CN103122132B - 用于医疗器械的可生物吸收聚合物组合物 - Google Patents

用于医疗器械的可生物吸收聚合物组合物 Download PDF

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CN103122132B
CN103122132B CN201310025670.4A CN201310025670A CN103122132B CN 103122132 B CN103122132 B CN 103122132B CN 201310025670 A CN201310025670 A CN 201310025670A CN 103122132 B CN103122132 B CN 103122132B
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CN103122132A (zh
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G·L·萨奇尔
R·J·科顿
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Obasnitz medical Sdn Bhd
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Orbus Medical Technologies Inc
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Abstract

本发明提供了一种生物可降解的生物相容性无毒聚合物组合物，它包括一种基质材料以及一种共聚物或三聚物添加剂，所述基质材料例如可结晶的聚合物、共聚物或三聚物。本发明还提供了由该组合物制备的医疗器械。

Description

用于医疗器械的可生物吸收聚合物组合物
本申请是申请日为2007年07月20日的200780034751.3号发明专利申请(发明名称：用于医疗器械的可生物吸收聚合物组合物)的分案申请。
相关申请的互相参引
本申请要求享有2006年7月20日提交的美国临时申请60/807,932以及2006年10月20日提交的美国临时申请60/862,433的优先权。
本说明书中所引用的所有参考文献以及它们的参考文献，当适用于教导其它的或备选的详情、特征和/或技术背景时，通过引证的方式全文纳入本说明书中。
技术领域
在本发明的实施方案中公开了一种新的聚合物组合物，它包括一种基质材料以及一种聚合物或共聚物或三聚物添加剂，所述基质材料包括一种或多种可生物吸收的聚合物、共聚物或三聚物。具体而言，当这种新的组合物被用于制造植入物时，容许发生一种“软”降解机理，从而使得该组分聚合物的降解对周围组织的伤害较小。
背景技术
发现使用金属支撑管(stenting)中一个长期的问题是位于血管中的支架会形成瘢痕组织包被层，即所谓的再狭窄过程。此外，金属或聚合物非可吸收的支架会阻止血管管腔重塑和扩张。已尝试多种方法来避免或愈合组织损伤以及降低免疫反应的补体激活。而且，在植入物和/或其组分材料降解后需要降低炎症应答以及降低发生创伤的可能性。发现想要的改善目标为需要提高用于植入——特别是血管中植入——的医疗器械的形状和结构的柔性。
多种市售可生物吸收聚合物中包括聚-α-酯(例如丙交酯(即L-丙交酯和D，L-丙交酯))和乙交酯、聚酯醚(即聚二噁烷酮)以及聚碳酸酯(即乙交酯或丙交酯-共-碳酸亚丙酯(Tri-methylene-carbonate))以及基于酪氨酸的聚碳酸酯。正在开发可市售的特别是用于不同的给药模式的许多其它的可生物吸收聚合物，所述聚合物包括聚乙二醇-共-丙交酯、聚酐、聚原酸酯、聚酯-酰胺或氰基丙烯酸酯。
本发明的发明人已认识到需要开发一种相容性的共混聚合物用于植入物，例如支架和血管合成植入物；所述共混聚合物在该医疗器械体内使用时可向基质聚合物提供一种韧化机制。他们已假设韧化机制可通过赋予基质聚合物额外的分子自由体积以促进充分的分子运动来使得在生理条件下——尤其是当将其它分子作用力(molecularstrain)赋予该植入物时——发生重结晶而被实施。他们已建立理论认为，增加的分子自由体积也可提高水吸收的速率从而增加塑化效果以及提高本体降解动力学。
参引文献
参引2003年8月19日授权的美国专利6,607,548B2(InionLtd)，该文献公开了多种使用一种基于乳酸或乙醇酸的聚合物或共聚物与一种或多种共聚物添加剂共混而制得的组合物是可生物相容的且可生物再吸收的。据称根据该548专利公开内容制得的植入物为可冷弯曲(coldbendable)且无裂纹或破裂。还参引EP0401844，其公开了一种聚L-丙交酯与聚L-DL-丙交酯的混合物。还参引美国专利5,317,064，其公开了多种聚丙交酯立体复合组合物。
发明内容
本发明提供了这样一种新的聚合物组合物，该组合物可在体内进行“软”降解从而使得降解时对周围组织友好(例如更少的炎症应答以及使得植入物降解时创伤的可能降低)。该聚合物组合物包括一种基质材料以及一种共聚物或三聚物添加剂；所述基质材料如可生物吸收聚合物、共聚物或三聚物，根据它们在体内进行水解和/或酶促降解和吸收的能力进行选择。
所述新的聚合物组合物可包括一种共混聚合物，该共混物被优化以获得提高的亲水性从而减少补体激活并尽可能减小或避免调理作用(见DongandFeng，JotBiomedicalMaterialsResearchpartADOI10.1002，2006)。为了改善亲水性，可配制所述新的聚合物组合物以提供增加的分子自由体积，使得水的吸收以及水吸收的速率提高，从而增加塑化效果以及提高本体降解动力学。附加的分子自由体积也可用于促进充分的分子运动来使得在生理条件下——尤其是当将组合物上的作用力产生其它的分子作用力时——发生重结晶。
在一个实施方案中，提供了这样一种包括一种生物可降解支架的聚合物/共混聚合物植入物，该支架显示出卷曲地固定在载体系统上的柔性并在植入体内后显示出由于聚合物/共混聚合物结晶而引起的弹性支撑力。该植入物可包括，例如具有可安装于器官空间——例如血管系统，包括心血管系统——中的结构的管形可膨胀的支架。所述支架可具有平衡了弹性、刚性和柔性的机械性能。
