CN1469759A - 带有包含磷腈的涂层的植入物 - Google Patents
带有包含磷腈的涂层的植入物 Download PDFInfo
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- CN1469759A CN1469759A CNA018173063A CN01817306A CN1469759A CN 1469759 A CN1469759 A CN 1469759A CN A018173063 A CNA018173063 A CN A018173063A CN 01817306 A CN01817306 A CN 01817306A CN 1469759 A CN1469759 A CN 1469759A
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/28—Materials for coating prostheses
- A61L27/34—Macromolecular materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
- A61L33/06—Use of macromolecular materials
- A61L33/068—Use of macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Abstract
本发明涉及有具有抗凝血酶性质并且还包含药学活性成分的生物适应性表面的人造植入物，以及它们的制备方法。
Description
本发明涉及有具有抗血栓形成(antithrombogene)性质和还包含药学活性物质的生物适应性包被(berzug)的人造植入物，以及它们的制备方法。
人们认为人造植入物带来的最严重的并发症是外源性表面上凝血细胞增加的沉积作用。现有技术描述了人血液与外源性表面例如人造心脏瓣膜接触形成这样的血栓(参见Metronic Hall公司，BadHomburg，Carmeda BioActive Oberflche(CBSA)的信息资料，第1-21页；B.D.Ratner，“血液适应性突变(The Blood CompatibilityCatastrophe)”，J.of Biomed.Mat.Res.，Vol.27，283-287；和C.W.Akins，“机械心血管修复术”(Mechanical Cardiac ValvularProstheses)，The Society of Thoracic Surgeons，161-171(1991))。例如全球市场上出现的人造心脏瓣膜都是由热解碳组成并且表现出增大的发生血栓的趋势(参考C.W.Akins，上文)。
在DE-C-19613048中使用聚合物聚[二(三氟乙氧基)磷腈]涂敷人造植入物，从下面的文献中得知它的有效抗血栓形成作用：Holleman Wiberg，“Stickstoffverbindung des Phosphors”[磷的氮化合物]，Lehrbuch der anorganischen Chemie[无机化学教科书]，666-669，91-100版，Walter de Gruyter Verlag(1985)，和Tur，Vinogradova等，“Entwicklungstendenzen beiPolymeranalogen Umsetzungen von Polyphosphazen”[聚磷腈的类聚合物反应发展趋势]，Acta Polymerica 39，424-429，No.8，(1988)。具体地，DE-C-19613048描述了一种人造植入物，其包括作为基质的植入物材料，和对该基质的表面至少部分涂敷的生物适应性包被，所述包被含有具有下面的通式(I)的抗血栓形成聚合物：其中R1至R6是相同或不同的，并且代表烷氧基，烷基磺酰基，二烷基氨基或芳基氧基，或者具有作为杂原子的氮原子的杂环烷基或杂芳基；该专利文献还描述了这样的人造植入物的制备方法。
与植入物是否涂敷有本发明的抗血栓形成材料无关，如心脏瓣膜和模型(Stents)(参见DE-A-19753123)存在的问题是它们有再狭窄倾向，即作为对植入物的生物学反应，血管由于平滑肌细胞在血管壁中的增殖而变窄。Swanson和Gershlick(Stent，Vol.2，66-73(1999))描述了对植入物涂敷合适的活性物质的多种途径。这些包括使用聚合物涂敷的模型，提示见第68页，其中聚合物可以作为活性物质的储备库。然而，该文献立即建议该方法不被推崇，因为在一项其中模型涂敷有各种生物可降解聚合物(另外已知所有的这些聚合物在体外是生物适应性的)的试验研究中体内发现有增加的发炎倾向。此外，美国专利5788979和5980972描述了用生物可降解聚合物的涂敷材料，其中所述涂层还可包含药物活性物质。
WO99/16477描述了防止过量细胞增殖和威胁形成的另一种方法。在这种情况下，对植入物涂敷上述式(I)的放射性标记聚合物，优选存在磷放射性同位素的聚合物。据说放射性辐射发射(32P的β-辐射)防止失控细胞生长，这导致例如对模型植入物的再狭窄。但是，当使用放射性材料时，一定要考虑阻碍这样的植入物无并发症使用的安全性要求和副作用。
因此，本发明的目的是提供不仅具有出色的机械性能而且还有抗血栓形成和抗再狭窄性能以改善这样的植入物的生物适应性和耐受性的人造植入物。此外，本发明的另一个目的是提供这样的植入物的制备方法。
令人惊奇地发现，上面定义的式(I)的聚合物具有对于药物活性物质的突出的基质性质，并且当对植入物材料涂敷这些活性物质时，活性物质以控制方式将它们递送到它的周围。还令人惊奇地证明，在式(I)的聚合物的生物降解中没有炎症反应。这使得有可能控制释放活性物质，不只是通过扩散和溶解过程，而且还通过基质的生物降解和加入的活性成分的相关释放，没有发生不期望的炎症反应。
因此，本发明涉及一种人造植入物，其包括作为基质的植入物材料和对该基质的表面至少部分涂敷的生物适应性包被(berzug)，所述包被含有具有下面的通式(I)的抗血栓形成聚合物：
其中R1至R6是相同或不同的，并且代表烷氧基，烷基磺酰基，二烷基氨基或芳基氧基，或者具有作为杂原子的氮原子的杂环烷基或杂芳基，和至少一种其他的(另外的)药学活性物质(下面简称为“活性物质”)。
在通式(I)的聚合物中，优选的是至少R1至R6之一是由至少一个氟原子取代的烷氧基。
在通式(I)的聚合物中，烷氧基，烷基磺酰基和二烷基氨基中的烷基是例如具有1-20个碳原子的直链或支链烷基，其中烷基可以例如由至少一个卤原子，例如氟原子取代。
烷氧基的例子是甲氧基，乙氧基，丙氧基和丁氧基，其优选可以由至少一个氟原子取代。特别优选2，2，2-三氟乙氧基。
烷基磺酰基的例子是甲基磺酰基，乙基磺酰基，丙基磺酰基和丁基磺酰基。
二烷基氨基的例子是二甲基氨基，二乙基氨基，二丙基氨基和二丁基氨基。
芳基氧基中的芳基是例如具有一个或多个芳香环系的化合物，其中芳基可以例如由至少一个上面定义的烷基取代。
芳基氧基的例子是苯氧基和萘氧基和它们的衍生物。
杂环烷基是例如含有3-7个原子，其中至少一个成环原子是氮原子的环系。所述杂环烷基可以例如由至少一个上面定义的烷基取代。杂环烷基的例子是哌啶基，哌嗪基，吡咯烷基和吗啉基和它们的衍生物。
杂芳基是例如具有一个或多个芳香环系的化合物，其中至少一个成环原子是氮原子。所述杂芳基可以例如由至少一个上面定义的烷基取代。杂芳基的例子是吡咯基，吡啶基，吡啶子基(Pyridinolyl)，异喹啉基和喹啉基和它们的衍生物。
