CN1329088C - 用于降低局部缺血性损伤后的组织损害的方法和设备 - Google Patents

用于降低局部缺血性损伤后的组织损害的方法和设备 Download PDF

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CN1329088C
CN1329088C CNB2003801053561A CN200380105356A CN1329088C CN 1329088 C CN1329088 C CN 1329088C CN B2003801053561 A CNB2003801053561 A CN B2003801053561A CN 200380105356 A CN200380105356 A CN 200380105356A CN 1329088 C CN1329088 C CN 1329088C
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insulin
medicine
medical apparatus
implantable medical
therapeutic dose
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CN1723050A (zh
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弗兰克·利特瓦克
西奥多·L·帕克
约翰·F·尚利
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Microport Cardiovascular LLC
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Conor Medsystems LLC
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Abstract

一种用于局部递送治疗药物的方法和设备，降低了由于局部缺血而对心肌组织造成的损害。一种局部递送装置用于将治疗药物递送到给局部缺血性心肌组织供血的冠状动脉中。根据本发明的一个实施例，用于将胰岛素局部递送到心肌组织的可植入的医用装置包括治疗剂量的胰岛素，其包含在附于支架上的生物相容性聚合物中。该治疗剂量的胰岛素以一次治疗剂量并在一个有效给药周期内从该支架中释放出来，用以降低心肌组织的缺血性损伤。

Description

用于降低局部缺血性损伤后的组织损害的 方法和设备
相关申请的交叉引用
本申请要求2002年11月8日提交的美国临时申请第No.60/425,096号的优先权，以引用方式将其全部内容合并于本文中。
背景技术
流向血管床的血流减少或停止说明需要进行各种临床处理以对受危害的器官或组织进行立即干预并恢复对受危害器官或组织的充分灌注。不同的组织可以承受不同程度的局部缺血性损伤。然而，如果不进行再灌注，组织可能会发展成为不可逆的损伤并且细胞会坏死。
由于心脏组织变得缺少氧和能量，心脏组织的灌注受损(局部缺血)会导致心脏正常运行能力的减弱。永久性损伤与心肌经历的缺氧持续时间直接相关。当血液流向不足以支持正常的新陈代谢活性的细胞区域时，就会发生局部缺血。发生急性心肌梗塞(MI)之后的外科和经皮腔内的血管再形成技术在针对心肌组织缺血方面的治疗是非常有效的。在发生急性心肌梗塞(MI)时，大量的血流被冠状动脉中的血栓堵塞，而组织只能通过例支血管来进行灌注。如果局部缺血的情况持续较长的时间，则对局部缺血区域内细胞的损害会发展成为不可逆的损伤和细胞坏死。再灌注是用来描述对局部缺血组织进行血流再建和进行供氧行为的术语。再灌注对局部缺血区域内细胞的继续存活是必需的。再灌注可以通过血流的再通疗法来完成，通常包括以下疗法之一：冠状动脉成形术、使用溶栓药物、冠状动脉搭桥术、或类似疗法。
对局部缺血性心肌进行及时的再灌注可以限制栓塞的大小，并且早期的伴随血管成形术和溶栓疗法的再灌注具有降低心肌损害、改善心室功能、降低急性心肌梗塞患者死亡率的益处。然而，对心肌的救治也会带来一些并发症，如冠状动脉再梗阻和严重的冠状动脉狭窄后遗症。
不能单独依靠对缺血性心肌进行再灌注来恢复心肌的所有功能。事实上，众所周知，再灌注本身会对幸免于缺血状况的很多细胞造成损害。研究表明，再灌注会加速受到不可逆损伤的心肌的死亡，还可能威胁到被危害的但通过再灌注救治仍然可以生存的心肌细胞的存活。这些所谓的再灌注损伤可能占最终的梗塞范围的百分之五十以上。多种细胞机理被认为是降低局部缺血性再灌注损伤的主要原因。因此，对保护局部缺血后心肌的辅助治疗的开发和使冠状动脉再灌注的益处最大化已经成为现代心血管研究的主要目标。
