CN102695501A - 碎裂水凝胶 - Google Patents

碎裂水凝胶 Download PDF

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CN102695501A
CN102695501A CN2010800605199A CN201080060519A CN102695501A CN 102695501 A CN102695501 A CN 102695501A CN 2010800605199 A CN2010800605199 A CN 2010800605199A CN 201080060519 A CN201080060519 A CN 201080060519A CN 102695501 A CN102695501 A CN 102695501A
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cracked
hydrogel composition
hydrogel
compositions
tissue
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G·宫
S·S·派
S·R·塞尔申
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Spotlight Technology Partners LLC
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Spotlight Technology Partners LLC
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Priority to CN201610885562.8A priority Critical patent/CN107033368A/zh
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Abstract

提供了碎裂的多糖基水凝胶组合物及制备和使用所述水凝胶组合物的方法。所述主题多糖基水凝胶组合物通过将多糖组分与亲水聚合物和交联剂混合来制备。还提供了用于制备所述主题组合物的试剂盒和系统。

Description

碎裂水凝胶
相关申请的交叉引用
本申请要求2009年11月9日提交的美国临时申请第61/259,566号的权益,所述美国临时申请以引用方式的方式整体并入本文。
发明背景
水凝胶是亲水性均聚物或共聚物的水溶胀性网络。这些网络可通过各种技术形成;然而,最常见的合成路线是使乙烯基单体在双官能团交联剂和溶胀剂存在下进行自由基聚合。所得聚合物同时表现出可归因于主要成分水的类似液体的性质和由于交联反应形成的网络的类似固体的性质。这些类似固体的性质的形式为在形变时具有明显的剪切模量。
水凝胶提供生物相容性并且已经证明在医疗器械中使用时具有降低诱导血栓、结皮(encrustation)和炎症的倾向。遗憾的是,水凝胶在生物医疗器械应用中的使用由于现有水凝胶的形式和机械特性所受到的限制而被阻碍。许多医疗器械使用水凝胶来改善器械的生物相容性;然而,许多水凝胶只能在涂层中使用。当与非溶胀性聚合物体系相比时,许多水凝胶受低模量、低屈服应力和低强度所困。较低的机械性能源于水凝胶的溶胀性质和溶胀剂的不承受应力性质。现有的原位固化水凝胶提供了有益效果,因为它们能流动以适合特定的组织、空隙或管腔。然而,这些材料一旦在其固化时就失去了这种能力,并且就会具有以上列出的缺点。完全固化的水凝胶易于操作,但是缺少原位固化体系的形状填充、适形的特性。
尤其要注意的是,虽然原位固化水凝胶的生物相容和适形特性是期望的,但是应用原位固化水凝胶的方法是繁杂的。在装运和储存这种类型的器械期间要保持两种或两种以上反应性组分彼此分离和稳定的限制给使用者带来显著的负担。通常,反应性组分的储存远离在器械试剂盒中的任何复原液体。在要使用时,需要使用者组装多个容器,复原材料并且在应用材料之前将复原的材料转移至递送系统。在一些情况下,该过程必须在一定时限内完成以防止水凝胶材料活性的损失。
因而,仍然需要开发能够原位形成提供具有改善的治疗效果的生物相容水凝胶结构的新组合物。
相关文献
