CN107249640A - 基于聚异烯烃类共聚物的聚合物‑药物结合物 - Google Patents
基于聚异烯烃类共聚物的聚合物‑药物结合物 Download PDFInfo
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Abstract
一种聚合物‑药物结合物,其可以用于医疗应用如支架,具有至少一种活性剂,其通过羧酸部分结合于源自至少一种异烯烃单体和至少一种可共聚单体的共聚物,其中可共聚单体是至少一种多烯烃单体、β‑蒎烯单体或它们的混合物。这样的结合物显示改善的与不锈钢的粘附性以及显著降低的紫杉醇由药物洗脱支架(DES)的突释。
Description
技术领域
本申请涉及聚合物-药物结合物,特别涉及药物与羧酸官能化的聚异烯烃类共聚物的结合物。
背景技术
丁基橡胶是合成弹性体,由于其许多有吸引力的性能,其用于许多高性能应用。这些性能包括水/气体不渗透性、化学稳定性、高弹性和生物相容性。市售丁基橡胶是异丁烯与少量的异戊二烯(IP)的共聚物。丁基橡胶和其共聚物是许多商业产品的重要组分,如用于机动车轮胎的内衬、运动器材、密封剂以及甚至口香糖。
最近聚异丁烯类材料用于一些生物医学应用有一些发展,包括聚异丁烯-共-聚苯乙烯(SIBS)三嵌段共聚物,其目前正用于在血管支架上的药物洗脱涂层。还已研究了这类聚合物作为合成主动脉瓣和作为用于青光眼的引流器。然而,当融入植入物时,即使市售的聚合物也已经表现出问题。例如,已研究SIBS作为在尿道中的移植物,但存在尿路病原体物种附着,如大肠杆菌67的显著附着。此外,在支架应用中,存在体内的涂层脱层的问题。涉及药物释放应用(特别是用于支架)的另一个主要问题是物理封装的药物由层压表面的突释,其引起支架的寿命减小和/或血栓形成事件。
仍然存在对于更适用于医疗应用,包括受控药物释放应用的新材料的需要。
发明内容
在一个方面,提供了聚合物-药物结合物,其包含至少一种活性剂,该活性剂通过羧酸部分结合于源自至少一种异烯烃单体和至少一种可共聚单体的共聚物,该可共聚单体包含至少一种多烯烃单体、β-蒎烯单体或它们的混合物。
还提供了治疗有效量的聚合物-药物结合物用于治疗或预防受试者的疾病或病症的用途。
还提供了治疗有效量的聚合物-药物结合物用于制造用于治疗或预防受试者的疾病或病症的药物的用途。
还提供了用于治疗或预防受试者的疾病的方法,包括将治疗有效量的聚合物-药物结合物给予需要治疗或预防的受试者。
还提供了官能化共聚物,包含至少一个游离羧酸(-COOH)基团,其键合于至少一种异烯烃单体和至少一种可共聚单体的共聚物,该可共聚单体包含至少一种多烯烃单体、β-蒎烯单体或它们的混合物。
还提供了沉积在基底上的聚合物-药物结合物或官能化共聚物的膜。
还提供了包含涂布有聚合物-药物结合物的网状管的支架。
本公开的聚合物-药物结合物可以有助于在医疗应用中控制药物释放。在聚异烯烃类共聚物上羧酸基团的引入可以用作药物的固定(例如共价固定)位点。固定可以通过化学键连,例如酯或酰胺键连,尤其是酯键连发生。固定有助于减少药物的突释,产生药物的更慢更受控的释放。另外,在共聚物上的游离羧酸基团(-COOH)可以用来增强与材料粘附,例如金属和骨的粘附,其将减少共聚物自材料的脱层,以及在各种应用,包括支架(例如药物洗脱支架(DES))、骨接合剂等中将是有益的。
聚合物-药物结合物特别有用于血管支架涂层。将血管支架引入狭窄的、患病的外周或冠状动脉以防止狭窄(血流的阻塞)。药物洗脱支架缓慢地释放药物分子以阻断细胞增殖,其减少纤维化的可能性,否则其连同血栓(血块)一起会阻断支架的动脉(再狭窄)。
在以下详细描述的过程中,进一步的特征将被描述或将变得显而易见。应该理解的是,本文描述的每个特征可以以与任何一个或多个其他描述的特征的任何组合来使用,以及,除了对本领域技术人员显而易见的之外,每个特征不一定依赖另一个特征的存在。
附图说明
为了更清楚的理解,现将通过举例的方式参照附图来详细描述优选的实施方式,其中:
图1描绘了对于紫杉醇(PTx)由聚合物基质的释放,释放的质量(μg)相对于时间(天)的图表,其中2C、7C和ArbC是本发明的聚合物-药物结合物,2P、7P和ArbP是可比较的聚合物-药物组合物,其中紫杉醇被物理包封在羧酸官能化的丁基橡胶中而不是结合于丁基橡胶,并且S1和S2是SIBS-紫杉醇组合物,其中紫杉醇被物理包封在SIBS中。应注意在大部分时间过程中,2C和7C重叠。
图2示出了C2C12细胞的共聚焦显微图像:A)2.1a;B)2.4a;C)2C,示出具有细胞粘附的罕见区域;D)2C,示出更典型的表面的区域;E)7C;F)对于不同薄膜的细胞/mm2,示出在2C和7C上统计学上减少的细胞数目(*P<0.05)。用DAPI来染色细胞核以及用Alexa Fluor568鬼笔环肽来染色细胞骨架。所有图像都是相同的放大倍数且每个图像表示0.4mm x0.4mm的区域。
图3示出C2C12细胞的共聚焦显微镜图像:A)载玻片;B)2.4c;C)ArbC;D)对于不同薄膜的细胞/mm2,示出在ArbC上统计学上减少的细胞数目(*P<0.05)。用DAPI来染色细胞核且用Alexa Fluor 568鬼笔环肽来染色细胞骨架。所有图像都是相同的放大倍数且每个图像表示0.4mm x 0.4mm的区域。
图4示出药物结合物的减少的膜脱层:A)左侧烧杯含有在35天处理以后的S1,其中完全脱层;右侧烧杯含有35天时的2C,其中脱层极小;B)左侧烧杯含有35天时的7P,示出轻微的脱层;右侧烧杯含有35天时的7C,未显示脱层。
