CN101622004B - 酰亚胺化的生物聚合物黏合剂及水凝胶 - Google Patents
酰亚胺化的生物聚合物黏合剂及水凝胶 Download PDFInfo
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Abstract
生物相容性聚合物担载酰胺,且可用作黏合剂、水凝胶或上述两者。与酰亚胺化的聚合物反应的第二生物相容性聚合物能与酰亚胺化的聚合物合用以封闭开口。
Description
技术领域
本发明关于一种经分离的酰亚胺化的生物相容性聚合物。
背景技术
天然衍生的生物聚合物并不总是具有生物医学应用所需的结构或功能特点。不过,聚合性生物材料已用于生物医学应用,包括医疗装置涂层、人造植入物及药物输送装置。例如,可通过交联水溶性聚合物溶液来形成不溶于水的聚合物网而形成聚合物网。可通过改变交联密度(控制网孔尺寸、含水量及机械性质)来操控机械及结构性质。
因为聚合物、基质或凝胶可包裹细胞,因此这些材料对于组织工程来说具有吸引力。部分聚合物或凝胶具有似组织的高含水量,能运送营养及废物。
发明内容
在某种程度上,本公开提供一种组合物,组合物包含至少一种单体单元的经酰亚胺官能化的生物相容性聚合物,以提供组织黏合剂、水凝胶或上述两者。
在另一具体实施例中,生物相容性聚合物的单体单元中的至少一个与第二官能基团共轭,所述第二官能基团可以是酰亚胺。如果不是酰亚胺,所述第二官能基团可以是任何已知的官能基团且能向聚合物提供指向性。
单体可经至少两种官能基团官能化。总体来说,当聚合物含有复数种官能基团时,聚合物实质上可含有相等摩尔量的不同官能基团,或比例可根据设计选择而改变。
再者,官能化的生物相容性聚合物组合物可包含至少一种与第一酰亚胺化生物聚合物反应的第二生物相容性聚合物。因此,第二聚合物可含有与酰亚胺或第一酰亚胺化聚合物上的其它官能基团反应的官能基团。例如,第二聚合物上的官能基团可以是胺基。
本公开组合物可以进一步包含一种生物活性剂如营养剂、细胞如血细胞或软骨细胞、或未分化细胞如干细胞如造血干细胞或间质干细胞。
在一些具体实施例中,感兴趣的组合物为具有黏合性质的水凝胶。
本发明提供一种组合物,该组合物包含经酰亚胺基团官能化的生物相容性第一聚合物,以及视需要包含桥联分子如官能化的第二聚合物,以提供一种医学黏合剂。在一些具体实施例中,第一聚合物包含至少10个单体单元,至少100个单体单元或至少1,000或更多个单体单元。桥联分子可含有复数个官能基团以确证其与第一聚合物的至少两个分子反应。
聚合物中,并非所有单体都需要经反应性部分(moiety)官能化。
第一聚合物可与结构如生物结构如器官、组织或细胞的表面,如软骨或骨的表面,或人造结构如假体的表面反应。第一酰亚胺化聚合物上的第二官能部分(可能是酰亚胺)也可以与表面反应。第一聚合物可与桥联分子反应。反应可通过提供与桥联分子一定程度粘合性的任何手段如:共价键、物理性交联、离子交联或将分子固附于表面、结构或与其反应的整体的其它分子机制。
在某些具体实施例中,多种聚合物一起反应以形成具有暴露表面的多层聚合物结构,暴露表面与表面如组织反应,且与桥联分子反应。桥联分子也可以是多层结构。
在下述具体实施方式中描述并清晰理解本发明的另外特征和优点。
附图说明
图1至图20描述可作为用于衍生感兴趣的单体或聚合物的反应物的各种酰亚胺。
具体实施方式
本发明在某种程度上关于填充或修复组织或器官缺陷的方法,如封闭切口或伤口。该方法包含将包含酰亚胺的生物相容性聚合物施加于表面上。视需要地,可先处理表面以提供可与感兴趣的第一酰亚胺化的聚合物反应的反应性官能基团。
与感兴趣的组合物制成的感兴趣的凝胶、网、支架、膜等激励细胞、组织及器官的整合及生长。视需要而存在的细胞如干细胞促进细胞、组织及器官的整合及生长。
对于感兴趣的产品,重要的是与周围组织增进的整合以提高安定性、与生物表面的结合以及形成新的组织。体外研究已经证实了与表面反应的化学机制的效率以及材料-细胞/组织/器官界面增加的机械强度。
本发明致力于解决外科手术方法中纤维软骨形成的问题。例如,本发明可通过使用贴片及凝胶用于治疗早期骨关节炎性关节来防止植入期间及植入后的酶促滑液退化(enzymaticsynovialdegradation)。本发明也可在不破坏软骨下骨(subchondralbone)完整性下进行骨髓刺激。举例来说,感兴趣的化合物可用于眼内、脊柱内、肌肉及骨骼系统内、软骨担载部位等。
本发明提供原位聚合技术以形成支架等,该支架等可模制成缺陷的期望形状、通过刺激自然细胞修复促使组织发展、以及可通过最小限度的侵入性注射而可能植入该支架等。
至少在某种程度上,本公开着重聚合物、基质、凝胶、以及制作和使用基质、聚合物和凝胶的方法。所述此等聚合物之一包含酰亚胺。
举例来说,本公开提供经酰亚胺取代的官能化生物相容性第一聚合物如透明质酸盐(hyaluronate)、硫酸角质素、硫酸软骨素等。举例来说,参见WO2006089119、WO2004029137、WO2006105161及WO2006036681揭示相似但不相关的化合物的各种应用,上述文献整体以引用形式并入本文。上述文献中未教导酰亚胺,也没有对酰亚胺的应用做出明确的反面教导。
生物表面指生物材料或实体如微生物、病毒、细胞、组织、器官等的外在、环境暴露部位,且生物相容性聚合物可与生物表面相互作用、反应及/或黏附于其上。
生物相容性聚合物指经官能化以作为施加于表面的组合物的聚合物。聚合物是天然存在的聚合物或对宿主无毒的聚合物。聚合物含有至少一酰亚胺。聚合物可以是全部单体均相同的均聚物或含有两种或多种单体的杂聚物。当术语“生物相容性聚合物(biocompatiblepolymer)”、“生物相容性交联聚合物基质”及“生物相容性”用于与本发明聚合物相关时为本领域中公认的,并被认为彼此相当,包括与生物相容性聚合物(biologicallycompatiblepolymer)相当。举例来说,生物相容性聚合物包括既对宿主(如动物或人类)无毒、又不会以在宿主产生有毒浓度的单体次单元或寡聚物次单元或其它副产物的速率降解(如果聚合物降解)的聚合物。
本文中活性剂和生物活性剂交替使用,均指诱导期望的药理效果及/或生理效果的化学或生物化合物,其中,该效果可以是预防性或治疗性。该术语也涵盖本文具体指出的那些活性剂的药学上可接受、药理上活性的衍生物,包括但不限于,盐、酯、酰胺、前药、活性代谢物、类似物等。那么,当使用术语“活性剂”、“药理上活性剂”及“药物”时,应当理解本发明包括活性剂本身以及药学上可接受、药理上活性的盐、酯、酰胺、前药、代谢物、类似物等。活性剂可以是生物实体如病毒或细胞,无论其是天然存在的或经操作如经转形的(transformed)。
生物相容性聚合物、生物相容性交联聚合物基质及生物相容性为本领域中公认的。举例来说,生物相容性聚合物包括本身对宿主(如动物或人类)无毒、又不会以在宿主产生有毒浓度的单体次单元或寡聚物次单元或其它副产物的速率降解(如果聚合物降解)的聚合物。本发明的某些具体实施例中,生物降解通常涉及聚合物在有机体内降解为例如:其单体次单元,而单体次单元可能已知是实际上无毒的。然而,来自这种降解得到的中间寡聚物产物可能具有不同的毒理性质,或生物降解可涉及生成不同于聚合物单体次单元的分子的氧化或其它生物化学反应。因此,某些具体实施例中,意欲体内应用如植入或注射至患者的生物降解性聚合物的毒理学可在一次或多次毒性分析后确定。任何目标组合物具有被认为是生物相容性的100%纯度是没有必要的;事实上,目标组合物仅需要如上所述为生物相容性。因此,目标组合物可以包括含有99%、98%、97%、96%、95%、90%、85%、80%、75%或甚至更少的生物相容性聚合物的聚合物,如包括聚合物和本文所述的其它材料及赋形剂,且目标组合物仍然是生物相容的。
为了确定聚合物或其它材料是否是生物相容的,实施毒性分析可能是必要的。这种分析法是在本领域中广知的。这种分析法的一个实例可与活体细胞如HeLa、293、CHO等进行。使用诸如本领域中已知的化学方法或酶方法而部分或全部降解样品。将处理过的样品产物的等分试样放入事先种植细胞的培养板中。将样品产物与细胞一起培养。分析法的结果可绘制成%相对生长对降解样品的浓度。
此外,本发明的单体、聚合物、聚合物基质及调配物也可以通过广知的体内测试如小鼠的皮下植入而评估,从而确认它们不会在皮下植入部位造成显着程度的刺激或炎症。
生物可降解为本领域中公认的,且包括单体、聚合物、聚合物基质、凝胶、组合物及调配物,例如本文所描述的那些,它们倾向在应用如体内应用过程中降解。生物可降解聚合物和基质与非生物可降解聚合物的典型区别在于前者可在应用过程中降解。某些具体实施例中,这类应用包括体内应用如体内治疗,而在另外某些具体实施例中,这类应用包括体外应用。通常,可归因于生物可降解性的降解包括生物可降解聚合物降解为其成分次单元,或通过诸如生物化学过程将聚合物消化为较小的、非聚合性的次单元。某些具体实施例中,通常可鉴别两种不同类型的生物降解。举例来说,一种类型的生物降解可涉及聚合物骨架中键(无论共价键或其它键)的断裂。这种生物降解中,典型获得单体和寡聚物,更典型地,这种生物降解通过断裂连接一个或多个聚合物次单元的键而发生。相比之下,另一种类型的生物降解可涉及侧链内部的键或连接侧链、官能基团等至聚合物骨架的键(无论共价键或其它键)的断裂。举例来说,作为侧链附着于聚合物骨架的治疗剂、生物活性剂或其它化学部分可通过生物降解释放。某些具体实施例中,一种或另一种或两种一般类型的生物降解可在聚合物的应用过程中出现。如本文使用的术语“生物降解”涵盖两种一般类型的生物降解。
生物可降解聚合物的降解速率通常在某种程度上依赖于各种因素,所述因素包括响应任何降解的链结的化学特性、分子量、结晶性、生物安定性、这种聚合物的交联度、植入体的物理特点、形状和尺寸、以及投予模式和位置。举例来说,分子量越大、结晶性越高、及/或生物安定性越好,则任何生物可降解聚合物的生物降解通常越慢。术语“生物可降解”意图包含也被称为“生物可蚀解(bioerodible)”的材料及过程。
某些具体实施例中,这种聚合物的生物降解速率可以酶如:软骨素酶的存在为特征。这种情形下,生物降解速率可不仅依赖于聚合物基质的化学特性及物理特点,也依赖于任何这种酶的特性。
在某些具体实施例中,本发明的聚合性调配物在期望应用中可接受的期间内生物降解。某些具体实施例如体内治疗中,当暴露于pH介于6至8之间、具有温度介于约25℃至37℃之间的生理溶液时,这种降解通常在少于约5年、1年、6个月、3个月、1个月、15天、5天、3天或甚至1天的期间内出现。在另外的具体实施例中,依所期望的应用,聚合物在介于约1小时至数周之间的期间内降解。在一些具体实施例中,聚合物或聚合物基质可包括降解中释放的可检测剂。
本文中,交联指包含通常源于共价键形成的分子间交联及视需要而定的分子内交联的组合物。介于两种可交联成分间的共价键合可以是直接的(这种情况下,一种成分的一个原子与另一种成分的一个原子直接键合)或间接的通过链接基键合。交联凝胶或聚合物基质除了包括共价键外,也可包括分子间及/或分子内非共价键如氢键和静电(离子)键。
官能化指修饰已存在的分子片段或基团以生成或引入新的反应性或更高反应性的基团(如酰亚胺基)(基团能与其它官能团(如氨基)反应以形成共价键)。举例来说,羧酸基团可使用已知的步骤与碳二酰亚胺(carbodiimide)及酰亚胺反应剂反应进行官能化,以提供呈现酰亚胺基团形式的新的反应性官能基团来取代羧基功能的羟基的氢。
凝胶指物质介于液体与固体之间的物质状态,通常定义为在液体介质中膨胀的交联聚合物网。典型地,凝胶是含有固体和液体两者的两相胶体状分散体,其中,固体量大于称为“溶胶”的两相胶体状分散体中的固体量。就本身而言,“凝胶”具有液体的一些性质(即其形状是弹性的并且是可变形的)和固体的一些性质(即其形状足够离散以在二维表面上保持三维状态)。
本文中“凝胶化时间”也指“凝胶时间”,指组合物在适度应力下变为非流动性所需的时间。通常表现为到达弹性模数G’等于或大于粘性模数G”的物理状态,即tan(delta)变为1(可使用习知流变技术测定)。
水凝胶是可吸收水以形成弹性凝胶的水膨胀性聚合性基质,其中,“基质”是通过共价或非共价交联保持的三维网的大分子。放入水性环境时,干燥水凝胶通过获得环境内液体而膨胀至交联度所允许的限度。
水凝胶由亲水性聚合物组成,该亲水性聚合物交联以形成水膨胀性的不溶性聚合物网。交联可通过多种物理或化学机制引发。光聚合是共价交联聚合物链的方法,借此,光引发剂和聚合物溶液(定义为“预凝胶”溶液)被暴露于对光引发剂专一的光源。活化下,光引发剂与聚合物链中的特定官能基团反应,交联它们以形成水凝胶。反应速度快(3至5分钟)并能在室温及体温下进行。光引发的凝胶化能对支架形成进行空间及时间控制、并准许在注射后及体内凝胶化期间进行形状操控。在光凝胶化前,通过细胞和生物活性因子与聚合物溶液简单混合,可将细胞和生物活性因子轻易并入水凝胶支架。