美国专利第4,963,489号;第5,080,655号;第5,250,020号;第5,266,480号;第5,278,201号;第5,278,204号;第5,324,775号;第5,443,950号;第5,599,916号;第5,609,629号;第5,618,622号;第5,652,347号;第5,690,955号;第5,725,498号;第5,741,223号;第5,827,937号;第5,836,970号;第5,852,024号;第5,874,417号;第5,874,500号;第6,071,301号;第6,344,272号;第6,418,934号;第6,428,811号;第6,444,797号;第6,530,994号;第6,551,610号;第6,566,406号;第6,602,952号;第6,645,517号;第7,166,574号;第7,303,757号;第7,414,028号;第7,482,427号;第7,528,105号和第7,670,592号。
美国专利申请第2006/0241777号、第2007/0196454号和第2007/0231366号;和
外国专利文献第WO 2009/028965号。
Braunova等,Collect.Czech.Chem.Commun.2004,69:1643-1656。
Carlson,R.P.等,Journal of Polymer Science,Polymer Edition.2008,19(8):1035-1046。
发明概述
提供了碎裂水凝胶组合物及制备和使用所述水凝胶组合物的方法。所述主题水凝胶组合物通过将聚合物组分和交联剂混合,随后进行碎裂过程以产生碎裂水凝胶的组合物来制备。还提供了用于制备所述主题组合物的试剂盒和系统。
通过阅读以下更全面地描述的本公开的细节,本发明的这些和其它目的、优点和特征将对本领域技术人员来说变得显而易见。
附图简述
当结合附图阅读以下详细描述时可最透彻地理解本发明。要强调的是,按照惯例,附图的各种特征不成比例。相反,为清楚起见,各种特征的尺寸任意地放大或缩小。在附图中包括以下各图:
图1展示示例性多糖基水凝胶的基质;
图2展示PEG琥珀酰亚胺琥珀酸酯的化学结构;
图3展示PEG琥珀酰亚胺戊二酸酯的化学结构;
图4展示示例性的PEG-PEG-壳聚糖水凝胶组合物;
图5展示碎裂水凝胶的小瓶;
图6展示用于碎裂水凝胶复水的示例性注射器构造;
图7展示示例性的复水水凝胶的组合物。
发明详述
在描述本发明之前,应理解本发明不限于所描述的特定实施方案,因而这些特定实施方案当然可以变化。还应理解的是,本文中使用的术语仅是为了描述特定的实施方案,并且不希望进行限制,因为本发明的范围仅由所附权利要求限定。
提供数值范围时,应理解,还明确公开了该范围的上下限之间的各中间值,其中下限精确到十分位,除非上下文另外明确地规定。在规定范围中的任何规定值或中间值和在该规定范围中的任何其它规定值或中间值之间的各个较小范围涵盖在本发明之内。这些较小范围的上下限可被独立地包括在所述范围中或排除在所述范围外,并且当两个界限之一、都不或全都包括在所述较小范围中时各个范围也被涵盖在本发明内,除非是所述规定范围中的任何明确排除的极限值。当规定范围包括极限值之一或两者时,将这些所包括的极限值的任一个或两个排除的范围也包括在本发明中。
除非另外定义,否则本文中使用的所有技术和科学术语均具有与本发明所属领域的普通技术人员通常理解的相同含义。虽然在实践或测试本发明时可以使用与本文中描述的那些类似或等效的任何方法和材料,但是现在描述一些可能和优选的方法和材料。本文中提到的所有公开文献均以引用的方式并入本文,以公开和描述与所引用的公开文献相关的方法和/或材料。应理解的是,如果有矛盾,本公开内容取代所并入公开文献的任何公开内容。
必须指出,除非上下文明确地另外规定,否则在本文和所附权利要求中使用的单数形式“一个”、“一种”和“所述”包括复数个指示物。因此,例如,对“一种化合物”的指代包括多种这些化合物并且对“所述聚合物”的指代包括指代一种或多种聚合物和本领域技术人员已知其等价物,等等。
提供本文中讨论的公开文献仅仅是因为它们在本申请的提交日期之前公开。本文中的任何内容均不应被理解为认可本发明未先于根据先前发明的这些公开文献授权。此外,提供的公布日期可能与可能需要单独确认的实际公布日期不同。
介绍