在本发明的一个优选的实施方案中，生物适应性包被含有抗血栓形成聚合物聚[二(三氟乙氧基)磷腈]。
所述其它药学活性物质优选是有机(低或较高分子量的)化合物，特别是抗促细胞分裂(antimitogener)活性物质，例如细胞抑制剂(例如Paclitaxel等)，PDGF抑制剂(例如Tyrphostine等)，Raf-1激酶抑制剂，白细胞整联蛋白阻断的单克隆抗体，反义活性剂(例如质粒DNA等)，过氧化物歧化酶，自由基捕获剂(例如丙丁酚等)，甾族化合物，他汀类(Statin)(例如色伐他汀(cerivastatin)等)，皮质类固醇(例如甲氨喋呤，地塞米松，甲基强的松龙(Methylprednisolan)等)，腺苷酸环化酶抑制剂(例如毛喉萜等)，生长激素抑制素类似物(例如Angiopeptin等)，抗凝血酶活性物质(例如阿加曲班等)，一氧化氮供体(Stickstoffoxiddonator)，糖蛋白-IIb/IIIa-受体拮抗剂(例如尿激酶衍生物，阿昔单抗，Tirofiban等)，抗凝血剂(例如活化的蛋白质C，PEG-水蛭素，前列腺素类似物等)，血管内皮生长因子(VEGF)，唑嘧胺等，和它们的混合物。
期望生物适应性包被中活性物质的含量尽可能高以有效防止再狭窄。已经可以证明了所述包被的至多50％重量可以由活性物质组成而对所述包被的机械性能基本上没有损伤。根据本发明，包被中活性物质的比例在0.01-50％重量的范围内，优选0.2-30％重量。这大约等于聚合物与活性物质重量比是1∶0.0001至1∶1，优选1∶0.05至1∶0.5。
根据本发明的人造植入物的生物适应性包被具有例如1nm至大约100微米的厚度，优选10nm至大约10微米，特别优选至大约1微米。
对用作本发明的基质的植入物材料没有特别的限制。可以是任何植入物材料，例如塑料，金属，金属合金和陶瓷。例如，所述植入物材料可以是热解碳的人造心脏瓣膜或如DE-A-19753123中描述的模型。
在根据本发明的一个优选的人造植入物的实施方案中，在基质表面和生物适应性包被之间提供有含有粘结促进剂的层。
所述粘结促进剂或间隔物是例如，有机硅化合物，优选氨基-终端的硅烷或者以氨基硅烷为基础的化合物或者烷基膦酸。氨基丙基三甲氧基硅烷是特别优选的。
粘结促进剂特别改善包被与植入物材料表面的粘结，这是通过粘结促进剂与植入物材料表面之间通过例如，离子键和/或共价键的偶联，和通过粘结促进剂与包被反应成分，特别是与抗血栓形成聚合物，通过例如，离子键和/或共价键的其它偶联进行的。
另外提供了根据本发明的人造植入物的制备方法，其中通过使基质与下面的物质反应而将生物适应性包被涂敷到基质上：(a)抗血栓形成聚合物或者其前体和活性物质的混合物或者(b)得到初始(primren)聚合物包被的抗血栓形成聚合物或者其前体，并且接着将活性物质涂敷/渗入到初始聚合物包被之中。
特别是对于变化方法(a)，特别优选的是湿法化学方法，因为活性物质常常对剧烈反应条件敏感。在这种情况下，基质浸到含有抗血栓形成聚合物和活性物质的溶液中，并任选地随后通过加热或通过用真空去除溶剂。反复该过程直到涂层具有期望的厚度。
用于该方法的合适的溶剂选自极性质子惰性溶剂，例如酯类(例如乙酸乙酯，乙酸丙酯，乙酸丁酯，丙酸乙酯，丁酸乙酯等)，酮类(例如丙酮，乙基甲基酮等)，酰胺类(例如二甲基甲酰胺等)，亚砜类(例如DMSO等)和砜类(例如环丁砜等)。乙酸乙酯是特别优选的。溶液中聚合物的浓度是0.001-0.5M，优选0.01-0.1M。活性物质的浓度取决于期望的聚合物与活性物质的比例。浸入时间优选是10秒至100小时的范围。在真空，在空气或者保护气体下进行干燥步骤，温度范围是例如大约-20℃至大约300℃，优选0℃至200℃，和特别优选20℃至100℃。
DE19613048中提到的另外的方法还可以用于稳定的活性物质，例如以涂敷聚二氯磷腈并且接着与反应性化合物反应的方法，熔融或升华的方法进行。这些方法特别对于变化方法(b)的第一步是可用的，其中活性物质在第二步被涂敷或渗入，然后优选通过例如上面描述的温和(schonend)湿法化学方法进行第二步。
在使用聚二氯磷腈的方法中，对基质的表面涂敷聚二氯磷腈和活性物质的混合物，并且与选自下面的反应性化合物中的至少一种反应：脂肪族或芳香族醇类或它们的盐，烷基砜类，二烷基胺类，和具有作为杂原子的氮原子的脂肪族或芳香族杂环，相应于R1至R6的上文定义。这里，优选在惰性气氛下对基质的表面涂敷聚二氯磷腈，任选地偶联在粘结促进剂上，并且与反应性化合物反应。或者可以在减压下或空气中涂敷聚二氯磷腈，并且任选地偶联在粘结促进剂上。
式(I)的聚合物例如聚[二(三氟乙氧基)磷腈]的制备由六氯环三磷腈起始在本领域是公知的。Korsak等，Acta Polymerica 30，No.5，第245-248页(1979)充分描述了六氯环三磷腈的聚合作用。Fear，Thower和Veitch，J.Chem.Soc.，第1324页(1958)描述了聚合作用制备的聚二氯磷腈的酯化。
在根据本发明方法的优选的实施方案中，在涂敷聚合物或聚合物前体和活性物质的混合物之前，或者在涂敷聚合物或聚合物前体之前对基质表面涂敷上面定义的粘结促进剂，并且例如通过离子键和/或共价键偶联至该表面。然后，将例如聚二氯磷腈的抗血栓形成聚合物涂敷给涂敷有粘结促进剂的基质表面，并且例如通过离子键和/或共价键偶联至粘结促进剂。
通过湿法化学方法或者在溶液中或者从熔融物或者通过升华或者喷雾法，可以对基质涂敷粘结促进剂。Marco Mantar，第23页，Univ.Heidelberg(1991)的毕业论文中描述了在羟基化表面上基于氨基酸的粘结促进剂的湿法化学偶联。
在涂敷聚二氯磷腈，粘结促进剂，或抗血栓形成聚合物之前用例如过氧一硫酸(Caroscher Sure)将基质表面氧化清洁。UlmanAbraham，表面性质分析(Analysis of Surface Properties)，“AnIntroduction to Ultrathin Organic Films”，108，1991中描述了以同时羟基化作用将表面氧化清洁，例如可以用于塑料，金属或陶瓷的植入物。
总之，已经确认根据本发明的人造植入物令人吃惊地保持作为基质的植入物材料的出色的机械性能并且由于根据本发明涂敷的包被是例如通过直接从溶液中的沉积，所以不只是具有抗血栓形成性而且还具有抗-再狭窄性质，这大大改善了这样的人造植入物的生物适应性和可实用性。通过X-射线光电子能谱(XPS)容易证明这些令人吃惊的结果。
通过下面的实施例进一步详细说明本发明。
实施例
实施例1
A：在直径是5.0毫米并且安瓿中压力是1.3Pa(10-2mmHg)的安瓿中在250±1℃下通过六氯环三磷腈的聚合作用制备基于聚[二(三氟乙氧基)磷腈]的聚二氯磷腈。为此首先在惰性气氛下制备0.1M的聚二氯磷腈溶液(5毫升溶剂中0.174克)。无水甲苯用作溶剂。然后在用作溶剂的无水四氢呋喃中的2，2，2-三氟乙醇钠(8毫升无水四氢呋喃，0.23克钠，1.46毫升2，2，2-三氟乙醇)在该溶液中进行酯化。
B：为了对人造植入物表面进行氧化清洁和同时的羟基化作用，将基质在1∶3的30％H2O2和浓硫酸(过氧一硫酸)的混合物中，在80℃的反应温度下放置2小时。该项处理之后，用18MΩ·cm并且大约pH5的0.5升的去离子水洗涤基质，并且随后在氮气流中干燥。