或者,反应物可含有补充性反应性基团如酰亚胺和胺以产生交联而不需要添加外来的引发剂。
感兴趣的水凝胶可以是半互相贯通的网以促成细胞、组织和器官的修复同时阻止疤痕形成。感兴趣的水凝胶被衍生成含有与表面及/或感兴趣的第二聚合物反应的酰亚胺。感兴趣的水凝胶也被构造成具有粘性以能使凝胶化的水凝胶保持附于细胞上或细胞内、组织上或组织内、器官上或器官内、或表面上或表面内。可通过所使用的单体和聚合物、通过截留于水凝胶内的水量以及并入的增稠剂(例如生物聚合物如蛋白质、脂质、糖类等)来控制粘性。这种增稠剂的实例为透明质酸(hyaluronicacid)或胶原。
聚合物用来指由重复单体单元组成的分子,包括均聚物、嵌段共聚物、杂聚物、无规共聚物、接枝共聚物等。“聚合物”也包括线形聚合物和分枝聚合物,分枝聚合物包括高度分枝聚合物、树枝状聚合物和星形聚合物。
单体是聚合物中的基本重复单元。单体自身可作为单体,或可以是至少两种不同单体的二聚体或寡聚体,而各二聚体或寡聚体在聚合物中重复。
聚合引发剂指可通过例如自由基生成而引发单体或大单体(macromer)聚合反应的任意物质。聚合引发剂一般是氧化剂。例示的聚合引发剂包括那些通过暴露于诸如电磁辐射或热而得以活化的聚合引发剂。
关于治疗剂、染料或其它材料及聚合性组合物如本发明组合物于使用时经合并、包入及捕捉(entrap)是所属技术领域公认的。某些具体实施例中,这些术语包括将这些试剂合并在、调配在或也可以包括在允许于期望的应用中持续释放这种试剂的组合物中。这些术语的任意方式均在考虑范围内,通过举例来说,包括:(通过共价或其它键结互相影响)附在这种聚合物的单体上并具有这种单体作为聚合反应的一部分而获得聚合性调配物、分布于整个聚合物基质、(通过共价或其它键结互相影响)附加在聚合物基质的表面上、包入在聚合物基质中等将治疗剂或其它材料合并入聚合物基质。术语“共合并”或“共包入”指将一种治疗剂或其它材料与至少一种其它治疗剂或其它材料合并在目标组合物中。
更具体而言,任何治疗剂或其它材料被包入聚合物中的物理形式可以随特定的具体实施例而变化。举例来说,治疗剂或其它材料可首先包入微球体(microsphere)中,随后以至少保留部分微球体结构的方式与聚合物结合。或者,治疗剂或其它材料可以完全不能与本发明聚合物共混,因此以小滴形式分散于聚合物中而非溶解于聚合物中。任何包入或合并的形式都在本发明的考虑范围内,甚至于,任何包入的治疗剂或其它材料的持续释放决定包入形式能否于任何特定应用被充分接受。
处理(treating或treatment)在所属技术领域上是公认的术语,该术语包括对任何病症或疾病的至少一种症状治疗及改善。处理包括在可能有疾病、失调及/或病症但未确诊及患有的动物中预防疾病、失调或病症的发生;抑制疾病、失调或病症,例如阻止其发展;以及缓解疾病、失调或病症,例如造成疾病、失调及/或病症的任何程度的减退。再者,处理疾病或病症包括改善特定疾病或病症的至少一种症状,纵使其根本的病理生理(pathophysiology)未受影响或其它症状仍维持在相同程度。
药学上可接受的盐是所属技术领域上公认的,且包括本发明组合物包括而不限于治疗剂、赋形剂、其它材料等的相对无毒性、无机酸及有机酸加成盐。药学上可接受的盐的实例包括那些衍生自矿物酸如盐酸和硫酸的盐、以及那些衍生自有机酸如乙磺酸、苯磺酸、对甲苯磺酸等的盐。形成盐的合适无机碱的实例包括铵、钠、锂、钾、钙、镁、铝、锌等的氢氧化物、碳酸盐和碳酸氢盐。也可以与合适的有机碱形成盐,有机碱包括那些无毒性且其碱性强到足以形成这种盐的有机碱。为了说明目的,这类有机碱可包括单、二及三烷基胺如甲胺、二甲胺及三乙胺;单、二或三羟基烷基胺如单、二及三乙醇胺;氨基酸如精氨酸和赖氨酸;胍;N-甲基葡萄糖胺(N-methylglucosamine);N-甲基葡糖胺(N-methylglucamine);L-谷氨酸;N-甲基哌嗪;吗啉;乙二胺;N-苄基苯乙胺;(三羟基甲基)胺基乙烷等,例如见J.Pharm.Sci,66:1-19(1977)。
预防或治疗处理在所属技术领域上是公认的,且包括将一种或多种目标组合物向宿主投予。如果在不期望的病症(如疾病或宿主动物的其它不期望的状态)的临床表现之前投予,则该处理是预防性的,即保护宿主对抗不期望的病症的发展;但是如果在不期望的病症的表现之后投予,则该处理是治疗性的(即意在减弱、改善或稳定现有不期望的病症或其副作用)。
术语“脂肪族”在所属技术领域上是公认的,且包括线形、支链和环状烷类、烯类或炔类。某些具体实施例中,本发明的脂肪族基团是线形或支链,且具有1至约20个碳原子。
术语“烷基”在所属技术领域上是公认的,且包括饱和脂肪族基团,包括直链烷基、支链烷基、环烷(脂环)基、经烷基取代的环烷基和经环烷基取代的烷基。某些具体实施例中,直链或支链烷基在其骨架中具有约30个或更少个碳原子(如C1-C30直链烷基、C3-C30支链烷基),以及或者,约20个或更少个碳原子。同样地,环烷基在其环结构中具有约3至约10个碳原子,以及或者在环结构中具有约5、6或7个碳原子。
此外,术语“烷基”(或“低碳数烷基”)包括“未经取代的烷基”和“经取代的烷基”两者,后者指烷基部分具有替代烃骨架的一个或多个碳上的氢的取代基。举例来说,这种取代基可包括卤素、羟基、羰基(如羧基、烷氧基羰基、甲酰基或酰基)、硫代羰基(如硫酯、硫代乙酸酯或硫代甲酸酯)、烷氧基、磷酰基、膦酸根(phosphonate)、亚膦酸根(phosphinate)、氨基、酰氨基、脒、亚胺、氰基、硝基、叠氮基、巯基、烷基硫基、硫酸酯、磺酸酯、氨磺酰基、磺酰氨基、磺酰基、杂环基、芳烷基或芳香部分或杂芳香部分。熟悉所属技术领域的人士应该理解,如果合适,在烃链上经取代的部分可本身被取代。比如,经取代的烷基的取代基可包括经取代和未经取代形式的氨基、叠氮基、亚胺基、酰氨基、磷酰基(包括膦酸根及亚膦酸根)、磺酰基(包括硫酸酯、磺酰氨基、氨磺酰基和磺酸酯)和硅基,以及醚类、烷基硫基、羰基(包括酮类、醛类、羧酸酯类和酯类)、-CF3、-CN等。例示的经取代的烷基如下所述。环烷基可进一步被烷基、烯基、烷氧基、烷基硫基、氨基烷基、经羰基取代的烷基、-CF3、-CN等。
术语“芳烷基”在所属技术领域上是公认的,且包括芳基(如芳香基团或杂芳香基团)。
术语“烯基”和“炔基”在所属技术领域上是公认的,且包括在长度及可能的取代上与上述烷基相似的未饱和脂肪族基团,但分别含有至少一个双键或三键。
术语“杂原子”在所属技术领域上是公认的,且在有机分子中,通常包括除了碳或氢之外任何元素的原子。说明性的杂原子包括硼、氮、氧、磷、硫和硒。
术语“芳基”在所属技术领域上是公认的,包括可包括0至4个杂原子的5元、6元或7元单环芳香基团,例如苯、吡咯、呋喃、噻吩、咪唑、恶唑(oxazole)、噻唑、三唑、吡唑、吡啶、吡嗪、哒嗪和嘧啶等。那些在环结构中具有杂原子的芳基也可以用“芳基杂环”或“杂芳香族化合物”指代。芳香环可被上述取代基如卤素、叠氮化物、烷基、芳烷基、烯基、炔基、环烷基、羟基、烷氧基、氨基、硝基、巯基、亚胺基、酰氨基、膦酸根、亚膦酸根、羰基、羧基、硅基、醚、烷基硫基、磺酰基、磺酰氨基、酮、醛、酯、杂环基、芳香部分或杂芳香部分、-CF3、-CN等在一个或多个环位置取代。术语“芳基”也包括具有两个或更多个环(cyclicring)的多环系统,其中两个或更多个碳是两个相邻环共享的(该环是“稠环”),其中,该两个相邻环中至少一个是芳香性的,例如,其它环可以是环烷基、环烯基、环炔基、芳基及/或杂环基,或由非环状部分连接的环。
术语“邻”、“间”和“对”在所属技术领域上是公认的,且分别应用于1,2-、1,3-和1,4-二经取代更环己烷。举例来说,1,2-二甲苯和邻二甲苯是同义的。
术语“杂环基”和“杂环状基团”在所属技术领域上是公认的,且包括3元至约10元环结构如3元至约7元环结构,该环结构包括1至4个杂原子。杂环也可以是多环。举例来说,杂环基包括噻吩、噻蒽、呋喃、吡喃(pyran)、异苯并呋喃、色烯(chromene)、氧杂蒽(xanthene)、啡恶噻(phenoxanthin)、吡咯、咪唑、吡唑、异噻唑、异恶唑、吡啶、吡嗪、嘧啶、哒嗪、吲嗪、异吲哚、吲哚、吲唑、嘌呤、喹嗪、异喹啉、喹啉、酞嗪、萘啶、喹喔啉基(quinoxaline)、喹唑啉、噌啉、喋啶、咔唑、咔啉、菲啶、吖啶、嘧啶、菲咯啉(phenanthroline)、吩嗪(phenazine)、吩吡嗪、吩噻嗪、呋咱(furazan)、吩恶嗪、吡咯烷(pyrrolidine)、氧杂环戊烷(oxolane)、硫杂环戊烷(thiolane)、恶唑、哌啶、哌嗪、吗啉、内酯、内酰胺如氮杂环丁酮(azetidinone)及吡咯烷酮(pyrrolidinone)、磺内酰胺、磺内酯等。杂环可被上述取代基如卤素、烷基、芳烷基、烯基、炔基、环烷基、羟基、氨基、硝基、巯基、亚胺基、酰氨基、膦酸根、亚膦酸根、羰基、羧基、硅基、醚、烷基硫基、磺酰基、酮、醛、酯、杂环基、芳香部分或杂芳香部分、-CF3、-CN等在一个或多个环位置取代。
术语“多环基”和“多环状基团”在所属技术领域上是公认的,且包括具有两个或更多个环(如环烷基、环烯基、环炔基、芳基及/或杂环基)的结构,其中两个或更多个碳是两个相邻环共享的,如该环是“稠环”。通过非相邻原子结合的环,如三个或更多个原子是两环共享的,这种环定义为“桥”环。多环的每个环可被上述取代基如卤素、烷基、芳烷基、烯基、炔基、环烷基、羟基、氨基、硝基、巯基、亚胺基、酰氨基、膦酸根、亚膦酸根、羰基、羧基、硅基、醚、烷基硫基、磺酰基、酮、醛、酯、杂环基、芳香部分或杂芳香部分、-CF3、-CN等取代。
术语“碳环”在所属技术领域上是公认的,且包括芳香环或非芳香环,其中每个环原子都是碳。下列在所属技术领域上公认的术语具有下列意义:“硝基”意指-NO2;术语“卤素”表示-F、-Cl、-Br或-I;术语“巯基”意指-SH;术语“羟基(hydroxyl或hydroxy)”意指-OH;以及术语“磺酰基”意指-SO2-。
术语“氨”和“氨基”在所属技术领域上是公认的,且包括未经取代的氨和经取代的氨两者。伯氨担载两个氢,仲氨担载一个氢和另一个取代基,以及叔氨的两个氢都被取代。举例来说,用于取代一个或两个氢的取代基可以是烷基、烯基、芳基、环烷基、环烯基、杂环、多环等。如果两个氢都被羰基取代,羰基框住的氮形成酰亚胺。
术语“烷基氨”包括如上述定义的氨基团,该氨基团具有经取代或未经取代的烷基接附其上。
术语“酰氨基”在所属技术领域上公认为经氨基取代的羰基。
术语“烷基硫基”在所属技术领域上是公认的,且包括如上述定义的烷基,该烷基具有硫自由基接附其上。某些具体实施例中,“烷基硫基”部分是以-S-烷基、-S-烯基、-S-炔基等中的一个表示。代表性的烷基硫基包括甲硫基、乙硫基等。
术语“羰基”在所属技术领域上是公认的,且包括C=O结构。羰基被包括在酯类、羧基、甲酸酯、硫代羰基、硫酯类、硫代羧酸、硫代甲酸酯、酮类和醛类中。
术语“烷氧基(alkoxyl或alkoxy)”在所属技术领域上是公认的,且包括如上述定义的烷基,该烷基具有氧自由基接附其上。代表性的烷氧基包括甲氧基、乙氧基、丙氧基、叔丁氧基等。
“醚”是通过氧共价链接的两个烃。即,致使烷基成为醚的烷基的取代基是烷氧基或类似烷氧基,如可以-O-烷基、-O-烯基、-O-炔基等中的一个表示。
术语“磺酸根(sulfonate)”在所属技术领域上是公认的,且包括其中硫原子担载两个以双键结合的氧和一个以单键结合的氧的部分。
术语“硫酸根(sulfate)”在所属技术领域上是公认的,且包括类似磺酸根,但包括两个以单键结合的氧的部分。
术语“磺酰氨基”、“氨磺酰基”、“磺酰基”和“亚砜(sulfoxido)”在所属技术领域上是公认的,且各自可包括本文所述的各种R基取代基。
术语“亚磷酰胺”和“膦酰胺(phosphonamidite)”在所属技术领域上是公认的。
术语“硒烷基(selenoalkyl)”在所属技术领域上是公认的,且包括具有经取代的硒基接附其上的烷基。可取代在烷基上的例示性“硒醚类”是选自-Se-烷基、-Se-烯基、-Se-炔基等之一。
可对烯基和炔基进行取代以生产如氨基烯基、氨基炔基、酰氨基烯基、酰氨基炔基、亚胺基烯基、亚胺基炔基、硫基烯基、硫基炔基、经羰基取代的烯基或炔基。
烃在所属技术领域上是公认的术语,且包括具有至少一个氢和一个碳原子的所有许可的化合物。举例来说,许可的烃包括非环状的和环状的、分枝的和未分枝的、碳环的和杂环的、芳香的和非芳香的有机化合物,该有机化合物可以是经取代的或未经取代的。
