂单一聚合物涂层的相似支架的药物释放情况。
实施例4
动物植入实验
A、猪的安全性和剂量研究的QCA结果
基本原理:
正如所知,药物洗脱支架治疗最具挑战性的病症是严重损伤的血管,因为已知血管损伤程度的增加直接导致再狭窄(新内膜形成)程度的增加。实验是在猪身上进行的,药物涂层支架植入的靶血管用血管成形术球囊严重损伤(血管过度拉伸损伤平均约36%)。这引起血管内膜层和中间层的严重撕裂和拉伸,导致植入支架28后的血管充溢再狭窄。用这种方法,可以在同一金属支架/聚合物平台上评估各种不同剂量的药物以及药物与聚合物的不同重量比率在支架植入28天后对减少再狭窄的相对有效性。
缩写:
“裸支架”指18.7mm裸金属波纹环支架(即,目前市场上由BiosensorsIntl.Inc制造的“S-支架”);
“C-高”指18.7mm的支架,在PDLA(聚-dl-乳酸)聚合物涂层中含有325mg的依维莫司。
“C-低”指18.7mm的支架,在PDLA聚合物涂层中含有180mg依维莫司。
“雷帕霉素-高”指18.7mm的支架,在PDLA聚合物涂层中含有325mg雷帕霉素。
“雷帕霉素-低”指18.7mm的支架,在PDLA聚合物涂层中含有180mg雷帕霉素。
“C-U高”指18.7mm的支架,在极薄的PDLA聚合物涂层中含有275mg依维莫司(药物与聚合物的重量比是37%)。
“C-U低”指18.7mm的支架,在极薄的PDLA聚合物涂层中含有180mg依维莫司或等同物(药物与聚合物的重量比是37%)。
“聚合物支架”指仅有PDLA聚合物涂层的18.7mm的S-支架。
“B/A”:最终扩张的球囊与动脉血管的比率,表示血管被过度拉伸的程度。
“平均内腔损失(MLL)”:植入时测量支架内腔3次,3次数据的平均值减去随访造影时3次测量的平均值的差,反映了支架内新内膜的形成量。
方法:
将由波状环的金属线网支架(即S-支架)和聚合物涂层组成的药物洗脱支架植入到远系繁殖的幼猪(也可植入犹卡塔小猪持续超过28天),涂层使用不同剂量的依维莫司或雷帕霉素。在植入时,用QCA(定量冠脉造影)测定植入支架前后的血管直径。在28天或在下表规定的更长时间,在安乐死之前对动物在支架区再做造影。
动物按许可的方案安乐死后,取出动物的心脏,用甲醛溶液加压注入冠状动脉。含支架的冠状动脉部分从心脏的表面被切除随后被固定在丙烯酸塑料板上,用钻石锯切割出横断面。含有血管最近端、中间、最远端的各50微米厚的丙烯酸材料切片经光学磨光后安装在显微镜的滑片上。
用一个带有数码像机的显微镜摄出安装在滑片上的血管横断面的高分辨率图象。图象按以下程序做组织形态分析。
使用计算机图象处理系统Image Pro Plus 4.0通过基于PC系统的A.G.Heinze显微镜进行组织形态的分析。
1、平均横截面面积和内腔厚度(由内膜/新内膜-内腔边划定的面积);新内膜(在内腔和内弹性薄层即IEL间的面积,当IEL消失,则为内腔和残留的中间膜或外弹性薄层EEL间的面积);中间(IEL和EEL间的面积);血管尺寸(由EEL圈定的面积,但不包括外膜面积);外膜面积(在周边外膜组织,脂肪组织和心肌以及EEL之间的面积)。
2、损伤度。为量化血管损伤的程度,使用以不同血管壁结构撕裂的长度和量为基础的评分。损伤度被计算如下:
0=完整的IEL;
1=IEL被轻度撕裂,暴露了表中层(较小损伤);
2=IEL被中度撕裂,暴露了更深的中层(中度切开);
3-EEL被撕裂,暴露了外层。mm2
下表是QCA分析的结果(测量由于再狭窄产生的平均内腔损失)。下表“新内膜面积”列中的数据显示了随访时从猪取下的血管和支架的形态学分析结果
表1“高损伤”实验的结果
装置说明 | (B/A)比(平均) | 随访时间 | 平均内腔损失(mm) | 新内膜面积(mm2) | 支架号 |
裸金属支架 | 1.33 | 28 | 1.69 | 5.89 | 31,39,40,45,47,50 |
聚合物涂层支架 | 1.36 | 28 | 2.10 | 5.82 | 32,41,43,48,51,60 |
R-高 | 1.39 | 28 | 1.07 | 3.75 | 42,44,49,65,69,73 |
R-低 | 1.42 | 28 | 0.99 | 2.80 | 52,56,61,64,68,72 |
C-高 | 1.37 | 28 | 0.84 | 3.54 | 54,55,59,63 |