C：为了用粘结促进剂涂敷植入物的表面，将根据实施例1.B用过氧一硫酸氧化清洁过的人造植入物在室温下在2％氨基丙基三甲氧基硅烷的无水乙醇溶液中浸入30分钟。然后用4-5毫升无水乙醇洗涤基质并且置于105℃的干燥柜中1小时。
实施例2：
A：在含有0.0121克丙丁酚的0.1M聚[二(三氟乙氧基)磷腈]的乙酸乙酯溶液(5毫升乙酸乙酯中0.121克)中在室温下将根据实施例1B和1C预处理过的人造植入物处理24小时。然后用4-5毫升乙酸乙酯洗涤如此制备的人造植入物，并且在氮气流中干燥。
B：在含有0.0242克唑嘧胺的0.1M聚[二(三氟乙氧基)磷腈]的乙酸乙酯溶液(5毫升乙酸乙酯中0.121克)中在室温下将根据实施例1B和1C预处理过的人造植入物处理24小时。然后用4-5毫升乙酸乙酯洗涤如此制备的人造植入物，并且在氮气流中干燥。
通过光电子能谱检查实施例2A和2B得到的人造植入物的表面，测定它们的元素组成，它们的化学计量和包被层的厚度。结果表明聚[二(三氟乙氧基)磷腈]成功地被作为粘结促进剂的氨基丙基三甲氧基硅烷固定，并且包被厚度达到大于2.4nm。此外，分析(NMR)还证明唑嘧胺和丙丁酚以相应的量包埋在包被中。
实施例3
在含有0.0121克丙丁酚的0.1M聚[二(三氟乙氧基)磷腈]的乙酸乙酯溶液(5毫升乙酸乙酯中0.121克)中，在70℃下将根据实施例1B清洁过的人造植入物处理24小时。然后用4-5毫升乙酸乙酯洗涤如此处理的人造植入物，并且在氮气流中干燥。
通过光电子能谱检查如此制备的人造植入物，测定它们的元素组成，它们的化学计量和包被层的厚度。结果表明聚[二(三氟乙氧基)磷腈]与植入物表面偶联，并且层厚度达到大于2.1nm。此外证明丙丁酚以相应的量包埋在包被中。
实施例4
A：在0.1M聚[二(三氟乙氧基)磷腈]的乙酸乙酯溶液(5毫升乙酸乙酯中0.121克)中，在室温下将根据实施例1B和1C预处理过的人造植入物处理24小时。然后用4-5毫升乙酸乙酯洗涤如此制备的人造植入物，并且在氮气流中干燥。
B：室温下将实施例4A获得的基质浸入色伐他汀的乙酸乙酯溶液(5毫升乙酸乙酯中0.0121克色伐他汀)。在氮气流中干燥之后，分析证明聚[二(三氟乙氧基)磷腈]层中含有色伐他汀。
Claims (12)
1.包括作为基质的植入物材料和对该基质的表面至少部分涂敷的生物适应性包被的人造植入物，所述包被包括具有下面通式(I)的抗血栓形成聚合物
其中R1至R6是相同或不同的，并且代表烷氧基，烷基磺酰基，二烷基氨基或芳基氧基，或者具有作为杂原子的氮原子的杂环烷基或杂芳基，和至少一种其它药学活性物质。
2.根据权利要求1的人造植入物，其中至少R1至R6之一是由至少一个氟原子取代的烷氧基。
3.根据权利要求2的人造植入物，其中所述抗血栓形成聚合物是聚[二(三氟乙氧基)磷腈]。
4.根据权利要求1-3之一的人造植入物，其中所述其它药学活性物质是抗促细胞分裂活性物质，特别是细胞抑制剂，PDGF拮抗剂，特别是唑嘧胺，或Raf-1激酶抑制剂。
5.根据权利要求1-3之一的人造植入物，其中所述其它药学活性物质是自由基捕获剂(特别是丙丁酚)，反义活性物质(特别是质粒DNA)，他汀类(特别是色伐他汀等)，或GP-IIb/IIIa受体拮抗剂(特别是阿昔单抗)。
6.根据权利要求1-5之一的人造植入物，其中抗血栓形成聚合物与活性物质之比是1∶0.0001至1∶1，优选1∶0.05至1∶0.5。
7.根据权利要求1-6之一的人造植入物，其中在基质表面和生物适应性包被之间提供有含有粘结促进剂的层。
8.根据权利要求7的人造植入物，其中所述粘结促进剂是有机硅化合物，特别是氨基丙基三甲氧基硅烷。
9.根据权利要求1-8之一的人造植入物的制备方法，其中通过使基质与下面的物质反应而将生物适应性包被涂敷到基质上：
(a)抗血栓形成聚合物或者其前体和活性物质的混合物或者
(b)得到初始聚合物包被的抗血栓形成聚合物或者其前体，并且接着将活性物质涂敷/渗入到初始聚合物包被之中。
10.根据权利要求9的方法，其中通过湿法化学方法，特别是通过使基质与抗血栓形成聚合物和活性物质的混合物反应而涂敷包被。
11.根据权利要求10的方法，其中用于湿法化学涂敷的溶剂选自极性质子惰性溶剂并且优选乙酸乙酯。
12.根据权利要求9-11的方法，其中在涂敷生物适应性包被之前在基质的表面涂敷粘结促进剂。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP00117191.7 | 2000-08-11 | ||
| EP00117191A EP1179353A1 (de) | 2000-08-11 | 2000-08-11 | Antithrombogene Implantate mit Beschichtung aus Polyphosphazenen und einem pharmakologisch aktiven Wirkstoff |
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| Publication Number | Publication Date |
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| CN1469759A true CN1469759A (zh) | 2004-01-21 |
| CN100467073C CN100467073C (zh) | 2009-03-11 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB018173063A Expired - Lifetime CN100467073C (zh) | 2000-08-11 | 2001-08-01 | 带有包含磷腈的涂层的植入物 |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US20030157142A1 (zh) |
| EP (2) | EP1179353A1 (zh) |
| JP (1) | JP4886156B2 (zh) |
| KR (1) | KR100809134B1 (zh) |
| CN (1) | CN100467073C (zh) |
| AT (1) | ATE374626T1 (zh) |
| AU (2) | AU9544701A (zh) |
| BR (1) | BR0113184B1 (zh) |
| CA (1) | CA2424359C (zh) |
| DE (1) | DE50113094D1 (zh) |
| DK (1) | DK1337285T3 (zh) |
| ES (1) | ES2296811T3 (zh) |
| WO (1) | WO2002013882A1 (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101032473B (zh) * | 2007-04-05 | 2010-04-07 | 上海交通大学 | 三明治型药物缓释膜及其制备方法 |
| CN102176868A (zh) * | 2008-02-11 | 2011-09-07 | 西洛诺瓦生物科学公司 | 组织紧固物品和装置以及相关方法 |
Families Citing this family (37)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001080919A2 (de) | 2000-04-11 | 2001-11-01 | Polyzenix Gmbh | Umhüllungen und folien aus poly-tri-fluor-ethoxypolyphosphazen |