片语“保护基”在所属技术领域上是公认的,且包括保护潜在反应性官能基团不参与非预期的化学转化的临时取代基。这种保护基的实例包括羧酸的酯类、醇类的硅基醚类、以及分别醛类和酮类的缩醛类和缩酮类。举例来说,回顾了保护基化学的领域,参见Greene等人的ProtectiveGroupsinOrganicSynthesis第二版,Wiley,NewYork,(1991)。
当每种表述如烷基、芳基等在任何结构中出现超过一次时,除了特别明确指出或根据上下文,每种表述的定义意于与在同一结构中别处出现的定义各自独立。
术语triflyl、tosyl、mesyl和nonaflyl在所属技术领域上是公认的,且分别指三氟甲磺酰基、对甲苯磺酰基、甲磺酰基和九氟丁磺酰基。术语triflate、tosylate、mesylate和nonaflate在所属技术领域上是公认的,且分别指三氟甲磺酸酯、对甲苯磺酸酯、甲磺酸酯和九氟丁磺酸酯官能基团和分别含有所述官能基团的分子。
缩略语Me、Et、Ph、Tf、Nf、Ts和Ms在所属技术领域上是公认的,且分别指甲基、乙基、苯基、三氟甲磺酰基、九氟丁磺酰基、对甲苯磺酰基和甲磺酰基。JournalofOrganicChemistry每一卷的第一期上都列有所属技术领域具有通常知识的有机化学家所使用的更广泛的缩略语名单,该名单典型以题为StandardListofAbbreviations的表呈现。
本发明的某些单体次单元可以特定的几何形式或立体异构形成存在。此外,本发明聚合物和其它组合物也可以是光学活性的。所有这些化合物包括顺式异构体和反式异构体、R-对映异构体和S-对映异构体、非对映体、(d)-异构体、(l)-异构体、它们的外消旋混合物和其它混合物都在本发明考虑范围内,并落入本发明范畴。额外的不对称碳原子可存在于取代基如烷基内。所有这些异构体和它们的混合物意于包括在本发明之内。
例如,如果本发明化合物的特定对映异构体是所预期的,那么这一对映异构体可通过不对称合成制备,或使用手性辅助剂衍生,其中分离所得到的非对映混合物并使辅助基团断裂以提供纯的所预期的对映异构体。或者,当分子含有碱性官能基团如氨基或酸性官能基团如羧基时,使用合适的光学活性酸或碱形成非对映的盐,再通过所属技术领域中广为人知的分级结晶或色谱手段对这样形成的非对映体解析,随后回收纯的对映异构体。
应理解取代或以...取代包括内含的前提:这种取代是根据被取代的原子和取代基的许可价数(valency),且取代导致稳定的化合物,如化合物不会自发进行转化如重排、环化、消除或其它反应。
术语“经取代的”也预期包括有机化合物的所有许可的取代基,如感兴趣的酰亚胺试剂。在广义的态样中,许可的取代基包括有机化合物的非环状的和环状的、分枝的和未分枝的、碳环的和杂环的、芳香的和非芳香的取代基。举例来说,说明性取代基包括本文上述取代基。许可的取代基可以是对于合适有机化合物的一个或多个、相同或不同的取代基。为了本发明的目的,杂原子如氮可具有氢取代基及/或本文描述的、满足杂原子价数的任意有机化合物许可的取代基。本发明未意于藉由有机化合物的许可的取代基以任何方式做出限制。
为了本发明目的,根据CAS版本,在1986-87出版的第67版的“HandbookofChemistryandPhysics”中的元素周期表确定化学元素。
可用于取代的官能基团或部分是能够媒介聚合物的形成或媒介与表面或其它分子反应的官能基团或部分。官能基团包括本文教导的各种自由基和化学整体,且包括烯基部分如丙烯酸根(acrylate)、甲基丙烯酸根(methacrylate)、二甲基丙烯酸根、寡丙烯酸根(oligoacrylate)、寡甲基丙烯酸根(oligomethacrylate)、乙基丙烯酸根(ethacrylate)、衣康酸根(itaconate)或丙烯酰胺(acrylamide)。更进一步的官能基团包括醛类。其它官能基团可包括烯型(ethylenically)不饱和单体,包括,举例来说,丙烯酸或甲基丙烯酸的烷基酯类如甲基丙烯酸甲酯、甲基丙烯酸乙酯、甲基丙烯酸丁酯、丙烯酸乙酯、丙烯酸丁酯、丙烯酸己酯、丙烯酸正辛酯、甲基丙烯酸月桂酯、甲基丙烯酸2-乙基己酯、丙烯酸壬酯、甲基丙烯酸苄酯,相同酸类的羟基烷基酯类如丙烯酸2-羟基乙酯、甲基丙烯酸2-羟基乙酯和甲基丙烯酸2-羟基丙酯,相同酸类的腈和酰胺类如丙烯腈、甲基丙烯腈和甲基丙烯酰胺,醋酸乙烯酯,丙酸乙烯酯,偏二氯乙烯,氯乙烯,乙烯基芳香化合物如苯乙烯、叔丁基苯乙烯和乙烯基甲苯,马来酸二烷基酯,衣康酸二烷基酯,亚甲基丙二酸二烷基酯,异戊二烯和丁二烯。适合的含有羧酸基的烯型不饱和单体包括丙烯酸类单体如丙烯酸,甲基丙烯酸,乙基丙烯酸,衣康酸,马来酸,富马酸,衣康酸单烷基酯包括衣康酸单甲酯、衣康酸单乙酯和衣康酸单丁酯,马来酸单烷基酯包括马来酸单甲酯、马来酸单乙酯和马来酸单丁酯,柠康酸和苯乙烯羧酸。合适的多烯型不饱和单体包括丁二烯、异戊二烯、甲基丙烯酸烯丙酯、烷基二醇的二丙烯酸酯如丁二醇二丙烯酸酯和己二醇二丙烯酸酯、二乙烯基苯等。
一些具体实施例中,生物相容性聚合物的单体单元可通过位于生物聚合物单体上的一个或多个硫基、羧酸或醇部分予以官能化。举例来说,对于硫酸软骨素的例子,可使用诸如碳二酰亚胺化学以酰亚胺基衍生羰基。可使用诸如Mitsunobu反应(Procteretal.,Tetra.Lett.47(29)5151-5154,2006)衍生醇基。
一些具体实施例中,本公开揭示包含经酰亚胺官能化的、生物相容性聚合物如透明质酸、硫酸肝素、硫酸角质素等的至少一种单体单元的组合物。那些起始分子是细胞外基质的天然成分。然而,通常来说,任意生物相容性聚合物可用作为担载至少一个酰亚胺的聚合物。其它合适的聚合物包括那些天然存在的聚合物如GAG、粘多糖、胶原蛋白或蛋白多糖成分如透明质酸、硫酸肝素、葡萄糖胺、皮肤素、角质素、类肝素、透明质素(hyalurunan)、聚集蛋白聚糖(aggrecan)等。
一些具体实施例中,本公开揭示包含糖或其它生物相容性单体或聚合物的至少一种单体单元的组合物,其中,单体具有将使单体至少包含酰亚胺和其它官能基团如硫酸软骨素的反应位。硫酸软骨素是软骨的天然成分,且可为有用的再生的支架材料。硫酸软骨素的成员包括10-60kDa粘多糖(glycosaminoglycan)。硫酸软骨素的重复单元或单体单元由二糖β(l→4)-链接的D-葡糖醛酸基β(l→3)N-乙酰基-D-半乳糖胺硫酸酯组成。
由于所属技术领域中已知许多反应物且可用于本发明情境,即提供不会迅速自发降解但稳定性足够与诸如预期分子上的氨反应的中间衍生物,因此本发明的酰亚胺不限制为任何反应物,其中,如果酰亚胺被羟基化且其氧是结合位,则酰亚胺重建为羟基酰亚胺并被预期分子上的官能基团所替代。图1至图20提供酰亚胺的实例,如琥珀酰亚胺。
本发明的交联聚合物基质可包括和形成水凝胶。水凝胶的含水量可提供孔结构的信息。再者,含水量可以是影响如包入在水凝胶内的细胞的存活因素。水凝胶能够吸收的水量可与交联密度及/或孔大小相关。举例来说,在官能化大单体如硫酸软骨素或硫酸角质素上的酰亚胺的百分比可支配可吸收的水量。
本发明的组合物可包含单体、大单体、寡聚物、聚合物或其混合物。聚合物组合物可仅由可共价交联的聚合物、或可离子交联的聚合物、或可通过氧化还原化学交联的聚合物、或通过氢键结交联的聚合物组成,或由其组合组成。试剂应是实质上亲水性的和生物相容性的。
作为第一和第二聚合物的合适的亲水性聚合物包括合成聚合物如聚(乙二醇)、聚(氧乙烯)(poly(ethyleneoxide))、部分或全部水解的聚(乙烯醇)、聚(乙烯吡咯烷酮)、聚(乙基恶唑啉)、聚(氧乙烯)-共-聚(氧丙烯)嵌段共聚物(泊咯沙姆(poloxamers)和美罗沙波(meroxapols))、泊洛沙胺(poloxamines)、羧甲基纤维素、以及羟烷基化纤维素如羟乙基纤维素和甲基羟丙基纤维素;以及天然聚合物如多肽、多糖或碳水化合物如FicollTM、聚蔗糖、透明质酸、葡聚糖(dextran)、硫酸乙酰肝素、硫酸软骨素、肝素或藻酸盐(alginate)、和蛋白质如明胶、胶原蛋白、白蛋白或卵白蛋白,或其共聚物或共混物。本文使用的“纤维素”包括纤维素和上述类型的衍生物;“葡聚糖”包括葡聚糖及其相似衍生物。
非常粘稠的液体或触变性的、且随着时间通过结构的缓慢进展而形成凝胶的多糖或其它生物相容性聚合物也是可用的。举例来说,可形成具有类似发胶粘稠度的可注射凝胶的透明质酸是可用的。改性的透明质酸衍生物尤其可用。本文所使用的术语“改性的透明质酸”指化学改性的透明质酸。改性的透明质酸可通过预先选择的化学改性来设计并合成,以调整交联和生物降解的速率和程度。例如,改性的透明质酸可通过相对疏水性基团如丙酸或苯甲酸(benzylicacid)进行酯化来设计并合成,使得聚合物具有更高疏水性并使其形成凝胶,或通过氨来接枝以促成静电自组装。这样改性后的透明质酸可合成为在应力下流动时是可注射的但没有应力时保持似凝胶结构。透明质酸和透明质酸衍生物可自Genzyme(Cambridge,Mass.)和Fidia(Italy)获得。
或者,生物相容性聚合物可合并入感兴趣的基质来形成复合物。因此,一个分子如透明质酸或胶原蛋白可合并入感兴趣的基质。经合并的生物聚合物的反应性可为所需的。因此,在经引入的聚合物上的氨基可与感兴趣的基质成分反应,可能得到具有较高模数的复合结构。或者,为了在不对模数造成实质性冲击情况下使复合物性质具有聚合物的好处如保留组织粘合性,可官能化经引入的聚合物以降低聚合物上任何反应性功能的活性。因此,举例来说,可官能化聚合物如胶原蛋白上的氨以例如担载本文所教导的烷基、乙酰基等,从而获得与酰亚胺基的较少反应性的聚合物。
对于所属技术领域的技术人员来说,合成上述聚合物的方法是已知的,参见例如E.Goethals编辑的ConciseEncyclopediaofPolymerScienceandPolymericAminesandAmmoniumSalts(PergamenPress,Elmsford,N.Y.1980)。很多聚合物如聚(丙烯酸)为商业上可获得的。天然存在的聚合物可从所属技术领域已知的生物来源中分离或为商业上可获得的。天然存在的或合成的聚合物可使用所属技术领域可获得的的化学反应或如“AdvancedOrganicChemistry”第四版(inMarch,1992,Wiley-IntersciencePublication,NewYork)所述的化学反应来改性。
本发明的代表性具体实施例包括生产酰亚胺化的糖、单体或聚合物部分的方法,其中,方法可包括使用诸如碳二酰亚胺中间物和酰亚胺反应物来形成经酰亚胺衍生的单体。碳二酰亚胺的实例包括N,N′-二环己基碳二酰亚胺(DCC)、N,N′-二异丙基碳二酰亚胺(DIC)和l-乙基-3-(3-二甲基氨基丙基)碳二酰亚胺盐酸盐(EDC)。其它用于酰亚胺化分子的方法是所属技术领域中已知的。
无数化学选择可用于改性聚合物而使聚合物随后进行自由基聚合反应。举例来说,可使用甲基丙烯酸酐、甲基丙烯酰氯化物和甲基丙烯酸缩水甘油酯向一个或多个聚合物链的单体上加成甲基丙烯酸根基团(methacrylategroup)。举例来说,为了反应效能,可使用甲基丙烯酸缩水甘油酯。再者,可选择改性试剂以最大限度减少细胞毒性副产物。
一些具体实施例中,每个聚合物单元中每种官能基团的数目可以为每约10个单体单元至少1个部分、每约10个单体单元至少约2个部分,直到每一单体一个或多个官能基团。或者,每个聚合物单元中每种官能基团的数目可以为每约12个单体单元、每约14个或更多单体单元至少约1个部分。举例来说,每10个单体单元可具有至少约1个酰亚胺基。
此外,沿着聚合物的整个长度,每个酰亚胺和其它官能基团的比例可以是5∶1、9∶2、4∶1、7∶2、3∶1、5∶2、2∶1、3∶2、1∶1、2∶3、1∶2、2∶5、1∶3、2∶7、1∶4、2∶9或1∶5。优选地,每个酰亚胺和其它官能基团沿着聚合物的长度规则分布。然而,官能基团的排列可以构造为非随机的或规则穿插的,如在聚合物骨架的某些部位集结以用于所需的应用。因此,基团可在聚合物的不同区段分离。如果除了酰亚胺外还有两个或更多个其它官能基团,每种官能基团相互间的比例可依设计所需自单一比例至任何其它比例改变。
提供包含交联聚合物基质的组合物,其中,所述交联聚合物基质包含至少一种酰亚胺化的生物相容性聚合物。一些具体实施例中,所述交联聚合物基质进一步包含至少两种酰亚胺化的生物相容性聚合物。其它具体实施例中,交联聚合物基质进一步包含第二生物相容性聚合物,该第二生物相容聚合物含有与所述第一酰亚胺化的聚合物上的官能基团,如于蛋白质上发现的氨基反应的一个或多个官能基团。
可将感兴趣的酰亚胺化的生物聚合物如担载氨的聚合物结合在一起的伴随分子-桥联分子,通常是含有复数个反应位的聚合物,其中,所述反应位为与感兴趣的酰亚胺化生物相容性聚合物上发现的位置反应的反应位。桥联分子优选是生物相容的。与酰亚胺化的生物相容性聚合物一样,桥联分子可以是生物可降解的。桥联分子可被构造为多层结构,其中,内层可为相同或不同,只要具暴露的官能基团(为了与酰亚胺化的聚合物上的位置反应)呈现的表面层、外层可以是组织粘附聚合物。
