CN101631513B - 可生物吸收的聚合物组合物和医疗设备 - Google Patents
可生物吸收的聚合物组合物和医疗设备 Download PDFInfo
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Abstract
一种制作具体的医疗设备的方法，包括步骤：制备可生物降解的聚合物结构；以包含药理药剂或生物药剂的聚合物包被物包被所述可生物降解的聚合物结构；切割所述结构成这样的模式，即所述模式具有可使得所述切割的结构皱缩、并且使得皱缩之后的所述切割结构膨胀成展开的构形的形状。
Description
背景技术
本说明书中引用的所有参考文献及它们的参考文献在适合用于教导额外的或备选的细节、特征和/或技术背景的情况下均通过引用的方式全文纳入本文。
本发明涉及一种用于植入体内脉管或管腔结构的医疗设备。在一个实施方案中，本发明涉及由如下物质包被的支架(stents)和合成的移植物：包含用于直接送递至周围组织的医药物质的控释基质，以及附着于其上的用于俘获该设备的血液接触面上的内皮祖细胞以在损伤部位形成成熟的功能性内皮的配体。具体而言，所述聚合物基质/药物/配体包被的设备(如支架)可用于例如疾病和病症(如再狭窄、动脉粥样硬化)的治疗以及管腔内的重建治疗。
本文的实施方案中公开的是一种新型的管状可膨胀骨架，所述骨架被制成适合于脉管结构内(包括心血管系统)的形状，并具有较低的生物排斥反应倾向。这种骨架可由使平衡了弹性、刚性和柔性的力学性能组合得以实现的可生物吸收的聚合组合物或混合物组成，或者包含这种组合物或混合物。所述聚合物组合物可包含包括可生物吸收的聚合物、二元共聚物或三元共聚物的基底材料，以及二元共聚物或三元共聚物的添加剂。有利的是，聚合物被选择用于进行酶降解及吸收。具体地，所述组合物可适用于“温和的”崩解机制，该机制使得所述组分聚合物的崩解对周围组织的损伤较小。
与使用金属设备(例如支架)相关的一个顽固问题是，会在植入部位形成覆盖在所述支架之上的瘢痕组织，即所谓的再狭窄过程。许多人已经得出这样的结论，即对于由金属支架的持久性方面所引起的支架血栓形成的持续风险，通过用以防止这种灾难为目的的药物包被所述金属并没有将其克服。相反，死亡率的增加也已经被与许多这些覆盖层关联起来。而且，金属支架和聚合物支架可阻止管腔重塑及膨胀。
关于支架，支架会妨碍组织的愈合，并会降低免疫应答的补体激活。支架在一些情况下还与炎症反应的降低以及在植入物和/或其组分材料破裂时发生创伤有关。常规支架还无法提供使植入(特别是植入至血管中)变得更容易的所需程度的形状柔性。
本发明人已经认识到开发医疗设备(如支架和脉管合成移植物)的需求，所述医疗设备是以生物相容的、可生物降解的、可生物吸收的聚合物混合物作为基底聚合物制备的，并且可用于治疗疾病(尤其是脉管系统的疾病)。所述医疗设备可改善现在使用的设备相关的问题。
正如本文所公开的那样，本发明人已经认识到，可对所述基底聚合物进行选择以使得有额外的分子自由体积来确保充分的分子运动，从而使得在生理条件下(例如在加入分子应变时)发生重结晶。增大的分子自由体积使水摄取率增加，除加速本体降解动力学(bulk degradationkinetics)之外，还增加了塑化效应。
在本文的实施方案中，所述组合物可适用于“温和的”崩解机制，该机制使得在进行崩解的同时又对周围组织友好(炎症反应更少，并且使得在植入物破裂时发生创伤的可能性更低)。通过选择具有增强的亲水性的聚合物或二元共聚物用作基底和/或添加剂，所述聚合物混合物可降低补体激活并使调理作用(opsonization)最小化或将其阻止。
在某些实施方案中，所述可生物吸收的骨架使得柔性和伸展性适宜于植入进行脉冲运动、收缩和舒张的例如心血管系统中。
参考文献
参考2003年8月19日授权的美国专利6,607,548 B2(Inion)，该专利公开了生物相容的且可生物再吸收的组合物，该组合物包含与一种或多种二元共聚物添加剂相混合的基于乳酸或乙醇酸的聚合物或二元共聚物。据称这类植入物是可冷冻弯曲的，而且无裂纹或裂缝。还参考了EP 0401844，它公开了聚-L-丙交酯与聚D-DL-丙交酯的混合物；以及美国专利6,001,395，它公开了使用片层状颗粒物的药物送递，所述片层状颗粒物为可生物降解的聚(L-丙交酯)或二元共聚物或者它们的混合物，并且至少部分是晶质的。美国专利7,070,607公开了动脉瘤修复螺圈(coil)，该螺圈含有携带栓塞剂的可生物吸收的聚合物材料，其中凝血活性受所述聚合物组合物的控制。
发明内容
本文公开的实施方案为制备可生物吸收的医疗设备的方法，所述医疗设备例如由可生物吸收的聚合物组合物制成的支架和合成移植物。所述医疗设备是生物相容的和可生物降解的，并且在植入至患者体内后，不仅可以将药物送递至受损器官，而且可以为其提供机械支持。
在一个实施方案中，所述医疗设备可被制成将治疗药剂封装至其结构的壁中的形状，用于治疗诸如动脉粥样硬化、再狭窄等的疾病。在一个实施方案中，随着所述可生物吸收的设备崩解，该设备可对封装于其壁中的药物的或所述聚合物组合物的组成部分进行控释。在该实施方案和其他实施方案中，药物可以共价结合于构成所述医疗设备的聚合物材料或混合于其中。在某些实施方案中，所述医疗设备可以具有用于刺激植入物部位的正常内皮恢复的包被层。