| US20090004240A1 (en) * | 2000-08-11 | 2009-01-01 | Celonova Biosciences, Inc. | Implants with a phosphazene-containing coating |
| DE10202467A1 (de) * | 2002-01-23 | 2003-07-24 | Polyzenix Gmbh | Vorrichtung auf Basis von Nitinol, ein Verfahren zu dessen Herstellung sowie dessen Verwendung |
| DE10100961B4 (de) | 2001-01-11 | 2005-08-04 | Polyzenix Gmbh | Körperverträglicher Werkstoff und mit diesem Werkstoff beschichtetes Substrat für die Züchtung von Zellen und künstlichen aus Zellen aufgebauten oder gewachsenen organischen Implantaten |
| US9080146B2 (en) | 2001-01-11 | 2015-07-14 | Celonova Biosciences, Inc. | Substrates containing polyphosphazene as matrices and substrates containing polyphosphazene with a micro-structured surface |
| US20080228284A1 (en) * | 2001-01-11 | 2008-09-18 | Celonova Biosciences, Inc. | Specific Polyphosphazene-Containing Three-Dimensional Bone Support Implants and Methods for Their Use |
| EP1432380B1 (de) | 2001-08-17 | 2006-09-27 | Polyzenix GmbH | Vorrichtung auf basis von nitinol mit polyphosphazenüberzug |
| CA2491282C (en) * | 2002-07-05 | 2013-02-12 | Polyzenix Gmbh | Implant for transport and release for pharmacologically active agents incorporated within polyphosphazenes and related methods |
| US20080138433A1 (en) * | 2002-07-05 | 2008-06-12 | Celonova Biosciences, Inc. | Vasodilator eluting blood storage and administration devices with a specific polyphosphazene coating and methods for their manufacture and use |
| US20050136093A1 (en) * | 2002-07-05 | 2005-06-23 | Polyzenix Gmbh | Implant for transport and release for pharmacologically active agents as well as a process for producing the same |
| DE602004030892D1 (de) * | 2003-03-26 | 2011-02-17 | Celonova Biosciences Germany Gmbh | Beschichtete dentalimplantate |
| US9107850B2 (en) | 2004-10-25 | 2015-08-18 | Celonova Biosciences, Inc. | Color-coded and sized loadable polymeric particles for therapeutic and/or diagnostic applications and methods of preparing and using the same |
| US20210299056A9 (en) | 2004-10-25 | 2021-09-30 | Varian Medical Systems, Inc. | Color-Coded Polymeric Particles of Predetermined Size for Therapeutic and/or Diagnostic Applications and Related Methods |
| US9114162B2 (en) | 2004-10-25 | 2015-08-25 | Celonova Biosciences, Inc. | Loadable polymeric particles for enhanced imaging in clinical applications and methods of preparing and using the same |
| EP1804773B1 (en) * | 2004-10-25 | 2011-03-30 | CeloNova BioSciences Germany GmbH | Loadable polyphosphazene-comprising particles for therapeutic and/or diagnostic applications and methods of preparing and using the same |
| CA2690539C (en) | 2006-10-10 | 2014-10-07 | Celonova Biosciences, Inc. | Bioprosthetic heart valve with polyphosphazene |
| CA2687031A1 (en) * | 2007-05-15 | 2008-11-20 | Chameleon Biosurfaces Limited | Polymer coatings on medical devices |
| CA2694408C (en) | 2007-07-25 | 2014-01-07 | Celonova Biosciences, Inc. | Color-coded and sized loadable polymeric particles for therapeutic and/or diagnostic applications and methods of preparing and using the same |
