CN111344025A - 颅内药物递送材料和方法 - Google Patents
颅内药物递送材料和方法 Download PDFInfo
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- CN111344025A CN111344025A CN201880072686.1A CN201880072686A CN111344025A CN 111344025 A CN111344025 A CN 111344025A CN 201880072686 A CN201880072686 A CN 201880072686A CN 111344025 A CN111344025 A CN 111344025A
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Abstract
本申请总体上涉及治疗剂的微创递送领域。具体地说，本发明提供了用于通过使用递送球囊导管将诸如药物、渗透剂、血液屏障增强剂或其他化合物之类的试剂微创地靶向递送至特定局部脑区域的材料和方法。
Description
技术领域
本申请总体上涉及治疗剂的微创递送领域。具体地说，本发明提供了用于通过使用递送球囊导管将诸如药物、渗透剂、血液屏障增强剂或其他化合物之类的试剂微创地靶向递送至特定局部脑区域的材料和方法。
背景技术
2012年，全球原发性恶性脑瘤和其他中枢神经系统(CNS)肿瘤的发病率是每100,000人中有3.4例，或同年的总数超过25万。较发达国家的发病率较高(GLOBOCAN 2012v1.0,Cancer Incidence and Mortality Worldwide:IARC CancerBase No.11[Internet],International Agency for Research on Cancer；2013)。多形性成胶质细胞瘤(GBM)是最常见、最致命的原发性脑肿瘤，并占所有颅内肿瘤的12％至15％(U.S.National Brain Tumor Society)。
在美国，儿童期原发性恶性和非恶性脑肿瘤及其他中枢神经系统肿瘤的发生率为每10万人中有5.5例(Ostrom QT,et al.,CBTRUS Statistical Report:Primary Brainand Central Nervous System Tumors Diagnosed in the United States in 2009-2013.Neuro Oncol.2016；18(sS):iv1-iv76)。
大多数原发性脑肿瘤的治疗通常包括癌性组织切除手术，然后进行放射和化学疗法以靶向任何剩余的和潜在侵袭性的肿瘤细胞。这些疗法的手术后递送提出重大挑战。
化学疗法已成为治疗原发性脑肿瘤以及许多其他类型癌症的关键部分。任何化学治疗方案的功效的前提条件是确保药物以治疗有效浓度到达肿瘤靶标。
卡莫司汀是一种非特异性烷化剂，并且在肿瘤手术切除后经常用于脑部治疗。由于卡莫司汀可能具有相当大的全身性副作用，因此在切除手术后，使用直接沿手术腔壁放置的释放卡莫司汀的聚酸酐可生物降解的晶片(wafer)(
wafer)实现局部递送。每个晶片可递送7.7mg卡莫司丁，而至多可放置8个晶片。
然而，使用
晶片并非没有潜在的并发症，因为晶片的实体存在已与后续常用的磁共振成像活动中的困难(Colen,R.R.et al.,World J.Radiol.3(11),2011,266-272)以及与手术相关的不良事件和局部毒性(Chowdhary S.A.,et al.,J.Neurooncol122,2015,367-382)相关联。
其他药物已被考虑，并且西罗莫司从可生物降解的聚合物珠粒的局部递送，当颅内递送至恶性神经胶质瘤模型大鼠中时，已经被报道(Tyler,B.et al.,Neuro Oncology13(7)2011,700-709)。与对照动物相比，西罗莫司治疗的动物具有明显更长的生存时间。有趣的是，在同时进行西罗莫司治疗外还进行放射疗法得到了比单独使用任何一种疗法都更长的生存期。