C-低 | 1.36 | 28 | 1.54 | 3.41 | 53,57,58,62,66,70,74 |
C-U高 | 1.36 | 28 | 0.85 | 2.97 | 67,75,92,103 |
B、低损伤研究:
为进一步确定在轻度损伤的血管中依维莫司的最佳剂量,尤其是对简单的冠状动脉疾病和单一的未处理过病变的患者,植入依维莫司药物洗脱支架造成中度到低度的过度拉伸损伤(约15%)。用农场猪进行30天的实验,用成年尤卡塔小猪进行植入3个月的安全性研究。血管造影结果如下:
表2“低损伤”实验的QCA结果
装置说明 | (B/A)比 | 植入后的天数 | 平均内腔损失(mm) | 新内膜面积(mm2) | 支架号 |
裸金属支架 | 1.14 | 28 | 0.95 | 2.89 | 20,22,26,29 |
裸金属支架 | 1.13 | 90 | 76,80,84,87,91 | ||
C-U高 | 1.15 | 28 | 0.60 | 2.14 | 94,96,98,102 |
C-U低 | 1.09 | 28 | 0.49 | 2.26 | 93,95,97,100,101 |
C-U高 | 1.15 | 90 | 77,81,85,86,90 |
以上数据预示,依维莫司的C-U低或C-U高剂量可在低至中度损伤的血管中降低新内膜形成45-48%。
C、形态测量分析
用计算机测量每个支架内总的截面面积和在支架内形成的新组织(新内膜)的截面面积,计算出狭窄面积百分比。每种药物和聚合物配方的平均血管损伤度、新内膜面积和狭窄面积百分比(每一支架测量三张片子,取平均值),显示在下表中。
表3“高损伤”实验结果
装置说明 | 损伤度 | 随访时间 | 新内膜面积(mm2) | 狭窄面积(%) | 支架号 |
裸金属支架 | 1.9 | 28 | 5.89 | 0.72 | 31,39,40,45,47,50 |
聚合物涂层支架 | 2.11 | 28 | 5.82 | 0.70 | 32,41,43,48,51,60 |
R-高 | 2.10 | 28 | 3.75 | 0.55 | 42,44,49,65,69,73 |
R-低 | 1.90 | 28 | 2.80 | 0.43 | 52,56,61,64,68,72 |
C-高 | 1.89 | 28 | 3.54 | 0.38 | 54,55,59,63 |
C-低 | 2.1 | 28 | 3.41 | 0.53 | 53,57,58,62,66,70,74 |
C-U高 | 2.13 | 28 | 2.97 | 0.45 | 67,75,92,103 |
形态测量分析是在猪冠状动脉模型中测量支架内再狭窄的高度精确的方法。在高损伤的模型中,C-高配方在高度损伤实验28天时产生最低量的新内膜形成;而C-U高组有最高的损伤程度,但仍能维持低百分比的狭窄面积-0.45。因此,此数据独立的证实了QCA分析的发现,支持人体实验优选的配方应是C-U高。
D、组织学分析
将C-U高和雷帕霉素-低的幻灯片呈给一个有经验的心脏病理学家,对血管横切面新愈合的血管内腔的炎症、纤维素蛋白、内皮化情况进行审视。未发现由雷帕霉素和依维莫司洗脱支架引起的组织学变化有不同。总的来说,28天时血管已形成完好的内皮层恢复其平衡,达到完全愈合。图13是一个放大91倍的血管横断面例子,显示支架植入28天后血管内腔的愈合及内皮层的建立。
E、与已发表结果的比较
Carter等人已发表了使用Palmaz Schatz金属支架的雷帕霉素涂层支架在猪身上实验的结果。下表是已发表的Carter的结果和Biosensors实验结果的比较:mm
表-4
装置说明 | 血管过度拉伸(%) | 平均后期损失(mm) | 标准偏差(mm) | 新内膜截面面积(mm2) |
S-支架裸金属对照 | 33.5%±9.2% | 1.80 | ±0.5 | 7.6 |
S-支架仅涂聚合物 | 34.9%±4.8% | 2.02 | ±0.8 | 8.5 |
S-支架聚合物/雷帕霉素(325mg) | 32.9%±10.1% | 0.66 | ±0.2 | 3.27(对照的-57%) |
S-支架聚合物/依维莫司(325mg) | 36.8%±8.5% | 0.74 | ±0.3 | 3.61(对照的-50%) |