一般来讲,本发明包括已经由多糖和两种或两种以上其它组分制备的水凝胶组合物。所述主题水凝胶组合物的特征在于在湿润(例如血液)和干燥环境中都能够粘合组织,其中所述组合物与组织的粘附力是生理学上可接受的。所述主题组合物的另一个特征是其良好地耐受并且不引起实质性的炎性反应(如果有炎性反应)。所述主题组合物可以提供多种希望的性质,如以下任何的组合:止血性质、粘合性质、血管再生、生物相容性、杀菌、抑菌和/或杀真菌性质、组织重塑和/或提供用于组织工程、再生和/或细胞接种的支架、酶催化或水解降解途径、溶胀、工程滞留时间、工程粘度、温度或能量活化、包含能够在影像仪器(X-射线、CT、MRI、US、PET、CTA等)下显像的试剂、工程级的亲水性或疏水性、缝隙和/或空间填充、表面涂层、吸收能量的能力、包含发泡剂、包含显像剂、作为药物递送平台的能力、用于声音传输的介质和工程硬度计(engineered durometer)。充分水化的碎裂水凝胶具有类似于液体溶液的流动特性,然而一旦所述材料组装使用就完全固化并且不经受其它交联反应。因此,本发明的碎裂水凝胶提供兼备原位固化水凝胶制剂的流动、适形特性与完全固化水凝胶制剂的操作和使用便利性的方法。
所述主题碎裂的多糖基水凝胶组合物通过将多糖成分和两种或两种以上组分(如聚合物和交联剂)组合或混合来制备。对所述组合物随后进行碎裂以形成可以随后悬浮在溶液中的聚合物基质小块。示例性的基质在图1中提供。现在更详细地分别叙述这些前体组分或组合物的每一种。
组合物
如上所述,本发明的组合物包括多糖组分。适于与本发明一起使用的多糖的实例包括但不限于壳聚糖、透明质酸、硫酸软骨素系列、肝素、硫酸角质素、糖原、葡萄糖、淀粉酶、支链淀粉和其衍生物。所述多糖可以是天然存在的或合成制备的。多糖具有若干可用于化学修饰的反应性基团。这些基团包括羟基(OH)、羧基(COOH)和乙酰胺基(COCH3)。其它官能团可以通过碱性脱乙酰化以胺基(NH2)的形式赋予特定的多糖,其中多糖在高温下暴露于碱性条件下。脱乙酰化的程度取决于碱性条件的强度、反应环境的温度和反应的持续时间。例如,可以控制脱乙酰化的百分比以从单一甲壳质源得到不同的壳聚糖分子。对多糖赋予官能团的其它方法在本领域是已知的,如按Prestwich和Marecak在美国专利第5,874,417号中教导的通过使用酰肼使天然透明质酸通过胺基而官能化,该专利以引用方式并入本文。在该方法中,二糖的羧基在酸性条件下在可溶性碳二亚胺存在下连接至多官能的酰肼上。
在某些实施方案中,多糖是壳聚糖。壳聚糖通过甲壳质的脱乙酰化形成的二糖,甲壳质是在甲壳动物壳和一些真菌中发现的天然存在的材料。壳聚糖是具有止血和抗菌特性的生物相容、亲水聚合物。壳聚糖可以来自天然存在的来源或可以通过合成方法合成。壳聚糖在美国专利第5,836,970号、第5,599,916号和第6,444,797号中描述,所述专利的公开内容以引用的方式并入本文。
水凝胶材料的非多糖组分可以包括亲水聚合物,如以下天然、合成或杂化聚合物中的任一种:聚(乙二醇)、聚(环氧乙烷)、聚(乙烯醇)、聚(烯丙醇)、聚(乙烯基吡硌烷酮)、聚(环氧烷)、聚(氧乙基化多元醇)、聚(乙烯亚胺)、聚(烯丙胺)、聚(乙烯胺)、聚(氨基酸)、聚(乙基噁唑啉)、聚(环氧乙烷)-共-聚(环氧丙烷)嵌段共聚物、多糖、碳水化合物、寡肽和多肽。所述聚合物链可以包括以上材料和其衍生物的均聚物、共聚物或三元共聚物(成直链或支链形式)。这些材料可以通过存在于多糖和对应亲水聚合物上的化学活性基团的作用,通过形成共价键而交联成水凝胶。在化学活性基团中,优选用于本发明的是那些可以与易于得到的亲核或亲电残基形成共价键的基团。
这些示例性材料可以通过存在于亲水聚合物上的化学活性基团的作用,通过形成共价键交联成水凝胶。在化学活性基团中,优选用于本发明的是那些可以与易于得到的亲核或亲电残基形成共价键的基团。
可以与存在于基质上的亲核基团反应的亲电基团的实例包括但不限于羧基、异氰酸酯基、硫氰酸酯基、N-羟基琥珀酰亚胺酯基、缩水甘油醚基、缩水甘油基环氧化物基团、乙烯砜基、马来酰亚胺基、邻二硫吡啶基、碘乙酰胺基和碳二亚胺基。可以与存在于基质上的亲电基团反应的亲核基团的实例包括但不限于酸酐、伯胺基、仲胺基、叔胺基或季胺基、酰胺基、尿烷基、脲基、酰肼基、硫氢基或硫醇基。前述列举的反应性基团作为说明性实例;向其它亲核和亲电部分的扩展对本领域技术人员来说应该是清楚的。
在一个实施方案中,所述水凝胶组合物是包括具有末端亲核基团的多官能团PEG、具有末端亲电基团的多官能团PEG和壳聚糖的三组分水凝胶。当将所述聚合物组分用适当的缓冲液复原并混合时,它们进行反应形成粘性水凝胶。
所述具有末端亲核基团的多官能团PEG可以包含双官能团活化的、三官能团活化的、四官能团活化的或星形支链的活化的聚合物。所述多官能团亲核PEG的分子量可以在1千道尔顿(kD)至100kD范围内;在5kD至40kD范围内;或在l0kD至20kD范围内。所述多官能团亲核PEG质量以至少1%;至少5%;至少10%;至少20%;至少40%;至少80%;至少99%的质量百分数存在。