图5示出了聚合物-PTX膜的SEM图像,其揭示由于释放研究的总体结构变化。A、C和E在释放前获得;B、D和F在释放后获得。A、B)S1;C、D)2P;E、F)2C。100x放大率(除了C,95x放大率,以及E,80x放大率);比例尺是500μm。
图6示出AFM图像的实例,其示出释放研究前后的聚合物表面:A-C)S1;D-F)7P;G-H)7C。相图:A、D、G;PTX释放前的形貌图像:B、E、H;PTX释放35天后的形貌图像:C、F、I。
图7描绘了示出用于评估有和没有紫杉醇的各种聚合物的毒性的MTT试验的结果的图表,其中:HDPE=高密度聚乙烯,作为对照;SIBS1和SIBS2是分别含有10和20%聚苯乙烯的苯乙烯-异丁烯-苯乙烯三嵌段共聚物;2.4a-c是羧酸官能化聚合物,其分别制备自2.2mol%、7mol%、和6mol%的树枝状橡胶(如在方案2中所定义的);2P=羧酸官能化丁基橡胶(2.2mol%IP),具有24wt%物理固定的紫杉醇;2C=羧酸官能化丁基橡胶(2.2mol%IP),具有约24wt%共价结合的紫杉醇;7P=羧酸官能化丁基橡胶(7mol%IP),具有48wt%物理固定的紫杉醇;7C=羧酸官能化丁基橡胶(7mol%IP),具有约48wt%共价结合的紫杉醇;ArbC=羧酸官能化树枝状丁基橡胶(6mol%IP),具有约38wt%共价结合的紫杉醇;S1=SIBS1,具有24wt%物理固定的紫杉醇;S2=SIBS2,具有48wt%物理固定的紫杉醇。
具体实施方式
聚合物-药物结合物包含丁基橡胶聚合物。丁基橡胶聚合物是源自至少一种异烯烃单体和至少一种可共聚单体的共聚物,可共聚单体包含至少一种多烯烃单体、β-蒎烯单体或它们的混合物。
丁基橡胶聚合物并不限于特定的聚异烯烃。然而,产生自具有4-16个碳原子,优选4-7个碳原子的异烯烃单体,如异丁烯、2-甲基-1-丁烯、3-甲基-1-丁烯、2-甲基-2-丁烯、4-甲基-1-戊烯以及它们的混合物的聚异烯烃是优选的。更优选的是异丁烯(isobutene)(IB,还被称为异丁烯(isobutylene))。
可共聚单体提供共聚物中的不饱和性。丁基橡胶聚合物不限于特定的多烯烃。与异烯烃可共聚的多烯烃,如本领域技术人员已知的,可用于本发明的实践。共轭二烯多烯烃单体是优选的。这样的多烯烃的实例包括,例如,具有4-14个范围内的碳原子的那些。适宜的多烯烃的实例包括异戊二烯、丁二烯、2-甲基丁二烯、2,4-二甲基丁二烯、戊间二烯、3-甲基-1,3-戊二烯、2,4-己二烯、2-新戊基丁二烯、2-甲基-1,5-己二烯、2,5-二甲基-2,4-己二烯、2-甲基-1,4-戊二烯、2-甲基-1,6-庚二烯、环戊二烯、甲基环戊二烯、环己二烯、1-乙烯基-环己二烯以及它们的混合物。优选的多烯烃包含异戊二烯(IP)。
在共聚物中的不饱和水平源于共聚物中存在的提供不饱和性的单体(例如β-蒎烯或至少一种多烯烃)的量。基于单体摩尔数的不饱和水平优选是约50%或更小。不饱和水平可以在约0.1-50mol%范围内,更优选约0.2-30mol%,还更优选约0.5-12mol%,还更优选约2-8mol%。在一些实施方式中,通过控制丁基橡胶聚合物的多烯烃和/或β-蒎烯含量,可以有利地控制羧酸官能化程度。通过控制羧酸官能化,可以调节聚合物-药物结合物的药物释放和/或表面粘附性能。
可选地,丁基橡胶聚合物可以包含不同于上面提到的多烯烃或β-蒎烯的共聚单体,如烷基取代的乙烯基芳族共聚单体,包括但不限于C1-C4烷基取代的苯乙烯。这种共聚单体的具体实例包括,例如,α-甲基苯乙烯、对甲基苯乙烯、氯苯乙烯、环戊二烯、甲基环戊二烯、茚以及它们的混合物。在一种实施方式中,丁基橡胶聚合物可以包括,例如异丁烯、异戊二烯和对甲基苯乙烯的无规共聚物。
丁基橡胶结构可以是线性的或树枝状的。树枝状聚合物包含接枝聚合物,该接枝聚合物包含树枝状(多水平)-支化结构,其通常来自在具有随机分布的结合位点的基质上线性链段的连续接枝反应。
聚合物-药物结合物包含羧酸部分。羧酸部分可以是聚合的、低聚的或非聚合的,优选非聚合的。羧酸部分更优选是包含羧基基团的C1-10有机残基。有机残基可以包含一个或多个杂原子,例如O、S、Cl或Br。优选地,羧酸部分是包含羧基基团和另外的O原子的C1-10有机残基。羧酸部分更优选是开环的环状酸酐,优选饱和环状酸酐的残基。在开环以前,环状酸酐可以包含,例如,四、五、六、七或八元环,优选五元或六元环。环状酸酐的残基的具体实例包括二甘醇酸酐、戊二酸酐(pentadioic anhydride)(戊二酸酐(glutaricanhydride))或琥珀酐的残基。二甘醇酸酐的残基是特别优选的。在特别优选的实施方式中,聚合物-药物结合物具有式(I):
聚合物-Rc-Ag (I)
其中聚合物是源自至少一种异烯烃单体和至少一种可共聚单体的共聚物,Ag是活性剂,且Rc包含饱和环状酸酐的开环残基。Rc优选是
在特别优选的实施方式中,Rc是
其包含二甘醇酸酐的残基。
聚合物-药物结合物包含至少一种活性剂。可以使用本公开的聚合物-药物结合物来递送任何活性剂,如小分子药物或生物分子药物。在一些实施方式中,至少一种活性剂是生物活性化合物,例如肽、蛋白质、治疗剂、诊断剂、非生物材料、或它们的组合。活性剂可以是任何生理或药理活性物质,其可以产生期望的生物效应,例如治疗或预防受试者的疾病或病症的效应。活性剂可以是,例如,化疗剂、免疫抑制剂、细胞因子、细胞毒性剂、溶核化合物、和前药酶,其可以是自然存在的或通过合成或重组方法或它们的组合所产生的。
受到经典的多重抗药性的影响的活性剂,如长春花生物碱(例如,长春碱、长春新碱)、蒽环霉素(例如,阿霉素和柔红霉素)、RNA转录抑制剂(例如,放线菌素-D)、和微管稳定药物(例如,紫杉醇)作为活性剂是特别值得注意的。在一些实施方式中,活性剂可以是疏水性药物或亲水性药物。癌症化疗剂可以是优选的活性剂。在一种实施方式中,活性剂是紫杉醇。在另一种实施方式中,活性剂是雷帕霉素。