能够使局部缺血性损害或再灌注损害最小化并抑制缺血性损害或再灌注损害的化合物(药物)是重要的治疗药物。在过去几年里已经证明，通过向局部缺血后的心脏组织递送优化能量传递的药物可以进一步降低心肌梗塞和再灌注之后的死亡率。例如，在急性心肌梗塞之后向动脉灌注和再灌注葡萄糖、胰岛素和钾的组合物(GIK)对已经损伤的但还有生存能力的心肌组织是有效果的，并且降低了死亡率。
研究表明：通过动脉灌注GIK产生的高水平的胰岛素，可以改善局部缺血和局部缺血后的心肌的收缩和舒张功能，同样还可以改善冠状动脉的血管舒张。此外，胰岛素的供给还可以保持和恢复心肌糖元的储存量。GIK还降低动脉中游离脂肪酸(FFAs)的循环水平和心肌的FFA摄取量。高的FFA水平对局部缺血性心肌是有害的，并且是与膜损害的增加、心律失常和心脏功能的降低相关的。因此，有很多有关胰岛素可以降低局部缺血性损伤的机理。然而，当通过动脉灌注将胰岛素递送到全身时，胰岛素会刺激全身对葡萄糖和钾的摄取，致使血管中葡萄糖和钾的水平降低到会导致低血糖和低血钾的不安全的水平。因此，GIK疗法包括在进行胰岛素给药的同时，也进行葡萄糖和钾的给药，以减轻进行全身胰岛素给药所带来的不希望的副作用，并且需要仔细监控葡萄糖和钾的水平。
通常，用于降低急性心肌梗塞后组织损害的药物是通过全身递送的，例如通过动脉灌注。这些治疗药物的全身递送有显著的缺点，包括需要额外使用保护剂，用以防止由全身递送所引起的对非目标组织的损害，比如在灌注胰岛素时需要进行葡萄糖和钾的递送。其他的缺点还有，需要进行连续的给药和监控、对缺血性区域进行最适度以下的递送、患者的不适感、全身递送所需要的高剂量、以及高剂量和全身递送引起的副作用。
发明内容
本发明涉及局部递送降低由局部缺血引起的心肌组织损伤的治疗药物。将治疗药物局部递送到心肌组织并经过一个足够的给药周期，用以达到降低心肌组织缺血性损伤的目的。
根据本发明的一个方面，一种用于降低在缺血性损伤之后降低组织损害的方法，包括：确定血管内的植入部位；将可膨胀医用装置递送到血管中所选定的植入部位，该医用装置含有保持心肌细胞活力的药物；将该医用装置植入在植入部位；并且将治疗药物从可膨胀医用装置中局部递送到植入部位的组织和植入部位下游的血管中，经过一足够的给药周期，用以降低周围心肌细胞的局部缺血性损伤。
根据本发明的另一个方面，一种局部递送胰岛素到心肌组织用以降低心肌梗塞和再灌注之后的组织损害的方法，包括：确定血管内的闭塞部位；对该闭塞部位进行治疗用以完成再灌注；并且将胰岛素局部递送到被治疗的闭塞部位的组织或其附近的组织以及闭塞部位的下游，用以降低局部缺血性损伤。
根据本发明的又一个方面，一种用于局部递送胰岛素到心肌组织的可植入医用装置，包括：用于植入在冠状动脉内的可植入医用装置，以及在附于可植入医用装置上的生物相容性聚合物内的治疗剂量的胰岛素，其中该治疗剂量的胰岛素是以治疗剂量并在有效的给药周期内被释放到心肌组织，用以降低心肌组织的局部缺血性损伤。
根据本发明的再一个方面，一种用于局部递送治疗药物到心肌组织的可植入医用装置，包括：用于植入在冠状动脉内的可植入医用装置，以及用于治疗在急性心肌梗塞之后的局部缺血性损伤的治疗剂量的治疗药物。该治疗药物是以这样的方式附于可植入医用装置的，使得该治疗药物以治疗剂量并在有效的给药周期内被释放到心肌组织，用以降低心肌组织的局部缺血性损伤。
根据本发明的另一个方面，一种用于局部递送胰岛素到心肌组织的支架，包括：用于植入在血管内的基本上为圆柱形的可膨胀装置主体，以及在附于该可植入医用装置主体上的生物相容性聚合物内的治疗剂量的胰岛素。
附图说明
现在，将通过参照在附图中所举例说明的优选具体实施方式来对本发明进行更为详细的描述，在图中，类似的元件具有类似的附图标号，其中：
图1是植入在动脉腔内的可膨胀医用装置的部分剖视透视图，该医用装置装有用于递送到动脉腔中的治疗药物；
图2是可膨胀医用装置的透视图，显示出有许多开口；
图3是图2中的可膨胀医用装置的部分侧视放大图；
图4是一个开口的放大剖视图，示出了用于直接递送到血管腔的治疗药物；
图5是一个开口的放大剖视图，示出了设置用于递送到血管腔的第一治疗药物，和设置用于递送到血管壁的第二治疗药物；以及
图6是一个开口的放大剖视图，示出了用于递送到血管腔的第一治疗药物和第二治疗药物。
具体实施方式
本发明涉及用于治疗急性局部缺血性综合症(包括急性心肌梗塞)的方法和设备。这些方法和装置用于将治疗药物局部递送到心肌组织，用以限制局部缺血性损伤中的坏死区域。治疗药物的局部递送避免了对全身递送的需求和与之相关的对保护性药物的额外给药的需求，因而避免了对非目标组织的损坏。
首先，如在本文中所使用的，以下术语具有下列含义：
术语“药物”和“治疗药物”可互换使用，是指任何治疗性活性物质，该物质被递送到活体的体内导管，用以产生所需要的、通常是有益的效果。
术语“基质”或者“生物相容性基质”可互换使用，是指在受治疗者体内的植入物上的介质或材料，其并不引起足以导致排斥基质的有害反应。该基质本身通常不提供任何治疗反应，虽然该基质可以含有或者包裹治疗药物、和/或调节治疗药物在体内的释放。基质还是一种仅用来提供支撑、结构整体性或结构屏障的介质。该基质可以是聚合物的、非聚合物的、疏水的、亲水的、亲脂的、两亲的、以及类似物质。该基质可以是生物可吸收的或者是非生物可吸收的。