所述具有末端亲电基团的多官能团PEG可以包含双官能团活化的、三官能团活化的、四官能团活化的或星形支链的活化的聚合物。所述多官能团亲电PEG的分子量可以在1kD至100kD范围内;在5kD至40kD范围内;或在l0kD至20kD范围内。所述多官能团亲电PEG质量以至少1%;至少5%;至少10%;至少20%;至少40%;至少80%;至少99%的质量百分数存在。
所述多糖(例如壳聚糖)可以以盐或胺的形成存在。所述壳聚糖的分子量可以在10道尔顿至1kD范围内;在1kD至10kD范围内;在l0kD至100kD范围内;在100kD至250kD范围内;在250kD至500kD范围内;或在500kD至1000kD范围内。所述壳聚糖的脱乙酰化程度可以在1%至10%范围内;在10%至20%范围内;在20%至30%范围内;在30%至40%范围内;在40%至50%范围内;在50%至60%范围内;在60%至70%范围内;在70%至80%范围内;在80%至90%范围内;或在90%至99%范围内。所述壳聚糖可以在.01%至.1%范围内;在.1%至.5%范围内;在.5%至1.0%范围内;在1.0%至5%范围内;在5%至10%范围内;在10%至20%范围内;在20%至40%范围内;在40%至80%范围内;或在80%至99%范围内的质量百分数存在于所述硬化的水凝胶中。在某些实施方案中,所述多糖是壳聚糖。在其它实施方案中,所述壳聚糖还可以包含壳聚糖的衍生物,如在美国专利第5,888,988号中描述的N,O羧甲基壳聚糖,或在WO2009/028965中描述的草酸衍生化的壳聚糖,所述专利的公开内容以引用的方式整体并入本文。例如,草酸衍生化的壳聚糖可以经由具有至少两个亲电反应性基团的聚乙二醇与具有至少两个亲核反应性基团的聚乙二醇交联。
可以适于在本发明中使用的生理学上可接受的聚合物的实例是聚(乙二醇),其已经用二酯修饰以产生在其主链上具有可水解降解的酯键和可以进一步修饰以实现与相容的化学基团交联的末端酯基。以下实例说明由这些类型的聚合物组成的水凝胶能够显示的水解速率的范围。
Braunova等(Collect.Czech.Chem.Commun.2004,69,1643-1656)证明在聚(乙二醇)聚合物中的酯键的水解速率随着邻近酯键的亚甲基数目的增加而降低。例如,LLL和多臂聚(乙二醇)琥珀酰亚胺琥珀酸酯的共聚物在生理学条件下在含水介质中将在大约8天内降解。如图2所示,所述琥珀酰亚胺琥珀酸酯具有两个位于邻近易水解酯键的两个甲基。
通过比较,LLL和多臂聚(乙二醇)琥珀酰亚胺戊二酸酯的共聚物将在在生理学条件下在含水介质中在大约50天内降解。如图3所示,所述琥珀酰亚胺戊二酸酯具有位于邻近易水解酯键的三个甲基。
随着邻近酯键的甲基的数目增加,酯键的水解速率降低。通过沿着以下进程增加PEG聚合物中的甲基的数目,将应实现酯键水解速率的进一步降低:PEG琥珀酰亚胺己二酸酯,PEG琥珀酰亚胺庚二酸酯、PEG琥珀酰亚胺辛二酸酯、PEG琥珀酰亚胺壬二酸酯、PEG琥珀酰亚胺癸二酸酯等。将这种控制降解时间的方法扩展到其它系统对本领域的技术人员来说应该是易于实现的。
还可以在不改变基本聚合物组分的情况下对合成PEG水凝胶的降解时间进行调整。如果降解时间介于以上列举的两种聚合物的降解时间就会出现这种情况。例如,由4臂、10千道尔顿、PEG-琥珀酰亚胺琥珀酸酯聚合物和三赖氨酸(SS-LLL)组成的水凝胶在37℃下暴露于含水介质时在大约7天内降解。由4臂、10千道尔顿、PEG-琥珀酰亚胺戊二酸酯聚合物和三赖氨酸(SG-LLL)组成的水凝胶在37℃下暴露于含水介质大约50天内降解。如果需要降解时间为大约14天水凝胶,则存在若干种可应用的通过使用此实例中所列聚合物来实现该降解时间对方法。一种方法是制备其中反应性亲电基团由两种PEG聚合物的共混物提供而亲核基团由三赖氨酸提供的水凝胶。可以改变两种PEG聚合物的化学计量共混物以提供希望的降解时间。例如,可以将由PEG琥珀酰亚胺琥珀酸酯提供的65%的所需亲电基团和由PEG琥珀酰亚胺戊二酸酯提供的35%的所需亲电基团的共混物与三赖氨酸混合(同时保持1:1的亲核基团:亲电基团化学计量比),以形成在37℃下暴露于含水介质时在大约14天内降解的水凝胶。
获得中等降解时间的第二种方法是改变水凝胶前体聚合物内的反应性亲核基团与反应性亲电基团的化学计量比。对于其中的亲核基团由多个供体提供的水凝胶,对于其中的亲核基团由单个供体提供的水凝胶,对于其中的亲电基团由多个供体提供的水凝胶,对于其中的亲电基团由单个供体提供的水凝胶,或其任何组合,可以这样进行。