为了产生聚合物-药物结合物,可以首先用羧酸基团来官能化共聚物以形成羧酸官能化共聚物,然后使羧酸官能化的共聚物与活性剂接触以形成结合物。羧酸官能化的共聚物可以具有足够的羧酸基团以适应与结合物中的期望的活性剂的量的相互作用,并且使得留下游离的羧酸基团(-COOH基团)以增强结合物与基质的粘附。
可以通过任何适宜的方法来形成羧酸官能化的共聚物。在一种实施方式中,可以在自由基引发的过程中将烯类不饱和羧酸接枝于共聚物链,如在例如US 2009/189118中所描述的。在另一种实施方式中,可以在烯丙基部分(多烯烃单元)处环氧化共聚物,接着酸化,以产生烯丙醇官能化的共聚物,随后以任何数量的方式,包括环状酸酐的开环加成、硫醇-烯点击反应和环状碳酸酯的开环聚合(ROP),将烯丙醇转化为羧酸,接着去保护,以产生多酸官能化的共聚物。在一种实施方式中,羧酸官能化的共聚物可以包含如上所述的羧酸部分,其被质子化而不是结合于活性剂。在优选的实施方式中,官能化共聚物包含游离的羧酸基团,其包含饱和环状酸酐的开环残基,例如
在特别优选的实施方式中,游离羧酸基团是
其包含二甘醇酸酐的残基。
活性剂应具有能够与共聚物上的羧酸基团相互作用的官能团。相互作用可以通过任何类型的键合,例如,离子、共价或氢键。在一些实施方式中,可以通过共价键连,将一种或多种药物分子附接至共聚物,在这种情况下,活性剂上的与羧酸基团反应的官能团可以是,例如,羟基或胺基团。催化剂可以用于协助共聚物上的羧酸基团和活性剂上的官能团之间的反应。还可以采用脱水剂(例如碳二亚胺)通过结合产生键连(例如酯键)。优选地,活性剂上的羟基基团与共聚物上的游离羧酸基团反应以形成酯键。共聚物可以与任何数目的活性剂分子结合。尤其是,应该理解的是,结合物可以包含单个药物分子或多个药物分子。在一些实施方式中,活性剂与共聚物的共价键连是通过可断裂的共价键。响应于靶细胞内的环境条件,例如pH、温度等,可断裂键可以是可断裂的。
在受试者中的靶细胞可以是,例如,癌细胞,尤其是治疗抗性癌细胞。在各种实施方式中,癌症可以是以下的至少一种:乳腺癌、肺癌、前列腺癌、卵巢癌、脑癌、肝癌、宫颈癌、骨癌、食道癌、膀胱癌、子宫癌、睾丸癌、白血病、淋巴瘤、胃癌、胰腺癌、平滑肌癌(例如血管平滑肌)或它们的组合。受试者优选是哺乳动物,例如人类、狗、猫、马、小鼠、大鼠、豚鼠、猴等。
可以以任何合适的方式将聚合物-药物结合物给予受试者。给予途径可以包括,例如,口服;通过注射,通过SC、IV、腹腔内、脑内(脑实质内)、脑室内、肌内、眼内、动脉内、门静脉内、或病灶内途径;通过缓释体系;或通过植入装置(例如支架)。在需要的情况下,可以通过推注或连续输液、或通过植入装置来给予组合物。可以作为单次剂量,作为随时间两次或更多次剂量(其可以或可以不包含相同量的期望的活性剂分子),或作为通过植入装置或导管的连续输液给予治疗有效量的聚合物-药物结合物。剂量水平将取决于活性剂和受试者并且可以由熟练的医生根据具体情况来确定。
在一种实施方式中,可以将聚合物-药物结合物涂覆在植入装置上,例如支架(例如血管支架),并将装置植入受试者。聚合物-药物结合物的涂覆可以包括在基质上产生聚合物-药物结合物的膜。基质可以包含适用于其中使用基质的应用的任何材料。一些材料包括钢(例如不锈钢)、陶瓷、玻璃和聚合物或聚合物复合材料。在支架应用中,材料优选是不锈钢。不锈钢上的聚合物-药物结合物的涂层可以具有如通过基于ASTM D-429方法A的粘附测试程序测量的约15psi或更大的粘附力,优选约25psi或更大,或甚至30psi或更大。
实施例
材料和方法:
LANXESS Butyl 402(Mw=4.69x105g/摩尔,PDI=2.4,聚合物2.1a)和含有7mol%异戊二烯的丁基橡胶(Mw=1.05x106g/摩尔,PDI=3.3,聚合物2.1b)获得自LANXESS Inc。具有6mol%异戊二烯(Mw=216kDa,PDI=1.4)的树枝状聚(异丁烯-共-异戊二烯)是如先前报道的(Puskas 2009)制备的并由LANXESS Inc.提供。紫杉醇购自LC laboratories(Woburn,Ma)。溶剂购自Caledon且所有其他化学品购自Sigma-Aldrich并且不经进一步纯化而使用,除非另有说明。干甲苯获得自溶剂纯化系统。在CDCl3中在400MHz下获得1H NMR谱。以ppm报道NMR化学位移(δ)并相对于CDCl3的残余溶剂信号(δ7.26)校准。使用Bruker Tensor 27仪器,作为NaCl板上的来自CH2Cl2的膜获得红外光谱。在THF中使用Waters 515泵,Wyatt Rex差示折射计,和串联的两个PolyPore柱(300x7.5mm2,Agilent),进行尺寸排阻色谱法(SEC)。使用聚苯乙烯标准进行校准。在Mettler Toledo DSC 822e上在10℃/分钟的加热速率下,从-120至+150℃,进行差示扫描量热法(DSC)和热重分析(TGA)。
烯丙醇官能化丁基橡胶的合成:
烯丙醇官能化丁基橡胶用作用于产生羧酸官能化丁基橡胶的起点。为了产生烯丙醇官能化丁基橡胶,通过现有技术的方法(Jian 1991;Puskas 1994)首先环氧化丁基橡胶,然后通过现有技术的方法(Bonduelle 2010),用酸来处理环氧化物,以形成烯丙醇。如方案1所示,在用间氯过氧苯甲酸(m-CPBA)处理丁基橡胶(2.1a-c)时,产生环氧化物官能化的丁基橡胶(2.2a-c)。然后可以用盐酸水溶液来处理环氧化物,以提供烯丙醇官能化丁基橡胶(2.3a-c)。