术语“生物可吸收的”是指一种基质，如在本文中所定义的，其可以在与生理环境相互作用的基础上，通过化学或物理过程而被分解。该基质可以受腐蚀或溶解。一种生物可吸收的基质在体内发挥暂时性作用，例如药物递送，然后在从几分钟到几年，优选少于1年的时间间隔内降解或被分解成可代谢或可排泄的成分，同时在相同的时间间隔内保持必要的结构完整性。
术语“局部缺血”是指由流至受影响的组织的血液受阻塞而产生的局部组织缺氧。
如在本文中所使用的，术语“局部缺血性损伤”是指由于受阻塞的血液流动而引起的损伤和除去阻塞而引起的再灌注损伤。
术语“开口”包括通孔和凹口。
术语“药学上可接受的”是指对移植接受体或患者无毒并且适用于保持有益药剂的稳定性和允许有益药剂递送到目标细胞或组织的特性。
术语“聚合物”是指两个或多个被称为单体的重复单元经化合而形成的分子。因此，包括在术语“聚合物”内物质的可以是，例如，二聚物，三聚物和低聚物。该聚合物可以是合成的，天然存在的或半合成的。在优选的形式中，术语“聚合物”是指这样的分子，其分子量Mw通常大于3000，优选大于约10,000，并且其分子量Mw小于约一千万，更优选小于约一百万，最优选小于约200,000。聚合物的实例包括但不限于，聚-α-羟基酸酯，如，聚乳酸(polylacticacid)(PLLA或DLPLA)、聚羟基乙酸、聚(乳酸-共-羟基乙酸)(PLGA)、聚(乳酸-共-己内酯)；聚(嵌段-环氧乙烷-嵌段-丙交酯-共-乙交酯)、聚合物(PEO-嵌段-PLGA和PEO-嵌段-PLGA-嵌段-PEO)；聚乙二醇和聚环氧乙烷、聚(嵌段-环氧乙烷-嵌段-环氧丙烷-嵌段-环氧乙烷)；聚N-乙烯基吡咯烷酮；聚原酸酯；多糖和多糖衍生物(如聚透明质酸、聚葡萄糖、聚藻酸、几丁质、脱乙酰壳多糖、脱乙酰壳多糖衍生物、纤维素、甲基纤维素、羟乙基纤维素、羟丙基纤维素、羧甲基纤维素、环糊精和取代的环糊精(如β-环糊精磺基丁基醚)；多肽和蛋白质(如多熔素、聚谷氨酸、白蛋白)；聚酐；烷基羧酸多羟基酯(如戊酸多羟基酯、丁酸多羟基酯)、以及类似物质。
与直接递送有关的术语“主要是”是指数量大于提供给血管的有益药剂总量的约50％。
术语“再狭窄”是指血管成形术过程之后动脉的再狭窄，其可以包括支架植入之后的狭窄。
用于局部递送药物用以保存心肌细胞活力的方法
当将支架形式的可植入医用装置直接植入到先前发生过闭塞的血管部位或其附近时，该支架形式的可植入医用装置能够用来将治疗药物递送到在植入部位和植入部位下游的心肌组织中。在局部缺血性损伤部位的药物的局部递送，通过降低对心肌细胞的局部缺血性损伤(其包括流到局部缺血组织的血液向上返回就可能发生的再灌注损伤)，从而提高了细胞的活力。在通过血管成形术进行再灌注治疗的情况下，经常将支架递送到重新打开的闭塞部位。可以将用于递送治疗局部缺血性损伤的治疗药物的药物递送支架在血管成形术之后以传统方法植入在植入部位。在再灌注治疗之后在闭塞部位或其附近植入的用于递送治疗药物的药物递送支架提供了以下优点：降低了局部缺血性损伤(其包括减少再灌注损伤)，而且没有与治疗药物的全身递送相关的困难。
再灌注损伤的代谢机理还不完全清楚。缺氧和代谢产物的积累改变了组织中的能量转移。在再灌注之后，葡萄糖的氧化如收缩功能那样保持下降的状态。另外，由于炎症反应也可出现再灌注损害。再灌注的局部缺血组织吸引白细胞，这些白细胞释放蛋白水解酶和氧化剂，这些蛋白水解酶和氧化剂依次引起最终复原和结疤之后的进一步发炎。因此，抑制炎症反应的抗炎药能够减少再灌注损伤。蛋白酶抑制剂、抗氧化剂、血管扩张剂和其它的保心药也可以提高再灌注之后的组织功能。当将血管扩张剂递送到急性或非急性闭塞的下游时，血管扩张剂能够膨胀血管直径，从而增加流到局部缺血区域的血液。
特别适用于降低急性心肌梗塞之后的局部缺血性损伤或者其它的局部缺血性损伤的药物，包括但不限于：血管扩张剂，如阿糖腺苷和双密达莫；氧化一氮供体；前列腺素及其衍生物；抗氧化剂；膜稳定剂；抗-TNF复合剂；抗炎药，包括地塞米松、阿斯匹林、哌非尼酮、甲氯芬那酸和曲尼司特；(抗)高血压药物，包括β阻断剂，ACE抑制剂和钙通道阻断剂；抗代谢物，如2-CdA；血管活性物质，包括血管活性肠多肽(VIP)；胰岛素；对胰岛素的细胞增敏剂，包括格列酮类，P蛋白酶激活受体激动剂(P par agonists)和二甲双胍；蛋白质激酶；反义寡核苷酸，包括resten-NG(第三代NEUGENE反义药物)；免疫抑制剂，包括西罗莫司、everolimus(一种雷帕霉素靶蛋白抑制剂)、他克莫司、依托泊苷和米托蒽醌；抗凝血酶；抗血小板的药物，包括替罗非班、表非替得和阿昔单抗；保心药，包括VIP、垂体核苷酸环化酶激活的多肽(PACAP)、apoA-I milano(一种apo A-I的变异体、一种高密度酯蛋白)、阿洛地平、尼可地尔、cilostaxone和噻吩并吡啶；抗白细胞药物(anti-leukocytes)；环加氧酶抑制剂，包括COX-1和COX-2抑制剂；以及提高糖酵解(glycolitic)代谢的petidose抑制剂，包括omnipatrilat。