获得中等降解时间的第三种方法是改变水凝胶中的聚合物的量。例如,如果给定的水凝胶在平衡时含有5重量%聚合物含量,那么所述水凝胶的降解时间可以通过将聚合物在平衡时的含量增加至5重量%以上的值来延长。类似地,所述水凝胶的降解时间可以通过将聚合物在平衡状态的含量降低至5重量%以下的值来缩短。
可通过使用不在生理学条件下降解的PEG基聚合物,如由PEG二丙烯酸酯制备的聚合物或其它类似的聚合物,来获得不可降解的制剂。
本发明的另一种形式是由具有末端亲核基团的多官能团PEG、醛组分和壳聚糖组成的三组分水凝胶。当将所述聚合物组分用适当的缓冲液复原并混合时,它们进行反应形成粘性水凝胶。
组合物中的亲核PEG和多糖(例如壳聚糖)组分如先前描述。在本文中所提供的组合物中的醛组分可以是具有低毒性的任何生物相容的醛。具体来讲,醛组分包括二醛、聚醛或其混合物。醛的实例包括但不限于乙二醛、硫酸软骨素醛、丁二醛、戊二醛和顺丁烯二醛。在一些实施方案中,醛组分是戊二醛。具有低毒性的其它合适的醛包括来源于天然存在的物质的多官能团醛,例如葡聚糖二醛或糖。醛组分可以是通过糖和其衍生物用高碘酸、臭氧等氧化裂解的醛产物。醛可以任选用热预处理。参见Schankereli的美国专利第7,303,757号“Biocompatible phase invertable proteinaceous compositions andmethods for making and using the same”,其以引用方式整体并入本文。可以分析醛组分的性质如粘度和同渗重摩。粘合组合物的醛组分本身可以进一步由组分和/或亚组分组成。因此,在混合之前或之后,可将醛组分以重量、重量与重量之比、重量与体积之比或体积与体积之比进行描述。例如,多糖可以经由用醛基衍生化的葡聚糖与具有至少两个反应性亲核基团的多官能团合成聚合物交联。
在一些实施方案中,醛组分包含约1-90%的醛浓度。在一些实施方案中,醛组分包含约1-75%的醛浓度。在一些实施方案中,醛组分包含约5-75%的醛浓度;约10-75%的醛浓度;约20-75%的醛浓度;约30-75%的醛浓度;约40-75%的醛浓度;约50-75%的醛浓度;或约60-75%的醛浓度。
所述组合物可以包含至少约1%的醛浓度;至少约5%的醛浓度;至少约10%的醛浓度;至少约20%的醛浓度;至少约30%的醛浓度;至少约40%的醛浓度;至少约50%的醛浓度;至少约60%的醛浓度;至少约70%的醛浓度;至少约80%的醛浓度;至少约90%的醛浓度;或至少约99%的醛浓度。在一些实施方案中,所述粘合组合物包含约1-30%、约25-75%、约50-75%或约75-99%的醛浓度。
在一些实施方案中,所述组合物包含至少约1%的戊二醛浓度;至少约5%的戊二醛浓度;至少约8%的戊二醛浓度;至少约10%的戊二醛浓度;至少约20%的戊二醛浓度;至少约30%的戊二醛浓度;至少约40%的戊二醛浓度;至少约50%的戊二醛浓度;至少约60%的戊二醛浓度;至少约70%的戊二醛浓度;至少约80%的戊二醛浓度;至少约90%的戊二醛浓度;或至少约99%的戊二醛浓度。在一些实施方案中,所述组合物包含约1-30%、约25-75%、约50-75%或约75-99%的戊二醛浓度。
可以向上述本发明的形式中加入增稠剂。增稠剂包括例如葡聚糖、羧甲基纤维素、聚乙二醇、脂质体、前体脂质体、甘油、淀粉、糖、聚维酮、聚环氧乙烷和聚乙烯醇。在一些实施方案中,增稠剂是葡聚糖、聚乙二醇或羧甲基纤维素。在一些实施方案中,所述组合物包含至少约1%的增稠剂浓度;至少约5%的增稠剂浓度;至少约10%的增稠剂浓度;至少约20%的增稠剂浓度;至少约30%的增稠剂浓度;至少约40%的增稠剂浓度;至少约50%的增稠剂浓度;至少约60%的增稠剂浓度;至少约70%的增稠剂浓度;至少约80%的增稠剂浓度;或至少约90%的增稠剂浓度。在一些实施方案中,所述组合物包含至少约0.5%-10%、至少约0.5%-25%或至少约0.5%-50%的增稠剂浓度。在一些实施方案中,增稠剂可以占所述组合物的至少约0.5%。增稠剂可以改变所述组合物的胶凝时间。