用于感兴趣的酰亚胺化的聚合物和桥联分子的合适聚合物包括具有发现于下列的重复单元的生物相容性单体:聚(磷酸酯)、聚(丙交酯)、聚(乙交酯)、聚(己内酯)、聚(酐)、聚(酰胺)、聚(氨基甲酸乙酯)、聚(酯酰胺)、聚(原酸酯)、聚(二氧杂环己酮)、聚(缩醛)、聚(缩酮)、聚(碳酸酯)、聚(原碳酸酯)(poly(orthocarbonate))、聚(磷)氮基)(poly(phosphazene)、聚(羟基丁酸酯)、聚(羟基戊酸酯)、聚(草酸亚烃酯)、聚(琥珀酸亚烃酯)、聚(苹果酸)、聚(氨基酸)、聚乙烯醇、聚(乙烯吡咯烷酮)、聚(乙二醇)、聚(羟基纤维素)、甲壳素、壳聚糖、以及上述材料的共聚物、三元共聚物或组合或混合物。例如,可将聚合物取代以使其担载胺基。
其它合适的合成聚合物包括含有氨基的聚合物,如化学合成的多肽。这种多肽可包括已经合成出的、合并含有伯氨基的氨基酸如赖氨酸及/或含有硫醇(如半胱氨酸)的氨基酸的多亲核性多肽(polynucleophilicpolypeptides)。更合适的合成聚合物包括聚(氨基)酸。
其它可包括氨基的化合物包括蛋白质如白蛋白。白蛋白可以是哺乳动物来源的,但也可以使用其它来源的白蛋白。例如可使用牛血清白蛋白(BSA)。或者,白蛋白可以是使用所属技术领域中已知方法从表现重组白蛋白基因的细胞中分离的重组白蛋白。无论是部分蛋白质水解制备的或通过重组手段制备的,包含至少100个白蛋白序列残基的白蛋白主要片段也可以用来代替完整白蛋白作为桥联分子。或者,可用的片段可含有至少50个残基,以及更优选地至少75个白蛋白序列残基。最后,也可以使用不同形式的白蛋白的混合物(如人白蛋白、牛白蛋白、重组白蛋白、片段白蛋白)和富含白蛋白的血浆部分。白蛋白可使用所属技术领域中广为人知的方法从组织或细胞中直接纯化。
使用时,聚合引发剂包括电机辐射(electromechanicalradiation)。聚合反应的引发可通过以波长介于约200至约700nm、或大于约320nm或更大、甚或约365nm的光照射来完成。
其它引发剂的实例是有机溶剂可溶性引发剂如过氧化苯甲酰、偶氮双异丁(AIBN)、过氧化二叔丁基等,水溶性引发剂如过硫酸铵(APS)、过硫酸钾、过硫酸钠、硫代硫酸钠等,以及为此类引发剂与四甲基乙撑、Fe2+盐、亚硫酸氢钠或类似还原剂等的组合的氧化还原型引发剂。
可用的光引发剂是那些能通过自由基产生用来引发具有最小细胞毒性的单体的聚合的光引发剂。一些具体实施例中,引发剂可在较短时间区间如几分钟或几秒钟内作用。用于UV或可见光引发的例示性染料包括乙基曙红2,2-二甲氧基-2-苯基苯乙酮、2-甲氧基-2-苯基苯乙酮、其它苯乙酮衍生物和莰醌。
可用于引发聚合反应的其它光可氧化和光可还原的染料包括吖啶染料如吖伯拉啉(acriblarine);噻嗪染料如劳氏紫(thionine);黄嘌呤染料如孟加拉国国玫红(rosebengal);和吩嗪染料如亚甲基蓝。这些染料可以和助催化剂如氨,例如三乙醇氨;硫化合物;杂环如咪唑;烯醇化物;有机金属;以及其它化合物如N-苯基甘氨酸一同使用。其它引发剂包括莰醌和苯乙酮衍生物。
也可以使用热聚合引发剂系统。这种系统在37℃是不稳定的,且将在生理温度下引发自由基聚合,举例来说,这种系统包括过硫酸钾,并与四甲基乙二胺合用或不和四甲基乙二胺合用;过氧化苯甲酰基,并与三乙醇氨合用或不和三乙醇氨合用;以及过硫酸铵,和亚硫酸氢钠合用。
或者,第一酰亚胺化的聚合物可自发地与表面如组织或假体反应。第一酰亚胺化的聚合物也可与第二生物相容性聚合物反应。如在所属技术领域中已知的,两种反应物可在应用前混合、同时应用等,以提供两种聚合物的聚合。若需要,根据设计选择使用引发剂。
本发明的交联聚合物基质可以形成及可以包括水凝胶。水凝胶的含水量可以提供孔结构的信息。再者,含水量可以是影响如包入在水凝胶内的细胞的存活因素。水凝胶能够吸收的水量可与交联密度及/或孔大小相关。举例来说,官能化聚合物上的甲基丙烯酸根基团(methacrylategroup)的百分比可支配可吸收的水量。
举例来说,担载酰亚胺的聚(氧乙烯)-二丙烯酸酯(PEODA)可用于组织工程的聚合物系统中,且交联聚合物基质可包括CS-I(硫酸软骨素-酰亚胺)和PEODA的共凝胶。
交联聚合物基质如支架的机械性质也可以与孔结构相关。对于组织工程中的应用,依据所预期的临床应用,具有不同机械性质的支架可能是理想的。举例来说,用于关节性接点中软骨组织工程的支架必须比其它身体位置中的软骨组织工程系统承受较高的机械应力。因此,具有可轻易操控的机械性质的聚合物可能是理想的,并且可以依设计选择而得到。
如上文所教导的以及所属所属技术领域中已知的,生物聚合物支架系统的细胞毒性可以任何合适的细胞如纤维母细胞(fibroblast)通过诸如使用生死荧光细胞分析(live-deadfluorescentcellassay)和MTT(一种被活性代谢细胞将黄色转变为紫色的化合物)来评估。
在本发明的一态样中,可制备包含交联聚合物基质或凝胶和一种或多种生物活性剂的组合物。生物活性剂可随着组合物的所需目地而广泛地变更。术语活性(active)在所属技术领域上是公认的,且指任何部分,该部分为在个体内局部或全身性作用的生物活性、生理活性或药理活性的物质。可称作为“药物”的生物活性剂的实例如在广为人知的参考文献如默克索引(MerckIndex)、医生案头参考(PhysiciansDeskReference)和治疗的药理学基础(ThePharmacologicalBasisofTherapeutics)所描述,且这些生物活性剂包括,但不限于药品;维生素;矿物补充剂;用于处理、预防、诊断、治愈或缓解疾病或不适的物质;影响身体结构或功能的物质;或在置于生理环境后变成生物活性或具有更高活性的前药。当投予至个体,能够将目标组合物释放入例如邻近的组织或流体中的各种生物活性剂的形式都可使用。一些具体实施例中,生物活性剂可用在本发明交联聚合物基质中,以诸如促成软骨形成。其它具体实施例中,生物活性剂可用于本发明交联聚合物基质中,以处理、缓解、抑制或预防疾病或症状,并诸如促成软骨形成。
生物活性剂的其它实例包括,并不限于,酶、受体拮抗剂或激动剂、激素、成长因子、自体骨髓(autogenousbonemarrow)、抗生素、抗微生物剂和抗体。术语“生物活性剂”也意图涵盖各种能被合并入本发明组合物的细胞类型和基因。
某些具体实施例中,以总组合物的重量计,目标组合物包含约1%至约75%或更多,或者约2.5%、5%、10%、20%、30%、40%、50%、60%或70%的生物活性剂。
生物活性剂的非限制性实例包括下列:肾上腺素性阻断剂、同化剂(anabolicagent)、雄性激素类固醇(androgenicsteroid)、解酸剂、抗哮喘剂、抗过敏剂、抗胆固醇及抗脂质剂、抗胆碱能药(anti-cholinergics)及拟交感神经药(sympathomimetics)、抗凝血药、抗惊厥药、抗腹泻药、止吐药、抗高血压剂、抗感染剂、抗炎剂如类固醇、非类固醇抗炎剂、抗疟疾药、抗躁狂剂、抗呕吐剂、抗肿瘤剂、抗肥胖剂、抗帕金森症剂、退热镇痛剂、抗痉挛剂、抗血栓形成剂、抗尿酸剂(anti-uricemicagent)、抗心绞痛剂、抗组胺药、止咳药、食欲抑制剂、苯并菲啶类生物碱、生物制品、心脏活性剂(cardioactiveagents)、脑扩张剂(cerebraldilators)、冠状动脉扩张剂、解充血剂、利尿剂、诊断剂、红细胞生成剂、雌激素、祛痰剂、肠胃镇静剂、升血糖剂(hyperglycemicagent)、安眠药、降血糖剂、离子交换树脂、泻剂、矿物补充剂、缩瞳剂(mitotics)、黏液溶解剂、生长因子、神经肌肉药物、营养物质、末梢血管扩张剂、促孕剂、前列腺素、心力加强剂(psychicenergizer)、精神药物、镇静剂、兴奋剂、甲状腺剂及抗甲状腺剂、止痛药、子宫弛缓药、维生素、抗原性材料和前药。
上述类别的可用生物活性剂的具体实例包括(a)抗肿瘤药如雄性激素抑制剂、抗代谢物、细胞毒素剂和免疫调节剂;(b)止咳药如氢溴酸右美沙芬(dextromethorphanhydrobromide)、那可汀(noscapine)、枸橼酸喷托维林(carbetapentanecitrate)和氯苯达诺盐酸盐(chlophedianolhydrochloride);(c)抗组胺药如氯苯那敏(chlorpheniramine)、酒石酸苯茚胺(phenindaminetartrate)、吡拉明(pyrilamine)、琥珀酸多西拉敏(doxylaminesuccinate)和柠檬酸苯托沙敏(phenyltoloxaminecitrate);(d)解充血药如盐酸盐、苯丙醇胺盐酸盐、伪麻黄碱盐酸盐和麻黄碱;(e)各种生物碱如磷酸可待因(codeinephosphate)、硫酸可待因和吗啡;(f)矿物补充剂如氯化钾、氯化锌、碳酸钙、氧化镁和其它碱金属和碱土金属盐;(g)离子交换树脂如N-乙酰普鲁卡因胺(N-acetylprocainamide);(i)退热药及镇痛药如醋胺酚(acetaminophen)、阿司匹林和布洛芬(ibuprofen);食欲抑制剂如苯丙醇胺或咖啡因;(k)祛痰剂如愈创甘油醚(guaifenesin);(1)解酸剂如氢氧化铝和氢氧化镁;生物制品如肽、多肽、蛋白质和氨基酸、激素、干扰素或细胞激素和其它生物活性肽化合物如降钙素、ANF、EPO和胰岛素;(n)抗感染剂如抗真菌药、抗病毒药、防腐剂和抗生素;以及(m)减敏剂和抗原性材料如可用于疫苗应用的。
更具体地,可用生物活性剂的非限制性实例包括下列治疗类别:镇痛药如非类固醇抗炎药、鸦片激动剂及水杨酸盐;抗阻胺药如H1-阻断剂和H2-阻断剂;抗感染剂如抗寄生虫药、抗厌氧菌药(antianaerobics)、抗生素、氨基葡糖苷类抗生素、抗真菌类抗生素、头孢菌素类抗生素、大环内酯类抗生素、其它抗生素、青霉素类抗生素、喹诺酮类抗生素、磺酰胺类抗生素、四环素类抗生素、抗分支杆菌药、抗结核类抗分支杆菌药、抗原虫药、抗疟疾性抗原虫药、抗病毒剂、抗逆转录病毒剂、灭疥癣药和尿道抗感染剂;抗肿瘤药如烷基化剂、氮芥烷基化剂、亚硝基脲烷基化剂、抗代谢物、嘌呤类似物抗代谢物、嘧啶类似物抗代谢物、激素类抗肿瘤药、天然抗肿瘤药、抗生素类天然抗肿瘤药和长春生物碱类天然抗肿瘤药;自主神经系统作用剂(autonomicagent)如抗胆碱能药、抗毒蕈碱类抗胆碱能药(antimuscarinicanticholinergics)、麦角生物碱、拟副交感神经药、胆碱能激动剂型拟副交感神经药、胆碱酯酶抑制剂型拟副交感神经药、交感神经阻滞药、α-阻断剂型交感神经阻滞药、交感神经阻滞药、拟交感神经药和肾上腺素激动剂型拟交感神经药;心血管药如防心绞痛药、钙通道阻断型防心绞痛药、硝酸盐类防心绞痛药、抗心律失常药、强心葡糖苷类抗心律失常药、第I型抗心律失常药、第II型抗心律失常药、第III型抗心律失常药、第IV型抗心律失常药、抗高血压剂、α-阻断剂型抗高血压药、血管紧张肽转换酶抑制剂(ACE抑制剂)类抗高血压药、β-阻断剂型抗高血压药、钙通道阻断剂型抗高血压药、中心作用型肾上腺素类抗高血压药、利尿剂类抗高血压药、末梢血管扩张剂型抗高血压药、降血脂药(antilipemics)、胆酸螯合剂降血脂药、还原酶抑制剂降血脂药、强心药物(inotrope)、强心葡糖苷类强心药和溶血栓剂;皮肤病药如抗组胺药、抗炎剂、皮质类固醇类抗炎剂、麻醉剂、局部抗感染剂、抗病毒性局部抗感染剂和局部抗肿瘤药;电解或肾解剂如酸化剂、碱化剂、利尿剂、碳酸酐酶抑制剂类利尿剂(carbonicanhydraseinhibitordiuretics)、髓袢利尿剂(loopdiuretics)、渗透性利尿剂、留钾利尿剂、噻嗪类利尿剂、电解质置换和排尿酸剂;酶如胰腺酶和溶血栓酶(thrombolyticenzyme);肠胃剂如止泻药、止吐药、肠胃抗炎剂、水杨酸(salicylate)类肠胃抗炎剂、解酸药型抗溃疡剂、胃酸泵浦抑制剂型抗溃疡剂、胃黏膜抗溃疡剂、H2-阻断剂型抗溃疡剂、胆石溶解剂(cholelitholyticagent)、助消化药、催吐剂、泻剂和大便软化剂、以及促动剂;常规麻醉剂如吸入型麻醉剂、卤代吸入型麻醉剂、静脉麻醉剂、巴比妥酸盐类静脉麻醉剂、苯并二吖庚因类静脉麻醉剂和鸦片激动剂类静脉麻醉剂;血液病治疗剂如抗贫血剂、造血性抗贫血剂、凝血剂、抗凝血剂、止血性凝血剂、血小板抑制剂型凝血剂、溶血栓酶型凝血剂和血浆容量扩充药;激素和激素改性剂如堕胎药、肾上腺剂、皮质类固醇类肾上腺剂、雄性激素类、抗雄性激素类、抗糖尿病剂、磺酰脲类抗糖尿病剂、抗低血糖剂、口服避孕药、黄体酮类避孕药、雌激素类、促生育剂、催产药、副甲状腺剂、脑垂体激素类、黄体酮、抗甲状腺剂、甲状腺激素和抗分娩药;免疫生物剂如免疫球蛋白、免疫抑制剂(immunosuppressives)、类毒素和疫苗;局部麻醉剂如酰胺局部麻醉剂和酯局部麻醉剂;肌肉骨骼剂如抗痛风抗炎剂、皮质类固醇类抗炎剂、金化合物类抗炎剂、免疫抑制类抗炎剂、非类固醇抗炎药、水杨酸类抗炎剂、骨骼肌弛缓药、神经肌肉阻断剂型骨骼肌弛缓药和反向神经肌肉阻断剂型骨骼肌弛缓药;神经药物如抗惊厥药、巴比妥酸盐类抗惊厥药、苯并二吖庚因类抗惊厥药、抗偏头痛剂、抗帕金森症剂、抗眩晕剂、鸦片激动剂和鸦片拮抗剂;眼药如抗青光眼剂、抗青光眼剂缩瞳剂、抗青光眼剂扩瞳剂、肾上腺素激动剂型扩瞳剂、抗毒蕈碱型扩瞳剂、眼科麻醉剂、眼科抗感染药、眼科氨基葡糖苷类抗感染药、眼科大环内酯类抗感染药、眼科喹诺酮类抗感染药、眼科磺酰胺类抗感染药、眼科四环素类抗感染药、眼科抗炎剂、眼科皮质类固醇类抗炎剂和眼科非类固醇抗炎药;精神药剂如抗抑郁药、杂环抗抑郁药、一元胺氧化酶抑制剂选择性血清素再摄取抑制剂类三环抗抑郁药、抗躁狂药、抗精神病药、吩噻嗪类抗精神病药、抗焦虑药、镇静剂和安眠药;巴比妥酸盐类镇静剂和安眠药、苯并二吖庚因类抗焦虑药、镇静剂和安眠药、以及精神兴奋剂;呼吸剂如止咳药、支气管扩张剂、肾上腺素激动剂型支气管扩张剂、抗毒蕈碱型支气管扩张剂、祛痰药、粘液溶解剂、呼吸抗炎剂和呼吸皮质类固醇类抗炎剂;毒理学剂如解毒剂、加重剂、物质滥用剂(substanceabuseagents)、抑制物质滥用剂(deterrentsubstanceabuseagents)和戒断物质滥用剂(withdrawalsubstanceabuseagents);矿物;以及维生素如维生素A、维生素B、维生素C、维生素D、维生素E和维生素K。