也可以使用与可膨胀医用装置结合的、基于基因治疗的方法来进行用于治疗局部缺血性损伤的药物的递送。基因治疗是指将外源基因递送到细胞或组织，从而导致目标细胞对外源基因产物进行表达。通常通过机械方法或载体介导的方法进行基因的递送。机械方法包括但不限于，直接DNA显微注射、弹道DNA颗粒递送、脂质体介导的转染和受体介导的基因转移。载体介导的递送通常涉及到重组病毒基因组，包括但不限于，逆转录酶病毒、腺病毒、腺相关病毒、疱疹病毒、牛痘病毒、细小核糖核酸病毒、α-病毒和乳多空病毒。
根据本发明的一个方面，在急性心肌梗塞(MI)和再灌注之后，将支架或其它局部递送装置用于胰岛素的局部递送。胰岛素是一种提高糖酵解(glycolic)代谢和ATP生成的激素。胰岛素还可以用作血管扩张剂、抗炎药和抗血小板药物。因此，胰岛素通过某些机理起作用，以便通过减少发炎、减缓局部缺血性坏死的速度、降低FFA的循环水平和心肌的FFA摄取、恢复心肌肝糖储备和改善收缩功能来降低梗塞的范围。
用在本发明中的胰岛素可以是人胰岛素、非人胰岛素、或合成胰岛素，可以是完整的胰岛素或胰岛素片断。优选的胰岛素是稳定的、耐辐射的短效形式。晶体形式的胰岛素可以用来改善对辐射的抗性。当将胰岛素与聚合物结合时，可以加入一种药物用以其保护生物活性。已经发现：当在聚(丙交酯-共-乙交酯)(PLGA)中递送胰岛素时，胰岛素至少在24小时的给药周期内保留其生物活性。对于更长的给药周期，可以用抗酸剂或其它药物来保持所需要的pH以便达到来自PLGA基质的持续的生物活性。
在一个实施例中，胰岛素可以与水凝胶或原水凝胶基质结合。将胰岛素/水凝胶装载入支架的开口中，并使之脱水。该水凝胶的再水合作用导致水凝胶膨胀，并使得胰岛素从水凝胶中释放出来。
尽管在本文中已经描述了自支架中的胰岛素递送主要是用于递送到血管腔以便降低局部缺血性损伤，但是也可以将胰岛素从支架壁上递送用来治疗再狭窄。
根据本发明的另一个方面，使用支架或其它局部递送装置用于在急性心肌梗塞(MI)和再灌注之后进行VIP的局部递送。VIP是一种在心肌梗塞期间由心脏自然释放的并且对心脏起保护作用的神经肽。VIP用作血管扩张剂、血小板抑制剂和抗增生剂。VIP通过抑制促炎剂的生成并刺激在激活的巨噬细胞中的抗炎细胞因子的生成而起作用。
在本发明的一种具体实施方式中，在心肌梗塞或其它急性局部缺血性综合症之后，将适于降低局部缺血性损伤的药物递送到重新打开的闭塞部位或其附近。在先前的闭塞部位或其附近的药物的递送使得该药物通过下游的血液流动而递送到再灌注组织。如下所述，该药物可以通过在其开口中容纳有药物的支架来进行递送。该药物还可以通过用药物涂布的支架、植入物、微球体、导管、螺管或其它局部递送装置来进行递送。
例如，可以用导管或药物递送支架将微球体、螺管、脂质体或其它的小药物载体局部递送到先前的闭塞部位或其附近。这些小的药物载体被释放并且通过顺流而下而进入心肌，在心肌中它们可以进行自植入，并且直接将药物释放到局部缺血组织。
该药物可以在给药周期内进行释放，给药周期取决于被递送的药物的作用方式。例如，可以在从几分钟到几个星期的给药周期内递送胰岛素，优选在至少1小时内，更优选在至少2小时内，以及更优选在约10-48小时期间内递送胰岛素。在另一个实施例中，可以在几秒钟到几分钟的更短的给药周期内递送快速作用的血管扩张剂，如阿糖腺苷或其衍生物。
在一个实施例中，将用于降低局部缺血性损伤的药物从支架上主要是以内腔方向递送，而使得从支架上以管壁方向直接递送的药物最小化。在与血管成形术过程连续进行时，可以将这个支架单独放置在闭塞处或者也可以与另外一个支架(裸露支架或者药物递送支架)一起放置。可以将用于递送治疗局部缺血性损伤药物的支架放置在另一个先前放置的支架之内或附近。支架植入部位可以在闭塞部位或附近。植入部位也可以选择在斑破裂部位或脉管狭窄部位的位置。
除了用于降低局部缺血性损伤主要是由支架的腔侧递送的第一药物之外，本发明还特别适用于主要是由支架的壁侧递送的第二治疗药物的递送。主要是由壁递送的药物可包括抗肿瘤药、抗血管生成药物、血管生成因子、抗再狭窄药、抗血栓形成药如肝素钠、抗增生药如紫杉醇和雷帕霉素以及它们的衍生物。
在一个双药物的实施例中，适用于降低局部缺血性损伤的药物主要是从支架的腔进行递送，而适用于治疗再狭窄的药物主要是从支架的壁进行递送。在一类似的实施例中，在第一给药周期内(例如在约1至24小时的期间内)以第一递送速率进行用于降低局部缺血性损伤的第一药物的递送，而在第二给药周期内(例如在约2天或更长的期间内，优选在约3天或更长的期间内，更优选在约10天或更长的期间内)以第二递送速率进行用于治疗血管再狭窄的第二药物的递送。