在一个实施方案中，提供了一种用于制备具有包被层的聚合物医疗设备的方法。所述方法包括用可生物吸收的聚合物组合物制备聚合物医疗设备，所述聚合物组合物包含可以为可结晶的聚合物的基底聚合物。所述方法包括：制备可结晶的聚合物组合物；形成结构例如医疗设备(如支架)形式的结构；以一层或多层组合物和配体包被所述结构的内腔表面(luminal surface)，所述组合物包含聚合物基质，并且包含或不包含一种或多种药物，所述配体用于识别及结合循环系统中的靶细胞。所述方法还包括包被医疗结构的相对面的步骤，对支架来说，就是以包含相同或不同的用于局部递送到周围组织中的药物的组合物包被管腔内表面(abluminal surface)。
在一个实施方案中，所述制备方法还包括这样的步骤，即在包被所述聚合物设备之前或之后将该设备设计并切割成特定的结构。在该实施方案中，组成所述包被层的所述药物和组合物可以在设计并切割所述设备结构之前或者在所述设备被包被之后施加。
在一个实施方案中，公开了一种心血管用管状可膨胀骨架(如支架)，由可生物吸收的聚合物组合物或混合物制备而成，所述聚合组合物或混合物具有平衡了弹性、刚性和柔性的力学性能组合，使得所述骨架管在与合适的血管内腔插入工具连接的可膨胀送递系统(例如气囊式导管)上面可弯曲并皱缩。展开的骨架可以从窄瘪的送递构造膨胀至内腔直径足以植入到血管壁组织上。所述柔软形式的聚合物骨架还可以提供过度伸展其构形的能力，目的是有利于以最少的血管壁接触插入至血管中。另外，可以操作所述骨架以从圆柱形变成截锥形，使得易于安装、重定位及调整植入物。
在一个实施方案中，提供了可膨胀骨架形式的医疗设备，所述骨架提供了可皱缩及可膨胀但无应力银纹(stress crazing)的的结构。在其中所述医疗设备为支架的实施方案中，所述可膨胀的骨架提供了一组联锁的支柱(strut)，用于将所述设备稳定于其展开的、膨胀的或植入的构造。
所述骨架聚合物的另一个实施方案在从皱缩状态向膨胀状态膨胀的径向应变过程中，通过分子重定向和结晶提供增强的力学性能。
在一个实施方案中，所述医疗设备被作为送递系统中的骨架植入物提供，所述送递系统包含与气囊式可逆膨胀或扩张工具相匹配的导管。在一个实施方案中，可以应用可被加热或冷却的气囊式膨胀设备。
在另一个实施方案中，提供的所述医疗设备具有在接触血管壁区域处是“友好的”的聚合物崩解部分。在某些实施方案中，所述崩解动力学缓慢到足以避免组织过载或其他炎症反应。
在一个实施方案中，提供了可在原位持续例如约3-4个月的最短保持30天的临床支持强度。对这类实施方案的骨架的评价标准可基于例如以分子量降低衡量的质量减少、力学性能的保持和组织的反应。
在另外的实施方案中，包含可膨胀支架的医疗设备被可操作地制成可从固态变成“橡胶态”的形状，使得外科介入更容易。在该实施方案中，所述设备在处于体内生理条件下时形成橡胶态。
任选地，可选择聚合物和设备结构，使之具有适宜于植入物与血管壁在心血管脉冲收缩和舒张过程中无摩擦接触的柔性和弹性。
优选地，一个实施方案中的所述骨架是可伸展的及有弹性的，但具有的硬度应足以能够抵抗血管中的心血管脉动压。
根据一个实施方案，所述可生物吸收的聚合物由聚(L-丙交酯)或聚(D-丙交酯)的基底聚合物构成。修饰性二元共聚物包括聚L(或D)-丙交酯-共-三-亚甲基碳酸酯或聚-L(或D)-丙交酯-共-e-己内酯，可用于连接所述基底聚合物。这些二元共聚物可被合成为嵌段二元共聚物或者为“嵌段状”无规二元共聚物，其中所述丙交酯链的长度长到足以进行结晶。晶质形态的形成可增强所述医疗设备的力学性能，提高加工条件，并提供交联部分结晶(例如热交联)的可能性。在该实施方案中，所述聚合物组合物使得在所述L和D部分之间形成丙交酯外消旋体晶体结构，以进一步提高所述医疗设备的力学性能。
还可以预见的是，所述组合物中的所述聚合物的降解时间可以通过提高降解动力学而缩短。例如，原料可以是较低分子量的组合物，并且/或者应用的基底聚合物可以是更加亲水的或易于水解链切割的。
根据本发明的实施方案，提供了用于制作基底二元共聚物的组合物和方法，所述基底二元共聚物具有一个长到足以进行结晶且不会在立体化学上阻碍结晶的部分(例如L-丙交酯或D-丙交酯)，并且具有一个较小部分，例如乙交酯、聚乙二醇(PEG)或以单甲氧为末端的PEG(PEG-MME)。
除了基底聚合物、修饰性聚合物或二元共聚合物外，所述组合物还可包括其他增强降解动力学的材料和化合物，例如e-己内酯(e-caprolactone)二元共聚物部分，其中所述己内酯保持非晶质形且所产生的链节(segment)对水解更敏感。例如，这类组合物可通过与所述基底聚合物混合物混合或者与所述基底聚合物反应而制备。
所述组合物可掺有PEG二元共聚物，例如具有约1％的PEG部分的AB二嵌段或ABA三嵌段。丙交酯的力学性能(见Enderlie andBuchholz SFB May 2006)可以得到保持。PEG或PEG-MME二元共聚物的掺入还可用于促进药物与所述聚合物的附着，例如与药物洗脱医疗设备的结合。
另一个实施方案提供了一种骨架基底聚合物，该聚合物结合了较低含量(少于5％)高MW的PEG聚合物，即2-3IV二元共聚物，它使得所述丙交酯嵌段可结晶并且赋予所述基底聚合物相等的强度。
本文的实施方案的骨架可提供一种聚合物核心材料，该材料包含至少一种封装用于血管壁和管腔的局部治疗的药物。所述骨架核心降解的进度可提供例如同时缓释用于组织炎症和血小板聚集的治疗及预防的药剂。
所述聚合物组合物或混合物的另一个实施方案提供了在原位均一降解，避免了聚合物的成团释放。所述骨架可携带至少一个附着的或埋入的由不透放射物质制备的识别标记物。
附图说明
图1显示一种代表性可生物吸收支架设计。
图2是一种代表性可生物吸收支架设备的照片。
图3A和图3B是含有聚(L-乳酸)的可生物吸收支架的照片。
图4A显示一种具有稳定联锁机制的可生物吸收支架设计。