在一个实施方案中，聚合物组合物和/或制剂含有一种作为基质的诸如聚(L-丙交酯)和/或聚(D-丙交酯)的聚合物或者其共聚物。对于共聚物组合物，该共聚物可以嵌段共聚物的形式或以“嵌段的”无规共聚物的形式合成。可选择共聚物的丙交酯链长度以使其充分长足以结晶。为了例如提高降解动力学而缩短的降解时间可通过使用较低分子量组合物和/或更具亲水性或可能进行水解链断裂的基质聚合物来获得。
任选地，所述实施方案组合物包括改性共聚物，其可被混合以连接基质聚合物；所述改性共聚物包括例如聚L(或D)-丙交酯-共-碳酸亚丙酯或聚L(或D)-丙交酯-共-ε-己内酯。在所述共聚物改性的共聚物实施方案中，该组合物使得可产生这样的晶体结构，即该晶体结构可提高医疗器械的机械性能、提高加工条件以及提供交联部分——例如作用力导致的热交联——结晶的可能。改性的聚合物或共聚物也可用于提高降解动力学，例如用一个ε-己内酯共聚物部分，其中己内酯仍为无定形的，而所得部分更易水解。
在另一个实施方案的组合物中，基质共聚物包括L-丙交酯/D-丙交酯，其中一个链部分足够长并且空间上不受阻，从而与另一个丙交酯的部分结晶。任选的与基质共聚物共聚的单体包括尺寸较小的部分，例如乙交酯、聚乙二醇(PEG)或单甲氧基封端的PEG(PEG-MME)。
在另一个实施方案中，可包括PEG共聚物，例如PEG部分约1％的AB二嵌段或ABA三嵌段，可在维持丙交酯的机械性能的情况下使用(见EnderlieandBuchholzSFBMay2006)。PEG或PEG-MME共聚物的引入也可用于促进药物附着到聚合物上，例如与药物洗脱医疗器械连接。
本发明实施方案中的亲水组合物想要容许适于一种“软”或非常缓慢的降解机理，从而使得降解进行时对周围组织友好(植入物降解时炎症应答更少以及使创伤的可能降低)。选择一种用于基质聚合物或添加剂或两者的具有提高的亲水性能的聚合物或共聚物，从而使得该共混聚合物可减少补体激活并尽可能减小或避免调理作用。
在一个实施方案的组合物中，选择聚合物以提供外消旋物或立体复合物晶体结构。例如，共聚物可以一个足以形成外消旋晶体结构的比例含有D-丙交酯和L-丙交酯。由所述聚合物组合物制得的支架可通过在从卷曲的状态膨胀至扩张或植入的状态的径向应变期间实现的分子再定向和结晶来提高机械性能。更具体而言，所述实施方案中的管状支架可在被卷曲到一个载体/植入器械上后于成更陡角度的曲折支柱处进行外消旋物结晶，同时在别处仍然保持基本无定形的基质。当管形支架包括箍结构时，可制备所述聚合物以能够在移植期间于正交展开延伸环或箍结构中结晶，对断裂产生强的抗性。
在另一个实施方案中，促进基质聚合物(如聚L-丙交酯或聚D-丙交酯)与分别具有相同的丙交酯部分的改性共聚物(如LPLA-TMC或DPLA-TMC)之间的交联部分结晶。
聚合物实施方案的组合物也可被改性以赋予医疗器械特定的功能。因此，该聚合物可含有药物形式或其它药剂形式的填充剂，例如内源酶的小分子抑制剂、不透射线标记物(粉末或其它合适的微粒)以及其它因子。
本发明的组合物可包括药剂如他克莫司(tacrolimus)、西罗莫司(sirolimus)、依维莫司(everolimus)、依前列醇(prostacyclin)、依前列醇类似物、α-降钙素基因相关多肽(α-CGRP)、α-降钙素基因相关多肽类似物或α-降钙素基因相关多肽受体激动剂，哌唑嗪(prazosin)，单核细胞趋化蛋白-1(MCP-1)，免疫抑制药如雷帕霉素(rapamycin)、抑制平滑肌细胞迁移和/或增殖的药物、抗凝血药如凝血酶抑制剂、免疫调节药如血小板因子4和CXC趋化因子，CX3CR1受体家族抑制剂，抗炎药、甾族化合物如双氢表雄甾酮(DHEA)、睾酮(testosterone)、雌激素如17β-雌二醇(17β-estradio1)，他汀类药物如辛伐他汀(simvastatin)和氟伐他汀(fluvastatin)，PPAR-α-配体如非诺贝特(fenofibrate)和其它降脂药物，PPAR-8和PPAR-γ激动剂如罗格列酮(rosiglitazone)，PPAR-双αγ激动剂、LBM-642、核因子如NF-κβ、胶原合成抑制剂、血管扩张药如乙酰胆碱(acetylcholine)、阿糖腺苷(adenosine)、5-羟色胺(5-hydroxytryptamine或serotonin)、P物质、肾上腺髓质素、促使内皮细胞生长以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剂如米哚妥林(Midostaurin)和伊马替尼(imatinib)或任何抗血管新生抑制剂化合物，抑制成熟白细胞粘附的肽或抗体、抗生素/杀菌剂以及其它物质如速激肽、神经激肽或唾液腺激肽(sialokinin)、速激肽NK受体激动剂，PDGF受体抑制剂如MLN-518及其衍生物、丁酸及丁酸衍生物葛根黄素(puerarin)、纤连蛋白、红细胞生成素(erythropoietin)、达贝泊汀(darbepotin)、丝氨酸蛋白酶-1(SERP-1)等。
本发明实施方案中包括由所述聚合物组合物制得的器械。所述器械包括植入患者体内的医疗器械，例如但不限于生物可降解的支架、支架移植物、血管合成移植物、矫形外科装置、神经导管、颌面颅器械、导管、血管分流器或瓣膜。所述器械可具有可生物吸收性能。所述植入器械可包括用于将植入物植入体内的结构。例如，所述植入物可包括使得该医疗器械的合适部件之间相互作用的卡扣结构以使得该器械保持在一种小尺寸的状态，该状态可帮助其植入，并且可帮助其与用于其植入的载体装置之间的相互作用(例如确保其在载体装置上而无移动)。
本发明的实施方案也涉及制备生物可降解聚合物组合物的方法以及由本文所公开的聚合物组合物制备医疗器械的方法。
因此，本发明具体地涉及以下各项：
1.一种可结晶的可生物吸收聚合物组合物，包括：一种选自聚(L-丙交酯)部分和/或聚(D-丙交酯)部分以及/或者其嵌段共聚物或嵌段无规共聚物的基质聚合物。
2.根据第1项的可结晶的可生物吸收聚合物组合物，还包括一种连有改性共聚物的基质聚合物，该基质聚合物包括聚(L-丙交酯)部分和/或聚(D-丙交酯)部分；所述改性共聚物包括嵌段共聚物形式或嵌段无规共聚物形式的聚(L-丙交酯-共-碳酸亚丙酯)或聚(D-丙交酯-共-碳酸亚丙酯)和(L-丙交酯-共-ε-己内酯)或聚(D-丙交酯-共-ε-己内酯)，其中丙交酯链长度足以使得进行交联部分结晶。