在另一双药物递送实施例中，两种用于治疗局部缺血性损伤的药物都是主要是以腔方向进行递送的。根据不同的药物作用方式，两种药物可以在不同的给药周期内进行递送。例如，可以在几分钟的短时间内递送快速起作用的药物，而在几小时或几天内递送起作用较慢的药物。
在另一个实施例中，将适用于降低局部缺血性损伤的治疗药物与一种或几种全身递送的治疗药物结合，用来进行局部递送。例如，当将胰岛素局部递送到先前闭塞的血管部位时，如果需要的话可以进行葡萄糖和/或钾的全身递送。然而，(此时)进行全身葡萄糖和/或钾给药所需的量比在进行全身胰岛素给药的情况下所需的量少很多。另外，可以通过相同的药物(如胰岛素)递送支架或者通过另一种局部递送载体，如另一个支架、导管或植入物，来进行葡萄糖和/或钾的局部递送。
虽然本发明使用的一些药物可以主要是以腔方向进行输送、或者主要是以壁方向进行输送、或者通过这两种方式进行输送，但是这些药物并不限于在本文中提到的单一药物或与在本文中提到的任何其它治疗药物的组合，其包括：抗增生药、抗凝血酶、免疫抑制剂、抗脂药物、抗炎药、抗肿瘤药、抗血小板药、血管生成药物、抗血管生成药物、维生素、抗有丝分裂物质、金属蛋白酶抑制剂、NO供体、雌二醇、抗硬化药物，以及血管活性药物、内皮生长因子、雌激素、β阻断剂、AZ阻断剂、激素、抑制素、胰岛素生长因子、抗氧化剂、膜稳定药物、钙拮抗剂、类维生素A(类维甲酸retenoid)、比伐卢定、phenoxodiol、依托泊苷、噻氯匹定、双密达莫和曲匹地尔(唑嘧胺)。此外，该治疗药物还包括肽、脂蛋白、多肽、多核苷酸编码的多肽、脂类、蛋白质类药物、蛋白质结合药物、酶、寡核苷酸及其衍生物、核酶、其它遗传物质、细胞、反义寡核苷酸、单克隆抗体、血小板、朊病毒、病毒、细菌、以及真核细胞，其是用诸如内皮细胞、干细胞、ACE抑制剂、单核细胞/巨噬细胞或血管平滑肌细胞命名的，但上述只是很少的一些实例。该治疗药物还可以是一种药物前体，当将该药物前体施于宿主时，其被代谢成为所需的药物。另外，还可以在将治疗药物结合入治疗层之前，将其预制成微胶囊、微球体、微泡、脂质体、多层囊泡(niosomes)、乳液、分散体或类似物。治疗药物还可以是放射性同位素或某些药物，该药物是通过某些其它形式的能量如光能或超声波能量激活的、或是通过可以进行全身给药的其它循环分子激活的。治疗药物可以发挥多重作用，包括对血管生成、再狭窄、细胞增生、血栓形成、血小板凝聚或凝结、血管舒张进行调节。抗炎药包括：非甾族抗炎药(NSAID)，如芳族乙酸衍生物，例如，双氯酚酸；芳族丙酸衍生物，如，甲氧萘丙酸；以及水杨酸衍生物，例如，阿斯匹林、二氟苯水杨酸。此外，抗炎药还包括：糖皮质激素(类固醇)，如地塞米松、泼尼松龙和氟羟泼尼松龙。抗炎药可以与抗增生药结合使用以便减轻对于抗增生药的组织反应。
在本文中描述的某些药物可以与保持其活性的添加剂结合使用。例如，这些添加剂包括表面活性剂、抗酸剂、抗氧化剂、以及可以用来使蛋白质药物(如胰岛素)的变性和凝聚最小化的洗涤剂。可以使用阴离子洗涤剂、阳离子性洗涤剂或非离子洗涤剂。非离子添加剂的实例包括但不限于：糖类，包括山梨糖醇、蔗糖、海藻糖；右旋糖苷类，包括右旋糖苷、羧甲基(CM)右旋糖苷、二乙氨基乙基(DEAE)右旋糖苷；糖类衍生物，包括D-葡糖胺酸和D-葡萄糖二乙基缩硫醛；合成聚醚类，包括聚乙二醇(PEO)和聚乙烯基吡咯烷酮(PVP)；羧酸类，包括D-乳酸、羟基乙酸和丙酸；对疏水界面具有亲和力的洗涤剂，包括正-十二烷基-β-D-麦芽糖苷、正-辛基-β-D-葡糖苷、PEO-脂肪酸酯类(如硬脂酸酯(密尔吉59)或油酸酯)、PEO-脱水山梨糖醇脂肪酸酯类(如吐温80(Tween 80)、PEO-20脱水山梨糖醇单油酸酯)、脱水山梨糖醇脂肪酸酯(如斯潘60(Span 60)、脱水山梨糖醇单硬脂酸酯)、PEO-甘油脂肪酸酯；甘油脂肪酸酯类(如甘油单硬脂酸酯)、PEO-烃基醚类(例如PEO-10油烯基醚)；曲通X-100(triton X-100)；以及脂肪醇[烷基酚]乙氧基加成物。离子型洗涤剂的实例包括但不限于：脂肪酸盐，包括硬脂酸钙、硬脂酸镁和硬脂酸锌；磷脂，包括卵磷脂和磷脂酰胆碱；CM-PEG；胆酸；十二烷基硫酸钠(SDS)；丁二酸二辛基磺酸盐(AOT)；以及牛磺胆酸(taumocholic acid)。
具有开口的可植入医用装置
图1示出了以支架形状植入在动脉100的腔116中的可膨胀医用装置10。动脉100的壁包括三个不同的组织层，内膜110、中膜112和外膜114。当可膨胀医用装置10被植入到动脉中的闭塞部位时，从该可膨胀医用装置释放到动脉100的腔116的治疗药物通过血液流动被局部分送到闭塞部位及下游的组织。