PS支架BARE*对照 | 10-20% | 1.19 | --- | 4.5 |
PS支架仅涂聚合物 | 10-20% | 1.38 | --- | 5.0 |
PS雷帕霉素洗脱支架*166mg | 10-20% | 0.70 | --- | 2.9(对照的-33.5%) |
PS雷帕霉素洗脱支架*166mg(缓释) | 10-20% | 0.67 | --- | 2.8(对照的-37.7%) |
PS雷帕霉素洗脱支架*450mg | 10-20% | 0.75 | --- | 3.1(对照的-31.1%) |
实施例5
高药物含量支架的制备
先用等离子沉积工艺在市售的14.6mm长的金属波状环支架(Biosensors Intl的S-支架,波状环设计)上涂上约2微米厚的聚对亚苯基二甲基“C”底层。然后将涂有聚对亚苯基二甲基的支架放在二甲苯中在环境温度下过夜。通过将100mg的聚乳酸(PDLA)溶解在2ml丙酮中制备含有50μg/μL PDLA的聚-d,l-乳酸储备液。
为了制备药物与聚合物的比率为50%的涂层支架,将5mg依维莫司溶于100μL PDLA储备液。另加20μL丙酮以促进溶液的分散。从二甲苯中取出支架,小心地把溶剂蘸干。在每个支架的外表面给料总共5.1μL涂层溶液。将支架在室温下干燥并置于干燥器中干燥过夜。由此使每个支架在212μg PDLA中含有212μg依维莫司。
为了制备药物与聚合物的比率为75%的涂层支架,将5mg依维莫司与33.3μL PDLA储备液混合。另加33.3μL丙酮使混合物溶解。按照以上描述从二甲苯中取出支架并蘸干。在每个支架的外表面给料总共2.8μL涂层溶液。将支架在室温下干燥并置于干燥器中干燥过夜。由此使每个支架在70μg PDLA中含有212μg依维莫司。
成品支架的依维莫司/PDLA涂层厚度为约5微米,或呈现浅乳白色外观,该涂层在顶面和侧面平滑分布并且与金属支柱表面牢固连接。
Claims (18)
1.一个用于放置在血管损伤部位以抑制该部位的再狭窄的血管内支架,其包含:
一个可径向扩张的、由连接的细丝形成的管状体,每个细丝均具有顶面、侧面和内部支撑表面,和
含有可抑制再狭窄的大环三烯免疫抑制药物和可生物降解的聚合物的可生物降解的药物释放层,其中药物的含量为所述药物释放层的40-80%(重量比),所述药物释放层仅涂在所述细丝的顶面和至少一部分侧面但不涂在其内表面。
2.权利要求1所述的支架,其还包含位于所述细丝和所述药物释放层之间的底层。
3.权利要求2所述的支架,其中所述的药物释放层由(i)20-60%(重量比)的聚-d1-丙交酯聚合物底材和(ii)40-80%(重量比)的抑制再狭窄的化合物组成,并且所述的底层是聚合物底层。
4.权利要求1所述的支架,其中所述的细丝由金属制成。
6.权利要求5所述的支架,其中X是-CH2。
7.权利要求1所述的支架,其中所述支架体的内表面涂有含有第二种药物的第二药物释放层。
8.权利要求1所述的支架,其中细丝顶面上的所述药物释放层的深度是不一致的。
9.权利要求1所述的支架,其中的管状体是可生物降解的。
10.权利要求1所述的支架,其中的管状体由聚L-乳酸制成。
11.一个用于放置在血管损伤部位以抑制该部位的再狭窄的可生物降解的血管内支架,其包含:
一个可径向扩张的、由连接的细丝形成的管状体,该管状体由聚L-乳酸制成,和
含有可抑制再狭窄的大环三烯免疫抑制药物和可生物降解的乳酸共聚物的可生物降解的药物释放层,其中药物的含量为所述药物释放层的40-80%(重量比),聚合物含量为所述药物释放层的20-60%(重量比)。
12.权利要求11所述的支架,其还包含位于所述细丝和所述药物释放层之间的底层。
13.权利要求12所述的支架,其中所述的药物释放层由(i)20-60%(重量比)的聚-dl-丙交酯聚合物底材和(ii)40-80%(重量比)的抑制再狭窄的化合物组成,并且所述的底层是聚合物底层。
14.权利要求11所述的支架,其中所述的药物释放层的厚度为3-20微米。
16.权利要求15所述的支架,其中X是-CH2。
17.权利要求11所述的支架,其中所述支架体的内表面涂有含有第二种药物的第二药物释放层。
18.权利要求11所述的支架,其中细丝顶面上的所述药物释放层的深度是不一致的。
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