图4B显示一种安装在气囊式导管上并且还在游离端呈现联锁机制的可生物吸收支架设计。
图5A和图5B显示一种末端具有稳定联锁机制的可生物吸收支架设计。
图6显示一种描绘了折叠的环形链节的可生物吸收支架设计。
图7显示一种描绘了环形链节的可生物吸收支架设计。
图8显示一种描绘了完全膨胀的直径的可生物吸收支架设计。
图9A和图9B显示一种描绘了所述骨架组件上应力点的方向的可生物吸收支架支柱设计。
图10显示一种可生物吸收支架设计的实施方案。
图11A显示一种描绘了折叠的环形链节以及开放构形的环形链节的可生物吸收支架设计。图11B从另一种角度示出了所述支架设计。
图12A和图12B显示另一种描绘了不同方式(state)环形链节的可生物吸收支架设计。
图13和图14显示描绘了支架壁及其链节的构形的可生物吸收支架设计。
图15显示一种包含整合至支架壁内的不透放射标记物的可生物吸收支架设计。
图16显示一种描绘了平均体塌陷压的可生物吸收支架设计。
图17为显示描绘了可生物吸收支架的径向强度的数据的柱状图。
图18所示显示了数据的柱状图，所述数据描绘了在血管中膨胀的可生物吸收支架材料的百分率。
图19为显示描绘了支架反弹(recoil)的百分率的数据的柱状图。
图20显示了一个可生物吸收支架支柱的横截面的图式表征，其具有将药物组合物封装于该支柱内的支架构形。在该实施方案中，所述支架被基质包被，包含抗体包被层以及药物包被的所述设备的内腔表面。
具体实施方式
本发明的聚合物组合物可用于制备植入至患者体内的医疗设备。所述医疗设备为具有可生物降解的、可生物吸收的性质的骨架，并且包括但不限于支架、支架移植物、血管合成移植物、导管、转流管(shunt)、血管转流管、瓣膜、移植物等。
本发明还涉及制备可生物降解的聚合物组合物的方法，以及由本文公开的聚合物组合物制备所述医疗设备的方法。
在一个实施方案中，所述医疗设备包括可皱缩的聚合物支架，它可被插入至气囊式送递系统用于植入。所述气囊可包括热气囊或非热气囊。所述医疗设备可具有这样的结构，即该结构在装载过程中是可皱缩的，并且在生理条件下是可膨胀的且无应力。所述医疗设备可包含这样的结构，即所述结构包含在展开应变下(例如在气囊膨胀过程中)可定向和/或结晶的聚合物，目的是提高所述医疗设备的力学性能。通过应用含有具有慢崩解动力学的聚合物的医疗设备，可避免植入部位处的组织过载或其他炎症反应。
本发明的医疗设备可以在结构上被制成可提供改变并匹配植入区域并且使局部组织得以正常重建的能力的形状。所述医疗设备可从固体转换成“橡胶态”，使得较例如不锈钢支架更容易进行外科介入。可以将医疗设备设计成具有保持最短30天的临床上足够的强度。
在一个实施方案中，所述医疗设备由这样的聚合物组合物构成，即该聚合物组合物包含占所述组合物约60％-约95％(以重量计)或约70％-约80％(以重量计)的基底聚合物。例如，所述聚合物制剂可包含按重量计约70％的聚L-丙交酯(约1.5-3.5或约2.5-3Ⅳ)和聚L-丙交酯-共-TMC(80/20w/w)(1.0-2.6Ⅳ或约1.4-1.6Ⅳ)。
在另一个实施方案中，所述聚合物制剂包含按重量计70％的三嵌段聚L-丙交酯-共-PEG(95/5-99/01或约98/2-99/01)(2,000-100MwPEG或6,000-8000Mw PEG)和聚L-丙交酯-共-TMC(70/30)(1.4-1.6Ⅳ)。所述聚合物组合物还可以包括这样的制剂，即按重量计约70％的二嵌段聚L-丙交酯-共-PEG-MME(95/05-99/01)(2,000-100MwPEG-MME或6,000-8000Mw PEG-MME)和聚L-丙交酯-共-TMC(70/30w/w)(1.4-1.6Ⅳ)。
药物组合物可通过以下方式与所述聚合物掺合：例如在形成所述医疗设备之前接枝至所述聚合物活性部位、在所述聚合物组合物内浸渗或封装入所述聚合物组合物中，目的是将所述组合物整合至所述设备壁中；并且/或者所述医疗设备一旦形成则在所述设备表面(尤其是内腔表面)包被所述设备。
在本文公开的实施方案中，所述医疗设备包括支架，所述支架在结构上被制成可在例如动脉或静脉中展开的形状，并且能够在原位膨胀并匹配血管内腔，所述支架可用于在损伤部位重建血管连续性。所述支架可被制成可以具有多种不同的排列的形状，使得它在加载时是可皱缩的并且一旦展开即在生理条件下是可膨胀的及可弯曲的。所述可生物降解的医疗设备可包含基底聚合物以及一种或多种修饰性二元共聚物，所述基底聚合物包括例如聚L-丙交酯或聚D-丙交酯，所述修饰性二元共聚物例如聚L(或D)丙交酯-共-三-亚甲基碳酸酯或者聚L(或D)-丙交酯-共-e-己内酯，如上文所述。
具有不同构形的可生物降解的聚合物支架和/或支架壁的不同实施方案显示于图1-15中。例如，所述支架为包含这样的支柱的管状结构，即该支柱被可操作地设计以使血液可穿过其壁，使得在血液流经该区域时邻近组织被浸润或者与之相接触。所选的具体支架设计可依赖于支架的径向尺寸及纵向尺寸。图11A显示了一个骨架，其中大量成环结构位于一个可塌陷的/可膨胀的悬架支柱之上，如图11A中所示所述成环结构a...an沿一个轴膨胀并且悬架支柱b沿相同轴膨胀。可以构造悬架支柱b以形成一个闭合环，如图11A和11B以及图12A和12B中所示的圆环。图11a的展开骨架的交联支柱可保持更高的环强度。图15显示了一种应用这种技术的管结构实施方案；还考虑到了其他的形状，如圆锥形或二分叉形。
本发明的骨架可被应用于多种生物区域，所述区域非限制性地包括气管、支气管(bracial)、输卵管、食管和血管。骨架可包含或包被有任何类型的药物，例如激素、serp-1、MPA等。