如图1～图3所示，一种可膨胀医用装置10的实例包括较大的不变形支柱12，该不变形支柱可以包括开口14，并且具有不损害该支柱、或作为整体的该医用装置的机械特性。可以通过使用有延展性的铰链(连接部)20而获得不变形支柱12，该铰链在美国专利第6,241,762号中进行了详细描述，将其全部内容以引用方式结合于本文中。开口14作为较大的保护性储存器用于将各种有益药剂递送至装置植入部位。
如上所述，相对较大的受保护的开口14使得本发明的可膨胀医用装置特别适于递送大量的治疗药物、更大分子的药物、或遗传药物、或细胞药物，以及用于药物的直接递送。在可膨胀器材10中的较大的不变形的开口14形成保护区域或接受器，以便于进行此类药物的装载，以及在递送和植入期间保护药物免受磨损、挤压或其它降解。
图1示出了用于治疗药物16定向递送的可膨胀医用装置。开口14包含有用于递送至血管腔116的治疗药物16以及在该开口的壁侧或其附近的可选的阻挡层18。
在相同的支架/管壁覆盖比下，能够用开口14递送的有益药剂的量大约比覆盖支架的5微米涂层的量大3至10倍。这种大得多的有益药剂容量提供了多种好处。更大的容量可以用来递送多种药物组合物，每种药物都具有独立的释放曲线(或外形，profile)，从而提高了效力。同样，更大的容量可以用来提供更大量的侵蚀性很小的药物，并达到临床效力而没有更强效药物所不希望的副作用，如内皮层的延迟愈合。
图4示出了医用装置10的部分剖视图，其中一种或多种有益药剂已经装入多重层中的开口14中。虽然示出了多重离散层以方便图示说明，但是该多重层可以是具有单独成分或混合成分的离散层以便形成连续的聚合物基质和药剂嵌体。例如，可以将这些层分别沉积在药物层、聚合物层、溶剂成分层中，然后通过溶剂的作用在开口中将其混合在一起。可以将药剂均匀地或以浓度梯度地分布在嵌体中。在于2002年6月27日公开的美国专利申请第2002/0082680号中描述了产生这样的层和层排列的一些方法的实例，将其全部内容以引用方式结合于本文中。在开口14中与聚合物结合的药物的使用使得将该医用装置10设计成具有与所需要的特定药物递送曲线相适应的药物释放动力学。
根据本发明的一个实施例，开口14的总深度是大约50至140微米，而典型的层的厚度是大约2至50微米，优选是大约12微米。因而每个典型的层分别是施于表面涂布支架的典型的涂层的2倍厚。在典型的开口中可以有至少2个这样的层，优选为约5至12个这样的层，而总的有益药剂的厚度比典型的表面涂层多大约4至28倍。根据本发明的一种具体实施方式，该开口的面积为至少5×10-6平方英寸，优选为至少10×10-6平方英寸。
在图4的实施例中，开口的壁侧设置有一阻挡层18，该阻挡层是聚合物层或其它材料层，具有足够慢的腐蚀速度使得在治疗药物层16中的所有治疗药物在该阻挡层完全腐蚀前基本上从开口的腔侧被递送完全。该阻挡层18防止了有益药剂在运输、储藏和在支架植入过程中的损失。然而，当该药物的壁递送和腔递送都可以接受时，可以将阻挡层18省略。
在一个实施例中，可以通过来自治疗药物层的不同溶剂中的可溶性物质形成阻挡层18和/或覆盖层22，用以避免各层的相互混杂。例如，当已经将溶剂中的治疗药物和基质的一层或多层(如在水中的胰岛素和PVP)沉积在开口中时，可以期望选择不同的聚合物和溶剂的组合(如在DMSO中的PLGA)用于阻挡层，以便防止治疗药物混入阻挡层中。可以通过第三种不相混合的聚合物和溶剂的组合(如在苯甲醚中的PLGA)来形成另外的层，如覆盖层。除了阻挡层和覆盖层之外，其它的治疗药物层、保护层或分离层也可以以这种方式由不相混合的聚合物/溶剂系统来形成。
可以提供覆盖层22，其作为在开口填充期间的密封。覆盖层22优选是快速降解的生物相容性材料。
由于独立形成了阻挡层18和治疗药物16的每一层，可以将单个化学成分和药物代谢动力学性能赋予每一层。可以形成此类层的众多有用的排列，下面将对其中一些进行描述。这些层的每一层都可以包括在层间的相同或不同比例的一种或多种药剂。可以用在层间的药物浓度变化来达到所需要的递送曲线。例如，可以达到在大约24小时期间内的药物的递减释放。在另一个实施例中，可以达到在最初的急剧释放之后的持续大约一周的稳定释放。还可以达到在从几个小时到几个月的一段时间内的基本上稳定的释放速率。这些层可以是固体的、多孔的、或由其它药物或赋形剂填充的。
图5是包括两种或多种治疗药物的可膨胀医用装置10的部分剖视图。如在图5中示出的双药物递送系统，能够针对不同的治疗条件或治疗条件的不同的阶段，以不同的方向递送两种或多种治疗药物。例如，双药物递送系统可以从同一药物递送装置的腔方向和壁方向递送不同的药物，用于治疗局部缺血和再狭窄。
在图5中，将一种抗再狭窄药物32设置于装置10的壁侧的一层或多层中，并将用于降低局部缺血性损伤的治疗药物36设置于在该装置腔侧的一层或多层中。可以在药物层之间提供分离层34。当两种药物的给药周期实质上不同，并且其中一种药物递送彻底完成而另一种药物还要继续递送时，分离层34是特别有用的。分离层34可以是任意的生物相容性材料，优选该材料是以等于或长于两种药物中较长的给药周期的时间速率进行降解的。