另一类经常使用的癌症疗法涉及将有效量的辐射递送至靶组织。
手术后通常要进行放射递送，并且可以通过外部和内部(近距离放射治疗(brachytherapy))方式来完成。最近，一种新型的近距离放射治疗技术
已被FDA批准用于治疗恶性脑肿瘤。
装置是一种可充气式球囊导管，其在手术移除肿瘤后被放置在切除腔中。球囊中装有水基辐射源，在移除之前，允许该装置保留3至6天。通常，将
卡莫司汀晶片另外与
导管组合放置。
在现有技术中，需要改进本领域的递送方法和治疗终点以及将已知药物与亲脂性化合物组合以改善原发性脑肿瘤的治疗范式。
发明内容
本发明提供了一种用于颅内递送治疗剂的医疗装置，该医疗装置包括球囊导管，其中，所述球囊包括第一涂层和第二涂层，并且其中所述第二涂层被施加在所述第一涂层的上面。优选的是，所述第一涂层包含水溶性聚合物。最优选的是，所述水溶性聚合物由具有大约50至200kD的分子量的蛋白质或聚合物组成，并且所述蛋白质优选为具有大约65至70kD的分子量的球状血清蛋白。在另一个实施方式中，所述水溶性聚合物选自分子量至多约160kD的血液蛋白例如球蛋白和/或纤维蛋白原。
优选的是，所述第二涂层包含治疗剂或由治疗剂组成，其中治疗剂选自由下文限定的化合物组成的组。可选的是，将放射溶液与球囊导管共同施用。
在另一方面，本发明提供了一种治疗原发性脑癌的方法，包括：
(a)提供球囊导管，所述球囊导管在球囊的表面上包括第一涂层和第二涂层，优选包括如本文所限定的第一涂层和第二涂层；
(b)进入个体的头骨中的硬膜下腔；
(c)将所述球囊导管插入所述硬膜下腔中；
(d)使所述球囊膨胀有效的时间，以允许所述第二涂层释放到组织中。
一方面，将所述水溶性聚合物作为第一涂层施加，使其干燥，然后施加所述第二涂层。
一方面，所述第二涂层由包含第一组分和可选的第二组分的制剂组成。优选的是，所述第一组分由亲脂性化合物组成，其中所述亲脂性化合物是具有以下结构的大环三烯免疫抑制化合物：
其中R是C(O)-(CH2)n-X，n是0、1或2，X是具有3-8个碳的环烃，可选地包含一个或更多个不饱和键。在一个优选的实施方式中，C(O)-(CH2)n-X具有以下结构之一：
更优选的是，所述第一组分由亲脂性化合物组成，其中所述亲脂性化合物是具有以下结构的大环三烯免疫抑制化合物：
其中R是C(O)-(CH2)n-X，n是0、1或2，X是具有3-9个碳的环烃，可选地包含一个或更多个不饱和键。在一个优选的实施方式中，C(O)-(CH2)n-X具有以下结构之一：
优选的是，所述可选的第二组分包括脂肪醇、脂肪醛或脂肪酸。在另一方面，所述第一组分仅由上述结构中的一个组成。
在又一方面，所述第一组分由卡莫司汀(carmustine)、替莫唑胺(temozolomide)、洛莫司汀(lomustine)、甲基苄肼(procarbazine)或长春新碱中的一种单独，或与本文所限定的所述大环三烯免疫抑制化合物组合组成。因此，一方面，所述第一组分由卡莫司汀、替莫唑胺、洛莫司汀、甲基苄肼或长春新碱中的一种组成。在另一方面，所述第一组分由卡莫司汀、替莫唑胺、洛莫司汀、甲基苄肼或长春新碱中的一种和本文所限定的大环三烯免疫抑制化合物中的一种组成。
一方面，本发明教导了一种制造作为球囊导管用于颅内递送治疗剂的医疗装置的方法，包括：(a)提供一种装置，优选为一旦膨胀就能够径向扩张的球囊导管；(b)提供如本文所限定的水溶性聚合物水溶液，优选为在水溶液中包含约10％至约30％的所述水溶性聚合物；(c)在(b)的所述溶液中涂覆优选浸涂所述装置；(d)使经涂覆的装置干燥；(e)将包含本文所限定的所述第一组分和所述可选的第二组分的溶液施加至(d)的所述装置；(f)使(e)的所述装置干燥。