骨架元件可以被制成可及早地变形成它们的最大长度及/或结构的形状，然后可塑性地延长以形成或产生二级结构，在该二级结构中具有与所述组合结构的一级结构不同的力学性能。对该结构的过度伸展可有利于使晶质结构形成排列，从而增加结构强度。所述一级结构中的二级结构可形成例如二分叉形。所述二级结构将使为简单的塑性形变所不能及的结构变化出现成为可能。
本发明的方法包括一种制备可生物吸收的聚合物植入物的方法，包括：(a)混合包含可结晶组合物的聚合物组合物，所述可结晶组合物包含聚L-丙交酯或聚D-丙交酯的基底聚合物，所述基底聚合物与包含嵌段二元共聚物形式的或作为嵌段状无规二元共聚物的聚L(或D)-丙交酯-共-三-亚甲基碳酸酯或聚L(或D)-丙交酯-共-e-己内酯的修饰性二元共聚物连接，其中所述丙交酯链的长度长到足以使得交联部分结晶；(b)塑造所述聚合物组合物以在结构上形成所述植入物的形状；以及(c)切割所述植入物。
在一个实施方案中，所述混合形式被塑造为管状物(其中有内腔)的形式。然后可以用激光、气刀、机械工具等切割所述管状物，以形成所需的设计(例如支架骨架)。在另一个实施方案中，所述混合形式被塑造成薄片。然后使用激光、气刀、机械工具等切割所述薄片，以形成所需的设计。根据需要，然后可以将所设计的经切割薄片与所述薄片的另一部分焊接、退火、接合等，以形成所需的整体结构。例如，可以将所设计的经切割薄片卷成管状形式并沿接缝焊接，形成随后可能会被切割成支架等的管状物。所述薄片本身可以在一面或两面包被有物质，尤其是包含生物药剂或药理药剂的组合物。一面可以具有由不同的基质及/或一种或多种不同的生物药剂或药理药剂形成的包被层。
一种制作所述医疗设备的方法可包括：(a)制备可生物降解的聚合物结构；(b)设计所述聚合物结构以使其被制成可植入至患者中的形状；(c)切割所述结构成这样的模式，即这些模式被制成具有使所述设备可穿过开口处并使得所述设备皱缩的形状。
本发明的医疗设备可以是用于植入至包含内腔的器官或躯体部位中的任何设备，并且可以是但不限于支架、支架移植物、合成的血管移植物、心脏瓣膜、导管、人造血管过滤器(vascular prosthetic filter)、起搏器、起搏器导线(pacemaker lead)、除颤器、卵圆孔未闭(PFO)间隔闭合设备、血管钳、血管动脉瘤封堵器、血液透析移植物、血液透析导管、房室转流管、主动脉瘤移植物设备或组件、静脉瓣、传感器、缝合线(suture)、血管吻合钳、留置静脉或动脉导管、血管鞘及药物送递端口(drug delivery port)。所述医疗设备可以用多种可生物吸收的材料制备，这取决于所述设备，可生物降解的材料例如聚丙交酯聚合物以及聚乙交酯聚合物或它们的二元共聚物是最适合的。
在一个实施方案中，所述医疗设备包含含有这样的基质的包被层，即该基质包含无毒的、生物相容的、可生物蚀解的且可生物降解的合成材料。所述包被层还可以包含用于送递至植入部位邻近组织的一种或多种药用物质或药物组合物，以及用于在所述医疗设备的血管接触面上俘获并固定内皮祖细胞的一种或多种配体，例如肽、小分子和/或大分子、及/或抗体或其结合物。
在一个实施方案中，所述可植入的医疗设备包括具有包被层的支架。根据一个实施方案，所述支架为可膨胀的腔内内用假体(endoprosthesis)，它被设计并制成具有用于附着将治疗物质控释或缓释至邻近组织中的包被层的表面的形状。
在一个实施方案中，所述控释基质可包含各种类型和来源的一种或多种聚合物和/或寡聚物，包括天然的聚合物或合成的聚合物，所述聚合物是生物相容的、可生物降解的、可生物吸收的并且可用于所述药剂的控释。例如，在一个实施方案中，所述天然存在的聚合物材料可包括诸如胶原、纤维蛋白、原弹性蛋白、弹性蛋白、交联的原弹性蛋白和细胞外基质组分的蛋白质，或者其他生物剂或其混合物。在本发明的该实施方案中，所述天然存在的材料可通过遗传工程技术由这样的外源基因制备，即该外源基因被载体(例如质粒载体)携带并且被人工地导入宿主(例如细菌)。在该实施方案中，所需的聚合物蛋白例如原弹性蛋白和弹性蛋白可以被产生并分离，用于所述基质中。在其他实施方案中，所述天然存在的聚合物基质可通过已知的方法从天然来源中纯化，或者它们可以通过所述蛋白质聚合物的化学合成获得。在某些实施方案中，所述天然存在的材料可以用化学方法修饰或者合成，例如通过将所述材料(如蛋白质)交联，或者通过甲基化、磷酸化等。在另一个实施方案中，所述基质可包含离体(denuded)血管或血管骨架和/或其组分。
在一个实施方案中，所述基质可包含合成材料，所述合成材料包括聚酯，例如聚乳酸、聚乙醇酸、或其二元共聚物和/或结合物；聚酸酐；聚己内酯；聚羟基丁酸戊酯；聚二氧环己酮(polydixanone)和其他可生物降解的聚合物；或者其混合物或二元共聚物。在该实施方案中，所述基质包含作为用于包被所述医疗设备的基质聚合物的聚(丙交酯-共乙交酯)。在该实施方案中，所述聚(丙交酯-共-乙交酯)组合物包含至少一种聚-DL-乙交酯的聚合物或其二元共聚物或混合物，并且将它和要送递至组织的药用物质混合。然后使用标准技术(例如喷涂、浸渍及/或化学汽化)将所述包被组合物施加于所述设备的表面。或者，所述聚(丙交酯-共-乙交酯)(PGLA)溶液可以分隔所述一层或多层药用物质的单层形式施加。
在另一个实施方案中，所述包被组合物还包含可药用聚合物和/或可药用载体，例如不可吸收的聚合物，如乙烯-乙酸乙烯酯(EVAC)和甲基丙烯酸甲酯(MMA)。例如，所述不可吸收的聚合物还可通过增加所述组合物的分子量帮助进一步控制所述物质的释放，从而延迟或减慢所述药用物质的释放速率。