图6示出了可膨胀医用装置10，其包括由生物相容性基质和设置在基质中的第一药物和第二药物形成的嵌体40，该第一药物和第二药物用于根据不同的药物递送曲线来进行递送。如图6所示，在基质中设置了由○表示的具有浓度梯度的第一药物，使得该药物浓度在与开口的壁侧相邻的阻挡层18处最高，而在开口的腔侧处最低。由△表示的第二药物被相对富集在靠近开口腔侧的区域中。在图6中示出的这种结构导致两种药物以不同的递送曲线从同一嵌体40进行递送。两种不同的药物可以是以不同的作用方式来治疗局部缺血性损伤的药物，如胰岛素和VIP。
在上述的具体实施方式中，可以将治疗药物设置于在可膨胀医用装置中的生物相容性基质中。该基质可以是生物可降解的(如下所述的)，或者也可以是该装置的永久部分，治疗药物从该永久部分进行扩散。可以用一个或多个阻挡层、分离层和覆盖层来分离开口中的治疗药物，或者防止治疗药物在医用装置植入之前的降解或递送。
实施例
实施例1
在这个实施例中，通过以下方式用胰岛素装填药物递送支架，该支架基本上等同于在图2和图3中示出的支架，其具有约3mm×17mm的膨胀面积。将该支架定位在心轴上，并将一可选的快速降解层沉积在支架的开口中。设置在腔例的该快速降解层是低分子量PLGA，用来在运输、贮存和递送过程中保护其后的各层。在本文中所描述的各层是以滴加方式沉积的，并通过使用适宜的有机溶剂，如DMSO、NMP或DMAc而以液体形式递送。然后将胰岛素和低分子量PLGA基质的多个层沉积在开口中，以便形成药物嵌体从而用于降低局部缺血性损伤。将胰岛素和聚合物基质结合，并以这样的方式沉积，以便达到总药物的约70％在最初的大约2小时内释放，而约80％在大约8小时内释放，并且在大约24至48小时内基本上释放100％这样的药物递送曲线的目的。将中等分子量或高分子量的PLGA(一种慢降解聚合物)的阻挡层沉积在胰岛素层之上，用以防止胰岛素迁移到支架的壁侧和血管壁。对阻挡层的降解速率进行选择，以使覆盖层直至约24～48小时的给药周期之后才开始实质上的降解。
设置在支架上的胰岛素剂量为大约230毫克。该剂量已经基于报道的胰岛素的全身扩散研究进行过计算，该研究估计：在24小时期间内递送到心脏的胰岛素为大约10毫克。支架上的总药物剂量可以在从约5毫克至约800毫克，优选从约200毫克至约400毫克的范围内变化。
实施例2
在这个实施例中，通过以下方式用总剂量为约230毫克的胰岛素装填药物递送支架，该支架基本上等同于图2和图3示出的支架，其具有约3mm×17mm的膨胀面积。将该支架定位在心轴上，并将一可选的快速降解层沉积在支架的开口中。该快速降解层是PLGA。然后将胰岛素和一种PEO和PPO的泊洛沙姆嵌段共聚物(Pluronic F127)的多个层沉积在开口中，以便形成用于降低局部缺血性损伤的药物嵌体。将胰岛素和聚合物以大约33∶67的比例结合，并以实现类似于实施例1所述的药物递送曲线的方式来进行沉积。将高分子量PLGA的阻挡层(一种慢降解聚合物)沉积在胰岛素层之上，用以防止胰岛素迁移到支架的壁侧和血管壁。对阻挡层的降解速率进行选择，以使覆盖层直至约24～48小时的给药周期之后才开始实质上的降解。
实施例3
在这个实施例中，通过以下方式用总剂量为约230毫克的胰岛素和总剂量为约10～30毫克的紫杉醇来装填药物递送支架，该支架基本上等同于图2和图3示出的支架，其具有约3mm×17mm的膨胀面积。对阻挡层的降解速率进行选择，以使覆盖层直至约24～48小时的给药周期之后才开始实质上的降解。将支架定位在心轴上，并将一可选的快速降解层沉积在支架的开口中。该快速降解层是PLGA。然后将胰岛素和低分子量PLGA的多个层沉积在开口中，以便形成用于降低局部缺血性损伤的药物嵌体。将胰岛素和聚合物基质结合，并以实现类似于实施例1所述的药物递送曲线的方式来进行沉积。将高分子量PLGA的多个层(一种慢降解聚合物)和紫杉醇沉积在胰岛素层之上，用以防止紫杉醇递送到支架的壁侧和血管壁。对紫杉醇的再吸收速率进行选择，以使这些层在约2天或更多天的给药周期内持续递送紫杉醇。

Claims (41)

1.一种用于局部递送胰岛素到心肌组织的可植入医用装置，所述装置包括：
一种用于植入冠状动脉的可植入医用装置；以及
在附于所述可植入医用装置上的生物相容性聚合物中的治疗剂量的胰岛素，其中所述治疗剂量的胰岛素以一次治疗剂量并在一个有效给药周期内被释放到所述心肌组织中，用以降低所述心肌组织的局部缺血性损伤。
2.根据权利要求1所述的装置，其中所述可植入医用装置是一种在冠状动脉内的可膨胀支架。
3.根据权利要求1所述的装置，其中所述胰岛素和生物相容性聚合物是沉积在所述可植入医用装置的开口内。
4.根据权利要求1所述的装置，其中所述胰岛素和生物相容性聚合物是沉积在所述可植入医用装置的表面上。
5.根据权利要求1所述的装置，其中所述给药周期是1小时或更长的时间。
6.根据权利要求1所述的装置，其中所述给药周期是10至48小时。
7.根据权利要求1所述的装置，其中所述治疗剂量是5至800毫克。