3.根据第1项的可结晶的可生物吸收聚合物组合物，其中该聚合物组合物熔体在聚L和聚D丙交酯部分之间形成丙交酯外消旋物立体复合物晶体结构。
4.根据第1项的可结晶的可生物吸收聚合物组合物，其中该聚合物组合物熔体通过以下部分形成丙交酯外消旋物立体复合物晶体结构，所述部分包括：
连有聚(L-丙交酯-共-碳酸亚丙酯)或聚(L-丙交酯-共-ε-己内酯)的聚L-丙交酯与聚D-丙交酯；
连有聚(L-丙交酯-共-碳酸亚丙酯)或聚(L-丙交酯-共-ε-己内酯)的聚D-丙交酯；
连有聚(D-丙交酯-共-碳酸亚丙酯)或聚(L-丙交酯-共-ε-己内酯)的聚L-丙交酯；
连有聚(D-丙交酯-共-碳酸亚丙酯)或聚(L-丙交酯-共-ε-己内酯)的聚L-丙交酯与聚D-丙交酯；
连有(聚D-丙交酯-共-碳酸亚丙酯)或聚(L-丙交酯-共-ε-己内酯)的聚L-丙交酯-共-PEG；以及
连有聚(L-丙交酯-共-碳酸亚丙酯)或聚(L-丙交酯-共-ε-己内酯)的聚D-丙交酯-共-PEG。
5.根据第1项的可结晶的可生物吸收聚合物组合物，其中所述基质聚合物以重量计占该组合物的约70％至约85％、或约70％至约80％。
6.根据第1项的可结晶的可生物吸收聚合物组合物，其中所述基质聚合物的70重量％为聚L-丙交酯且30重量％为改性共聚物聚L-丙交酯-共-TMC。
7.根据第1项的可结晶的可生物吸收聚合物组合物，其中所述改性共聚物不高于该组合物的约40％。
8.根据第1项的可结晶的可生物吸收聚合物组合物，其中该组合物的残留单体浓度小于0.5％或优选小于0.3％。
9.一种可生物吸收的支架聚合物，包括一种可结晶的组合物，该组合物包括一种连有改性共聚物的聚L-丙交酯或聚D-丙交酯的基质聚合物；所述改性共聚物包括嵌段共聚物形式或嵌段无规共聚物形式的聚L(或D)-丙交酯-共-碳酸亚丙酯或聚L(或D)-丙交酯-共-ε-己内酯，其中丙交酯链长度足以进行交联部分结晶。
10.根据第9项的可生物吸收的支架聚合物，其中所述基质聚合物以重量计占该组合物的约60％至约90％、或约70％至约80％。
11.根据第9项的可生物吸收的支架聚合物，其中所述基质聚合物的70重量％为聚L-丙交酯且30重量％为改性共聚物聚L-丙交酯-共-TMC。
12.根据第9项的可生物吸收的支架聚合物，其中所述改性共聚物不高于该组合物的约40％。
13.根据第9项的可生物吸收的支架聚合物，其中该组合物的残留单体浓度小于0.5％或优选小于0.3％。
14.根据第9项的可生物吸收的支架聚合物，其中该组合物被制备成在结构上可在聚合物基质内包含或结合药物。
15.根据第9项的可生物吸收支架聚合物，其中该药物或其它添加剂可通过共价键、非极性键以及酯或类似的生物可逆结合而被结合。
16.一种用于心血管的可膨胀的管状支架的聚合物组合物，其中所述支架包括一种连有改性共聚物的聚L-丙交酯或聚D-丙交酯的基质聚合物；所述改性共聚物包括嵌段共聚物形式或嵌段无规共聚物形式的聚L(或D)-丙交酯-共-碳酸亚丙酯或聚L(或D)-丙交酯-共-ε-己内酯，其中丙交酯链长度足以进行交联部分结晶。
17.根据第16项的组合物，其中所述支架包括一种以重量计占该组合物约60％至约90％、或约70％至约80％的基质聚合物。
18.根据第16项的组合物，其中所述支架包括一种具有70重量％聚L-丙交酯与30重量％改性共聚物聚L-丙交酯-共-TMC的基质聚合物。
19.根据第16项的组合物，其中所述改性共聚物不高于该组合物的约40％。
20.根据第16项的组合物，其中该支架显示出通过刚性和柔性特征的结合而具有的结构弹性，以使得该聚合物器械的合适部件之间具有卡扣的相互作用。
21.根据第16项的组合物，其中该组合物的残留单体浓度小于0.5％或优选小于0.3％。
22.一种可生物吸收的聚合物植入物，包括一种在单一步骤中熔融共混挤压制备的聚合物组合物，该聚合物组合物包括一种可结晶的组合物，该可结晶的组合物包括一种包括了聚(L-丙交酯)部分和/或聚(D-丙交酯)部分以及/或者其共聚物的基质聚合物。
23.制备一种根据第22项的可生物吸收的聚合物植入物的方法，还包括：
将一种包括一种可结晶组合物的聚合物组合物共混，所述可结晶组合物包括一种连有改性共聚物的基质聚合物，所述基质聚合物包括聚(L-丙交酯)部分和/或聚(D-丙交酯)部分；所述改性共聚物包括嵌段共聚物形式或嵌段无规共聚物形式的聚(L-丙交酯-共-碳酸亚丙酯)和/或聚(D-丙交酯-共-碳酸亚丙酯)和/或聚(L-丙交酯-共-ε-己内酯)和/或(D-丙交酯-共-ε-己内酯)，其中丙交酯链长足够长以便于发生交联部分结晶；
将所述聚合物组合物成型或挤出形成所述具有管状结构的植入物；以及
切割所述植入物以形成所需式样。
24.根据第23项的方法，其中所述聚合物组合物通过刚性和柔性特征的结合而影响结构弹性，以使得该聚合物器械的合适部件之间具有卡扣相互作用。
25.根据第23项的方法，其中该聚合物组合物熔体在L-丙交酯和D-丙交酯部分之间形成丙交酯外消旋物立体复合物晶体结构。
26.根据第23项的方法，其中该聚合物组合物在以下各部分之间形成丙交酯外消旋物立体复合物晶体结构，所述部分包括：
连有聚(L-丙交酯-共-碳酸亚丙酯)或聚(L-丙交酯-共-ε-己内酯)的聚D-丙交酯和聚L-丙交酯；
连有聚(L-丙交酯-共-碳酸亚丙酯)或聚(L-丙交酯-共-ε-己内酯)的聚D-丙交酯；
连有聚(D-丙交酯-共-碳酸亚丙酯)或聚(L-丙交酯-共-ε-己内酯)的聚L-丙交酯；
连有聚(D-丙交酯-共-碳酸亚丙酯)或与聚(L-丙交酯-共-ε-己内酯)的聚D-丙交酯和聚L-丙交酯；
连有(聚D-丙交酯-共-碳酸亚丙酯)或聚(L-丙交酯-共-ε-己内酯)的聚L-丙交酯-共-PEG；以及
连有聚(L-丙交酯-共-碳酸亚丙酯)或聚(L-丙交酯-共-ε-己内酯)的聚D-丙交酯-共-PEG。
27.根据第23项的方法，其中所述改性共聚物不高于该组合物的约40％。
28.根据第23项的方法，其中该组合物的残留单体浓度小于0.5％或优选小于0.3％。
附图说明
图1图示了LPLA/LPLA/TMC非外消旋混合物与仅交联部分外消旋的DPLA/LPA/TMC和具有其它外消旋结构的DPLA/LPLA/LPLA-TMC的再结晶的模数变化；
图2A和图2B分别图示了外消旋聚合物和无外消旋结构的聚合物的DSC曲线：如图所示，显示出外消旋熔化物的+外消旋物曲线和-外消旋物曲线明显不同。