方案1
产生三种类型的烯丙醇官能化丁基橡胶,一种具有2.2mol%异戊二烯(2.3a),一种具有7.0mol%异戊二烯(2.3b)且一种为树枝状,具有6.0mol%异戊二烯(2.3c)。
使用环状酸酐的羧酸官能化丁基橡胶的合成:
如方案2所示,在三乙胺(TEA)的存在下,通过各种环状酸酐的开环攻击,可以将烯丙醇官能化丁基橡胶(2.3a-c)转化为羧酸官能化丁基橡胶(2.4-2.6a-c)。
方案2
表1提供了在以下提供的合成中使用的环状酸酐的结构、使用的当量数以及到最终产物的百分比转化率。类似于聚合物2.4a来制备聚合物2.5和2.6。
表1
聚合物2.4a的合成
将烯丙醇官能化丁基橡胶(2.3a)(10g,3.9mmol的–OH)溶解于350mL甲苯。将溶液加热到70℃,然后添加20当量的三乙胺(10.9mL,78mmol),随后2当量的4-(二甲基氨基)吡啶(0.99g,7.8mmol)。然后,通过注射器添加二甘醇酸酐(10当量,4.5g,39mmol)溶解于甲苯中的溶液并在70℃下搅拌反应混合物过夜。然后用蒸馏水和6M HCl来洗涤产物两次,随后在减压下浓缩。通过沉淀(2:1丙酮/甲苯),进一步纯化产物(聚合物2.4a),然后在真空下干燥。转化率=>95%。产率=90%。1H NMR(400MHz,CDCl3)5.29(br s,1H),5.12(s,1H),4.95(s,1H),4.20-4.40(m,4H),1.42(s,145H),1.12(s,431H)。SEC:Mw=308,900g/mol,PDI=2.52。IR:1230,1365.1390,1475,1733,1758,2974cm-1。Tg=-61℃。
聚合物2.4b的合成
将环氧化物官能化的丁基橡胶(2.2b)(10g,12.1mmol的环氧化物)溶解于350mL甲苯。用一当量HCl(1.0mL,12.1mmol)来处理溶液并使其在室温下反应1小时。由于溶解度问题,没有分离烯丙醇官能化丁基橡胶2.3b。代替地,用碳酸钠来中和HCl,然后用MgSO4干燥。然后离心混合物并从MgSO4中倾析2.3b。将溶液加热到70℃,然后添加20当量的三乙胺(33.7mL,242mmol),随后2当量的4-(二甲基氨基)吡啶(3.1g,24.2mmol)。然后,通过注射器添加二甘醇酸酐(10当量,14.0g,121mmol)溶解在甲苯中的溶液并在70℃下搅拌反应混合物过夜。然后用蒸馏水和6M HCl来洗涤产物两次,接着在减压下浓缩。通过沉淀(2:1丙酮/甲苯)来进一步纯化产物,然后在真空下干燥。转化率=100%。产率=90%。1H NMR(400MHz,CDCl3)5.29(br s,1H),5.12(s,1H),4.95(s,1H),4.20-4.40(m,4H),1.42(s,69H),1.12(s,209H)。IR:1230,1365.1390,1475,1733,1758,2974cm-1。Tg=-53℃。
聚合物2.4c的合成
将烯丙醇官能化聚合物(2.3c)(7.0g,7.3mmol的醇)溶解于甲苯(300mL)。然后通过共沸蒸发来除去甲苯和任何残留的水并用新鲜无水甲苯(300mL)替换。连同新鲜蒸馏的三乙胺(21mL,150mmol)和4-(二甲基氨基)氨基吡啶(DMAP)(1.8g,15mmol)一起,添加二甘醇酸酐(17g,150mmol)。在70℃下加热反应混合物36小时,然后冷却至环境温度。然后用1MHCl、饱和NaHCO3、和水将其洗涤。然后将反应混合物沉淀至丙酮(1L)中,再溶解于甲苯(250mL)并再沉淀至丙酮(1L)中,以提供作为灰白色橡胶状固体的聚合物(2.4c)(7.0g,>98%)。Tg=-66℃;1H NMR*(600MHz,CDCl3)δ5.29-5.21(m,0.02H),5.13-5.10(m,0.02H),4.97-4.85(m,0.04H),4.32-4.16(m,0.53H),1.41(s,29H),1.10(s,88H);IR(NaCl上的薄膜,氯仿):923,950,1228,1367,1390,1486,1756,3006cm-1。SEC:Mw=228kDa,PDI=1.6。
羧酸官能化丁基橡胶与基质的粘附:
围绕作为生物材料的丁基橡胶的一个问题是丁基橡胶涂层自基质如不锈钢的脱层。这限制了丁基橡胶在生物医学应用中的应用,因为在发生脱层以后,其可以在体内引起重大影响并且特别相关于在药物洗脱支架上的涂层。在此实施例中,相比与未官能化丁基橡胶(聚合物2.1a/b)、环氧化丁基橡胶(聚合物2.2a/b)和烯丙醇官能化丁基橡胶(聚合物2.3a/b)的粘附性能,检查了羧酸官能化丁基橡胶(聚合物2.4a/b)的粘附性能。如上所述,以5-10克规模,进行聚合物2.2a/b、2.3a/b、和2.4a/b的合成。聚合物2.1a/b获得自LANXESSInc。由从基质除去聚合物样品所需要的力的量来确定表面粘附或粘性。由于不锈钢对支架的适用性,所以选用316L不锈钢基质。
使用Monsanto Tel-TakTM Model TT-1来确定未固化橡胶样品与不锈钢基质表面的粘附。粘附测试程序基于ASTM D-429方法A。此测试确定实现弹性体与固体基质的平面分离所需要的力。待测试的化合物最初由双辊磨机压片并切割成5"x3"的不同厚度(0.5mm至3.3mm)的样品片材。然后,在100℃下,使用15磅的重物,将样品片材压入12.7cm x 7.6cm含有方形织物的模具5分钟。模具由由一侧的MylarTM和另一侧的TeflonTM衬背以保持样品表面的完整性。清洗不锈钢表面,然后将其保存在含有乙醇的玻璃罐中,同时,在测试以前,直接用乙醇来擦掉TeflonTM和MylarTM。将所有表面切割成6.35mm x 50.8mm的测试条。在样品制备的16小时内进行测试。小心制备和保持所有样品表面的完整性。