| DE102007038799A1 (de) * | 2007-08-17 | 2009-02-19 | Biotronik Vi Patent Ag | Implantat aus einer biokorrodierbaren Magnesiumlegierung und mit einer Beschichtung aus einem biokorrodierbaren Polyphosphazen |
| WO2009110858A2 (en) * | 2007-10-31 | 2009-09-11 | Celonova Biosciences, Inc. | Vasodilator eluting dynamic blood handling devices with a specific polyphosphazene coating and methods for their manufacture and use |
| WO2009058145A1 (en) * | 2007-10-31 | 2009-05-07 | Celonova Biosciences, Inc. | Vasodilator eluting luminal stent devices with a specific polyphosphazene coating and methods for their manufacture and use |
| WO2009105761A2 (en) * | 2008-02-22 | 2009-08-27 | Celonova Biosciences, Inc. | Multi-functional wound dressing matrices and related methods |
| US8579964B2 (en) | 2010-05-05 | 2013-11-12 | Neovasc Inc. | Transcatheter mitral valve prosthesis |
| EP2616131A4 (en) * | 2010-09-16 | 2014-12-03 | Univ Kyoto | SPIELS LOADED WITH STATINES TO ACCELERATE THE ORGANIZATION AFTER THE PLACEMENT OF AN ENDOVASCULAR SPIRE IN ANEVISM |
| US9308087B2 (en) | 2011-04-28 | 2016-04-12 | Neovasc Tiara Inc. | Sequentially deployed transcatheter mitral valve prosthesis |
| US9554897B2 (en) | 2011-04-28 | 2017-01-31 | Neovasc Tiara Inc. | Methods and apparatus for engaging a valve prosthesis with tissue |
| US9550011B2 (en) | 2012-05-03 | 2017-01-24 | Indiana University Research And Technology Corporation | Surface coatings for biological implants and prostheses |
| US9345573B2 (en) | 2012-05-30 | 2016-05-24 | Neovasc Tiara Inc. | Methods and apparatus for loading a prosthesis onto a delivery system |
| US9572665B2 (en) | 2013-04-04 | 2017-02-21 | Neovasc Tiara Inc. | Methods and apparatus for delivering a prosthetic valve to a beating heart |
| CN113633435A (zh) | 2016-01-29 | 2021-11-12 | 内奥瓦斯克迪亚拉公司 | 用于防止流出阻塞的假体瓣膜 |
| CN113893064A (zh) | 2016-11-21 | 2022-01-07 | 内奥瓦斯克迪亚拉公司 | 用于快速收回经导管心脏瓣膜递送系统的方法和系统 |
| CA3073834A1 (en) | 2017-08-25 | 2019-02-28 | Neovasc Tiara Inc. | Sequentially deployed transcatheter mitral valve prosthesis |
| AU2019374743B2 (en) | 2018-11-08 | 2022-03-03 | Neovasc Tiara Inc. | Ventricular deployment of a transcatheter mitral valve prosthesis |
| US11602429B2 (en) | 2019-04-01 | 2023-03-14 | Neovasc Tiara Inc. | Controllably deployable prosthetic valve |
| WO2020210652A1 (en) | 2019-04-10 | 2020-10-15 | Neovasc Tiara Inc. | Prosthetic valve with natural blood flow |
| CA3140925A1 (en) | 2019-05-20 | 2020-11-26 | Neovasc Tiara Inc. | Introducer with hemostasis mechanism |
| AU2020295566B2 (en) | 2019-06-20 | 2023-07-20 | Neovasc Tiara Inc. | Low profile prosthetic mitral valve |
Family Cites Families (63)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4311736A (en) * | 1979-03-19 | 1982-01-19 | The Kendall Company | Article having organo-phosphonitrile rubber coating bonded to natural or synthetic rubber and method of making |
| US4341844A (en) * | 1979-10-25 | 1982-07-27 | The Kendall Company | Article having organo-phosphonitrile rubber coating bonded to natural or synthetic rubber and method of making |
| US4318947A (en) * | 1979-12-26 | 1982-03-09 | The Kendall Company | Polymer coating and curing process for catheters |