图3A-3G图示了支架医疗器械的不透射线标记储存处的实施方案方法：如(a)-(d)中所示，不透射线材料可被挤入装置(g)中所含的空穴中。如截面图(e)和(f)所示，所述空穴可为一个透孔。
图4A-4C图示了具有不透射线标记物的支架的不同支架式样。如图所示，不透射线标记物可被置于支架式样上的不同位置，同时仍可用不透射线检测方法进行检测。
图5A和图5B图示了具有不透射线标记物的支架材料的平面图。如图5A和图5B所示，不透射线标记物可被排列成在成像时或使用其它检测方法时更容易识别的结构。
图6示出了具有实施方案中所述的不透射线标记物式样的实际支架的总透视图，所述不透射线标记物式样各自位于曲折支柱的连接点处。图7示出了图6的被不透射线标记的支架的一部分的近视图。
图8示出了配置于带囊导管上的本发明的支架实施方案的透视图。
图9图示了包含环结构的充分膨胀的可生物吸收支架，该环结构表示充分结晶的定位(holding)环或箍。
图10A和图10B图示了表明单Tg的DSC热流曲线，并且10B示出了表明双Tg的DSC热流曲线。
具体实施方式
在本文的实施方案中，举例说明了多种用于可生物吸收共混聚合物的组合物、制备该组合物的方法以及由所述可生物吸收共混聚合物制得的医疗器械。
现将以下命名法以及基于所存在的单体类型的聚合物命名法一起使用。
LPLA：聚(L-丙交酯)
LPLA-PEG：聚(聚-L-丙交酯-聚乙二醇)
DPLA：聚(D-丙交酯)
DPLA-TMC：聚(聚-D-丙交酯-共-碳酸亚丙酯)
DLPLA：聚(DL-丙交酯)，外消旋共聚物D-共-L-丙交酯
LDPLA：聚(L-共-D-丙交酯)
LDLPLA：聚(L-共-D-丙交酯)，根据单体引入的方法命名
PGA：聚(乙交酯)
PDO：聚(二噁烷酮)(商标为PDS)
SR：“自增强”(一种加工方法)
TMC：碳酸亚丙酯
PCL：聚(ε-己内酯)
LPLA-TMC：聚(聚L-丙交酯-共-碳酸亚丙酯)
LPLG：聚(L-丙交酯-共-乙交酯)
POE：聚原酸酯
在本发明的一个实施方案中，该组合物包括一种聚(L-丙交酯)或聚(D-丙交酯)的基质聚合物。有利的基质聚合物组合物包括聚(L-丙交酯)和聚(D-丙交酯)的共混物。其它有利的基质聚合物组合物包括含有单体摩尔配比为10-30％的D，L-丙交酯的聚(L-丙交酯-共-D，L-丙交酯)或聚(D-丙交酯-共-D，L-丙交酯)，以及含有单体摩尔配比为10-20％的乙交酯的聚(L-丙交酯-共-乙交酯)或聚(D-丙交酯-共-乙交酯)。
另一个实施方案体现一种基质聚合物，其特征为改性共聚物连接于基质聚合物的聚(L-丙交酯)部分和/或聚(D-丙交酯)部分上；所述改性共聚物包括嵌段共聚物形式或嵌段无规共聚物形式的聚(L-丙交酯-共-碳酸亚丙酯)或聚(D-丙交酯-共-碳酸亚丙酯)和(L-丙交酯-共-ε-己内酯)，或者聚(D-丙交酯-共-ε-己内酯)，其中丙交酯链的长度足以进行交联部分结晶。
在另一个实施方案中，该聚合物组合物使得在L和D部分之间形成丙交酯外消旋物(立体复合物)晶体结构，以进一步提高可生物吸收聚合物医疗器械的机械性能。该外消旋物(立体复合物)晶体结构的形成可由例如以下的物质的配制得到：
聚L-丙交酯与聚D-丙交酯与聚L-丙交酯-共-TMC；
聚D-丙交酯与聚L-丙交酯-共-TMC；
聚L-丙交酯与聚D-丙交酯-共-TMC；
聚L-丙交酯与聚D-丙交酯与聚D-丙交酯-共-TMC；
聚L-丙交酯-共-PEG与聚D-丙交酯-共-TMC；以及
聚D-丙交酯-共-PEG与聚L-丙交酯-共-TMC。
该实施方案的聚丙交酯外消旋组合物可具有一个特别有利的特征，该特征在于该组合物“可冷形成或弯曲”而不需加热。本发明的可冷弯曲支架不需要加热就可变得足够柔韧以卷曲于载体装置上或容纳在不规则形状的器官空间内。冷弯曲环境温度被定义为不超过30℃的室温。可冷弯曲支架，例如在进行移植时可提供足够的柔性，从而使得膨胀的支架器械可进入器官空间如搏动的血管腔中。例如对于支架而言，需要利用这样的聚合物组合物，它在制造后提供大部分的无定形聚合物部分，该部分可结晶——特别是当二级嵌套或末端定位的曲折支柱时，同时该支架在为植入而进行球囊扩张时由于被拉伸而拉紧。实施方案的所述可冷弯曲的聚合物支架不易碎并且在植入体内的具有表面轮廓的空间上之前不必预热即可处于柔韧的状态。可冷弯曲性使得这些共混物可在室温下进行卷曲且无裂纹；并且此外，这些共混物可在生理条件下进行卷曲且无裂纹。
可加工本发明实施方案的聚-丙交酯外消旋组合物和非外消旋组合物以具有嵌段部分，从而使得甚至在将抗压改性剂加入该共混组合物的情况下交联部分结晶。所述共混物使得通过获得单Tg或双Tg的(熔融玻璃转化温度)来设计专用于器械的聚合物组合物或共混物成为可能。
相对于例如非外消旋PLDL-丙交酯共混物，聚-丙交酯外消旋组合物可表现出再结晶能力的显著改进。不同聚丙交酯部分的有利外消旋物排列可例如通过将聚-D-丙交酯与共聚物聚L-丙交酯-共-TMC共混来实现，所述共聚物能形成不同聚丙交酯立体部分间的外消旋晶体，例如但不限于在扩张到所需安装直径的过程中进行膨胀时。该作用力引起无有害裂纹的结晶，导致了机械性能的提高，这也反映在模数数据相对于基质材料的基数发生正向变化。
具有共聚物的组合物的交联部分结晶似乎限于单体摩尔配比范围为约90∶10至50∶50的共聚物。实际上，以50∶50的摩尔比，该聚合物部分在空间上阻碍了结晶，而较大的比例远远更适合于交联部分结晶。基于实验诱导的结晶，向具有多种丙交酯共聚物(如TMC或εCL)浓度的不同共混物中加入为了与L-丙交酯组分外消旋排列的过量的聚(D-丙交酯)，在外消旋组合物中该共聚物的有效浓度可等于或小于40％。因此，通过交联部分结晶所形成热交联可以减少伸长或蠕动，同时保持想要的韧化结构。有利地浓的外消旋组合物提高了拉伸试验中的模数数据，从而避免使用降低共混聚合物中拉伸强度的方法。
有利的外消旋组合物实施方案提供了一种就高残留单体水平而言降解作用最小的可生物吸收聚合物，使得污染物单体残留分数不超过约0.5％或优选不超过约0.3％。在实施方案中，本发明聚合物的单体污染物的浓度低至约0.2％。