当进行粘附测试时,将丁基橡胶样品面朝上放入Tel-TakTM仪器的样品架的底部并除去保护MylarTM层。用乙醇来抛光不锈钢基质表面并将其放入在样品上方的顶部样品架。然后将两个样品架放入仪器。移动表面彼此接触并自动激活设置为60秒的内置定时器。使用仪器,用450g重量施加32psi的接触压力。在60秒接触时间以后,以2.54cm/分钟的速度,彼此分离样品和基质表面,同时恒定维持在表面之间的平行关系。使用具有2270克的上限和内置的最大值指示器的校准的测力计来测量为自表面分离样品所需要的力。最大力值可以以磅/平方英寸(psi)直接读取自测力计。测试重复进行三次并报道平均值。结果在表2中给出。
表2
可商购的丁基橡胶2.1a/b的粘附性是众所周知的,并测试各种氧化丁基橡胶(2.2a/b、2.3a/b、2.4a/b),并与2.1a/b比较。所有氧化丁基橡胶显示与不锈钢基质的粘附的显着改善。对于羧酸官能化丁基橡胶2.4a,观察到粘附的最大改善,其需要32.8±1.3psi来分离。高异戊二烯羧酸官能化丁基橡胶2.4b的粘附也较高,但这种聚合物的流动性的减少使得难以处理用于此测试的样品,因而对3.4b所观测到的值可能会低于实际粘附值。高异戊二烯羧酸官能化树枝状的丁基橡胶2.4c的粘附未加以测试,但预计具有源自羧酸部分的类似的粘附改善。结果表明,羧酸官能化丁基橡胶与不锈钢的增强的粘附使它们成为有希望的用于在不锈钢支架中减少脱层问题的材料。
紫杉醇与羧酸官能化丁基橡胶的结合和紫杉醇由羧酸官能化丁基橡胶的释放:
在此实施例中,相较于物理包封的药物,抗增殖药物紫杉醇共价结合于羧酸官能化丁基橡胶,以提供持续释放。
结合物3.0a/b的合成
方案3说明结合物的合成。通常,合成紫杉醇-丁基橡胶结合物(3.0a/b)包括在溶剂中在脱水剂(例如碳二亚胺)和催化剂(例如4-二甲基氨基吡啶(DMAP))的存在下,使紫杉醇与羧酸官能化丁基橡胶(2.4a/b)接触。可以使用各种碳二亚胺脱水剂(例如二环己基碳二亚胺(DCC)、1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(EDC·HCl)),然而EDC·HCl是优选的,因为DCC的使用会产生更难以消除的副产物。可以使用各种催化剂,但亲核催化剂是优选的。
方案3
在丁基橡胶中具有2.2mol%异戊二烯的结合物3.0a制备如下。将2.4a的干燥样品(10g,每克聚合物0.39mmol CO2H)溶解于干甲苯并置于惰性条件下。将1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(EDC)(1.25当量/CO2H,4.9mmol,0.76g)、和4-二甲基氨基吡啶(DMAP)(0.5当量/CO2H,1.95mmol,0.25g)、以及N,N-二异丙基乙胺(2.0当量/CO2H,1.2mL,6.8mmol)的溶液溶解于干燥CH2Cl2并加入4.2a。在添加溶解于CH2Cl2中的紫杉醇(PTX)(1.1当量/CO2H,4.29mmol,3.65g)以前,搅拌溶液10-20分钟。在室温下放置溶液过夜。然后通过旋转蒸发,从CH2Cl2汽提反应混合物,然后用去离子(DI)水、1M HCl和1M NaHCO3洗涤两次。最后在乙醇中沉淀所得的溶液并在真空下干燥。1H NMR(400MHz,CDCl3)δppm 8.15(d,J=7.4Hz,2H,PTX),7.76(t,J=7.1Hz,2H,PTX),7.60(t,J=7.1Hz,1H),7.56-7.45(m,3H,PTX),7.44-7.36(m,5H,PTX),7.34(m,1H,PTX),7.15-7.10(m,1H,PTX),6.30(s,1H,PTX),6.29-6.20(m,1H,PTX),6.08-6.01(m,1H,PTX),5.69(t,J=6.1Hz,1H,PTX),5.62-5.57(m,1H,PTX),5.29-5.19(m,1.1H,PIB),5.13-5.06(m,1H,PIB),4.97(d,J=9.1Hz,1H,PTX),4.91(m,2H,PIB),4.44(m,1H,PTX),4.37-4.12(m,6H,IB/PTX),3.82(pseudo-d,J=6.5Hz,1H,PTX),3.68(t,J=6.4Hz,1H,PTX),2.62-2.52(m,1H,PTX),2.49-2.46(s,3H,PTX),2.41-2.35(m,1H,PTX),2.26(m,2H,PTX),2.22(s,3H,PTX)1.96-1.92(m,4H,PTX),1.69(s,3H,PTX)1.42(s,315H,PIB),1.26-0.91(PIB,m,950H,PIB/PTX)。IR(NaCl上的薄膜,氯仿)1232,1367,1390,1475,1670,1737,2960cm-1。SEC:Mw=337,000g/mol,PDI=1.47。Tg=-62℃。