在一个特定方面，本发明教导了一种制造作为球囊导管用于颅内输送治疗剂的医疗装置的方法，包括：(a)提供一旦膨胀就能够径向扩张的球囊导管；(b)提供一种水溶性聚合物的水溶液，优选在水溶液中包含约10％至约30％的水溶性聚合物；(c)在(b)的所述溶液中浸涂所述球囊导管；(d)使经浸涂的球囊导管干燥；(e)将包含大环三烯免疫抑制化合物和可选的至少一种饱和脂肪醇的溶液施加至(d)的所述球囊导管；(f)使(e)的所述球囊导管干燥。
具体实施方式
如本文所用，术语“大环三烯免疫抑制化合物”包括雷帕霉素(西罗莫司)、依维莫司(everolimus)、佐他莫司(zotarolimus)、拜尔莫司(biolimus)、诺维莫司(novolimus)、米尔莫司(myolimus)、替西罗莫司(temsirolimus)和本发明中描述的雷帕霉素衍生物。
本发明提供了能够适应个体中原发性脑肿瘤的治疗的装置和方法。本发明的医疗装置提供了具有第一涂层和第二涂层的球囊导管。
优选的是，所述第一涂层由水溶性材料组成，并且在所述医疗装置，优选为球囊导管，的表面上形成所述第一涂层。优选通过浸涂来涂覆所述第一涂层，其中将所述医疗装置，优选为球囊导管，放置在包含所述水溶性聚合物的溶液中，所述溶液被涂覆到所述医疗装置的表面上。其他适合的方法例如喷涂或通过线、针、套管、海绵或布来涂覆所述溶液都可以用于涂覆过程。在如此施加所述第一涂层之后，从所述溶液或所述涂覆装置中移除所述医疗装置，优选为所述球囊导管，并且使其干燥，例如在环境室温下干燥少于24小时的时间。
应包含大部分所述第一涂层的水溶性聚合物是分子量约为50至200kD的聚合物或蛋白质。在一个实施方式中，所述水溶性聚合物选自水溶性人血清蛋白或水溶性血液蛋白，所述蛋白优选具有约50至200kD的分子量。在一实施方式中，所述水溶性聚合物是具有约65至70kD的分子量的蛋白质或聚合物，优选具有约65至70kD的分子量的球状血清蛋白。在另一个实施方式中，所述水溶性聚合物选自血蛋白，例如分子量多至约160kD的球蛋白和/或纤维蛋白原。更优选的是，所述水溶性聚合物是人纤维蛋白原或免疫球蛋白。最优选的是，所述水溶性聚合物是与以下序列具有至少90％同一性的人血清蛋白：
DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLVAASQAALGL(SEQ ID NO:1)
在本发明最优选的实施方式中，所述水溶性聚合物是人血清白蛋白。
所述第二涂层可以由还包含第一组分和可选的第二组分的制剂组成。优选的是，所述制剂的所述第一组分由卡莫司汀、替莫唑胺、洛莫司汀、甲基苄肼、长春新碱或选自由雷帕霉素(西罗莫司)、依维莫司、佐他莫司、拜尔莫司、诺维莫司、米尔莫司、替西罗莫司及其相关衍生物组成的组的大环三烯免疫抑制化合物组成，或者，所述第二涂层中的所述制剂的所述第一组分的所述大环三烯免疫抑制化合物是雷帕霉素-40酯类似物，该类似物具有如下结构：
其中R是C(O)-(CH2)n-X，n是0、1或2，X是具有3-8个碳的环烃并且可选地包含一个或更多个不饱和键。在最优选的实施方式中，C(O)-(CH2)n-X具有以下结构之一：
更优选的是，所述制剂的所述第一组分由卡莫司汀、替莫唑胺、洛莫司汀、甲基苄肼、长春新碱或选自由雷帕霉素(西罗莫司)、依维莫司、唑他莫司、拜尔莫司、诺维莫司、米尔莫司、替西罗莫司及其相关衍生物组成的组的大环三烯免疫抑制化合物组成，或者所述第二涂层中的所述制剂的所述第一组分的所述大环三烯免疫抑制化合物是具有如下结构的雷帕霉素-40酯类似物：
其中R是C(O)-(CH2)n-X，n是0、1或2，X是具有3-9个碳的环烃并且可选地包含一个或更多个不饱和键。在最优选的实施方式中，C(O)-(CH2)n-X具有以下结构之一：