本文所述实施方案的聚合物组合物可包括一种以该组合物的重量计约70％至95％、或约70％至80％存在的基质聚合物。例如，在一个实施方案中，该聚合物制剂可包括约70重量％的聚L-丙交酯(约2.5至3IV)与聚L-丙交酯-共-TMC(70/30摩尔/摩尔)(1.4至1.6IV)。在另一个实施方案中，该聚合物制剂可包括70重量％的三嵌段聚L-丙交酯-共-PEG(99/01摩尔/摩尔)(2.5至3IV)与聚L-丙交酯-共-TMC(70/30摩尔/摩尔)(1.4至1.6IV)。此外，该聚合物组合物可包括一种占约70重量％的二嵌段聚L-丙交酯-共-PEG-MME(95/05摩尔/摩尔)(2.5至3IV)与聚L-丙交酯-共-TMC(70/30摩尔/摩尔)(1.4至1.6IV)的制剂。其它实施方案提供了一些其中在组合物中用ε-己内酯替代前述TMC的制剂。类似地，一个实施方案可提供其中可用PEG-MME替代PEG的制剂。
正如该领域所理解的，可定制本发明的聚合物组合物以适应所选定的医疗器械的多种需求。所述需求包括机械强度、弹性、柔性、弹回性以及在生理和局部解剖条件下的降解速率。一种具体组合物的其它效果涉及代谢产物的溶解度、亲水性和水吸收以及基质附着或包含的药物的任何释放率。
聚合植入物的效用可通过测量质量损失、分子量降低、机械性能的保持和/或组织反应来评估。对于支架性能来说更关键的是水解稳定性、热转化结晶度和取向。对支架性能造成不利影响的其它决定因素包括但非限于单体杂质、环状的和非环状的低聚物、结构缺陷和陈化。
由以上聚合物组合物形成的医疗器械可在挤出或成型后可为显著无定形的。所述器械可进行受控再结晶以引起结晶度的增量和机械强度增强。其它结晶可通过在器械膨胀时引入拉力而引起。所述增加的再结晶可于二次或最终制造(例如通过激光切割)之前在器械“空白处”上进行或于所述二次制造之后使用。结晶化(以及由此产生的机械性能)也可通过在进一步制造之前诱导作用力而被最大化，所述作用力的诱导通过例如“冷”拉伸聚合物管、中空纤维、板或薄膜或者单丝实现。已观察到结晶度可为该医疗器械提供更大的刚性。因此，该支架的聚合物组合物和空间复合物既具无定形部分又有次晶部分。最初半结晶的聚合物部分可通过对给定器械进行拉伸或扩张的行为来处理。然而足量的无定性聚合物特征是该聚合物器械的柔性和弹性所需的。常规单体组分包括丙交酯、乙交酯、己内酯、二噁烷酮和碳酸亚丙酯。
在一个实施方案中，由所述组合物制造的医疗器械为一种用于植入体内的支架支柱结构，例如支架。这些结构将是可卷曲的以环绕拉紧并从而固定于载体装置上。相反，相同的支架是可膨胀的而无应力裂纹或断裂。支架可生物降解的支架植入物的机械性能要求强度、弹性和柔性以在所想要的支架支柱逐渐可生物降解和吸收的整个过程中应对周围组织的波动脉冲压缩，而在植入位点处不发生位错和有害冲击。因此，从某些标准来说必须使支架聚合物内含物和结构具有这些性能。该支架应该能够通过一个热增强气囊或非热气囊而膨胀的聚合物性能。该聚合实施方案提供当通过例如气球膨胀而在膨胀时的正交应变作用下在支架支柱中定向和/或结晶的能力。因此，结晶效应提供了改善的机械性能例如周向强度，如压缩阻力、弹性反冲以及聚合物稳定性中的周向强度。该支架也可被建造成使其在生物吸收期间相对均匀地暴露于局部组织或布满并作用于聚合物结构的循环性生物活性因子以及酶。
有利地，器官空间植入物(例如心血管支架)的聚合基质的原位降解动力学速率，可足够平缓以避免组织过载、炎性反应或其它更多的不利后果。在一个实施方案中，该支架被制造成存在至少一个月。
如以下实施例所示，可将相当程度的无定形和结晶特性设计入聚合物中。由此，发现L-丙交酯聚合物产生半结晶形态学，而外消旋的聚(D，L-丙交酯)产生了无定形聚合物。聚(L-乙交酯)为半结晶。以下实施例示出了一种制备可生物吸收支架PLDL-丙交酯共混物的方法。
实施例1：
由聚(L-丙交酯)和聚(D-丙交酯)的外消旋混合物的组合物注射浇铸一个试验圆片，所述组合物中含有15重量％50∶50摩尔比的聚(L-丙交酯-共-TMC)的共聚物改性剂。压射缸温度在110℃与225℃之间，并且成型温度为50°F至82°F，以浇铸无定形圆片。注射压力设定在1300与1450psi之间，且循环时间为50秒。发现可在该聚合物中得到合适的结晶度。DSC分析证实了常规丙交酯晶体和外消旋晶体形态学的形成。
实施例2：
将该聚合物混合物共混挤入窄管中，并且可用激光在显微镜下切成支架形式，以制得一种与位于器械一端和/或中间部分处的箍状环相连的曲折支柱的笼状网筛器械。所得到的支架器械包括一个形成周缘筛网结构的一级曲折支柱，所述筛网结构包含第二曲折支柱式样，所述式样位于支架内并位于该支架末端处或接近其末端处。可制造第二曲折支柱以在植入物完全膨胀时在垂直于管形器械纵向轴的方向上形成与第一曲折支柱相比具有更小正弦曲线或更直的箍或环状形状。具有较小或较短曲折箍或曲线的膨胀的第二曲折支柱在膨胀期间被进一步拉伸。这些支柱由此可形成具有更大结晶度并因此具有更大刚性及弹性的箍，从而使得该植入物对蠕动变化或移位具有抗性。
实施例3：
聚合物组合物可由市售的颗粒材料和共聚物添加剂制备。根据想要的重量比将干的组分称量放入一个容器中，将该容器进行30分钟或直到获得均一混合物的合适旋转，随后在真空、60℃下进一步干燥8-12小时或过夜。如上所述，可将已充分混合的组分熔融共混并注射浇铸入一对匹配盘中。使得聚合物板在偏振光源下表现出合适的弹性以及无定形形态学的外观或极低的结晶度的组合物可于120-160℃的熔化温度下用40-50巴的后压力挤出，同时将其用28叶螺旋桨以40-80rpm的转速均质化。在该方法的测定阶段期间该材料的挤压熔融共混和均质化条件可包括60-100rpm的转动速度。相对温和的注射浇铸法可使用120℃-150℃的出口温度、80-300mm/s的速率、2500巴的最大注射压、3至8秒1000-2300巴的充填压力、进入铸模内时保持室温。从注射到由铸模盘排出的总循环时间可为一分钟或更短。
实施例4：
将聚(D-丙交酯)和聚(L-丙交酯-共-TMC)的干的聚合物外消旋混合物以70∶30的重量比共混并在185-225℃下用单熔融挤塑步骤进行处理，成为管状无定形可生物吸收外消旋的共混聚合物。由于过多暴露于热和剪应力下，本实施例的熔融挤塑方法使得聚合物的降解最小化。随后的试验表明了结晶的有效诱导以及外消旋晶体形态的形成。已发现所述外消旋的共聚杂化物可用来证实有效的交联部分结晶。此外，外消旋材料可制造成具有象征多形态和或多晶结构的多个转化温度。由此，已发现本实施例的聚合物支架十分柔韧而能卷曲于橡胶球形载体上，但对于组织内的展开而言，聚合物部分的强度可随着膨胀应变成比例增加。