来自上述类别的其它类生物活性剂包括:(1)常规镇痛药如利多卡因(lidocaine)、其它“卡因(caine)”类镇痛药或其衍生物、以及非类固醇抗炎药(NSAIDs)型镇痛药包括双氯芬酸(diclofenac)、布洛芬、酮洛芬(ketoprofen)和萘普生(naproxen);(2)鸦片激动剂型镇痛药如可待因、芬太尼(fentanyl)、氢化吗啡和吗啡;(3)水杨酸类镇痛药如阿司匹林(ASA)(肠衣ASA);(4)H1-阻断剂型抗组胺药如克里马丁(clemastine)和特非那定(terfenadine);(5)H2-阻断剂型抗组胺药如西咪替丁(cimetidine)、法莫替丁(famotidine)、尼杂定(nizadine)和雷尼替丁(ranitidine);(6)抗感染剂如莫匹罗星(mupirocin);(7)抗厌氧菌型抗感染药如氯霉素(chloramphenicol)和克林达霉素(clindarnycin);(8)抗真菌型抗生素类抗感染药如两性霉素(amphotericin)b、克霉唑(clotrimazole)、氟康唑(fluconazole)和酮康唑(ketoconazole);(9)大环内酯类抗生素抗感染药如阿奇霉素(azithromycin)和红霉素(erythromycin);(10)其它抗生素类抗感染药如亚胺培南(imipenem);青霉素抗生素类抗感染药如乙氧萘青霉素(nafcillin)、苯甲异恶唑青霉素(oxacillin)、青霉素G和青霉素V;(12)喹诺酮抗生素类抗感染药如环丙沙星(ciprofloxacin)和诺氟沙星(norfloxacin);(13)四环素抗生素类抗感染药如强力霉素(doxycycline)、米诺霉素(minocycline)和四环素;(14)抗结核抗分支杆菌型抗感染药如异烟肼(isoniazid)和利福平(rifampin);(15)抗原虫型抗感染药如阿托伐醌(atovaquone)和氨苯砜(dapsone);(16)抗疟疾抗原虫型抗感染药如氯喹(chloroquine)和乙胺嘧啶(pyrimethamine);(17)抗逆转录病毒抗感染药如利托那韦(ritonavir)和齐多夫定(zidovudine);(18)抗病毒型抗感染剂如阿昔洛韦(acyclovir)、更昔洛韦(ganciclovir)、干扰素-α和金刚乙烷(rimantadine);(19)烷基化抗肿瘤剂如卡波铂(carboplatin)和顺铂(cisplatin);(20)亚硝基脲型烷基化抗肿瘤剂如亚硝脲氮芥(carmustine,BCNU);(21)抗代谢物类抗肿瘤剂如氨甲喋呤;(22)嘧啶类似物类抗肿瘤剂如氟尿嘧啶(5-FU)和吉西他滨(gemcitabine);(23)激素类抗肿瘤药如戈舍瑞林(goserelin)、亮丙瑞林(leuprolide)和他莫昔芬(tamoxifen);(24)天然抗肿瘤药如阿地白介素(aldesleukin)、白介素-2、多烯紫杉醇(docetaxel)、依托泊苷(etoposide)干扰素α、紫杉醇(paclitaxel)、其它紫杉烷(taxane)衍生物和维甲酸(ATRA);(25)抗生素型天然抗肿瘤药如博来霉素(bleomycin)、更生霉素(dactinomycin)、柔红霉素(daunorubicin)、阿霉素(doxorubicin)和丝裂霉素(mitomycin);(26)长春生物碱型天然抗肿瘤药如长春碱和长春新碱;(27)自主神经系统作用剂如尼古丁;(28)抗胆碱能型自主神经系统作用剂如苯托品(benztropine)和三己芬迪(trihexyphenidyl);(29)抗毒蕈碱抗胆碱能型自主神经系统作用剂如阿托品(atropine)和奥昔布宁(oxybutynin);(30)麦角生物碱型自主神经系统作用剂如溴隐亭(bromocriptine);(31)胆碱能激动剂型拟副交感神经药如匹鲁卡品(pilocarpine);(32)胆碱酯酶抑制剂型拟副交感神经药如吡斯的明(pyridostigmine);(33)a-阻断剂型交感神经阻滞药如哌唑嗪(prazosin);(34)D-阻断剂型交感神经阻滞药如阿替洛尔(atenolol);(35)肾上腺素型拟交感神经药如沙丁胺醇(albuterol)和多巴酚丁胺(dobutamine);(36)心血管药剂如阿司匹林(ASA)(肠衣ASA);(37)D-阻断剂型防心绞痛药如阿替洛尔和普萘洛尔(propranolol);(38)钙通道阻断剂型防心绞痛药如硝苯地平(nifedipine)和维拉帕米(verapamil);(39)硝酸酯型防心绞痛药如二硝酸异山梨酯(ISDN);(40)强心葡糖苷型抗心律失常药如(41)第I型抗心律失常药如利多卡因、美西律(mexiletine)、苯妥英(phenytoin)、普鲁卡因胺和奎尼丁(quinidine);(42)第II型抗心律失常药如阿替洛尔、美托洛尔(metoprolol)、普萘洛尔(propranolol)和噻吗洛尔(timolol);(43)第III型抗心律失常药如胺碘酮(aminodarone);(44)第IV型抗心律失常药如地尔硫卓(diltiazem)和维拉帕米;(45)抗高血压药如哌唑嗪;(46)血管紧张肽转换酶抑制剂(ACE抑制剂)型抗高血压药如卡托普利(captopril)和依拉普利(enalapril);(47)抗高血压药如阿替洛尔、美托洛尔、纳多洛尔(nadolol)和普萘洛尔;(48)钙通道阻断剂型抗高血压药如地尔硫卓和硝苯地平;(49)中心作用型肾上腺素类抗高血压药如可乐定(clonidine)和甲基多巴(methyldopa);(50)利尿型抗高血压药如阿米洛利(amiloride)、利尿磺胺(furosemide)、双氢克尿噻(hydrochlorothiazine,HCTZ)和螺甾内酯(spironolactone);(51)末梢血管扩张型抗高血压药如米诺地尔(minoxidil);(52)降血脂药如吉非罗齐(gemfibrozil)和普罗布可(probucol);(53)胆酸螯合剂型降血脂药如消胆胺(cholestyramine);(54)还原酶抑制剂型降血脂药如洛伐他汀(lovastatin)和普伐他汀(pravastatin);(55)强心药物如氨利酮(amrinone)、多巴酚丁胺(dobutamine)和多巴胺(dopamine);(56)强心葡糖苷类强心药物如(57)溶血栓剂如阿替普酶(alteplase,TPA)、阿尼普酶(anistreplase)、链激酶和尿激酶;(58)皮肤病药物如秋水仙素、异维甲酸、氨甲喋呤、米诺地尔、维甲酸;(59)皮肤病皮质类固醇类抗炎剂如倍他米松(betamethasone)和地塞米松(dexamethasone);(60)抗真菌型局部抗感染药如两性霉素克霉唑、咪康唑(miconazole)和制霉菌素(nystatin);(61)抗病毒型局部抗感染药如阿昔洛韦;(62)局部抗肿瘤药如(63)电解和肾解剂如乳果糖;(64)髓袢利尿剂如利尿磺胺;(65)留钾型利尿剂如氨苯蝶啶(triarnterene);(66)噻嗪类利尿剂如双氢克尿噻(HCTZ);(67)排尿酸剂如丙磺舒(probenecid);(68)酶如以及(69)溶血栓酶如阿替普酶(alteplase)、阿尼普酶(anistreplase)、链激酶和尿激酶;(70)止吐剂如丙氯拉嗪(prochlorperazine);(71)水杨酸类肠胃抗炎剂如水杨酸偶氮磺胺吡啶(sulfasalazine);(72)胃酸泵浦抑制剂类抗溃疡剂如奥美拉唑(omeprazole);(73)H2-阻断剂型抗溃疡剂如西咪替丁(cimetidine)、法莫替丁(famotidine)、尼扎替丁(nizatidine)、雷尼替丁;(74)助消化药如胰脂肪酶;(75)促动剂如红霉素;(76)鸦片激动剂型静脉麻醉剂如芬太尼;(77)造血型抗贫血剂如G-CSF和GM-CSF;(78)凝血剂如因子1-10(AHF1-10);(79)抗凝血药如华法林(warfarin);(80)溶血栓酶类凝血剂如阿替普酶、阿尼普酶、链激酶和尿激酶;(81)激素和激素改性剂如溴隐亭;(82)堕胎药如氨甲喋呤;(83)抗糖尿病剂如胰岛素;(84)口服避孕药如雌激素和黄体酮;(85)黄体酮类避孕药如左炔诺孕酮(levonorgestrel)和炔诺孕酮(norgestrel);(86)雌激素类如共轭雌激素类、乙芪酚(diethylstilbestrol,DES)、雌激素(雌二醇、雌酮和雌酮硫酸酯哌嗪(estropipate));(87)促生育剂如克罗米酚(clomiphene)、人绒毛膜促性腺激素(HCG)和美诺陀品(menotropin);(88)副甲状腺剂如降钙素;(89)脑垂体激素如去氨加压素(desmopressin)、戈舍瑞林、催产素和血管加压素(ADH);(90)黄体酮如甲羟孕酮、炔诺酮和孕酮;(91)甲状腺激素如左旋甲状腺素;(92)免疫生物剂如干扰素β-lb和干扰素γ-lb;(93)免疫球蛋白如免疫球蛋白IM、IMIG、IGIM和免疫球蛋白IVIG、IGIV;(94)酰胺局部麻醉药如利多卡因(lidocaine);(95)酯局部麻醉药如苯佐卡因(benzocaine)和普鲁卡因;(96)肌肉骨骼皮质类固醇类抗炎剂如倍氯米松(beclomethasone)、倍他米松、可的松(cortisone)、地塞米松、氢化可的松(hydrocortisone)和泼尼松(prednisone);(97)肌肉骨骼抗炎型免疫抑制剂如咪唑硫嘌呤(azathioprine)、环磷酰胺和氨甲喋呤;(98)肌肉骨骼非类固醇抗炎药如双氯芬酸、布洛芬、酮洛芬、酮咯酸(ketorlac)和萘普生;(99)骨骼肌弛缓剂如地西泮(diazepam);(100)反向神经肌肉阻断剂型骨骼肌弛缓剂如吡斯的明(pyridostigmine);(101)神经剂如尼莫地平(nimodipine)、利鲁唑(riluzole)、他克林(tacrine)和噻氯匹定(ticlopidine);(102)抗惊厥药如卡马西平(carbamazepine)、加巴喷丁(gabapentin)、拉莫三嗪(lamotrigine)、苯妥英和丙戊酸;(103)巴比妥酸盐类抗惊厥药如苯巴比妥和普里米酮(primidone);(104)苯并二吖庚因抗惊厥药如氯硝西泮(clonazepam)、地西泮和劳拉西泮(lorazepam);(105)抗剂如溴隐亭、左旋多巴(levodopa)、卡比多巴(carbidopa)和培高利特(pergolide);(106)抗眩晕剂如敏可静(meclizine);(107)鸦片激动剂如可待因、芬太尼、氢化吗啡、美沙酮(methadone)和吗啡;(108)鸦片拮抗剂如纳洛酮(naloxone);(109)抗青光眼剂如噻吗洛尔;(110)缩瞳性(mitotic)抗青光眼剂如匹鲁卡品(pilocarpine);(111)眼科氨基葡糖苷类抗感染剂如庆大霉素(gentamicin)、新霉素(neomycin)和妥布拉霉素(tobramycin);(112)眼科喹诺酮抗感染剂如环丙沙星(ciprofloxacin)、诺氟沙星(norfloxacin)和氧氟沙星(ofloxacin);(113)眼科皮质类固醇类抗剂如地塞米松和泼尼松;(114)眼科非类固醇抗炎药如双氯芬酸;(115)抗精神病药如氯扎平(clozapine)、氟哌啶醇(haloperidol)和利培酮(risperidone);(116)苯并二吖庚因类抗焦虑药、镇静剂和安眠药如氯硝西泮、地西泮、劳拉西泮、奥沙西泮和普拉西泮;(117)精神兴奋药如哌醋甲酯(methylphenidate)和匹莫林(pemoline);(118)如可待因;(119)支气管扩张药如(120)肾上腺素激动剂型支气管扩张药如沙丁胺醇(albuterol);(121)呼吸皮质类固醇类抗炎剂如地塞米松;(122)解毒剂如氟吗西尼(flumazenil)和纳洛酮;(123)重金属剂如青霉胺;(124)抑制物质滥用剂如戒酒硫(disulfiram)、纳曲酮(naltrexone)和尼古丁;(125)戒断物质滥用剂如溴隐亭;(126)矿物如铁、钙和镁;(127)维生素B化合物如氰钴胺(维生素B12)和烟酸(维生素B3);(128)维生素C化合物如抗坏血酸;以及(129)维生素D如骨化三醇。