所述第二涂层的所述可选的第二组分是选自由亲脂性脂肪醇(lipoic fattyalcohol)或脂肪醛或脂肪酸或其组合组成的组的表面活性剂或非聚合物的、非离子性的、线性的烃。优选的是，所述第二涂层是选自由如下物质组成的成员：月桂醇、十一烷基醇、肉豆蔻醇、十五烷基醇、棕榈油醇、棕榈醇、异鲸蜡醇、十七烷基醇、羊毛脂醇、硬脂醇、异硬脂醇、12-羟基硬脂醇、二十一烷基醇、二十二烷基醇(山嵛醇)、瓢儿菜基醇(erucylalcohol)、1-二十三烷基醇、二十四烷基醇(lignoceryl alcohol)、1-二十五烷基醇、二十六烷基醇、1-二十七烷基醇、二十八烷基醇(蒙旦醇montanyl alcohol)、1-二十九烷基醇、三十烷基醇、1-三十一烷基醇、三十二烷基醇(laccerylanol)、1-三十三烷基醇(1-tritriacontanol)、三十四烷基醇(geddyl alcohol)、二十酸(花生酸arachidic acid)、二十二酸(山嵛酸behenic acid)、二十四酸(lignoceric acid)和二十六酸(蜡酸ceroticacid)等以及它们各自的醛形式。
优选的是，所述脂肪醇或脂肪醛或非离子表面活性剂是线性的并且包含至少12个碳原子。可选的是，更优选所述第二涂层的所述第二组分包含具有化学式CxHyO的化合物，其中x为至少16并且y为至少26。再更优选的是，所述第二涂层的所述第二组分包含具有化学式CxHyO的化合物，其中x为至少18且至多35，且y为至少36且至多72。在另一个实施方式中，所述第二涂层的所述第二组分包含具有化学式CxHyO的化合物，其中x为至少16且y为至少26，并且该化合物为非聚合物的、直链的、支链的或环状的、饱和或不饱和的脂肪醇。进一步更优选的是，所述第二涂层的所述第二组分包含具有化学式CxHyO的化合物，其中x为至少15且至多35，并且y为至少30且至多72，并且该化合物为非聚合物的、直链、支链或环状的、饱和或不饱和的脂肪醇。在一个优选的实施方式中，提供了一种医疗装置，优选为球囊导管，该球囊导管优选具有缺乏结构修饰的表面和第二涂层，该第二涂层由本文所述的非聚合物的、饱和或不饱和脂肪醇或饱和或不饱和脂肪醛和至少一种本文所述的治疗剂组成。在另一个优选的实施方式中，提供了一种医疗装置，优选为球囊导管，该球囊导管优选具有在此表面上没有结构修饰的表面和第二涂层，该第二涂层由本文所述的非聚合物的饱和或不饱和脂肪醇和本文所述的至少一种治疗剂组成。
在一个实施方式中，所述第二涂层的制剂包含100重量％的所述第一组分。在另一个实施方式中，所述第二涂层的制剂包含按重量计为至少80％的本文所限定的第一组分和按重量计为至少15％的本文所限定的第二组分。在本发明的一个优选的实施方式中，所述第二涂层的制剂包含按重量计为60％至95％的本文所限定的第一组分和按重量计为5％至40％的本文所限定的第二组分。所述制剂可进一步包含足够量的增溶剂，例如合适的有机溶剂，特别是非极性有机溶剂，以促进所述制剂的适当涂覆例如喷涂。类似地，根据植入物的大小，每个药物洗脱装置，特别是每个球囊导管所施加的本文所限定的第一组分的量为5μg至25mg，优选为约1mg至约10mg。所述第二组分的量为1μg至16.7mg，优选为约2μg至约2.9mg。在最优选的实施方式中，导管球囊每单位长度的本文所限定的药物的载药量为约0.5μg/mm2至10μg/mm2，优选为约1μg/mm2至3μg/mm2。
在一个优选的实施方式中，在所述第一涂层干燥之后，将包含所述第一组分和所述第二组分的所述第二涂层涂覆于所述球囊的表面。在一个优选的实施方式中，所述第二涂层通过喷涂方式涂覆在第一涂层的上面。一方面，所述第二涂层在高于环境室温的温度，优选在30℃至50℃范围内，最优选在40℃真空干燥。
另外，本发明提供了一种治疗患有原发性脑肿瘤的个体的方法，所述方法包括：
(a)提供一种球囊导管，在该球囊的表面上包括第一涂层和第二涂层；
(b)进入个体的头骨中的硬膜下腔；
(c)将所述球囊导管插入到所述硬膜下腔中；
(d)使所述球囊膨胀有效时间，以使所述第二涂层释放到组织中。
例子
本发明的大环三烯免疫抑制化合物具有一个以上的实施方式，并且可以被描述为包含来自表1的至少一种以下物质：
表1.
CRC-015物质的描述
CRC-015是意在涵盖一类物质并用于指称表1中的每个下述物质的术语：CRC-015a、CRC-015b、CRC-015c、CRC-015d、CRC-015e、CRC-015f、CRC-015g和CRC-015h。
I.