除了该聚合物含有每克聚合物1.2mmol CO2H,因而增加EDC、DMAP、DIPEA和PTx的量以保留这些试剂的比率分别为1.25、0.5、2.0和1.1当量/CO2H之外,如上文针对3.0a所描述的来制备在丁基橡胶中具有7mol%异戊二烯的结合物3.0b。1H NMR(400MHz,CDCl3 8.15(d,J=7.3Hz,2H,PTX),7.74(d,J=6.4Hz,2H,PTX),7.60(t,J=7.2Hz,1H,PTX),7.52(t,J=7.6Hz,2H,PTX),7.49(t,J=7.6Hz,1H,PTX),7.44-7.31(m,8H,PTX),7.02-6.96(m,1H,PTX),6.29(s,1H,PTX),6.28-6.20(m,2H,PTX),6.08-6.00(m,1H,PTX),5.69(d,J=6.8Hz,1H,PTX),5.62-5.56(m,1H,PTX),5.28-5.19(m,1.4H,PIB),5.12-5.07(m,1.4H,PIB),4.97(d,J=9.4Hz,1.2H,PTX),4.91-4.89(m,1.6H,PIB),4.47-4.41(m,1H,PTX)4.40-4.10(m,9H,PTX/PIB),3.82(d,J=6.5Hz,1H,PTX),3.70-3.64(m,1H,PTX),2.62-2.52(m,1H,PTX),2.52-2.44(m,4H,PTX),2.42-2.34(m,2H,PTX),2.23(s,3H,PTX),1.94(bs,4H),1.68(bs,3H,PTX),1.41(s,112H,PIB),1.29-0.87(m,400H,PTX/PIB);IR:1232,1367,1390,1475,1670,1737,2960cm-1;SEC:Mw=501,400g/mol,PDI=2.66。Tg=-56℃。
除了该聚合物含有每克聚合物1.1mmol CO2H,因而增加EDC、DMAP、DIPEA和PTx的量以保留这些比率分别为1.25、0.5、2.0和1.5当量/CO2H之外,如对3.0a所描述的来制备在树枝状丁基橡胶中具有6mol%异戊二烯的结合物3.0c。1H NMR*(600MHz,CDCl3)δ8.14(bd,J=6.4Hz,0.055H),7.75(bd,J=6.9Hz,0.051H),7.63-7.58(m,0.027H),7.53-7.47(m,0.17H),7.45-7.33(m,0.19H),7.22-7.19(m,0.062H),7.10-7.05(m,0.027H),6.31-6.20(m,0.057H),6.07-5.97(m,0.026H)5.70-5.65(m,0.028H),5.64-5.56(m,0.032H),5.29-5.17(m,0.067H),5.15-5.08(m,0.061H),4.99-4.87(m,0.16H),4.49-4.04(m,0.53H),3.83-3.78(m,0.15H),2.69-2.51(m,0.034H),2.50-2.42(m,0.099H),2.41-2.38(m,0.036H),2.25-2.23(m,0.22H),1.97-1.80(m,0.18H),1.69(s,0.29H),1.47-1.33(m,29.7H),1.11(s,92H);SEC:Mw=234kDa,PDI=1.82。IR(NaCl上的薄膜,氯仿):923,949,1231,1366,1389,1472,1645,1743,2952cm-1;Tg=-65℃。
如由1H NMR数据所证实的,紫杉醇与羧酸官能化丁基橡胶的结合是成功的,其示出特征紫杉醇和丁基橡胶峰以及在4.81ppm处峰的消失,其对应于相邻于发生结合的紫杉醇羟基基团的质子。在结合以后此峰移动到5.60ppm。此外,在5.80ppm处的紫杉醇峰,其对应于相邻于苄基环的质子,移动到6.05ppm。基于1H NMR谱,对于3.0a,转化率是大约95%,对于3.0b为85%,以及对于3.0c为50%。结合物3.0a含有约24wt%紫杉醇,3.0b含有约48wt%紫杉醇,且3.0c含有约38%紫杉醇,其与相关的异戊二烯含量和反应转化率一致。
3.0a-c的释放分布
为了研究紫杉醇释放分布,制备了结合物3.0a-c和未结合的羧酸官能化丁基橡胶2.4a-c的膜。为了制备膜,制备了聚合物的100mg/mL溶液(CH2Cl2中)。对于包括物理包封(2P、7P、ArbP)而不是结合的样品,随后添加紫杉醇(PTX),以获得相当的重量百分比(即,24wt%、48wt%、38wt%)。此外,具有不同量的苯乙烯含量(S1-10%和S2-20%)的苯乙烯-异丁烯-苯乙烯(SIBS)三嵌段共聚物和24wt%的物理包封的紫杉醇的两个实例用作与其它体系的比较。
将100-μL等份的每种聚合物溶液滴浇在抛光的不锈钢板(3cm x 1cm)上,不锈钢板的表面已用台式磨床来抛光以给出光滑表面。在释放研究以前,在减压下干燥样品。每种样品制备和研究三次。表3提供样品的描述。
表3
样品名称 | 聚合物组成 | PTx wt.% | PTx固定 |
2C | 3.0a | ~24 | 共价 |
7C | 3.0b | ~48 | 共价 |
ArbC | 3.0c | ~38 | 共价 |
2P | 2.4a | 24 | 物理 |
7P | 2.4b | 48 | 物理 |
ArbP | 2.4c | 38 | 物理 |
S1 | SIBS-10%苯乙烯 | 24 | 物理 |
S2 | SIBS-20%苯乙烯 | 24 | 物理 |
在0.01M磷酸盐缓冲的pH=7.4的溶液中进行释放研究。最终缓冲液还含有0.138MNaCl、0.0027M KCl和0.05%TweenTM 20,其作为表面活性剂以帮助溶解紫杉醇。将不锈钢板放入含有10mL缓冲溶液的小瓶。将上述溶液保持在37℃下并每7天除去缓冲液,用于紫杉醇的分析,并用新鲜培养基替换。由于释放的紫杉醇的低浓度,所以在HPLC分析以前,将释放介质从10mL浓缩至2mL。通过冷冻干燥来除去水并将固体再溶解于2mL的80:20的水:乙腈。