| US4424395A (en) * | 1982-03-11 | 1984-01-03 | The Dow Chemical Company | Carbamates of biphenyls |
| US4451647A (en) * | 1982-06-21 | 1984-05-29 | Research Corporation | Heparinized polyorganophosphazenes |
| US4480642A (en) * | 1982-07-26 | 1984-11-06 | Health Products Research, Inc. | Dilation device for the cervix |
| JPS6038307A (ja) * | 1983-08-11 | 1985-02-27 | Nippon Daigaku | 充填用複合材 |
| US4911691A (en) * | 1984-09-21 | 1990-03-27 | Menlo Care, Inc. | Assembly for adminstering IV solution |
| US4883699A (en) * | 1984-09-21 | 1989-11-28 | Menlo Care, Inc. | Polymeric article having high tensile energy to break when hydrated |
| US4592755A (en) * | 1985-06-11 | 1986-06-03 | Ethyl Corporation | Mammary implant |
| US4798876A (en) * | 1985-11-12 | 1989-01-17 | Tyndale Plains-Hunter Ltd. | Hydrophilic polyurethane composition |
| US4880622A (en) * | 1986-05-20 | 1989-11-14 | Research Corporation Technologies, Inc. | Water-soluble phosphazene polymers having pharmacological applications |
| US5634946A (en) * | 1988-08-24 | 1997-06-03 | Focal, Inc. | Polymeric endoluminal paving process |
| US4975280A (en) * | 1989-01-23 | 1990-12-04 | Ethyl Corporation | Bioerodable sustained release implants |
| US5439446A (en) * | 1994-06-30 | 1995-08-08 | Boston Scientific Corporation | Stent and therapeutic delivery system |
| FR2679466B1 (fr) * | 1991-07-25 | 1994-04-15 | Ceramique Technique | Membrane de filtration et procede de fabrication. |
| DE4138513A1 (de) * | 1991-11-23 | 1993-05-27 | Basf Ag | Feste pharmazeutische retardform |
| US5464650A (en) * | 1993-04-26 | 1995-11-07 | Medtronic, Inc. | Intravascular stent and method |
| ES2290074T3 (es) * | 1993-07-19 | 2008-02-16 | Angiotech Pharmaceuticals, Inc. | Composiciones anti-angiogenicas que contienen taxol y un vehiculo no biodegradable y su uso. |
| US5716981A (en) * | 1993-07-19 | 1998-02-10 | Angiogenesis Technologies, Inc. | Anti-angiogenic compositions and methods of use |
| WO1995028124A2 (en) * | 1994-04-08 | 1995-10-26 | Atrix Laboratories, Inc. | An adjunctive polymer system for use with medical device |
| US5788979A (en) * | 1994-07-22 | 1998-08-04 | Inflow Dynamics Inc. | Biodegradable coating with inhibitory properties for application to biocompatible materials |
| US5548060A (en) * | 1994-08-08 | 1996-08-20 | Penn State Research Foundation, Inc. | Sulfonation of polyphosphazenes |
| US5605696A (en) * | 1995-03-30 | 1997-02-25 | Advanced Cardiovascular Systems, Inc. | Drug loaded polymeric material and method of manufacture |
| DE19613048C2 (de) * | 1995-03-30 | 1997-12-18 | Michael Prof Dr Grunze | Künstliche Implantate mit antithrombogenen Eigenschaften und Verfahren zu deren Herstellung |
| US5914388A (en) * | 1995-04-26 | 1999-06-22 | The Penn State Research Foundation | Synthesis polyphosphazenes with controlled molecular weight and polydisperity |
| US5603722A (en) * | 1995-06-06 | 1997-02-18 | Quanam Medical Corporation | Intravascular stent |
| CA2178541C (en) * | 1995-06-07 | 2009-11-24 | Neal E. Fearnot | Implantable medical device |
| US6007573A (en) * | 1996-09-18 | 1999-12-28 | Microtherapeutics, Inc. | Intracranial stent and method of use |