药物递送：
直接从
球囊递送药物可能会消除药物递送晶片的使用。药物也可以从与常规
装置结合使用的单独球囊导管递送。作为原理验证，从
球囊的球囊导管模拟物递送卡莫司汀。
A.首先将PTCA 5×40mm
球囊导管球囊扩张，并使用在去离子(D.I)水中的40质量/体积％的人血清白蛋白(Sigma A7736)(HSA)溶液进行浸涂，并在环境温度
下干燥过夜，以制备第一涂层。对于第二次涂层，将HSA涂覆的球囊收缩，然后使用100微升玻璃注射器将溶解在50微升丙酮中的7mg卡莫司汀(Sigma CO400)手动涂覆到每个球囊上。
如前，使药物涂覆的球囊在环境温度下干燥过夜。经干燥的球囊在20倍放大倍率下检查，与有光泽的未涂覆球囊相比，该球囊显示出暗淡的不透明涂层外观。为了进行药物释放测试，将球囊各自在环境温度下放入30mL的pH 7.4的PBS缓冲液中并膨胀。60分钟后，将所述球囊从溶液中移出并干燥以评估药物转移。以20倍率进行的检查显示没有涂层的并且与未涂覆的对照球囊相当的光亮的球囊表面，表明已发生卡莫司汀的释放。对于近距离放射疗法(brachytherapy)和化学疗法的组合，只需简单地以与通常的
使用说明一致的方式使用涂有药物的
球囊导管。
B.首先将PTCA 3.5×20mm
球囊导管球囊扩张，并使用在去离子水中的40质量/体积％的人血清白蛋白(HSA)溶液进行浸涂，并在环境温度下干燥过夜，从而制备第一层涂层。对于第二层涂层，将HSA涂覆球囊收缩，然后将40微升的CRC-015在丙酮中的50毫克/毫升溶液手动涂覆所述球囊，然后使该球囊在环境温度下干燥过夜。
C.如上文B中那样制备具有药物释放层的球囊。使用包含12.5毫克/毫升的CRC-015和4.16毫克/毫升硬脂醇(Sigma 8.07680.0100)的混合物的丙酮溶液对球囊进行喷涂，得到每个球囊2毫克CRC-015的药物剂量。当从球囊释放到组织中时，药物/脂肪醇混合物可用于提供用于持续的药物洗脱的原位沉积。
II.猪模型中的钻孔(Burr Hole)球囊导管药物递送
钻孔手术是在颅骨上开孔，进入硬膜下腔，以去除血块或插入导管排液的程序。通常的孔尺寸是直径14毫米，是用专门的电钻或手钻形成的。本发明提供了一种球囊技术，其能够结合常规的钻孔手术或结合利用小得多的颅孔直径的钻孔手术进行局部药物递送，从而使得可以将精确的药物量方便地递送到需要治疗的明确限定的硬膜下位置。手术完成后，只需将开口上的头皮封闭，即可简单地留下较小的孔愈合。
从两只最近因不相关的医疗程序被安乐死的动物中的每只动物形成一个5/8英寸直径的颅钻孔。将100微升无菌盐水放入到钻孔腔中，然后插入CRC-015涂覆的球囊导管。然后将球囊以稳定的速度膨胀并保持60秒。然后将球囊收缩并收回。
用乙腈从球囊中萃取所有残留的药物，然后通过HPLC进行测量。结果记录在表2中，并且表明药物从球囊迅速且方便地释放到组织。可以预期的是，其他药物/赋形剂和药物组合可以在颅侵袭最小的情况下在相同或不同位置一起或单独地进行递送。还可以预期的是，钻孔尺寸的减小以及球囊到球囊的定量释放和精度的提高可以通过额外的开发活动来实现。
表2.