使用Waters Separations Module 2695、光电二极管阵列检测器(Waters 2998)和Nova-Pak C18 4μm(3.9mm x 150mm)柱(其连接于C18保护柱)来进行紫杉醇的HPLC分析。使用PDA检测器监测在228nm处的紫杉醇。使用梯度法,用溶剂A(水中的5%乙腈)和溶剂B(水中的80%乙腈,0.1%H3PO4),以1mL/分钟流动,来获得紫杉醇分离。在10分钟内,将溶剂A的梯度从65%下降到30%,并在接下来的5分钟内增加回到65%,其中使得柱在另外5分钟内平衡由紫杉醇(LC Laboratories,>99%,P-9600)标准溶液获得。校准曲线。制备1000μg/mL、100μg/mL和50μg/mL的紫杉醇在乙腈中的储备溶液。使用储备溶液制备在20:80的乙腈:PBS的溶液中的25、20、15、10、7.5、5、2、1、0.5μg/mL的标准溶液。使用以上仪器方法,过滤并注射100μL的标准溶液。使用与上述相同的条件在20:80的乙腈:PBS溶液中制备样品,通过0.2μm过滤器过滤并注射100μL。紫杉醇的检测限度确定为0.02μg。表4提供了在不同的时间点由聚合物膜释放的PTX的质量(以μg计)。提供了三次测量的标准偏差。
表4
7天 | 14天 | 21天 | 28天 | 35天 | |
2C | 0.40±0.03 | 0.80±0.02 | 1.21±0.03 | 1.63±0.04 | 2.06±0.04 |
7C | 0.30±0.02 | 0.70±0.02 | 1.30±0.03 | 1.65±0.03 | 2.10±0.03 |
ArbC | 0.0±0.0 | 1.4±0.4 | 2.7±0.9 | 3.3±0.4 | 4.4±0.9 |
2P | 2.3±0.7 | 6.0±0.4 | 9.0±0.4 | 12.3±0.4 | 14.4±0.8 |
7P | 4±2 | 8±1 | 12±2 | 15.2±0.4 | 18±1 |
ArbP | 0.5±0.2 | 5±2 | 6±2 | 6±2 | 8±2 |
S1 | 5±4 | 12±7 | 20±2 | 27±4 | 39±4 |
S2 | 4±3 | 8±3 | 10±5 | 13±6 | 16±6 |
图1示出测试的样品的紫杉醇释放分布。以释放的紫杉醇的累积质量来示出该分布,并且应注意的是,在HPLC追踪中还看到紫杉醇的一些降解产物,例如已知的差向异构体。相较于物理固定的样品,共价结合的紫杉醇样品显示持续、缓慢的释放。相较于SIBS样品,共价结合的紫杉醇样品还显示更慢的释放。如在现有技术中观察到的,亲水性嵌段的引入会增加紫杉醇的突释。然而,对于本共价结合的结合物,此问题不会出现。由紫杉醇结合的羧酸官能化丁基橡胶样品呈现的缓慢持续释放消除了药物的突释。尽管紫杉醇由共价结合物膜缓慢释放,但药物仍然能够防止细胞在膜上的附着和增殖,其对于它们在药物洗脱支架中作为聚合物-药物结合物的应用是重要的(图2和图3)。
用于表面上的细胞生长的步骤
在补充有10%胎牛血清(Invitrogen)以及补充有1%Glutamax(100x)溶液和1%Penstrep(100x)的达尔伯克改良伊格尔培养基(Dulbecco’s Modified Eagle Medium)(Invitrogen)中将C2C12细胞维持在37℃和5%CO2下。首先,通过施加聚合物在甲苯中的35mg/mL溶液并使溶剂完全干燥,在显微镜盖玻片(圆形,25mm直径)上涂覆最小层的聚合物。通过浸没在70%乙醇中来消毒表面,然后使其处于减压下96小时至完全干燥。将消毒的样品放入6孔板的孔中并在每个表面上接种2mL细胞培养基中的5×105个细胞。温育样品48小时,然后用4%多聚甲醛溶液固定10分钟。在pH 7.2下,用磷酸盐缓冲盐水(PBS)(Invitrogen)洗涤样品两次,然后在-20℃下用2mL丙酮处理5分钟使膜可渗透。此后,再次用PBS洗涤它们,并遵循制造商的指示用Alexa Fluor 568鬼笔环肽(Invitrogen)和DAPI(Invitrogen)染色。用PBS来再次洗涤样品并将其面朝下地放置在具有GoldAntifade Reagent(Invitrogen)的显微镜载玻片上,然后密封。使用共聚焦激光扫描显微镜(LSM 510 Duo Vario,Carl Zeiss)使用20×物镜以及405(DAPI)和578nm(鬼笔环肽)的激发波长来获得共聚焦图像。使用Image Pro Plus软件对5个不同的图像计数细胞。使用软件Excel来进行统计分析(ANOVA,接着图基(Tukey)检验)。
3.0a/b与不锈钢的粘附
在释放研究的35天期间,针对聚合物涂层由不锈钢基质的脱层,通过扫描电子显微(SEM)和原子力显微(AFM),视觉检验了来自上述的样品2C、7C、2P、7P、S1和S2的膜。相较于对照(2P、7P、S1、S2),共价结合的样品(2C、7C)表现出增强的膜与不锈钢基质的粘附。如图4所示,在超过35天的温育期内,目视观察到物理固定的样品的脱层,然而对于共价结合的样品(2C、7C、ArbC)则没有目视观察到脱层。SEM(图5)表明,膜最初是光滑且均匀的,但在释放介质中35天以后,基于SIBS的膜(S1、S2)和物理固定的样品(2P、7P)的完整性已急剧下降。基于SIBS的膜(S1、S2)的表面变得不均匀,具有可见的表面降解。物理固定的样品(2P、7P、ArbP)的膜在聚合物表面各处产生裂纹。然而,在35天以后,共价结合的样品(2C、7C)的膜看上去保持完整。这也通过原子力显微(AFM)观察到,相比结合物,其显示具有非共价PTX的膜的显着侵蚀(图6)。
毒性
还使用MTT试验来进行毒性研究以评估在限定的细胞培养基中的温育期期间,不锈钢上的3.0a-c的膜是否释放毒性水平的紫杉醇或任何其它沥出物。