在某些实施方案中，所述聚合物材料或多种聚合物的混合物可以与所述药物一块作为组合物施加于所述医疗设备的表面，并构成一个单层。多层组合物可被施加来形成所述包被层。在另一个实施方案中，多层聚合物材料或其混合物可被施加于所述药用物质层之间。例如，这些层可被以以下方式连续地施加：第一层直接与所述设备未包被的表面相接触；第二层包含所述药用物质且一个表面与所述第一层相接触，另一面与第三层聚合物相接触；所述第三层与周围组织相接触。可以根据需要添加包含所述聚合物材料和药物组合物的附加层，每种组分或其组分混合物交替出现。
在另一个实施方案中，所述基质可包含非聚合物材料，如由例如金属合金或其他材料形成的纳米颗粒。在该实施方案中，所述医疗设备上的包被层可以是有孔的，并且所述药用物质可以被封装于所述颗粒之中及之间。在该实施方案中，可根据患者的需要改变所述颗粒的大小，以控制封装于所述颗粒中的药用物质的释放速率。在一个实施方案中，所述药物组合物可以为缓释/控释药物组合物。
或者，所述包被层的药用物质可以以多层组合物的形式施加，每层均可包含被聚合物材料包围的一种或多种药物。在该实施方案中，所述多层药用物质可包括包含多层单独一种药物的药物组合物；每层含一种或多种药物，并且/或者在交替层中施加不同的药物组合物。在一个实施方案中，这些包含药用物质的层可由聚合物材料层将其彼此分开。在另一个实施方案中，可以为所述设备提供药物组合物层，用于在植入后立即释放所述药用物质。
在一个实施方案中，所述药用物质或组合物可包含一种或多种药物或物质，所述药物或物质能够抑制平滑肌细胞在植入部位的迁移及增殖，可抑制血栓形成，可促进内皮细胞生长及分化，并且/或者可抑制移植所述医疗设备后的再狭窄。另外，将内皮祖细胞俘获在所述医疗设备的内腔表面可加速在损伤部位形成功能性内皮。
能够被掺合至基质中并且/或者被浸渗至所述医疗设备中的化合物或药物组合物的实例包括但不限于前列环素、前列环素类似物、α-CGRP、α-CGRP类似物或α-CGRP受体激动药；哌唑嗪；单核细胞趋化蛋白-1(MCP-1)；免疫抑制药物(如雷帕霉素)、抑制平滑肌细胞迁移及/或增殖的药物、抗血栓药物(如凝血酶抑制药)、免疫调节药(如血小板因子4和CXC-趋化因子)；CX3CR1受体家族的抑制药；抗炎药物、类固醇(如去氢表雄酮(DHEA)、睾酮)、雌激素(如17β-雌二醇)；他汀类(statin)(如辛伐他汀(simvastatin)和氟伐他汀(fluvastatin))；PPAR-α配体(如非诺贝特(fenofibrate)和其他降脂药物)、PPAR-δ和PPAR-γ激动药(如罗格列酮(rosiglitazone))；PPAR-二重-αγ激动药、LBM-642、核因子(如NF-κβ)、胶原合成抑制药、血管扩张药(如乙酰胆碱、腺苷、5-羟色胺即血清素、P物质、肾上腺髓质素)、诱导内皮细胞生长及分化的生长因子(如碱性成纤维细胞生长因子(bFGF)、血小板源性生长因子(PDGF)、内皮细胞生长因子(EGF)、血管内皮细胞生长因子(VEGF))；蛋白酪氨酸激酶抑制药(如米哚妥林(Midostaurin)、伊马替尼(imatinib)或任何血管生成抑制剂化合物)；抑制成熟白细胞粘附的肽或抗体、抗生素/抗微生物剂以及其他物质(如速激肽、神经激肽或唾液腺激肽(sialokinin)、速激肽NK受体激动药)；PDGF受体抑制药(如MLN-518及其衍生物、丁酸及丁酸衍生物、葛根素(puerarin)、纤连蛋白、红细胞生成素、达贝泊汀(darbepotin)、丝氨酸蛋白酶-1(SERP-1)等)。上述的化合物及药用物质可以单独地或者以其结合物和/或混合物的形式被施加于所述设备上的包被层中。
在一个实施方案中，所述可植入的医疗设备可包含这样的包被层，即该包被层包含位于包含所述药用物质的所述一层或多层基质层之间的一层或多层屏障层。在该实施方案中，所述屏障层可包含合适的可生物降解的材料，包括但不限于以下适合的可生物降解的聚合物：聚酯(如PLA、PGA、PLGA、PPF、PCL、PCC、TMC及它们的任何二元共聚物)；聚羧酸、聚酸酐包括马来酸酐聚合物；聚原酸酯；聚氨基酸；聚氧化乙烯；聚磷腈；聚乳酸、聚乙醇酸及它们的二元共聚物和混合物(如聚(L-乳酸)(PLLA)、聚(D，L-丙交酯)、聚(乳酸-共-乙醇酸)、50/50(DL-丙交酯-共-乙交酯))；聚二氧环己酮；聚丙烯延胡索酸酯；聚缩酚酸肽(polydepsipeptide)；聚己内酯及它的二元共聚合物和混合物(如聚(D，L-丙交酯-共-己内酯)和聚己内酯共-丙烯酸丁酯)；聚羟基丁酸戊酯及混合物；聚碳酸酯(如酪氨酸衍生的聚碳酸酯和芳基化物、聚亚胺碳酸酯(polyiminocarbonates)和聚二甲基三甲基-碳酸酯；氰基丙烯酸酯；磷酸钙；聚糖胺聚糖(polyglycosaminoglycans)；大分子如多糖(包括透明质酸；纤维素和羟丙基甲基纤维素；明胶；淀粉；葡聚糖；藻酸酯及它们的衍生物)、蛋白质和多肽；以及前述任一种的混合物和二元共聚物。所述可生物降解的聚合物还可以是一种表面可蚀解的聚合物，如聚羟基丁酸酯及其二元共聚物、聚己内酯、聚酸酐(晶质和非晶质)、马来酸酐二元共聚物以及磷酸锌-钙(zinc-calcium phosphate)。设备上的包被层可具有的屏障层数依赖于由患者所需治疗所决定的必需治疗药剂量。例如，治疗时间越长、在一个时间阶段内需要的治疗物质越多，则需要越多的屏障层来及时地提供所述药用物质。