8.根据权利要求1所述的装置，其中所述胰岛素和生物相容性聚合物是沉积在所述可植入医用装置的开口内，并且在其中设置阻挡层，所述阻挡层防止将所述胰岛素递送到所述动脉壁。
9.根据权利要求1所述的装置，进一步包括一种抗再狭窄成分。
10.根据权利要求9所述的装置，其中所述装置是一种具有腔侧和壁侧的圆柱形的装置。
11.根据权利要求10所述的装置，其中所述胰岛素是沉积在所述可植入医用装置上的，主要是用于将所述胰岛素递送到所述装置的腔侧，并且所述抗再狭窄成分是沉积在所述可植入医用装置上，主要是用于将所述抗再狭窄成分递送到所述装置的壁侧。
12.根据权利要求1所述的装置，其中所述胰岛素选自由人胰岛素、非人胰岛素和合成胰岛素组成的组。
13.根据权利要求1所述的装置，其中所述胰岛素的治疗剂量为至少200毫克。
14.根据权利要求1所述的装置，其中所述胰岛素的治疗剂量为200至400毫克。
15.一种用于局部递送治疗药物到心肌组织的可植入医用装置，所述装置包括：
一种用于植入到冠状动脉内的可植入医用装置；以及
一种用于治疗急性心肌梗塞之后的局部缺血性损伤的治疗剂量的治疗药物，所述治疗药物以这样一种方式附于可植入医用装置中，使得所述治疗药物以一次治疗剂量并在一个有效给药周期内被释放到所述心肌组织，用以降低所述心肌组织的局部缺血性损伤。
16.根据权利要求15所述的装置，其中所述治疗药物是一种血管舒张药。
17.根据权利要求15所述的装置，其中所述治疗药物是一种高血压药物。
18.根据权利要求15所述的装置，其中所述治疗药物是一种血管活性物质。
19.根据权利要求15所述的装置，其中所述治疗药物是一种保心药。
20.根据权利要求15所述的装置，其中所述治疗药物是一种膜稳定剂。
21.根据权利要求15所述的装置，其中所述治疗药物是一种抗炎药。
22.根据权利要求15所述的装置，其中所述治疗药物是一种抗氧化剂。
23.根据权利要求15所述的装置，其中所述治疗药物是胰岛素。
24.根据权利要求23所述的装置，其中所述胰岛素的治疗剂量为200至400毫克。
25.根据权利要求15所述的装置，其中所述用以降低局部缺血性损伤的治疗药物附于所述医用装置上，主要是用于从所述医用装置的腔侧递送所述用以降低局部缺血性损伤的治疗药物，以及进一步包括附于所述医用装置上的主要是用于从所述医用装置的壁侧递送的抗再狭窄药物。
26.根据权利要求15所述的装置，其中所述可植入医用装置是一种在冠状动脉内可膨胀的支架。
27.根据权利要求15所述的装置，其中所述治疗药物沉积在所述可膨胀医用装置的开口内。
28.根据权利要求15所述的装置，其中所述治疗药物附于所述具有一种生物相容性聚合物的可植入医用装置上。
29.根据权利要求15所述的装置，其中所述治疗药物是阿糖腺苷。
30.一种用于局部递送胰岛素到心肌组织的支架，所述支架包括：
用于植入在血管内的圆柱形的可膨胀装置主体；以及
在附于所述可植入医用装置主体上的生物相容性聚合物内的治疗剂量的胰岛素。
31.根据权利要求30所述的装置，其中所述胰岛素和生物相容性聚合物沉积在所述可植入医用装置的开口内。
32.根据权利要求30所述的装置，其中所述胰岛素和生物相容性聚合物沉积在所述可植入医用装置的表面上。
33.根据权利要求30所述的装置，其中所述治疗剂量是用于在1小时或更长时间的给药周期内进行递送的。
34.根据权利要求30所述的装置，其中所述治疗剂量是用于在10至48小时的给药周期内进行递送的。
35.根据权利要求30所述的装置，其中所述治疗剂量为5至800毫克。
36.根据权利要求30所述的装置，其中所述胰岛素和生物相容性聚合物沉积在所述可植入医用装置的开口内，并且在其中设置一阻挡层，所述阻挡层基本上避免了到所述动脉壁的所述胰岛素递送。
37.根据权利要求30所述的装置，进一步包括一种抗再狭窄成分。
38.根据权利要求37所述的装置，其中所述胰岛素沉积在所述可植入医用装置上，主要是用于将所述胰岛素递送到所述装置的腔侧，以及所述抗再狭窄成分沉积在所述可植入医用装置上，主要是用于将抗再狭窄成分递送到所述装置的壁侧。
39.根据权利要求30所述的装置，其中所述胰岛素选自由人胰岛素、非人胰岛素和合成胰岛素组成的组。
40.根据权利要求30所述的装置，其中所述胰岛素的治疗剂量为至少5毫克。
41.根据权利要求30所述的装置，其中所述胰岛素的治疗剂量为200至400毫克。
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CA2513721C (en) 2013-04-16
KR20050086440A (ko) 2005-08-30
CN1723050A (zh) 2006-01-18
WO2004043511A1 (en) 2004-05-27
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