再者,可使用重组蛋白质或源于细胞的蛋白质如重组β-葡聚糖;牛免疫球蛋白浓缩物;牛过氧化物歧化酶;包含氟尿嘧啶、肾上腺素和牛胶原蛋白的调配物;重组水蛭素(r-Hir)、HIV-I免疫原;重组人类生长激素重组EPO(r-EPO);基因活化的EPO(GA-EPO);重组人类血红蛋白(r-Hb);重组人类美卡舍明(mecasermin)(r-IGF-1)、重组干扰素β;来格司亭(lenograstim,G-CSF);奥氮平(olanzapine)、重组甲状腺刺激激素(r-TSH);以及拓扑替康(topotecan)。
再者,也可使用下列肽、蛋白质和其它大分子如白介素1至18,包括突变物和类似物;干扰素a、干扰素y和可用于软骨再生的干扰素;激素释放激素(LHRH)及类似物、促性腺激素释放激素;转化生长因子(TGF);纤维母细胞生长因子(FGF);肿瘤坏死因子-a和肿瘤坏死因子-y;神经生长因子(NGF);生长激素释放因子(GHRF)、表皮生长因子(EGF)、连接组织活化的成骨因子、纤维母细胞生长因子同源因子(FGFHF);肝细胞生长因子(HGF);胰岛素生长因子(IGF);侵入抑制因子-2(IIF-2);骨形态发生蛋白质1-7(BMP1-7);生长激素抑制素;胸腺素-a-y-球蛋白;过氧化物歧化酶(SOD);以及补充因子,以及这些因子如生长因子的生物活性类似物、片段和衍生物。
是多功能调整蛋白质的转化生长因子(TGF)超基因家族的成员可以合并入本发明聚合物基质。TGF超基因家族的成员包括β转化生长因子(如TGF-β1、TGF-β2、TGF-β3);骨形态发生蛋白质(如BMP-1、BMP-2、BMP-3、BMP-4、BMP-5、BMP-6、BMP-7、BMP-8、BMP-9);肝素结合生长因子(如纤维母细胞生长因子(FGF)、表皮生长因子(EGF)、血小板源生长因子(PDGF)、类胰岛素生长因子(IGF)(如抑制素(Inhibin)A和抑制素B)、生长分化因子(如GDF-1);以及激活素(Activin)(如激活素A、激活素B、激活素AB)。生长因子可以从天然或自然的来源中分离,如从哺乳动物细胞中分离,或可合成性制备如通过重组DNA技术或各种化学制程制备。此外,可使用这些因子的类似物、片段或衍生物,只要它们显示至少一些天然分子的生物活性。举例来说,可通过位置专一性引起突变或其它基因工程技术的改变基因表现来制备类似物。
可使用各种形式的生物活性剂。各种形式包括但不限于这些形式为不带电的分子、分子复合物、盐类、醚类、酯类、酰胺类、前药形式等,当植入、注射或以其它模式放入个体中时,上述形式被生物活化。
某些具体实施例中,除了一种或多种生物活性剂外,其它材料也可以被合并入目标组合物中。举例来说,所属技术领域中已知的增塑剂和稳定剂可合并入本发明组合物中。某些具体实施例中,为了添加剂的生物相容性或为了试剂、凝结或凝胶化的基质或经凝结或经凝胶化的基质的所得物理性质而选择添加剂如增塑剂和稳定剂。
本发明组合物可进一步含有一种或多种辅剂物质等。这些添加材料可影响所得组合物的特点。举例来说,填料如牛血清白蛋白(BSA)或小鼠血清白蛋白(MSA)可与聚合物组合物联合使用。某些具体实施例中,以组合物的重量计,填料的量的范围为约0.1%至约50%或更多。这种填料的合并可影响任何包入物质的持续释放速率。其它所属技术领域的技术人员所熟知的填料如碳水化合物、糖、淀粉、糖类、纤维素和多糖类包括蔗糖可用于本发明某些具体实施例中。
可将缓冲剂、酸和碱合并入组合物以调节pH。也可包括用来增加从组合物释放的试剂扩散距离的试剂。
目标组合物的电荷、亲油性或亲水性可通过使用添加剂而改变。举例来说,可使用表面活性剂来提高难互溶液体的互溶性。合适的表面活性剂的实例包括葡聚糖、聚山梨醇酯和月桂基硫酸钠。通常,表面活性剂的使用浓度较小,通常低于约5%。
本发明中用于调配本文所描述的新调配物的特殊方法并不严苛,且可选自生理缓冲液(Feigneretal.,U.S.Pat.No.5,589,466(1996))。
产品的治疗调配物可通过将具有所需纯度的产品与任选的所属技术领域中典型使用的药学上可接受的载剂、稀释剂、赋形剂或稳定剂,即缓冲剂、稳定剂、防腐剂、等渗剂(isotonifiers)、非离子洗涤剂、抗氧化剂和其它各种添加剂混合而制备成用于储存的冻干调配物或水溶液,参见Remington′sPharmaceuticalSciences,第16版,Osol,ed.(1980)。这些添加剂在所使用的剂量和浓度下,通常对接受者无毒,因此,赋形剂、稀释剂、载剂等是药学上可接受的。
“分离的”或“纯化的”感兴趣的聚合物实质上不含有来自获得聚合物的培养基或组织来源中的污染蛋白质,或实质上不含有在所使用的培养基或反应混合物(含有化学合成的成分)中的化学前体或其它化学物质或反应物。因此,分离的或纯化的酰亚胺化的聚合物实质上不含有非酰亚胺化的聚合物材料,且包括含有少于约30%、20%、25%、20%、10%、5%、4%、3%、2.5%、2%、1.5%或1%或更少(以干重计)的非酰亚胺化的生物聚合物杂质的制剂。
在包含感兴趣的生物聚合物的液体调配物的背景下,本文所使用的术语“稳定性”和“稳定的”指在给定的制造、制备、运输和储存条件下,例如达1个月、2个月、3个月、4个月、5个月、6个月或更长时间对热凝聚和化学凝聚、降解或碎裂具有抗性。“稳定的”本发明调配物在给定的制造、制备、运输和储存条件下保留等于或大于80%、85%、90%、95%、98%、99%或99.5%的生物活性。所述制剂的稳定性可通过所属技术领域的技术人员已知的方法根据凝聚、降解或碎裂的程度来评估。
术语“载剂”指与治疗剂一起投予的稀释剂、辅剂、赋形剂或媒体。这些生理载剂可以是无菌液体如水和油,包括那些来自石油、动物、植物或合成来源的油如花生油、大豆油、矿物油、芝麻油等。当将药学组合物以静脉内投予时,水是合适的载剂。盐水溶液和右旋糖及甘油水溶液也可以用作液体载剂,尤其用于可注射溶液。合适的药学赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩、硅胶、硬脂酸钠、甘油单硬脂酸酯、云母、氯化钠、干的脱脂奶粉、甘油、丙二醇、水、乙醇等。如果需要,组合物也可以包含少量的润湿剂或乳化剂、或pH缓冲剂。
组合物可以是溶液、悬浮液、乳液、粉末、持续释放调配物、储存药剂(depot)等形式。在“Remington′sPharmaceuticalSciences”中,Martin描述了合适载剂的实例。这些组合物将含有优选呈纯化形式的有效量的感兴趣的生物聚合物,与合适量的载剂以向患者提供适当投予的形式。如所属技术领域中已知的,调配物将构造成与适合投予的模式。
缓冲剂帮助保持在近似生理条件范围内的pH值。缓冲剂优选以约2mM至约50mM的浓度范围存在。适合与本发明使用的缓冲剂包括有机酸和无机酸两者及其盐,如柠檬酸盐缓冲剂(例如柠檬酸单钠-柠檬酸二钠混合物、柠檬酸-柠檬酸三钠混合物、柠檬酸-柠檬酸单钠混合物等)、琥珀酸盐缓冲剂(如琥珀酸-琥珀酸单钠混合物、琥珀酸-氢氧化钠混合物、琥珀酸-琥珀酸二钠混合物等)、酒石酸盐缓冲剂(如酒石酸-酒石酸钠混合物、酒石酸-酒石酸钾混合物、酒石酸-氢氧化钠混合物等)、富马酸盐缓冲剂(如富马酸-富马酸单钠混合物、富马酸-富马酸二钠混合物、富马酸单钠-富马酸二钠混合物等)、葡萄糖酸盐缓冲剂(如葡萄糖酸-葡萄糖酸钠混合物、葡萄糖酸-氢氧化钠混合物、葡萄糖酸-葡萄糖酸钾混合物等)、草酸盐缓冲剂(如草酸-草酸钠混合物、草酸-氢氧化钠混合物、草酸-草酸钾混合物等)、乳酸盐缓冲剂(如乳酸-乳酸钠混合物、乳酸-氢氧化钠混合物、乳酸-乳酸钾混合物等)和醋酸盐缓冲剂(如醋酸-醋酸钠混合物、醋酸-氢氧化钠混合物等)。可使用磷酸盐缓冲剂、碳酸盐缓冲剂、组氨酸缓冲剂、三甲氨盐如Tris、HEPES和其它此类已知缓冲剂。
可加入防腐剂以延缓微生物生长,加入量范围可为0.2%至1%(w/v)。合适与本发明使用的防腐剂包括酚、苯甲醇、间甲酚、十八烷基二甲基苄基氯化铵、苯甲烷铵(benzyaconium)卤化物(如氯化物、溴化物和碘化物)、氯化六甲铵、烷基尼泊金(paraben)如甲基或丙基尼泊金、儿茶酚、间苯二酚、环己醇和3-戊醇。
存在等渗剂以保证本发明液体组合物的生理等渗性,且等渗剂包括多羟基糖醇,优选为三羟基的或更高羟基的糖醇如甘油、赤藓醇、阿糖醇、木糖醇、山梨醇和甘露醇。考虑其它成分的相对量,多羟基醇可以介于约0.1%至约25%(以重量计)之间、优选1%至5%的量存在。
稳定剂指赋形剂的广义范畴,根据功能,可以涵盖从膨胀剂(bulkingagent)到溶解治疗剂或帮助防止变性或粘附至容器壁的添加剂。典型的稳定剂可以是多羟基糖醇;氨基酸如精氨酸、赖氨酸、甘氨酸、谷氨酰胺、天冬氨酸、组氨酸、丙氨酸、鸟氨酸、L-亮氨酸、2-苯基丙氨酸、谷氨酸、苏氨酸等;有机糖或糖醇如乳糖、海藻糖、水苏糖、阿糖醇、赤藓醇、甘露醇、山梨醇、木糖醇、核糖醇、中肌醇(myoinisitol)、半乳糖醇、甘油等,包括环多醇如肌醇;聚乙二醇;氨基酸聚合物;含硫还原剂如尿素、谷胱甘肽、硫代乙酸、巯基乙酸钠、硫甘油、α-单硫代甘油和硫代硫酸钠;低分子量多肽(如<10个残基);蛋白质如人类血清白蛋白、牛血清白蛋白、明胶或免疫球蛋白;亲水性聚合物如聚乙烯吡咯烷酮、糖类、单糖类如木糖、甘露糖、果糖和葡萄糖;二糖类如乳糖、麦芽糖和蔗糖;三糖类如棉子糖;多糖如葡聚糖等。对于每分生物聚合物,稳定剂可以0.1至10,000w/w的范围存在。
另外的其它赋形剂包括膨胀剂(如淀粉)、螯合剂(如EDTA)、抗氧化剂(如抗坏血酸、甲硫氨酸或维生素E)和共溶剂(cosolvent)。
本文使用的术语“表面活性剂”指具有两亲结构的有机物质,即由相反溶解趋势的基团,典型为油溶性烃链和水溶性离子基组成。根据表面活性部分的电荷,表面活性剂可归类为阴离子表面活性剂、阳离子表面活性剂和非离子表面活性剂。表面活性剂一般用作各种药学组合物和生物材料制剂的润湿剂、乳化剂、增溶剂和分散剂。
可加入非离子表面活性剂或洗涤剂(也被认为是“润湿剂”)来帮助溶解治疗剂及保护治疗剂不形成搅拌引起的凝聚,这也准许调配物在不造成蛋白质变性情况下被暴露于剪切表面应力下。合适的非离子表面活性剂包括聚山梨醇酯(20、80等)、泊洛沙姆(polyoxamers)(184、188等)、多元醇和聚氧乙烯脱水山梨醇单醚(TWEEN-TWEEN-等)。非离子表面活性剂可以约0.05mg/ml至约1.0mg/ml、优选约0.07mg/ml至约0.2mg/ml范围内存在。
本文使用的术语“无机盐”指不含有碳、得自将部分或全部酸的氢或酸用金属或作用类似金属的基团替代的任何化合物,且一般用作药学组合物和生物材料制剂的张力调节化合物。最常见的无机盐是NaCl、KCl、NaH2PO4等。
本发明提供生物聚合物的液体调配物,液体调配物具有从约5.0至约7.0、或约5.5至约6.5、或约5.8至约6.2、或约6.0、或约6.0至约7.5、或约6.5至约7.0的pH值范围。
本发明涵盖调配物,如在医生办公室或实验室内发现的商用冰箱和冷冻机的温度如约-20℃至约5℃下具有稳定性的液体调配物,稳定性通过例如显微分析评估,所述稳定性是为了储存目的,例如达约60天、约120天、约180天、约1年、约2年或更长时间。例如,通过颗粒分析,使用前在室温下达至少几小时,如1小时、2小时或约3小时评估本发明的液体调配物也显示稳定性。