从2mg药物输送颅球囊递送CRC-015
| 动物 | 球囊残留药物 | 药物释放百分比 |
| 1 | 179 | 91.0 |
| 2 | 373 | 81.3 |
可以在没有任何一个或多个要素、一个或多个限定，在本文中没有具体公开的情况下，适当地实践本文中示例性描述的发明。因此，例如，术语“包含”、“包括”、“含有”等应被广泛地理解且没有限制。另外，本文所采用的术语和表达应被当作描述的术语使用而非限制，并且不打算使用这样的术语和表达来排除所示出和描述的未来的任何等同形式或其任何部分，并且应当认识到的是，在本发明的要求保护的范围内可以进行各种修改。因此，应该理解的是，尽管已经通过优选实施方式和可选特征具体公开了本发明，但是本领域技术人员可以对本文公开的发明采取修改和变型，并且认为这样的修改和变型处在本文公开的发明范围内。在此已经广泛地和一般性地描述了本发明。落入一般公开范围内的每个较窄的种类和亚组也构成这些发明的一部分。这包括对每个发明的一般性描述，但附带条件或否定限制时，可以从上位概念中删除任何主题，无论所删除的内容是否描述于其中。
另外，在以马库什组来描述本发明的特征或方面的情况下，本领域技术人员将认识到的是，由此也以马库什组的任何单个成员或成员子组来描述本发明。还应理解的是，以上描述旨在说明而非限制。通过阅读以上描述，许多实施例对于本领域普通技术人员将是显而易见的。因此，本发明的范围不应参考上面的描述来确定，而应根据所附的权利要求书以及与这些权利要求书等同的全部范围来确定。所有文章和参考文献(包括专利出版物)的公开内容通过引用并入本文。
对于本领域技术人员将显而易见的是，根据以上教导，所描述的实施例和实施方式的多种修改和变化是可能的。所公开的实施例和实施方式可以包括本文所公开的一些或全部特征。因此，意图涵盖可能落入本发明的真实范围内的所有这样的修改和替代的实施方式。
序列表
<110> 百多力股份公司（BIOTRONIK AG）
<120> 颅内药物递送材料和方法（INTRACRANIAL DRUG DELIVERY MATERIALS ANDMETHODS）
<130> 17.033P-WO
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 585
<212> PRT
<213> 智人（Homo sapiens）
<400> 1
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Claims (10)
1.一种用于颅内递送治疗剂的医疗装置，所述医疗装置包括球囊导管，其中，所述球囊包括第一涂层和第二涂层，并且其中，所述第二涂层被施加在所述第一涂层的上面。
2.根据前述权利要求中任一项所述的医疗装置，其中，所述第一涂层包含至少一种水溶性聚合物。
3.根据前述权利要求中任一项所述的医疗装置，其中，所述至少一种水溶性聚合物包括具有约65kD至70kD的分子量的球形血清蛋白。
4.根据前述权利要求中任一项所述的医疗装置，其中，所述第二涂层由具有第一组分和可选的第二组分的制剂组成。
5.根据权利要求4所述的医疗装置，其中，所述制剂的所述第一组分包括卡莫司汀、替莫唑胺、洛莫司汀、甲基苄肼、长春新碱或大环三烯免疫抑制化合物，所述大环三烯免疫抑制化合物选自由雷帕霉素(西罗莫司)、依维莫司、佐他莫司、拜尔莫司(biolimus)、诺维莫司(novolimus)、米尔莫司(myolimus)、替西罗莫司及其相关衍生物或雷帕霉素-40酯类似物组成的组，所述类似物具有以下结构：
其中R是C(O)-(CH2)n-X，n是0、1或2，X是具有3-9个碳的环烃并且可选地包含一个或更多个不饱和键。
6.根据权利要求5所述的医疗装置，其中，C(O)-(CH2)n-X具有以下结构之一：
7.根据权利要求4所述的医疗装置，其中，所述制剂的所述第一组分由卡莫司汀、替莫唑胺、洛莫司汀、甲基苄肼或长春新碱中的一种组成。
8.根据权利要求4所述的医疗装置，其中，所述第二组分是非聚合物的、非离子性的、线性的烃或选自由亲脂性脂肪醇或脂肪醛或脂肪酸或其组合组成的组的表面活性剂。
9.根据权利要求8所述的医疗装置，其中，烃或表面活性剂是具有化学式CxHyO的脂肪醇，其中x为至少18且至多35，并且y为至少38且至多72。
10.一种治疗患有原发性脑肿瘤的个体的方法，所述方法包括：
(a)提供一种球囊导管，所述球囊导管在球囊的表面上包括第一涂层和第二涂层；
(b)进入个体的头骨中的硬膜下腔；
(c)将所述球囊导管插入所述硬膜下腔中；
(d)使所述球囊膨胀有效的时间，以使所述第二涂层释放到组织中。
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Also Published As
| Publication number | Publication date |
|---|---|
| EP3720517A1 (en) | 2020-10-14 |
| US20230364016A1 (en) | 2023-11-16 |
| JP2021505237A (ja) | 2021-02-18 |
| JP7382933B2 (ja) | 2023-11-17 |
| WO2019110600A1 (en) | 2019-06-13 |
| US20210186872A1 (en) | 2021-06-24 |
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