沥出物的制备:熔融压制测试样品至0.4mm的厚度。然后将熔融压制膜切割成1cmx 1cm的正方形。通过用70%乙醇洗涤以及随后在UV光下干燥2小时来消毒样品。将样品放入有盖培养皿,然后在37℃的温箱中,在补充有10%胎牛血清(Invitrogen)以及补充有1%Glutamax(100x)溶液和1%Penstrep(100x)的2mL的达尔伯克改良伊格尔培养基(DMEM,Invitrogen)中温育24小时。然后除去沥出物并通过0.2μm过滤器。
MTT试验:将C2C12小鼠成肌细胞接种在NunclonTM 96孔U形形底透明聚苯乙烯(polystrol)板中以在如上所述的含有血清、glutamax和抗生素的100μL的DMEM中获得10,000个细胞/孔。在5%CO2温箱中在37℃下,细胞附着24小时。然后抽吸生长培养基并用阳性对照(在细胞培养基中浓度为0.2、0.15、0.10、或0.05mg/mL的十二烷基硫酸钠(SDS))、阴性对照(高密度聚乙烯(HDPE))、沥出物的连续两倍稀释物、或仅培养基替换。然后在37℃(5%CO2)下温育细胞24小时。然后抽吸培养基并用110μL的含有0.5mg/mL(3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四唑)(MTT)试剂替换。在温育(37℃,5%CO2)4小时以后,小心抽吸MTT溶液并通过添加50μL的光谱级二甲亚砜(DMSO)来溶解紫色晶体。在摇动(1秒,2mm振幅,654rpm)以后,使用M1000-Pro酶标仪(plate reader)(Tecan),读出在540nm处孔的吸光度。减去不含有细胞但通过所有上述步骤处理的孔的吸光度作为背景,并相对于含有仅暴露于培养基的细胞的孔来计算细胞存活率。对于暴露于最高浓度的阳性对照月桂基磺酸钠的细胞,检测到(0%)细胞存活率,这证实了试验的灵敏度。
作为已知的无毒对照,高密度聚乙烯(HDPE)是阴性对照。十二烷基硫酸钠(SDS)用作阳性对照并且在0.2μg/mL下检测到高毒性(<10%细胞存活率),其显示该试验在检测毒性中的功效。为了检测任何潜在毒性分子的浸出,还测试了紫杉醇结合的羧酸官能化丁基橡胶(2C、7C、ArbC)、物理固定的样品(2P、7P)、具有物理固定的紫杉醇的SIBS样品(S1、S2)、没有紫杉醇的SIBS样品(SIBS1、SIBS2)以及没有紫杉醇的羧酸官能化丁基橡胶2.4a-c。
如图7所示,大多数的材料并不导致任何可检测的毒性,其中仅几种膜在最高沥出物浓度下呈现中度的毒性。表现出中度毒性的膜是物理固定的紫杉醇材料(2P、7P)以及SIBS材料(S1、S2),其在释放研究中最快速地释放紫杉醇。应注意的是,虽然紫杉醇非常毒性的药物,但在24小时温育期间内释放的紫杉醇的量仍然极小。在此试验中,没有紫杉醇的聚合物没有显示任何毒性。这些结果进一步支持基于其的羧酸官能化丁基橡胶以及聚合物-药物结合物用于生物医学应用的用途。
在审阅说明书后,新特征将对于本领域的技术人员变得显而易见。然而,应当理解,权利要求的范围不应该受到实施方式的限制,而应给予最广泛的解释,其与作为整体的权利要求和说明书的措词一致。
Claims (19)
1.一种聚合物-药物结合物,包含至少一种活性剂,所述活性剂通过羧酸部分结合于源自至少一种异烯烃单体和至少一种可共聚单体的共聚物,所述可共聚单体包含至少一种多烯烃单体或β-蒎烯单体或它们的混合物。
2.根据权利要求1所述的结合物,具有式(I):
聚合物-Rc-Ag (I)
其中
聚合物是源自至少一种异烯烃单体和至少一种可共聚单体的共聚物,
Ag是所述活性剂,并且
Rc包含饱和环状酸酐的开环残基。
3.根据权利要求2所述的结合物,其中,所述饱和环状酸酐在开环之前具有五元或六元环。
4.根据权利要求2所述的结合物,其中,Rc是
5.根据权利要求2所述的结合物,其中Rc是
6.根据权利要求1至5中任一项所述的结合物,其中,所述至少一种异烯烃单体包含聚异丁烯。
7.根据权利要求1至6中任一项所述的结合物,其中,所述可共聚单体包含至少一种共轭二烯。
8.根据权利要求1至6中任一项所述的结合物,其中,所述可共聚单体包含异戊二烯。
9.根据权利要求1至8中任一项所述的结合物,其中,所述共聚物是直链的。
10.根据权利要求1至8中任一项所述的结合物,其中,所述共聚物是树枝状的。
11.根据权利要求1至10中任一项所述的结合物,其中,所述活性剂包含微管稳定药物。
12.根据权利要求1至10中任一项所述的结合物,其中,所述活性剂包含紫杉醇。
13.治疗有效量的如权利要求1至12中任一项所限定的聚合物-药物结合物用于治疗或预防受试者的疾病或病症的用途。
14.治疗有效量的如权利要求1至12中任一项所限定的聚合物-药物结合物用于制造用于治疗或预防受试者的疾病或病症的药物的用途。
15.一种治疗或预防受试者的疾病的方法,包括将治疗有效量的如权利要求1至12中任一项所限定的聚合物-药物结合物给予需要所述治疗或预防的受试者。
16.一种支架,包含涂覆有如权利要求1至12中任一项所限定的聚合物-药物结合物的网状管。
17.根据权利要求16所述的支架,所述支架是血管支架。
18.根据权利要求16或17所述的支架,其中,所述管包含不锈钢。
19.根据权利要求18所述的支架,其中,所述聚合物-药物结合物具有约15psi或更大的与316L不锈钢的粘附力。
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Application publication date: 20171013 |