本发明的上述方面的一些实施方案可以进一步包含不透射线材料。所述不透射线材料包括例如氧化铋(Bi2O3)、氧化锌(ZnO)、硫酸钡(BaSO4)、氧化镧(La2O3)、氧化铈(CeO2)、氧化铽、氧化镱、氧化钕、氧化锆(ZrO2)、氧化锶(SrO)、氧化锡(SnO2)、不透射线玻璃和硅酸盐玻璃。不透射线玻璃包括例如硅酸钡、含有硅-铝钡(silico-aluminobarium)或锶的玻璃。硅酸盐玻璃包括例如含有钡或锶的玻璃。在一些实施方案中,所述不透射线材料占所述粘合组合物的至少约0.001%;至少约0.05%;至少约0.1%;至少约0.2%;至少约0.5%;至少约1%;至少约2%;至少约5%;至少约8%;或至少约10%。
本文中提供的水凝胶组合物可以任选含有各种天然存在的或合成制备的添加剂,例如但不限于水、缓冲液、盐水溶液、中性盐、碳水化合物、纤维、其它生物材料、润湿剂、抗生素、防腐剂、染料、增稠剂、稀释剂、纤维蛋白原、聚合物如聚乙二醇或其组合。聚合物包括合成聚合物如聚酰胺、聚酯、聚苯乙烯、聚丙烯酸酯、乙烯基聚合物(例如聚乙烯、聚四氟乙烯、聚丙烯和聚氯乙烯)、聚碳酸酯、聚氨酯、聚二甲基硅氧烷、醋酸纤维素、聚甲基丙烯酸甲酯、乙烯-醋酸乙烯、聚砜、硝基纤维素和类似的共聚物。聚合物进一步包括可以是天然存在或通过发酵等体外制备的生物聚合物。生物聚合物包括不限于胶原、弹性蛋白、丝、角蛋白、明胶、聚氨基酸、多糖(例如纤维素和淀粉)和其共聚物。
在所述水凝胶组合物中可以包括增韧剂以在固化时向所述材料提供柔韧性。增韧剂可以是天然存在的组合物或合成制备的。合适的增韧剂包括合成和天然橡胶、合成聚合物、天然非天然(non-native)生物相容的蛋白质(如外源性(即非天然)胶原等)、粘多糖(GAG)(如透明质酸(hyaluronin)和硫酸软骨素)和血液组分(如纤维蛋白、纤维蛋白原、白蛋白和其它血液因子)。
本文中提供的组合物可以任选包括盐和/或缓冲液。盐的实例包括但不限于氯化钠、氯化钾等。合适的缓冲液可以包括例如氨水、磷酸盐、硼酸盐、碳酸氢盐、碳酸盐、二甲胂酸盐、柠檬酸盐和其它有机缓冲液如三(羟甲基)氨基甲烷(TRIS)、吗啉基丙磺酸(MOPS)和N-(2-羟乙基)哌嗪-N'(2-乙磺酸)(HEPES)。合适的缓冲液可以根据所述水凝胶组合物的所需pH范围来选择。
在所述制剂中可以存在其它添加剂来改进所述组合物的机械性能。一些添加剂包括例如填充剂、软化剂和稳定剂。填充剂的实例包括但不限于炭黑、金属氧化物、硅酸盐、丙烯酸树脂粉末和各种陶瓷粉末。软化剂的实例包括但不限于磷酸二丁酯、磷酸二辛酯、磷酸三甲苯酯、磷酸三丁氧乙酯和其它酯。稳定剂的实例包括但不限于三甲基二氢醌、苯基-β-萘基胺、对-异丙氧二苯基胺、二苯基-对-苯二胺等。
在所述组合物中可以包括的一类添加剂的是纳米粒子或纳米级构造。已经设计出具有特定物理特性的纳米粒子的实例是纳米壳,如Oldenburg等教导的(美国专利第6,344,272号,其以引用的方式整体并入本文)。纳米壳由环绕不传导的核的金属壳组成;通过改变核的直径和壳的厚度,可以将材料的吸收波长调整至特定的光谱区。West等在美国专利第6,428,811号和第6,645,517号中公开了将纳米壳掺入用于药物递送的热敏聚合物基质中,并且在美国专利第6,530,994号中进一步教导使用纳米壳通过局部的高温来治疗肿瘤(以上专利均以引用的方式整体并入本文)。纳米粒子或其它纳米级结构与本发明的组合物的组合物可以对所述组合物提供其它功能性(即可调的吸收光谱)。在一个实例中,在应用近红外激光诱导局部高温之前可以使用所述组合物将调整至吸收近红外光的纳米粒子固定在希望的物理位置。将纳米壳掺入所述水凝胶基质中以防止纳米壳从目标区域浸出。
所述组合物还可以任选包括增塑剂。增塑剂提供若干功能,包括表面的湿润,或者,增加材料的弹性模量,或再进一步,有助于材料的混合和施加。存在大量的增塑剂,包括脂肪酸,例如油酸、棕榈酸等,邻苯二甲酸二辛酯、磷脂和磷脂酸。因为增塑剂通常是水不溶性的有机物质并且不容易与水混溶,所以有时有利的是通过将适当的增塑剂与醇预混合以降低与所述溶液相关的表面张力来改进其与水的混溶性。为此,可以使用任何醇。在本发明的一个代表性的实施方案中,将油酸与乙醇混合以形成50%(w/w)溶液并且随后在配制过程期间将该溶液用于对聚合物基质增塑。然而增塑剂的类型和浓度取决于应用,在某些实施方案中,增塑剂的最终浓度是约.01至10%(w/w),包括约2至约4%(w/w)。值得关注的其它增塑剂包括但不限于:聚乙二醇、甘油、丁基羟基甲苯等。
值得关注的填充剂包括补强填充剂和非补强填充剂。可以包括的补强填充剂,如切碎的纤维丝、聚酯、PTFE、NYLON、碳纤维、聚丙烯、聚氨酯、玻璃等。可以按需要改进纤维(例如以上对于其它组分所描述的),从而(例如)增加可润湿性、混合程度等。补强填充剂可以以约0至40%,如约10至约30%存在。还可以包括非补强填充剂,例如粘土、云母、羟基磷灰石、硫酸钙、骨碎片等。需要时,也可以改进这些填充剂,例如如上所述。非补强填充剂可以以约0至40%,如约10至约30%存在。