在一个实施方案中，所述包被层包括被施加于所述医疗设备的血液接触面上的配体，并且所述配体特异性识别并结合循环血液中靶细胞表面上的所需组分或表位。在一个实施方案中，所述配体被特异性地设计成通过以下方式仅识别并结合遗传改变的哺乳动物细胞：仅识别遗传改变细胞的细胞膜上的遗传工程的标记物分子。对所述靶细胞的结合将所述细胞固定在所述设备的表面上。
在另一个实施方案中，对在所述医疗设备上用于结合所述遗传改变细胞的配体的选择依赖于所述遗传工程细胞的膜标记物分子。即，所述配体仅结合由所述细胞用给予所述细胞的染色体外遗传物质表达的细胞膜标记物分子或抗原，使得仅遗传修饰细胞可以被所述医疗设备表面上的配体识别。以这种方式，仅遗传修饰细胞可以结合至所述医疗设备表面。例如，如果所述哺乳动物细胞为内皮细胞，那么所述配体可以为至少一种类型的抗体、抗体片段或它们的结合物；所述抗体特异性地对抗所述靶细胞表面上的特定靶表位或标记物分子。在本发明的该方面，所述抗体可以为这样的单克隆抗体、多克隆抗体、嵌合抗体或人源化抗体，即该抗体通过与所述表面标记物分子相互作用仅识别并结合遗传改变的内皮细胞，从而调整所述细胞向所述医疗设备表面的附着力。本发明的抗体或抗体片段可以共价地或非共价地连接至所述基质表面，或者通过连接分子共价地系附于包被所述医疗设备的基质的最外层。例如，在该实施方案中，所述单克隆抗体还可以包括Fab或F(ab′)2片段。本发明的抗体片段包含任何大小的片段，例如保留以抗体形式识别并结合靶抗原的特征的大分子和小分子。
在另一个实施方案中，本发明的抗体或抗体片段特异地识别并结合被处理哺乳动物的抗原，并且它们的特异性不依赖于细胞谱系。例如，在一个实施方案中，在治疗再狭窄中，其中没有对所述细胞进行遗传修饰以使其包含特定的细胞膜标记物分子，所述抗体或片段特异性地选择并结合循环的内皮祖细胞表面抗原，例如CD133、CD34、CD14、CDw90、CD117、HLA-DR、VEGFR-1、VEGFR-2、Muc-18(CD146)、CD130、干细胞抗原(Sca-1)、干细胞因子1(SCF/c-Kit配体)、Tie-2、MHC(如H-2Kk和HLA-DR抗原)。
在另一个实施方案中，所述医疗设备的包被层包括至少一层上述的生物相容基质，所述基质构成用于粘附治疗有效量的至少一种类型的天然小分子或合成小分子的外表面。例如，所述小分子在再狭窄治疗中识别内皮祖细胞并与其相互作用，以在所述设备表面上固定所述细胞以形成内皮层。所述小分子可以与所述医疗设备结合用于多种疾病的治疗；可以有多种来源，例如细胞组分(如脂肪酸、蛋白质、核酸、糖类等)；并且可与内皮祖细胞表面上的抗原相互作用，产生与抗体相同的结果或效应。在本发明的该方面，所述医疗设备上的包被层还可包含一种化合物，例如在本文中与包含抗体或抗体片段的包被层一并描述的生长因子。
在另一个实施方案中，所述医疗设备的包被层包括至少一层上述的生物相容基质，所述基质包含用于粘附治疗有效量的至少一种类型的天然小分子或合成小分子的内腔表面。所述小分子识别靶细胞(如内皮祖细胞)表面上的抗原并与其相互作用，以将所述内皮祖细胞固定在所述设备表面上以形成内皮。所述小分子可以有多种来源，例如细胞组分(包括脂肪酸、肽、蛋白质、核酸、糖类等)；并且例如，可与诸如内皮祖细胞表面上的抗原等的结构相互作用，产生与抗体相同的结果或效应。
在另一个实施方案中，提供了一种治疗血管疾病(如再狭窄和动脉粥样硬化)的方法，包括向需要药用物质的患者局部地给予该物质。所述方法包括向患者的脉管或中空器官中植入一种具有包被层的医疗设备，所述包被层包含含有用于抑制平滑肌细胞迁移并藉此抑制再狭窄的药物或物质的药物组合物，以及可生物相容的、可生物降解的、可生物蚀解的无毒聚合物或非聚合物基质，其中所述药物组合物包含用于延迟所述药物释放的缓释或控释制剂。所述医疗设备的包被层还可以包含用于将诸如内皮细胞和/或祖细胞等的细胞俘获于所述设备的内腔表面上从而形成功能性内皮的配体例如抗体。
在另一个实施方案中，提供了一种制备经包被的医疗设备或具有包被层的医疗设备的方法，所述方法包括向医疗设备的表面上施加聚合物或非聚合物基质以及包含一种或多种药物的药物组合物；并向所述医疗设备上施加配体使得所述配体粘附至所述设备的表面上，并且所述配体被设计来结合循环的天然细胞或基因工程细胞的细胞膜上的分子。在该实施方案中，所述聚合物基质包含可生物相容的、可生物降解的无毒聚合物基质(例如胶原、原胶原、弹性蛋白、原弹性蛋白、交联的原弹性蛋白、聚(丙交酯-共-乙交酯)二元共聚物、多糖)及一种或多种药用物质，其中可在被施加于所述医疗设备上之前将所述基质和一种或多种物质混合。在该实施方案中，至少一种类型的配体被施加于所述设备的表面，并且可以与接触所述设备表面的所述药物/基质组合物一起添加于所述设备的上表面或外表面。该方法另外可包括这样的步骤，即向所述医疗设备上施加至少一层包含一种或多种药物和可药用载体的药物组合物，并且施加至少一层聚合物基质。
在一个实施方案中，所述基质可被施加为一层或多层并且有或无所述药用物质，所述配体可以通过多种使用标准技术的方法(如浸渍、喷涂或气体凝华)来被独立地施加于所述医疗设备上。在另一个实施方案中，所述聚合物基质可以在有或无所述药用物质的情况下被施加于所述设备上。在本发明的该方面(其中所施加的聚合物基质不含所述药物)，所述药物可以被作为基质层之间的层施加。在另一个实施方案中，屏障层被施加于所述包含药用物质的层之间。