稀释剂的实例包括磷酸盐缓冲盐水,缓冲对抗囊内胃酸的缓冲剂如含有蔗糖的柠檬酸盐缓冲剂(pH7.4),单独的碳酸氢盐缓冲剂(pH7.4),或含有抗坏血酸、乳糖或天冬氨酸的碳酸氢盐缓冲剂(pH7.4)。载剂的实例包括蛋白质如在脱脂奶粉中得到的蛋白质、糖如蔗糖、或聚乙烯吡咯烷酮。典型地,这些载剂将在约0.1%至90%(w/v)、但优选1%至10%(w/v)的浓度范围下使用。
用于体内投予的调配物必须是无菌的。举例来说,可通过无菌滤膜过滤达成。例如,本发明调配物可通过过滤而无菌化。
生物聚合物组合物将以与良好医学实施一致的方式被调配、剂量化及投予。这一情境下考虑的因素包括被处理的特定失调、被处理的特定哺乳动物、个体患者的临床状况、失调的起因、试剂输送的位置、投予方法、投予排程和其它医学业者已知的因素。待投予的生物聚合物的“治疗有效量”将由这些考虑因素支配,且量可以是足以预防、改善或处理感兴趣的失调的最小量。本文使用的术语“有效量”是一个等义片语,指治疗(如预防剂或治疗剂)的量,该量足以降低疾病的严重性及/或持续时间、改善该疾病的一种或多种症状、防止疾病的发展或造成疾病的消退,或该量足以造成防止疾病或其一种或多种症状的发展、复发、发作或进展,或提高或改善用于处理疾病的另一种治疗(如另一种治疗剂)的预防及/或治疗效果。举例来说,以受伤的或有病的关节的基准线计,一种感兴趣的处理可将宿主中关节的使用提高至少5%,优选至少10%、至少15%、至少20%、至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少95%或至少100%。在另一具体实施例中,有效量的感兴趣的治疗剂或预防剂将疾病症状如关节炎症状减轻至少5%,优选至少10%、至少15%、至少20%、至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少95%或至少100%。本文使用的同义语为术语“治疗有效量”。
如果需要,组合物也可包括增溶剂和局部麻醉剂如利多卡因或其它“卡因”类麻醉剂以减弱注射位置的疼痛。
通常,成分分开供给或一起混合成单位剂型供给,举例来说,是装入密闭容器如安瓿或标示活性剂质量的小袋中的冻干粉或无水浓缩物。若组合物将通过注入投予,组合物可分配于含有无菌药用级水或盐水的注入瓶子中。若组合物将通过注射投予,举例来说,可在试剂盒中提供装有注射用无菌水或盐水的安瓿,从而可在投予前混合成分。
提供含有上述用于处理失调的材料的制品。制品包含容器和标签。例如,合适的容器包括瓶子、小瓶、注射器和试管。容器可由多种材料如玻璃或塑料形成。容器容纳对预防或处理诸如伤口或关节疾病有效的组合物,且可具有无菌出入口(如容器可以是具有可被皮下注射针刺穿的塞子的小瓶)。位于容器上或与容器联合的标签标示组合物用于处理选择的状况。制品可进一步包含第二容器,该第二容器包含药学上可接受的缓冲剂如磷酸盐缓冲盐水、林格氏溶液(Ringer′ssolution)和葡萄糖溶液。可进一步包括其它根据商业和使用者立场而定的材料,包括缓冲剂、稀释剂、过滤器、针、注射器和具有使用说明的包装插入物。
生物活性剂和其它添加剂可通过混合或将其加入试剂制剂而合并入交联合成聚合物组合物中。或者,可通过将生物活性剂和其它添加剂与感兴趣的聚合物上的官能团结合而把这些试剂合并入交联聚合物基质中。这些组合物可包括可轻易生物降解(如由于酶降解)的链接,导致将活性剂或添加剂释放至发挥其所欲治疗效果的目标组织中。
将含有亲核基团的生物活性剂合并入交联聚合物组合物的简单方法包括,在添加多亲核性(polynucleophilic)成分之前,混合活性剂和多亲电性(polyelectrophilic)成分。为了制备用于输送带电化合物如蛋白质或可离子化药物的基质,可通过改变反应组合物不同成分的相对摩尔量来改变所得交联聚合物组合物的净电荷。这样,可控制那些正常下是迅速地扩散离开中性载剂基质的带电蛋白质或药物的输送。
例如,如果使用过量摩尔浓度(molar)的多亲核性成分,所得基质可具有净正电荷并能用于离子性结合以及输送带负电的化合物。可通过这些基质输送的带负电的化合物的实例包括各种药物、细胞、蛋白质和多糖类。
如果使用过量摩尔浓度(molar)的多亲电性成分,所得基质具有净负电荷并能用于离子性结合以及输送带正电的化合物。可通过这些基质输送的带正电的化合物的实例包括各种药物、细胞、蛋白质和多糖类。
本发明的交联聚合物基质组合物也能用于将各种类型的活体细胞或基因输送至预期投予的位置,以形成新组织。本文所用术语“基因”意图涵盖来自天然来源、合成核酸、DNA、反义DNA和RNA的基因材料。
例如,可使用聚合物基质输送间质干细胞以生产与被运送到的组织相同类型的细胞。间质干细胞可能未分化,因此可能由于活性剂的存在或局部组织环境的影响(化学影响、物理影响等)而分化,进而形成各种类型的新细胞。间质干细胞的实例包括成骨细胞、软骨细胞和纤维母细胞。例如,可将成骨细胞输送至骨骼缺陷处以生产新骨;可将软骨细胞输送至软骨缺陷处以生产新软骨;可将纤维母细胞输送至需要新连接组织处以生产胶原蛋白;可输送神经外胚层细胞(neurectodermalcells)以形成新神经组织;可输送上皮细胞以形成新上皮组织如肝、胰等。
在起源方面,细胞可以是同种异基因的或异种的。组合物可用于输送基因改性物种的细胞。
一些具体实施例中,本发明组合物可能不容易在体内降解。因此,留在交联聚合物基质组合物中的细胞将与宿主细胞分离,且不激发宿主的免疫反应或将延迟宿主的免疫反应。
举例来说,为了将细胞或基因留在交联聚合物基质中,细胞或基因可预先与试剂组合物混合,或视需要在形成交联聚合物基质之前与混合物混合,从而将细胞或基因留在基质中。
在有效处理哺乳动物个体体内脊骨等中的关节表面或盘或关节的通用方法中,反应组合物的成分被注入至需要处理的位置。本发明可制备成包括用于这种注射、植入、注入或导向的适宜媒剂。一旦酰亚胺化的生物相容性聚合物位于感兴趣的身体位置,聚合物就与表面如组织或假体反应并变成固定于表面上。因此,酰亚胺化聚合物是“生物锚固”在宿主组织上,并随后能与其它表面或聚合物如感兴趣的桥联分子反应。
或者,可将聚合物基质形成为半固体、或作为可植入解剖区域的固体物体、或作为可用于覆盖一区域或表面区间的膜或网。对于所属技术领域的技术人员而言,用于将固体物体植入相关解剖区域的多种技术同样熟悉。
一些具体实施例中,本文揭露的组合物可放在待重建的外科手术造成的缺陷处,并在重建完成后留在该处。本发明适用于局部组织重建、带茎皮瓣重建(pedicleflapreconstructions)、角膜瓣封闭或游离瓣重建。
一些具体实施例中,本发明揭示用于桥联组织或组织部分至邻近如封闭或愈合的试剂盒。
本文所揭露的试剂盒包括用于装载感兴趣的酰亚胺化聚合物的容器。试剂盒可包括输送装置。试剂盒视需要可包括用于装载感兴趣的第二聚合物的容器。也可包括其使用说明。
举例来说,这种试剂盒的用途包括治疗性应用。本发明提供用于处理疾病或病症的试剂盒。举例来说,试剂盒可包含酰亚胺化的生物相容性聚合物如酰亚胺化的硫酸软骨素,以及生物相容性聚合物或包含氨部分的化合物如PEG-氨。
某些具体实施例中,感兴趣的聚合物可形成为预期结构如膜、泡沫、支架或其它感兴趣的三维结构。这种情形下,除了一种或多种生物活性剂外,可将其它材料合并入目标组合物中。举例来说,可将所属技术领域中已知的增塑剂和稳定剂合并入本发明组合物中。固体结构可以是试剂盒的成分。因此,感兴趣的酰亚胺化的生物相容性聚合物可作为固体结构施加到生物表面上并能与生物表面反应。随后将桥联分子送至具固定的生物相容性聚合物的邻近以使桥联分子与生物相容性聚合物反应。
其它具体实施例中,使用生物相容性聚合物而不使用桥联分子。因此,酰亚胺化的生物相容性聚合物用作黏合剂。可以液体形式将聚合物施加到感兴趣的生物表面。或者,将聚合物与能提供支撑或作为聚合物载体的惰性结构如黏合绷带的衬里相联合,或与具有预期功能的结构或装置联合。
可使感兴趣的酰亚胺化的聚合物暴露于第一组织和第二组织并允许聚合物同时与第一组织和第二组织反应。酰亚胺基团与组织上的官能基团如蛋白质赖氨酸上的氨基反应。
另一具体实施例中,酰亚胺或多个酰亚胺中的一个或其它官能团不与组织反应,而与用于身体的另一物质如假体、水凝胶、支架、基质等反应。因此,感兴趣的官能化聚合物可用于将物质固定于组织或身体中特定位置。
本文所揭露的组合物可用于任意数量的组织修复应用,例如但不限于,预防血清肿和血肿、附着皮肤和肌肉皮瓣、修复和预防内漏(endoleaks)、大动脉切割修复、肺体积还原、修复神经管、封闭角膜切口、再附着视网膜以及微血管和神经吻合术。
一具体实施例中,可在任何允许通向并修复组织的标准外科手术过程包括开刀手术(opensurgery)和腹腔镜技术的情境下实现受损组织的修复。一旦通向受损组织,如果需要,本发明组合物就与任何外科手术可接受的贴片(patch)或植入物放置成与受损组织接触。例如,当组合物用于在外科手术过程后如接合两个或更多个组织表面的修复撕裂的或分离的组织时,组合物可施加到一个或多个组织表面,随后将表面放置为彼此接触而在表面间出现黏合。
当用于修复破裂组织时,可将外科手术可接受的贴片粘附于环绕破裂组织的组织区域,以覆盖破裂区域,从而强化受损组织并修复缺陷。当将贴片粘附于环绕组织时,可将本发明组合物施加至贴片,再至环绕组织,或将贴片放置在破裂组织上后再向贴片施加本发明组合物。一旦贴片和组织彼此接触,则于贴片和组织区域之间出现黏合。
在交联反应进行直到完成时,待黏合的表面可手工保持在一起或使用其它适宜手段如胶带、临时缝合等保持在一起。除非希望得到延迟凝结,典型地,在混合黏合组合物的成分后约5至60秒内发生足以完成黏合的交联。然而,出现完全交联所需的时间依赖于很多因素包括每种反应成分的类型和分子量、官能化程度和可交联组合物中成分的浓度(如较高的成分浓度造成较快的交联时间)。
一个具体实施例中,使用允许分开输送各成分如依序输送或同时输送的仪器将本发明组合物输送至投予位置。这种输送系统可包括多室喷雾装置。
或者,可使用任意类型的可控制挤出系统而分开输送成分,或以分离的糊、液体或干粉形式手工输送成分,再在投予位置手工混合在一起。多种适用于输送多成分组织密封剂/止血剂的装置为所属技术领域中广为人知的,也可以用在本发明实践中。
输送本发明组合物的另一种方法是将反应成分制备成非活性的形式,为液体或粉末。这种组合物可在施加到组织位置后被活化,或例如预先水合或施加活化剂后立即被活化。一具体实施例中,活化剂是能在一旦与组合物混合就能活化组合物的具有pH值的缓冲溶液。另一种输送组合物的方法是制备预制板,再将该板施加到投予位置。熟悉所属技术领域的技术人员可使用具有已知凝胶强度和凝胶化时间的任何特定组合物而轻易确定适宜的投予方案。
本文所描述的组合物可用于需要涂层或封闭层来防止气体、液体或固体泄露的医学状况。该方法必须将试剂施加到受损组织或器官来封闭1)血管及/或其它组织或器官以停止或最少化流血;2)胸组织以停止或最小化空气泄露;3)胃肠道或胰组织以停止或最少化排泄物或组织内容物泄露;4)膀胱或输尿管以停止或最少化尿液泄露;5)硬脑膜以停止或最少化CSF泄露;以及6)皮肤或浆膜组织以停止浆膜流体泄露。这些组合物也可以用于黏合与如小血管、神经或真皮组织一起的组织。可通过:1)将材料施加到一个组织的表面,再迅速将第二组织压到第一组织上;或2)将组织紧密排列,再施加材料来使用材料。此外,组合物可用于填充由疾病或外科手术造成的软组织和硬组织间的空间。
举例来说,本发明聚合物基质组合物可用于阻挡或填充哺乳动物个体身体内的各种腔管和空洞。组合物也可以用作生物封闭剂来封闭组织或结构(如血管)内的裂缝或裂隙,或用封闭介于相邻组织或结构间的接合处来防止血液或其它生物流体的泄露。
组合物也可以用作在外科手术或辐射过程中用于体腔内器官置换的大空间填充装置,以例如在向骨盆辐射的计划路线中保护肠。
本发明组合物也可以涂布到生理腔管如血管或输卵管内表面上,从而用作封闭剂来防止医学处理后腔管的再狭窄,该医学处理例如用于从血管内表面移除动脉斑块沉积物(arterialplaquedeposit)的气囊导管插入术、或从输卵管内部移除瘢痕组织或子宫内膜组织。优选在混合第一合成聚合物与第二合成聚合物后,立即将反应混合物的薄层施加(例如通过导管施加)到血管内表面。因为本发明组合物在体内不容易降解,由于涂层的降解造成的再狭窄可能性被降至最低。
本发明组合物也可以用于增大哺乳动物个体体内软组织或硬组织。增大软组织的应用实例包括增大括约肌(如泌尿括约肌、肛门括约肌、食道括约肌)和处理皱纹和伤疤。增大硬组织的应用实例包括修复及/或替代骨组织及/或软骨组织。
现在本发明已经一般性描述,参考下述实施例将更容易理解本发明,该实施例仅用于说明本发明的某些态样及具体实施例的目的而非用于限制本发明。