实施例5：
在干氮气下将含有外消旋的过量聚(D-丙交酯)的干的聚(L-丙交酯)与30重量％的聚(L-丙交酯-共-TMC)共混，随后进行熔体混合并挤出，然后进行快速空气急冷。随后的再结晶和测试证实了相对于实施例4的制剂而言显著更多的外消旋物的形成以及模数的提高。
合成受几种不同因素的影响，这些因素影响适用于可移植结构的可生物吸收聚合物机械性能；所述因素例如单体选择、引发剂选择、聚合条件以及添加剂或残留物的存在。此外，决定植入物效果的聚合特性包括亲水性、结晶度、熔化和玻璃化转变温度、分子量、分子量分布、端基、序列分布(即无规的和嵌段的)、残留单体或添加剂的存在、以及转化期间的稳定性。
在一个实施方案中，药物组合物可通过例如接到聚合物活性位点或涂覆的方式被加入到聚合物中。本发明聚合物的一个实施方案将生物愈合因子或其它药物附着或加入到聚合物基质或聚合物涂层中。
在另一实施方案中，该组合物可被制造，以使其在聚合物基质中结构上包含或附着药物。所述添加剂的目的可为，例如通过使用支架，提供心血管系统或在与医疗器械聚合物接触的血管位点处的治疗。聚合物中药物的包含或附着类型可决定其由该器械释放的速率。例如，在聚合物基质中可通过多种已知方法结合该药物或其它添加剂，所述方法包括但不限于共价键、非极性键以及酯或类似的生物可逆结合方式。
可植入装置的可生物吸收聚合物支架的实施方案被认为可用于药物递送。因此如下所述，许多化合物都是可用于在植入处治疗或缓解受伤组织以及可进一步例如在整个心血管系统或其它受伤器官中治疗或缓解受伤组织的药剂。
可被加入到基质和/或注入到医疗器械中的化合物或药物组合物的实例，包括但不限于他克莫司、西罗莫司、依维莫司、依前列醇、依前列醇类似物、α-降钙素基因相关多肽(α-CGRP)、α-降钙素基因相关多肽类似物或α-降钙素基因相关多肽受体激动剂，哌唑嗪，单核细胞趋化蛋白-1(MCP-1)，免疫抑制药如雷帕霉素、抑制平滑肌细胞迁移和/或增殖的药物、抗凝血药如凝血酶抑制剂、免疫调节药如血小板因子4和CXC趋化因子，CX3CR1受体家族抑制剂，抗炎药、甾族化合物如双氢表雄甾酮(DHEA)、睾酮、雌激素如17β-雌二醇，他汀类药物如辛伐他汀和氟伐他汀，PPAR-α-配体如非诺贝特和其它降脂药物，PPAR-δ和PPAR-γ激动剂如罗格列酮，PPAR-双αγ激动剂、LBM-642、核因子如NF-kβ、胶原合成抑制剂、血管扩张药如乙酰胆碱、阿糖腺苷、5-羟色胺(5-hydroxytryptamine或serotonin)、P物质、肾上腺髓质素、促使内皮细胞生长以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剂如米哚妥林(Midostaurin)和伊马替尼(imatinib)或任何抗血管新生抑制剂化合物，抑制成熟白细胞粘附的肽或抗体、抗生素/杀菌剂以及其它物质如速激肽、神经激肽或唾液腺激肽、速激肽NK受体激动剂，PDGF受体抑制剂如MLN-518及其衍生物、丁酸及丁酸衍生物葛根黄素、纤连蛋白、红细胞生成素、达贝泊汀、丝氨酸蛋白酶-1(SERP-1)等。上述化合物和药物可被单独或者以其结合物和/或混合物的方式施用到器械的支架上。此外，聚合物附着或包含的药物物质可以共价键或离子键的方式结合到聚合部分上以及物理包埋于聚合物基质中。只要合适，该药物可以酯型交联物、微粒或胶束簇的形式存在。
在一个实施方案中，可生物吸收可植入医疗器械用含有一个或多个隔离层的可生物降解和生物可吸收涂层覆盖，其中聚合物基质含有一种或多种前述药物物质。在该实施方案中，隔离层可包括一种合适的可生物降解材料，包括但不限于，合适的可生物降解聚合物，其包括：聚酯如PLA、PGA、PLGA、PPF、PCL、PCC、TMC以及这些物质的任何共聚物；聚羧酸、包括马来酐聚合物在内的聚酐；聚原酸酯；聚氨基酸；聚环氧乙烷；polyphosphacene；聚乳酸、聚羟基乙酸，以及它们的共聚物和混合物如聚(L-乳酸)(PLLA)、聚(D，L-丙交酯)、聚(乳酸-共-羟基乙酸)、50/50(DL-丙交酯-共-乙交酯)；聚二噁烷酮；聚富马酸亚丙酯；聚羧酚酸肽(polydesipeptide)；聚己内酯以及其共聚物和混合物如聚(D，L-丙交酯-共-己内酯)和聚己内酯共-丙烯酸丁酯；聚羟基丁酸酯戊酸酯(polyhydroxybutyratevalerate)和混合物；聚碳酸酯如酪氨酸衍生的聚碳酸酯和芳基化物(arylate)、聚亚氨基碳酸酯，以及聚二甲基三甲基-碳酸酯；氰基丙烯酸酯；磷酸钙；聚葡糖胺多糖；大分子如多糖(包括透明质酸；纤维素以及羟丙基甲基纤维素；明胶；淀粉；葡聚糖；藻酸盐及它们的衍生物)、蛋白质和多肽；以及前述任意物质的混合物和共聚物。可生物降解聚合物也可为一种表面可蚀解聚合物，例如聚羟基丁酸酯及其共聚物、聚己内酯、聚酐(晶体和无定形两种)、马来酐共聚物以及磷酸锌钙。器械上聚合物支架可具有的隔离层的数目取决于患者所需疗法所要求的治疗需求量。例如，治疗时间越长，在一段时间内所需要的治疗物质越多，隔离层越多，从而适时地提供医药物质。
在另一个实施方案中，该聚合物组合物中的添加剂可以多组分医药组合物的形式存在于基质中，例如含有一种快速释放药剂以阻碍早期新内膜增生(neointimalhyperplasia)/平滑肌细胞迁移和增殖的基质，以及一种用于释放维持血管通畅的长效剂或积极的血管重塑剂的二次生物稳定基质；所述积极的血管重塑剂例如内皮型一氧化氮合酶(eNOS)、一氧化氮供体以及衍生物如阿司匹林(aspirin)或其衍生物，生成一氧化氮的水凝胶，PPAR激动剂例如PPAR-α配体，组织纤维蛋白溶酶原激活剂，他汀类药物如阿托伐他汀(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)，甾族化合物，以及/或者抗生素。
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，所述方法包括向需要此类医药物质的患者局部施用该物质。该方法包括将具有涂层的本发明医疗器械植入患者的血管或具有空腔的器官中，所述涂层包括一种药物组合物，该药物组合物含一种用于抑制或减缓平滑肌细胞迁移并从而抑制或减缓再狭窄的药物或物质，以及一种生物相容的、可生物降解的、可生物蚀解的、无毒的聚合物或非聚合物基质，其中该药物组合物包括一种用于延缓释放该药物的缓慢或控制释放的制剂。该医疗器械上的涂层也可包括一种配体，例如一种用于在该器械腔表面上捕捉诸如内皮细胞和/或祖细胞的细胞抗体，从而形成一种功能性内皮。