| US6254628B1 (en) * | 1996-12-09 | 2001-07-03 | Micro Therapeutics, Inc. | Intracranial stent |
| US5707597A (en) * | 1996-11-13 | 1998-01-13 | Virus Research Institute, Inc. | Polyhalophosphazene solutions stable against gelation |
| US5980972A (en) * | 1996-12-20 | 1999-11-09 | Schneider (Usa) Inc | Method of applying drug-release coatings |
| US5814704A (en) * | 1997-03-04 | 1998-09-29 | Virus Research Institute, Inc. | Recovery of polyphosphazene polyacids or acids salts thereof |
| US5843172A (en) * | 1997-04-15 | 1998-12-01 | Advanced Cardiovascular Systems, Inc. | Porous medicated stent |
| US6273913B1 (en) * | 1997-04-18 | 2001-08-14 | Cordis Corporation | Modified stent useful for delivery of drugs along stent strut |
| US6077916A (en) * | 1997-06-04 | 2000-06-20 | The Penn State Research Foundation | Biodegradable mixtures of polyphoshazene and other polymers |
| DE19744135C1 (de) * | 1997-09-29 | 1999-03-25 | Schering Ag | Beschichtete medizinische Implantate, Verfahren zu ihrer Herstellung und ihre Verwendung zur Restenoseprophylaxe |
| DE19743373A1 (de) * | 1997-09-30 | 1999-04-15 | Univ Heidelberg | ·3··2·P-Polyphosphazen |
| US6485514B1 (en) * | 1997-12-12 | 2002-11-26 | Supergen, Inc. | Local delivery of therapeutic agents |
| US20010029351A1 (en) * | 1998-04-16 | 2001-10-11 | Robert Falotico | Drug combinations and delivery devices for the prevention and treatment of vascular disease |
| JP4583597B2 (ja) * | 1998-05-05 | 2010-11-17 | ボストン サイエンティフィック リミテッド | 末端が滑らかなステント |
| US6254634B1 (en) * | 1998-06-10 | 2001-07-03 | Surmodics, Inc. | Coating compositions |
| US5997301A (en) * | 1998-10-20 | 1999-12-07 | Linden; Lars Ake | Treatment of tooth surfaces and substances therefor |
| US6958147B1 (en) * | 1998-10-26 | 2005-10-25 | Licentia Ltd | Use of VEGF-C to prevent restenosis |
| US6258121B1 (en) * | 1999-07-02 | 2001-07-10 | Scimed Life Systems, Inc. | Stent coating |
| US6790228B2 (en) * | 1999-12-23 | 2004-09-14 | Advanced Cardiovascular Systems, Inc. | Coating for implantable devices and a method of forming the same |
| US6503556B2 (en) * | 2000-12-28 | 2003-01-07 | Advanced Cardiovascular Systems, Inc. | Methods of forming a coating for a prosthesis |
| US6203551B1 (en) * | 1999-10-04 | 2001-03-20 | Advanced Cardiovascular Systems, Inc. | Chamber for applying therapeutic substances to an implant device |
| KR100315630B1 (ko) * | 1999-11-17 | 2001-12-12 | 박호군 | 온도변화에 따라 상전이 거동을 갖는 분해성폴리포스파젠계 고분자 및 그 제조방법 |
| CA2402949C (en) * | 2000-03-18 | 2009-09-08 | Polyzenix Gmbh | Polyphosphazene derivatives having bacterial resistance and use thereof |
| WO2001080919A2 (de) * | 2000-04-11 | 2001-11-01 | Polyzenix Gmbh | Umhüllungen und folien aus poly-tri-fluor-ethoxypolyphosphazen |
| US20020005206A1 (en) * | 2000-05-19 | 2002-01-17 | Robert Falotico | Antiproliferative drug and delivery device |
| US6689807B1 (en) * | 2000-06-08 | 2004-02-10 | Caritas St. Elizabeth's Medical Center Of Boston, Inc. | HMG CoA reductase inhibitors for promoting angiogenesis |
| US20020111590A1 (en) * | 2000-09-29 | 2002-08-15 | Davila Luis A. | Medical devices, drug coatings and methods for maintaining the drug coatings thereon |
| US6863685B2 (en) * | 2001-03-29 | 2005-03-08 | Cordis Corporation | Radiopacity intraluminal medical device |