在某些实施方案中,所述组合物可以包括发泡剂,当其与交联剂组合物组合时产生发泡组合物,例如包括四处散布的气态空气气泡的组合物。可以存在任何适当的发泡剂,其中所述发泡剂可以是当与交联组合物接触时产生提供产生气泡的气体并且从而产生所述组合物的希望的发泡特性。例如,在基质中可以存在范围为约2至约5%w/w的量的盐(如碳酸氢钠)。当基质与酸性交联剂组合物(例如具有约5的pH)组合时会产生发泡组合物。
可以将生物活性剂掺入本发明的聚合物网络;这些试剂包括但不限于血浆蛋白、激素、酶、抗生素、防腐剂、抗肿瘤剂、抗真菌剂、抗病毒剂、抗炎剂、生长因子、麻醉剂、类固醇、细胞悬浮液、细胞毒素、细胞增殖抑制剂和仿生剂(biomimetics)。生物活性剂可以通过任何本领域已知的方法掺入本发明的水凝胶中。作为一个非限制性实例,在混合之前可以向组分溶液中加入一种试剂或多种试剂,从而使水凝胶基质在所述试剂或多种试剂周围形成并以机械方式包封所述试剂。或者,可以将所述一种或多种试剂在混合之前加入一种或所有组分溶液中。在另一个实例中,可以将所述一种或多种试剂进行修饰或衍生化以与水凝胶的组分反应并与所述水凝胶形成共价键。可以使所述一种或多种试剂与呈侧链构型的水凝胶结构的主链结合或作为水凝胶结构的完全一体的部分。在又一个实例中,所述一种或多种试剂可以悬浮在包封在水凝胶中或贯穿水凝胶分布的疏水性区域内。或者,所述一种或多种试剂可以通过静电、范德华力(van Der Walls)或疏水作用与水凝胶的主链相连。同样涵盖任何上述技术的组合(例如以物理方式包封在带正电的水凝胶基质中的带负电的试剂)。掺入的确切方法将由所述生物活性剂的性质决定。
方法
所述水凝胶可以用适合于其各个组分的方式来制备。例如,由多臂胺封端的PEG、壳聚糖和多臂酯封端的PEG组成的水凝胶可以通过在含水碱性缓冲液中将所述三种聚合物以10%的质量分数、以1:1的官能团摩尔比进行混合来制备。
碎裂
术语“碎裂”是指将单个、完整的聚合物材料破碎成保留母体材料的材料性质的较小片段的过程。这可以通过若干方法实现,包括流动性聚合物材料的注射器至注射器混合,用刀片、转片、锤子、超声振动或其它合适的技术、锉磨、砂磨、碾压和研磨和/或碾磨方法将聚合物材料捣碎,如圆锥和回旋破碎、圆盘式碾磨、胶体和辊轧碾磨、筛磨和粉碎、锤式碾磨和笼式碾磨、销式和通用碾磨(pin and universalmilling)、喷射或流能碾磨、冲挤式碾磨和破碎、颚式破碎、辊轧破碎、圆盘式碾磨和垂直辊轧,包括冷冻粉碎和/或冷冻碾磨。
冷冻碾磨或冷冻粉碎是指在液氮中冷冻样品并粉碎以将其减少至所需粒径的方法。将样品冷却至大约-200℃以用于使柔性的样品更易碎并且容易研磨。低温还使样品保持在传统的研磨或碾磨方法中的较高温度下可能失去的特性。例如,这可以通过将样品连同磁致冲击器一起放置在密封容器中实现。随后可以将密封容器浸入由磁性线圈围绕的液氮室中。随后样品的温度一旦达到大约-200℃就可以激活线圈,使冲击器在容器内往复运动以粉碎样品。颗粒的大小可以通过改变各研磨时间段的长度和/或进行多个研磨时间段来控制。在研磨时间段之间可以冷却样品容器以保持足够冷的温度。
冷冻碾磨或研磨的另一个实例将液氮与搅拌球磨机结合使用。在该方法中,将目标样品连同选择的研磨介质一起载入搅拌球磨机的滚筒中。介质的类型可以根据希望的研磨方法的结果(颗粒表面积、宽高比、形状、致密性、分散稳定性、不透明性、流动性等)和样品的材料特性而变化。研磨介质的典型实例包括充分硬化的钢粒、硅酸锆、氧化锆、燧石、矾土、氮化硅、莫来石、碳化钨、陶瓷、铬钢、玻璃、碳化硅、不锈钢和碳钢。研磨介质的大小也可以根据特定的研磨方法的要求而变化。该列举并不完全,其它研磨介质的特性对本领域的技术人员来说应该是容易获得的。随后将滚筒密封并通过使液氮流经环绕所述滚筒的外部的夹套将滚筒的温度降低至低温。一旦滚筒的内容物下降至足够的温度,穿过滚筒中央的轴就开始转动。连接到所述轴的臂或叶轮搅拌样品和介质,将样品粉碎至所需大小(或可选择的规格)。
可以使用的另一种冷冻粉碎技术是使用液氮冷却常规球磨机的滚筒。在该方法中,将样品和介质载入滚筒并按照以上针对搅拌球磨机所述进行冷却。一旦达到足够低的滚筒温度,滚筒本身就转动以提供样品碎裂需要的剪切力和冲击力。可能容易进行低温处理的其它碎裂类型包括但不限于圆锥和回旋破碎、圆盘式碾磨、胶体和辊轧碾磨、筛磨和粉碎、锤式和笼式碾磨、销式和通用碾磨、喷射或流能碾磨、冲挤式碾磨和破碎、颚式破碎、辊轧破碎、圆盘式碾磨和垂直辊轧。