可由本发明公开内容的组合物制备的医疗器械可包括任何用于植入的医疗器械，所述用于植入的医疗器械包括但不限于支架、植入物、支架植入物、合成的血管植入物、分流器、导管等。本发明的医疗器械实施方案可提供这样一种药物递送系统，该系统的特征在于用于有效治疗组织或器官结构中移植位点上的药物或药物混合物的不同的逐步释放速率。所述器械也可在该组合物或由该组合物组成的结构中包括提高该医疗器械原位追踪能力的不透射线物质。所述不透射线物质可包括可能干扰想要的愈合过程的无毒材料。
本发明的医疗器械可在结构上成形以提供改变的能力并使其适应植入区域，以进行标准的局部组织重建。该医疗器械可由固态转化为“橡胶态”，这样可进行较之于例如不锈钢支架而言更容易的外科手术。此外，该器械的橡胶状态使得在将其从血管位置移出时血管壁遭受任何损伤的风险较小。
在本文中所公开的实施方案中，该医疗器械包括一个支架，其具有被展开入例如动脉或静脉中、并能原位膨胀、且适应血管腔，从而在损伤位点处重建血管连续性的结构。该支架形成的结构使其具有多种不同的排列，从而使得其在填充时可卷曲并在生理条件下一旦展开即可膨胀和具有柔性。如共同未决的专利申请中所解释说明的那样，可预想具有不同构造的可生物降解的聚合物支架和/或支架壁的多种实施方案。例如，该支架为管状结构，其包括可行地设计用于使得血液穿过其壁的支柱，从而使得当血液流动通过该区域时相邻组织被浸没或者与其接触。具体的支架设计取决于支架的半径大小和纵向大小。
关于支架，该聚合物的组合物可设计为能提供一种刚性、弹性和柔性的组合，从而使得该支架的原位作用引起有效的用于心血管体系的愈合和药物治疗的管腔支撑。具体而言，关于支架，可调整并选择该聚合物的组合物，从而使其提供足以抵抗波动性血管压缩力和血流速度的聚合物强度。该结构强度和弯曲强度可设计成在长达多日或几个月的聚合材料原位生物蚀解期间持续不变。该聚合物的残余强度可在经处理血管断裂之前适当测定至少足够的时间来监测并维持愈合过程正常。用于支架的组合物可被设计用于在血管位置中提供由最初刚性支撑的性质到橡胶状或“橡胶态”稠度的缓慢转变，所述稠度可维持临床功能，如防止再狭窄。该聚合物组合物可被进一步选择以提供接近以及远离涉及血管的区域的光滑聚合表面，从而使组织刺激或损伤最小化并因此不会引起临床上显著的免疫应答。可选择聚合物以使气球驱动的膨胀发生。所述可膨胀的医疗器械可包括热气球或非热气球，其中该医疗器械可具有一种在填充期间可卷曲并且可在生理条件下膨胀的而无应力裂纹的结构。有利地，可选择聚合物组合物以在施用应力时——例如在气球膨胀期间——定向和/或结晶，从而改善其机械性能。
通过仔细选择医疗器械的聚合物组合物和结构构造，可使免疫原性和炎症应答降至最低。例如，如果该器械成形为不具有突出的轮廓，则可排除或至少使聚合抗原性和结构抗原性最少，以减缓免疫应答。类似地，通过选择合适比例的合适共聚物，组成医疗器械的聚合物的降解产品对于宿主如血管壁而言，可更“友好”或者具有更小的刺激性或免疫原性。当该聚合物组合物被设计为可引发缓慢的降解动力学时，可避免移植位点处的组织过载或其它炎症应答。
本发明所进一步公开的为一种制造本发明的可生物吸收医疗器械的方法，所述方法包括：将一种含有与改性共聚物相连的聚L-丙交酯或聚D-丙交酯的基质聚合物的可结晶的组合物共混，所述改性共聚物包括嵌段共聚物或嵌段无规共聚物形式的聚L(或D)-丙交酯-共-碳酸亚丙酯或聚L(或D)-丙交酯-共-ε-己内酯，其中丙交酯链长足够长以便于发生交联部分结晶；将该聚合物组合物成型以使所述植入物结构成形；并且切割该植入物以形成所需式样。
制备本申请医疗器械的另一种方法包括：制备一种生物可降解的聚合物结构；设计所述聚合物结构以使其具有能够植入患者体内的形状；将所述结构切割成能使该器械穿过开口并使该器械卷曲的式样(如与本专利同时提交的共同未决的专利申请11/781,225中所述)。利用了膨胀至结晶箍形的第二曲折支柱的实施方案(如与本专利同时提交的共同未决的专利申请11/781,225中所述)尤其适用于确保支架植入物在器官空间中安全，因为晶体部分较缓慢地降解并被生物吸收，因此能有利地维持支架的位置和完整性，从而避免支架过早瓦解以及危险的大量破碎。
正如本领域中所公知的，上述实施方案的聚合物支架可能缺乏通过目前可获得检测设备如X-射线探测器进行检测的对比。因此，通过电子致密或X射线折射标记物对组织植入物提高对比检测是有利的。所述标记物可见于生物可降解的斑点储藏处，所述储藏处用由已知折射X射线的材料制备的不透射线组合物填充，从而在摄影图像中变得可见(图3-7)。合适的材料包括但不限于10-90％的可包埋于生物可降解部分中的不透射线化合物或微粒，特别是沉积于多个位于预形成的聚合支架支柱元件中的杯状容器中的膏状组合物形式。
不透射线化合物可选自不透X射线化合物或折射X射线化合物，例如金属颗粒或盐。合适的标记物金属可包括铁、金、胶体银、锌、镁，这些金属可以是纯的形式或者是有机化合物的形式。其它的不透射线材料为钽、钨、铂/铱或铂。不透射线标记物可用一种或多种前述生物可降解聚合物的结合剂构成，所述聚合物如PLLA、PDLA、PLGA、PEG等。为了获得标记物材料的合适混合物，一种溶剂体系包括以下物质中的两种或多种：丙酮、甲苯、甲苯、DMSO等。此外，标记物储藏处可用于选自以下类别的抗炎药：例如PPAR激动剂、甾族化合物、mTOR抑制剂、钙调磷酸酶抑制剂等。
在一个实施方案中，不透射线标记物包括被包于PLA聚合物基质中的含铁的化合物或铁颗粒，以得到这样一种膏状物质，其可被注射于或通过其它方式沉积于聚合支柱元件中所含的合适的中空容器中。将所述杯状容器制成大小在支架支柱元件的宽度内。重金属和重稀土元素可用于多种化合物如亚铁盐、有机碘物质、铋盐或钡盐等。其它可利用的实施方案可包括天然的被包裹的铁颗粒如可进一步由交联剂交联的铁蛋白。此外，铁蛋白凝胶可通过用低浓度(0.1-2％)的戊二醛交联构成。