在一个实施方案中，所述方法包括将所述药物组合物施加成为多层形式，且将所述配体施加于所述医疗设备最外表面上，使得所述配体(如抗体)可附着于所述设备的内腔表面。在一个实施方案中，所述用于包被所述医疗设备的方法包括：向所述医疗设备的表面施加至少一层或多层基质、一种或多种药用物质和基膜组分；向所述医疗设备上的所述至少一层所述组合物上施加一种这样的溶液，即该溶液包含至少一种类型的用于结合并固定遗传修饰的靶细胞的配体；以及在真空低温下干燥所述支架上的包被层。
在另一个实施方案中，所述包被层由所述基质中的多组分药物组合物构成，例如包含速释药剂以延缓早期的新内膜增生/平滑肌细胞迁移及增殖，以及释放长效的保持血管能力的药剂或积极的血管重塑剂的次级生物态基质(secondary biostable matrix)，例如内皮型一氧化氮合成酶(eNOS)、一氧化氮供体及衍生物(如阿司匹林或其衍生物)、产生一氧化氮的水凝胶、PPAR激动药(如PPAR-α配体)、组织型纤溶酶原激活物、他汀类(如阿托伐他汀(atorvastatin))、红细胞生成素、达贝泊汀、丝氨酸蛋白酶-1(SERP-1)和普伐他汀(pravastatin)、类固醇以及/或者抗生素。
随本文提供的附图描述被作为示例性实例描述的实施方案，所述示例性实例不能被认为以任何方式限制了本发明。
虽然已经参考具体的实施方案对本发明进行了具体地显示并描述，但要理解的是，以上所公开的实施方案的变化方案以及它们的其他特征和效用或者其他方案可根据需要被结合至其他多种不同的系统或应用中。同时，本领域技术人员接下来可进行多种本文未预知的或未预期的其他方案、修正、变更或改良，这些也意欲被囊括在如下的权利要求的范围内。
Claims (20)
1.一种制备可生物吸收的聚合物植入物的方法，包括：
(a)混合包含聚L-丙交酯或聚D-丙交酯的基底聚合物的组合物，所述基底聚合物与包含嵌段二元共聚物形式或作为嵌段状无规二元共聚物的聚L(或D)-丙交酯-共-三-亚甲基碳酸酯或聚L(或D)-丙交酯-共-ε-己内酯的修饰性二元共聚物连接，其中所述丙交酯链的长度长到足以使得交联部分结晶以形成聚合物组合物；
(b)使所述聚合物组合物固化以形成所需块状物；以及
(c)切割所述块状物以形成成形的植入物。
2.根据权利要求1的方法，在步骤(a)后还包括挤出所述聚合物组合物的步骤(a’)。
3.根据权利要求2的方法，在步骤(a’)后或与步骤(a’)同时还包括步骤：(a”)塑造或铸造所述挤出的聚合物组合物以形成模制的聚合物组合物。
4.根据权利要求1的方法，其中所述所需的块状物选自：薄片、管、杆和块。
5.根据权利要求3的方法，在步骤(b)后还包括步骤：(b”)用喷涂组合物喷涂所述固化的块状物。
6.根据权利要求5的方法，其中所述步骤(b”)的喷涂组合物包含生物药剂或药理药剂。
7.根据权利要求5的方法，其中所述喷涂组合物包含不透放射物质或可检测到放射的材料。
8.根据权利要求1的方法，其中在步骤(a)中所述混合还需要将药理药剂和/或生物药剂和/或不透放射物质或可检测到放射的材料掺合至所述聚合物组合物中。
9.权利要求6的方法，其中所述药理药剂包括以下的至少一种：环孢素A、霉酚酸、霉酚酸酯酸(mycophenolate mofetil acid)、雷帕霉素、雷帕霉素衍生物、biolimus A9、CCI-779、RAD 001、AP23573、咪唑硫嘌呤(azathioprene)、FK506、曲尼司特、地塞米松、皮质类固醇、依维莫司、吡美莫司、视黄酸、维生素E、罗格列酮(rosglitazone)、辛伐他汀、氟伐他汀、雌激素、17β-雌二醇、氢化可的松、对乙酰氨基酚、布洛芬、萘普生、氟替卡松、氯倍他索、阿达木单抗、舒林酸、去氢表雄酮、睾酮、葛根素、血小板因子4、碱性成纤维细胞生长因子、纤连蛋白、丁酸、丁酸衍生物、紫杉醇(paclitaxel)、紫杉醇衍生物、LBM-642、4，2-(二甲基亚膦酰)雷帕霉素(deforolimus)和普罗布考。
10.权利要求6的方法，其中所述生物药剂包括以下的至少一种：抗生素/抗微生物剂、抗增殖剂、抗肿瘤剂、抗氧剂、内皮细胞生长因子、平滑肌细胞生长和/或迁移抑制药、凝血酶抑制药、免疫抑制剂、抗血小板聚集剂、胶原合成抑制药、治疗性抗体、一氧化氮供体、反义寡核苷酸、伤口愈合剂、治疗性基因转移构建体、肽、蛋白质、细胞外基质组分、血管舒张剂、溶血栓药、抗代谢药、生长因子激动药、抗有丝分裂剂、类固醇、类固醇类抗炎剂、趋化因子、增殖物激活受体γ激动药、增殖物激活受体α激动药、增殖物激活受体β激动药、增殖物激活受体α/β激动药、增殖物激活受体δ激动药、NFκβ、增殖物激活受体α-γ激动药、非类固醇类抗炎剂、抗血管紧张素转换酶(ACE)抑制药、自由基清除剂、CX3CR1受体的抑制药及抗癌症化学治疗剂。
11.根据权利要求3的方法，在步骤(b)后还包括步骤(b”)将所述固化的块状物浸在含有药理药剂和/或生物药剂的组合物中。
12.一种制作医疗设备的方法，包括：
(a)制备可生物降解的聚合物结构；
(b)以包括药理药剂或生物药剂的聚合物包被物包被步骤(a)的所述可生物降解的聚合物结构；
(c)在步骤(b)之后将所述结构切割成这样的模式，即该模式具有可使得所述切割的结构皱缩、并使得所述皱缩后的切割结构膨胀成展开的构形的形状，
其中：所述可生物降解的聚合物结构包含聚L-丙交酯或聚D-丙交酯的基底聚合物，所述基底聚合物与包含嵌段二元共聚物形式或作为嵌段状无规二元共聚物的聚L(或D)-丙交酯-共-三-亚甲基碳酸酯或聚L(或D)-丙交酯-共-ε-己内酯的修饰性二元共聚物连接，其中所述丙交酯链的长度长到足以使得交联部分结晶。
13.根据权利要求12的方法，其中制备的所述可生物降解的聚合物结构为管状物形式。
14.根据权利要求12的方法，其中所述聚合物包被物是可生物降解的。