| US6746773B2 (en) * | 2000-09-29 | 2004-06-08 | Ethicon, Inc. | Coatings for medical devices |
| US8303609B2 (en) * | 2000-09-29 | 2012-11-06 | Cordis Corporation | Coated medical devices |
| US7261735B2 (en) * | 2001-05-07 | 2007-08-28 | Cordis Corporation | Local drug delivery devices and methods for maintaining the drug coatings thereon |
| AU2002340749A1 (en) * | 2001-05-04 | 2002-11-18 | Concentric Medical | Coated combination vaso-occlusive device |
| US7195640B2 (en) * | 2001-09-25 | 2007-03-27 | Cordis Corporation | Coated medical devices for the treatment of vulnerable plaque |
| US20030065377A1 (en) * | 2001-09-28 | 2003-04-03 | Davila Luis A. | Coated medical devices |
| US20030065345A1 (en) * | 2001-09-28 | 2003-04-03 | Kevin Weadock | Anastomosis devices and methods for treating anastomotic sites |
| US6887270B2 (en) * | 2002-02-08 | 2005-05-03 | Boston Scientific Scimed, Inc. | Implantable or insertable medical device resistant to microbial growth and biofilm formation |
-
2000
- 2000-08-11 EP EP00117191A patent/EP1179353A1/de not_active Withdrawn
-
2001
- 2001-08-01 JP JP2002519020A patent/JP4886156B2/ja not_active Expired - Lifetime
- 2001-08-01 US US10/344,216 patent/US20030157142A1/en not_active Abandoned
- 2001-08-01 BR BRPI0113184-2A patent/BR0113184B1/pt not_active IP Right Cessation
- 2001-08-01 CN CNB018173063A patent/CN100467073C/zh not_active Expired - Lifetime
- 2001-08-01 KR KR1020037001952A patent/KR100809134B1/ko not_active IP Right Cessation
- 2001-08-01 AU AU9544701A patent/AU9544701A/xx active Pending
- 2001-08-01 AU AU2001295447A patent/AU2001295447B2/en not_active Expired
- 2001-08-01 EP EP01976054A patent/EP1337285B1/de not_active Expired - Lifetime
- 2001-08-01 WO PCT/EP2001/008913 patent/WO2002013882A1/de active IP Right Grant
- 2001-08-01 DK DK01976054T patent/DK1337285T3/da active
- 2001-08-01 CA CA2424359A patent/CA2424359C/en not_active Expired - Lifetime
- 2001-08-01 AT AT01976054T patent/ATE374626T1/de active
- 2001-08-01 DE DE50113094T patent/DE50113094D1/de not_active Expired - Lifetime
- 2001-08-01 ES ES01976054T patent/ES2296811T3/es not_active Expired - Lifetime
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101032473B (zh) * | 2007-04-05 | 2010-04-07 | 上海交通大学 | 三明治型药物缓释膜及其制备方法 |
| CN102176868A (zh) * | 2008-02-11 | 2011-09-07 | 西洛诺瓦生物科学公司 | 组织紧固物品和装置以及相关方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| KR100809134B1 (ko) | 2008-02-29 |
| CA2424359A1 (en) | 2003-02-06 |
| US20030157142A1 (en) | 2003-08-21 |
| AU2001295447B2 (en) | 2007-01-04 |
| BR0113184B1 (pt) | 2014-12-02 |
| ATE374626T1 (de) | 2007-10-15 |
| AU9544701A (en) | 2002-02-25 |
| WO2002013882A1 (de) | 2002-02-21 |
| ES2296811T3 (es) | 2008-05-01 |
| JP2004522461A (ja) | 2004-07-29 |
| EP1179353A1 (de) | 2002-02-13 |
| DE50113094D1 (de) | 2007-11-15 |
| CA2424359C (en) | 2012-03-20 |
| CN100467073C (zh) | 2009-03-11 |
| JP4886156B2 (ja) | 2012-02-29 |
| KR20030061780A (ko) | 2003-07-22 |
| DK1337285T3 (da) | 2008-02-11 |
| EP1337285A1 (de) | 2003-08-27 |
| BR0113184A (pt) | 2003-07-01 |
| EP1337285B1 (de) | 2007-10-03 |
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