不透射线标记物可以多种方式与聚合物联合使用并结合。例如，标记物的流体或膏状混合物可填充于注射器中并通过针尖缓慢注射入可生物降解的支架支柱内预先形成的空腔或杯状孔中。流体混合物中所含的溶剂可使标记物材料结合到空腔壁上。含不透射线标记物点的支架可在加热/真空条件下干燥。在植入后，可生物降解的结合剂可降解为由身体吸收/排出的简单分子。因此，不透射线材料将分散在首先移植处的附近区域中。
尽管参照具体实施方案已对本发明特别示出并描述，应理解，以上所公开的以及其它的特征和功能的变型、或者它们的替换物，可根据需要结合到多种其它的不同系统或应用中。同样，本文中多种可由本领域普通技术人员随后作出的目前无法预料的或意料之外的替换物、变化、变型或改进也将意欲包含于所附权利要求中。
现描述剩下的附图：
图1图示了LPLA/LPLA/TMC非外消旋混合物与仅交联部分外消旋的DPLA/LPA/TMC和具有其它外消旋结构的DPLA/LPLA/LPLA-TMC的再结晶的模数变化；
图2A和图2B分别图示了外消旋聚合物和无外消旋结构的聚合物的DSC曲线：如图所示，显示出外消旋熔化物的+外消旋物和-外消旋物的曲线明显不同。
图3A-3G图示了制造支架医疗器械的不透射线标记储存处的实施方案方法：如(a)-(d)中所示，不透射线材料可被挤入装置(g)中所含的空穴中。如截断图(e)和(f)所示，所述空穴可为一个透孔。
图4A-4C图示了具有不透射线标记物的支架的不同支架式样。如图所示，不透射线标记物可被置于支架式样上的不同位置，同时仍可用不透射线检测方法进行检测。
图5A和图5B图示了具有不透射线标记物的支架材料的平面图。如图5A和图5B所示，不透射线标记物可被排列成在成像时或使用其它检测方法时可更容易识别的结构。
图6示出了具有实施方案中所述的不透射线标记物式样的实际支架的总透视图，所述不透射线标记物式样各自位于曲折支柱的连接点处。图7示出了图6的被不透射线标记的支架的一部分的近视图。
图8示出了配置于带囊导管上的本发明支架实施方案的透视图。
图9图示了包含环结构的充分展开的可生物吸收支架，该环结构表示充分结晶的定位环或箍。
图10A和图10B图示了表明单Tg的DSC热流曲线，并且10B示出了表明双Tg的DSC热流曲线。
参照图10A，使用德州仪器(TAinstrument)的Q10DSC对聚合物样品进行热转化温度分析。样品为(A)聚(L-共-DL-丙交酯)70∶30共聚物，(B)聚(L-丙交酯/聚L-丙交酯-共-ε-己内酯)以及(C)聚(L-丙交酯/聚L-丙交酯-共-TMC)。这些聚合物在Tg为30℃和50℃处存在宽转化峰，这些峰仅存在于初始运行中。后来运行的转化温度和曲线在下表中给出。
表
参照图10B，其它聚合物样品(LPLA/TMC杂化物)通过示出双Tg的DSC进行分析。

Claims (16)

1.一种可结晶的可生物吸收聚合物组合物，包括含有聚(L-丙交酯)部分和/或聚(D-丙交酯)部分和/或聚L-丙交酯-共-PEG部分和/或聚D-丙交酯-共-PEG部分的基质聚合物，该基质聚合物与其改性共聚物连接，其中所述改性共聚物包含嵌段共聚物或嵌段无规共聚物形式的聚(L-丙交酯-共-碳酸亚丙酯)或聚(D-丙交酯-共-碳酸亚丙酯)或聚(L-丙交酯-共-ε-己内酯)或聚(D-丙交酯-共-ε-己内酯)，其中丙交酯链长度足以使得进行交联部分结晶。
2.权利要求1的可结晶的可生物吸收聚合物组合物，其中该聚合物组合物在L和D丙交酯部分之间形成丙交酯外消旋物立体复合物晶体结构。
3.权利要求1的可结晶的可生物吸收聚合物组合物，其中该聚合物组合物利用以下部分形成丙交酯外消旋物立体复合物晶体结构，所述部分包括：
连有聚(L-丙交酯-共-碳酸亚丙酯)或聚(L-丙交酯-共-ε-己内酯)的聚L-丙交酯与聚D-丙交酯；
连有聚(L-丙交酯-共-碳酸亚丙酯)或聚(L-丙交酯-共-ε-己内酯)的聚D-丙交酯；
连有聚(D-丙交酯-共-碳酸亚丙酯)或聚(D-丙交酯-共-ε-己内酯)的聚L-丙交酯；
连有聚(D-丙交酯-共-碳酸亚丙酯)或聚(D-丙交酯-共-ε-己内酯)的聚L-丙交酯与聚D-丙交酯；
连有(聚D-丙交酯-共-碳酸亚丙酯)或聚(D-丙交酯-共-ε-己内酯)的聚L-丙交酯-共-PEG；以及
连有聚(L-丙交酯-共-碳酸亚丙酯)或聚(L-丙交酯-共-ε-己内酯)的聚D-丙交酯-共-PEG。
4.权利要求1的可结晶的可生物吸收聚合物组合物，其中所述基质聚合物以重量计占该组合物的70％至85％。
5.权利要求1的可结晶的可生物吸收聚合物组合物，其中所述基质聚合物的70重量％为聚L-丙交酯且30重量％为改性共聚物聚L-丙交酯-共-碳酸亚丙酯。
6.权利要求1的可结晶的可生物吸收聚合物组合物，其中所述改性共聚物不高于该组合物的40％。
7.权利要求1的可结晶的可生物吸收聚合物组合物，其中该组合物的残留单体浓度小于0.5％。
8.一种可生物吸收的支架，包括可结晶的组合物，该组合物包括含有聚L-丙交酯部分或聚D-丙交酯部分和/或聚L-丙交酯-共-PEG部分和/或聚D-丙交酯-共-PEG部分的基质聚合物，该基质聚合物与其改性共聚物连接；其中所述改性共聚物包括嵌段共聚物形式或嵌段无规共聚物形式的聚(L-丙交酯-共-碳酸亚丙酯)或聚(D-丙交酯-共-碳酸亚丙酯)或聚(L-丙交酯-共-ε-己内酯)或聚(D-丙交酯-共-ε-己内酯)，其中丙交酯链长度足以使得进行交联部分结晶。
9.权利要求8的可生物吸收的支架，其中所述基质聚合物以重量计占该组合物的70％至80％。
10.权利要求8的可生物吸收的支架，其中所述基质聚合物的70重量％为聚L-丙交酯且30重量％为改性共聚物聚L-丙交酯-共-碳酸亚丙酯。
11.权利要求8的可生物吸收的支架，其中所述所述改性共聚物不高于该组合物的40％。
12.权利要求8的可生物吸收的支架，其中所述组合物的残留单体浓度小于0.5％。
13.权利要求8的可生物吸收的支架，其中至少一种药物组合物附着或加入到所述聚合物组合物中。
14.权利要求8的可生物吸收的支架，其中至少一种药物组合物通过共价键结合到所述聚合物组合物上。
15.权利要求8的可生物吸收的支架，其中至少一种药物组合物通过、非极性键以及酯键结合到所述聚合物组合物上。
16.权利要求8的可生物吸收的支架，其中所述可结晶的聚合物组合物在L和D丙交酯部分之间形成丙交酯外消旋物立体复合物晶体结构。
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