实施例1
获得不适用于移植的供体角膜巩膜缘(donorcorneoscleralrim)。将角膜保存在4℃标准眼储存所条件下的Optisol-GS培养基(Bausch&LombSurgical,Inc,SanDimas,CA)中。如Reyes等人在Invest.Ophthal.Vis.Sci.46(4)1247(2005)中所教导的,该过程在死亡后不超过10天内进行,Reyes等人报导使用醛衍生的硫酸软骨素和聚乙烯醇来封闭角膜切口。然而,该些试剂的毒性并未得以确定。
在获得大铰合部的方法中,使用手动微型角膜刀(microkeratome)(LSKOne;MoriaUSA,Doylestown,PA)以进行恰巧通过腔室(chamber)中央开口的铰翻式角膜切除术(hinged-flapkeratectomy)。这一开口类似于人造非扩大瞳孔并且可作为临床设置的参考点。在所有角膜使用顶部厚度(headthickness)为300μm。如所属技术领域中已知的,使用人造前房(ALTKSystem;MoriaUSA)来支撑角膜巩膜缘。人造前房基板上的无齿轨道被设计成与微型角膜刀配合,使得微型角膜刀穿过角膜时保持相同平面和方向。所有具有后基质(posteriorstroma)、弹力膜(Descemet′smembrane)和内皮细胞层的盘(disc)均使用6.25mm徒手环锯(freehandtrephine)获得。
在将角膜巩膜缘放在前房底部(base)之前,开始注入等渗氯化钠来清理注入线和角膜下的残留空气。将溶剂瓶升至高于腔室水平线1.5m处以获得使微型角膜刀通过的足够的腔室内压(60-70mmHg)。根据腔室底部上的环形导向线将角膜置中。使用2.5mm直圆头新月刀(crescentknife)(Beaver,BectonDickinsonSurgicalSystems,FranklinLakes,NJ)进行机械上皮刮削来避免由松弛表皮造成的表面不规则,该不规则可能引起角膜厚度测量和影像角膜检查测量的错误。
人造前房被设置为在任何情况下实现最大角膜瓣直径。该策略意图在基质床(stromalbed)内遗留尽可能大的用于进行角膜瓣的环锯和缝合的区域。这些外科手术全部由同一外科医生使用外科手术显微镜(Ophthamic900S;Moeller-Wedel,Hamburg,Germany)进行,以避免不同医生带来的变化。
在微型角膜刀行进到类似临床状况前,将几滴丙美卡因(proparacaine)盐酸盐施加到角膜表面。将微型角膜刀头的震动刃以相对恒定的速度跨过该板的方式使微型角膜刀头行进并在恰巧通过腔室的中央开口后停止,来进行部分角膜瓣切除(partialflapkeratectomy)。这方法与先前出版的技术不同,尝试通过相对较小的角膜瓣滑动类似度获得宽角膜瓣铰合部,从而增加角膜瓣的稳定性并减少角膜开口。为了遗留用于进行中央环锯的足够空间,使用2mm宽的Culler虹膜刮刀(SpartaSurgicalCorporation,Concord,CA)切断角膜瓣铰合部下的残留基质。将等渗氯化钠溶液瓶的高度降低至角膜水平线上25em处使腔室内压变回18至20mmHg,并根据角膜切除术和腔室的中央开口人工提供的“瞳孔”边缘将环锯置于中心处。使用直径为6.25mm的手动环锯进行基质床的环切。小心转动环锯刃直到穿透,再使用角膜剪完成剩余环切。将供体钮状物(donorbuttons)放置在受体床(recipientbed)上,保留在未缝合状态并重置角膜瓣。
本实验由两组组成,每组为4个角膜。一组(第一组)中,使用5次间断缝合(10-0Nylon,SharpointSurgicalSpecialtiesCorporation,Reading,PA)固定角膜瓣。缝合技术在所有角膜中相同以保证一致性。
另一组(第二组)中,使用以酰亚胺化的硫酸软骨素和PEG氨为基础的组织黏合剂固定角膜瓣。
使用桥联成分10%PEG-氨来覆盖CS-I。特意用生物相容性染料(汽巴蓝,CibacronBlue;Sigma-Aldrich)将PEG也染成蓝色。将桥联成分染色许可直接观察关于切口的聚合性胶联并保证胶联并未进一步进入前房。
使用2.5mm直圆头新月刀(Beaver;BDSurgicalSystems)将CS-酰亚胺施加到伤口边缘。使用薄层涂布切口和内伤口唇的表面。随后使用第二新月刀将黏合剂(PEG-氨)的桥联成分的薄层施加到第一层上。允许两种成分聚合30秒。胶联一旦固化即注入盐水。
在内压达到15-18mmHg后,移植盘倾向通过表面张力留在适当的地方,因此,两组中的移植盘均保留在未缝合或未胶联状态。
移除表皮后,停止注入等渗氯化钠,且使用超声角膜厚度测量器(pachymeter)(PachIV,AccutomeInc,Malvern,PA)测量角膜中心的角膜厚度。从基质床创造并向后弯曲铰合瓣后进行第二次测量。随后计算中心角膜瓣的厚度。
使用商用影像角膜镜(EyeSysLaboratories,Inc,Houston,TX)进行表面曲率分析。根据监视控制将散光盘放在腔室中心的垂直位置。小心谨慎地保存定位在外科手术前和手术后的记录。对每个角膜在外科手术前和手术后进行三次测量。
逐渐升高腔室内压以评估移植物(graft)稳定性。监视泄露的存在并用数字压力表(Digimano1000,NetechCorp.,Hicksville,NY)记录压力。
使用适用于Windows系统的StatsDirect(version1.9.0,CamCode,Ashwell,England)进行计算。描述平均值、SD值、最小值和最大值。
组织黏合剂产生良好的封闭性和与其它微型角膜刀辅助后板层角膜移植术(posteriorlamellarkeratoplasty)报告相比更弱的散光。再者,不进行缝合使得技术简单并大大减少所耗时间。
本发明组合物可用于黏合两个分开的表面,至少一个表面是生物表面。因此,本组合物可用于通过将开口边缘并排在一起来封闭伤口或开口。基于本发明黏合剂成分的生物可降解性程度,封闭可以是长期的也可以是短期的。短期封闭可提供合适的愈合或自然封闭开口发生的时间。或者,感兴趣的黏合剂可用于将非生物的但生物相容性表面黏合到生物表面上。举例来说,这种非生物表面可在假体、医学装置等找到。
实施例2
使用碳二酰亚胺CS-NHS合成的方法在所属技术领域中是已知的。酰亚胺衍生物极大提高效率和生物相容性。也合成了作为氨供体的CS-氨。举例来说,约3∶3∶1比例的CS、琥珀酰亚胺和二酰亚胺分别可在小体积的盐水中进行短时间反应。作为一种设计选择,三种试剂的合适比例可以是75∶100∶38。
另一具体实施例中,将CS(750mg)溶于6mLPBS(磷酸盐缓冲盐水)中。将l-乙基-3-[3-二甲氨-丙基]碳二酰亚胺(EDC,1.572g,8.2mmol)溶于1.5mLPBS中。将380mgN-羟基琥珀酰亚胺(NHS)溶于1.5mLPBS中得到3.3mmolNHS溶液。将NHS溶液和EDC加入CS溶液中,涡旋,再在37℃下反应10分钟。随后将反应在-80℃冷却30分钟再用乙醇沉淀。随后离心溶液5分钟,移除上清液并洗涤。
使用下表中所列不同比例的NHS∶NH2合成交联CS网。将1∶1、1∶2和2∶1比例的CS-NHS和PEG-(NH2)6制成浓度为10%(w/v)的聚合物溶液。将PEG-(NH2)6和CS-NHS溶于DMEM中得到3种不同浓度的溶液:13.3%、10%和6.67%(w/v)。将CS-NHS(50μL)加入模具中,再加入50μLPEG-(NH2)6并混合。10分钟后,将网从模具中移除并转移到PBS中测量膨胀率。
随后对交联网进行关于膨胀和细胞相容性(包入网内的细胞或在邻近网处培养的细胞)的评估。对于眼科的黏合应用,膨胀性质为重要,盖因过度膨胀能撑开已封闭的伤口或造成红斑(stigmatism)。网被创造成包有细胞或不包有细胞。细胞可在黏合剂内输送的潜力对于除了封闭伤口外还需要形成新组织的较大角膜伤口具有应用性。CS网比得上所有报告的PEG对照网。
以1∶1、1∶2和2∶1的不同比例将纤维母细胞包入CS-PEG氨网中。生产浓度为5%、10%和20%w/v的对照PEG网。使用商用试剂盒将细胞染色以显示其生存性。所有凝胶中活体细胞的量具有可比性,表示CS-I基凝胶是生物相容性。
另一实验中,将CS-NHS和功能化的PEG(armedPEG)溶于担载不同量如10mM、100mM、500mM和1000mMHEPES的HEPES缓冲剂的PBS中。混合试剂直到出现凝胶化且不能将试剂用吸管移动为止。值得注意的是,凝胶化时间在约100mM的HEPES中出现稳定。注意到,随着HEPES浓度的增加,凝胶体积有轻微下降,暗示交联度随着HEPES浓度的增加而增加。通常,模数或凝胶硬度也随着HEPES浓度的增加而增加。由于标准误差较大,模数在500mM处略有下跌。
使用本发明的各种凝胶测试来自髓核、纤维环、软骨细胞、角膜细胞、角膜内皮细胞、角膜表皮细胞和间质干细胞的细胞的细胞毒性。也将细胞包入各种感兴趣的凝胶中。在至少21天的期间监视细胞。作为对照,将细胞暴露于5%PEG二丙烯酸酯。凝胶含有CS与PEG比例为1∶2、1∶1或2∶1。一些凝胶含有透明质酸(HA)或葡糖胺(GlcN),通常为1∶1的CS与含有相等部分的HA或GlcN的PEG凝胶。所有情形中,在21天的测试期间,细胞生存性均得以维持。在第8天,角膜内皮细胞仍以细胞增殖程度存在,观察到抗细胞凋亡效果。
另一套实验中,向以上述方式构筑的CS-PEG凝胶中加入胶原蛋白至最终浓度为约0.15%(w/v)。与不含有胶原蛋白的CS-PEG凝胶相比,观察到模数增加1.75±0.08倍。预计胶原蛋白作为凝胶基质中的微粒,并因此赋予凝胶复合性质。
胶原蛋白上的伯氨基可与感兴趣的凝胶中的CS-NHS基团相互反应。因此,胶原蛋白可通过共价键合与凝胶基质交联。因为可用CS-NHS基团数目的降低,这种交联度的增加可能导致凝胶粘合性的降低。避免胶原蛋白与凝胶基质间共价反应的方法是使用官能化胶原蛋白,如氨基被取代的胶原蛋白,来最小化氨基的反应性。如上述教导的,举例来说,氨基可被改性为包含乙酰基、烷基等。这将导致凝胶具有增加的模数而不牺牲其组织粘合性。
本文所描述的聚合物、聚合性基质、次单元和其它组合物的预期等义物包括:与上述分子或组合物相当的材料、具有与上述分子或组合物相同通常性质的材料,其中,通过对上述分子或组合物的取代基做一个或多个简单但不对这些分子或组合物的效能产生负面影响的变化来实现预期目的。通常,本发明的化合物可使用容易得到的起始材料、试剂及习知合成过程通过诸如上述常规反应图说明的方法或其修饰后方法而制备。这些反应中,也可能使用本身已知但本文未提及的变体。
本文涉及的全部出版物及专利均以全文引用方式并入本文作为参考,相当于每一出版物或专利被具体且独立指出并入作为参考。
Claims (7)
1.一种组合物,其包含亲水生物相容性第一聚合物,其中所述第一聚合物是分离且纯化的琥珀酰亚胺化的硫酸软骨素,和第二亲水生物相容性聚合物,其中所述第二聚合物为PEG-氨。
2.根据权利要求1所述的组合物,其中,所述第一聚合物包含至少10个单体单元。
3.根据权利要求1所述的组合物,其中,所述第一聚合物适于与生物结构或人造结构的表面反应。
4.根据权利要求3所述的组合物,其中,所述人造结构包括假体。
5.一种药物组合物,所述药物组合物包含权利要求1所述的组合物及药学上可接受的载剂、赋形剂或稀释剂。
6.根据权利要求5所述的药物组合物,所述药物组合物包括权利要求1-4中任一项所述的组合物,和药学上可接受的载体、赋形剂或稀释剂,所述药物组合物适合用作药物。
7.根据权利要求5所述的药物组合物,所述药物组合物包括权利要求1-4中任一项所述的组合物,和药学上可接受的载体、赋形剂或稀释剂,所述药物组合物适合作为组织黏合剂、水凝胶或上述两者用于个体。
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RU2696232C1 (ru) * | 2018-06-26 | 2019-07-31 | федеральное государственное бюджетное образовательное учреждение высшего образования "Северо-Западный государственный медицинский университет им. И.И. Мечникова" Министерства здравоохранения Российской Федерации | Способ лечения костного дефекта в эксперименте |
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