15.根据权利要求12的方法，其中步骤(b)中的所述药理药剂为以下的至少一种：环孢素A、霉酚酸、霉酚酸酯酸、雷帕霉素、雷帕霉素衍生物、biolimus A9、CCI-779、RAD 001、AP23573、咪唑硫嘌呤、FK506、曲尼司特、地塞米松、皮质类固醇、依维莫司、视黄酸、维生素E、罗格列酮、辛伐他汀、氟伐他汀、雌激素、17β-雌二醇、氢化可的松、对乙酰氨基酚、布洛芬、萘普生、氟替卡松、氯倍他索、阿达木单抗、舒林酸、去氢表雄酮、睾酮、葛根素、血小板因子4、碱性成纤维细胞生长因子、纤连蛋白、丁酸、丁酸衍生物、紫杉醇、紫杉醇衍生物、LBM-642、4，2-(二甲基亚膦酰)雷帕霉素和普罗布考。
16.根据权利要求12的方法，其中步骤(b)的所述生物药剂为以下的至少一种：抗生素/抗微生物剂、抗增殖剂、抗肿瘤剂、抗氧剂、内皮细胞生长因子、平滑肌细胞生长和/或迁移抑制药、凝血酶抑制药、免疫抑制剂、抗血小板聚集剂、胶原合成抑制药、治疗性抗体、一氧化氮供体、反义寡核苷酸、伤口愈合剂、治疗性基因转移构建体、肽、蛋白质、细胞外基质组分、血管舒张剂、溶血栓药、抗代谢药、生长因子激动药、抗有丝分裂剂、类固醇、类固醇类抗炎剂、趋化因子、增殖物激活受体γ激动药、增殖物激活受体α激动药、增殖物激活受体β激动药、增殖物激活受体α/β激动药、增殖物激活受体δ激动药、NFκβ、增殖物激活受体α-γ激动药、非类固醇类抗炎剂、抗血管紧张素转换酶(ACE)抑制药、自由基清除剂、CX3CR1受体的抑制药及抗癌症化学治疗剂。
17.一种制作医疗设备的方法，包括：
(a)混合包含聚L-丙交酯或聚D-丙交酯的基底聚合物的组合物，所述基底聚合物与包含嵌段二元共聚物形式或作为嵌段状无规二元共聚物的聚L(或D)-丙交酯-共-三-亚甲基碳酸酯或聚L(或D)-丙交酯-共-ε-己内酯的修饰性二元共聚物连接，其中所述丙交酯链的长度长到足以使得交联部分结晶以形成聚合物组合物；
(b)通过挤出设备挤出所述聚合物组合物；
(c)以包含药理药剂或生物药剂的包被物包被步骤(b)中的所述挤出的聚合物组合物；
(d)切割步骤(c)中的所述被包被的聚合物组合物，以在所述聚合物组合物中形成这样的模式，即所述模式具有可使得所述切割的结构皱缩、并且使得所述皱缩之后的切割结构膨胀成展开的构形的形状。
18.根据权利要求17的方法，在步骤(c)之后还包括步骤(c’)挤出同一种或另一种聚合物组合物至如步骤(c)中所包被的步骤(b)的挤出聚合物组合物上，这种共挤出的聚合物组合物包含药理药剂或生物药剂。
19.根据权利要求18的方法，其中步骤(c’)重复多次，以产生多层挤出物。
20.一种制作心血管用的可膨胀骨架的方法，包括：
混合包含可结晶组合物的聚合物组合物，所述可结晶组合物包含聚L-丙交酯或聚D-丙交酯的基底聚合物，所述基底聚合物与包含嵌段二元共聚物形式或作为嵌段状无规二元共聚物的聚L(或D)-丙交酯-共-三-亚甲基碳酸酯或聚L(或D)-丙交酯-共-ε-己内酯的修饰性二元共聚物连接，其中所述丙交酯链的长度长到足以使得交联部分结晶；
塑造所述聚合物组合物以在结构上形成所述骨架；
以包含药物的药物组合物和配体包被所述聚合物骨架；并且切割所述骨架以形成所需的模式。
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- 2007-10-20 EP EP07871194A patent/EP2073754A4/en not_active Withdrawn
- 2007-10-20 CN CN201310128411.4A patent/CN103212115B/zh active Active
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Also Published As
| Publication number | Publication date |
|---|---|
| CN103212115A (zh) | 2013-07-24 |
| WO2008070304A9 (en) | 2008-07-31 |
| EP2073754A4 (en) | 2012-09-26 |
| US9724864B2 (en) | 2017-08-08 |
| WO2008070304A3 (en) | 2008-09-18 |
| WO2008070304A2 (en) | 2008-06-12 |
| US8691321B2 (en) | 2014-04-08 |
| US20080206440A1 (en) | 2008-08-28 |
| CN103212115B (zh) | 2016-09-14 |
| CN101631513A (zh) | 2010-01-20 |
| US20150028513A1 (en) | 2015-01-29 |
| EP2073754A2 (en) | 2009-07-01 |
| US20180056569A1 (en) | 2018-03-01 |
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Effective date of registration: 20191101 Address after: Singapore City Patentee after: Obasnitz medical Sdn Bhd Address before: Florida, USA Patentee before: Orbusneich Medical, Inc. |