该列举并未涵盖将完整的聚合物碎裂成较小颗粒的全部潜在方法。其它方法的适用性对本领域的技术人员来说是可以理解的。
干燥
可将所述水凝胶在进行碎裂之前或之后干燥。术语“干燥”是指将候选聚合物材料的含水量从初始值减少至较低值的任何方法。这可以通过在各种温度和压力条件下将材料放置在具有比聚合物材料更低含水量的环境中实现,其中一些条件在表1中列举。
表1
Figure BDA00001848262600171
除本文中列举那些以外,干燥技术的应用对本领域的技术人员来说应该是容易实现的。例如,美国公开的美国申请第2007/0231366号教导了一种干燥水凝胶的方法,所述方法包括在反应完成之前通过将溶液的温度降低至所述反应溶液的凝固点以下使进行交联反应的组分溶液停止,随后接着冷冻干燥部分交联的水凝胶以从所述部分交联的水凝胶除去溶剂。随后通过一系列用来完成所述交联反应的处理来处理所述部分交联的水凝胶。这种制备方法对液体和固体之间的相变过度依赖,并且限制可以在通过所述教导的方法制备的水凝胶中使用的制备方法。例如,所述溶液从液体向固态(即冷冻)的转变时间很大程度上取决于模具的物理和材料特性(壁厚、传热系数、模具表面的亲水性或疏水性)、冷冻方法(冷却板、冷冻机、浸入液氮中等)和交联反应等等。面对这些变量要保持一致的处理是有挑战性的,并且可对通过所述教导方法扩大水凝胶生产造成障碍。
一种用于降低在美国公开专利申请第2007/0231366号中教导的方法的复杂性的方法是使用停止或减慢不经受与冷冻同样多的参数的交联反应速率的方法,如将反应组分的溶液的pH改变至不支持进一步交联的水平。例如,在N-羟基琥珀酰亚胺和伯胺之间的二级亲核取代的反应速率随着反应介质的pH碱性更强而加速并且随着反应介质的pH酸性更强而减速。因此,以足以将反应介质的pH改变至酸性条件的摩尔浓度和体积添加一定分量的酸性溶液将会停止或减慢所述亲核取代的反应速率。改变反应速度的又一个方法是改变反应介质的离子强度。水凝胶组分的溶液随后准备进行冷冻干燥。该新颖方法的有益效果是反应速率的改变可以在水凝胶组分处于液相(例如在室温下)时进行,并且不依赖于浇注模具的大小、形状或材料。所述方法独立于上述限制将会通过降低所述方法步骤的复杂性和使用者依赖性来改善批次间生产批量的一致性并且通过简化较大模具的使用而适用于扩大生产。
碎裂之后,可对收集到的的聚合物颗粒进行分选以获得特定的粒径分布。这可以通过使干燥聚合物材料经过一组筛网、使水溶性聚合物材料通过尺寸排阻柱或其它常用的分选技术来实现。
在一个实例中,所述水凝胶在适当的反应介质中制备,随后使用适当的方法干燥并碎裂。随后可以将干燥颗粒载入合适的载体或递送装置中。在使用时,可以将无菌盐水引入干燥材料以使其复水成悬浮水凝胶颗粒的溶液。在第二个实例中,所述聚合物在适当的反应介质中制备,被碎裂成希望的大小并且在载入合适的载体或递送装置之前进行干燥。同样,在使用时,可以将无菌盐水引入干燥材料以使其复水成悬浮水凝胶颗粒的溶液。
在适当的介质中复水
用适当的缓冲液将所述颗粒复水的方法使所得浆液的物理特性得以控制。例如,容易在碱性条件下水解的碎裂水凝胶可以在酸性含水缓冲液中复水以延长浆液的功能寿命。在另一个实例中,所述浆液的稠度可以通过调节干燥材料在复原溶液中的质量分数从稠浆调节至稀薄、流动的液体。
在本发明的一个实施方案中,将多糖和合成聚合物溶于中性或碱性的缓冲液中。将交联剂溶于适当pH的平衡缓冲液中。将两种溶液混合以允许在所述多糖、合成聚合物和交联剂之间形成水凝胶网络。随后将水凝胶风干至恒重并进行冷冻碾磨或冷冻粉碎以产生具有一定粒径分布的一批颗粒。
在本发明的第二实施方案中,将多糖和合成聚合物溶于中性或碱性的缓冲液中。将交联剂溶于适当pH的平衡缓冲液中。将两种溶液混合以允许在所述多糖、合成聚合物和交联剂之间形成水凝胶网络。随后通过注射器至注射器混合将所述水凝胶碎裂并以部分水化的状态储存。或者,可以将所述水凝胶放入适当的含水介质以溶胀指定的时间长度,或直到溶胀已经达到指定的程度,然后通过注射器至注射器混合进行碎裂。所述溶胀介质可以包含但不限于增稠剂、造影剂、防腐剂、染料、稀释剂、增韧剂、盐和或缓冲液、填充剂、软化剂、稳定剂、纳米粒子、增塑剂、生物活性剂、药物活性剂等。
在本发明的第三实施方案中,将多糖和合成聚合物溶于中性或碱性的缓冲液中。将交联剂连同一种或多种类固醇(例如(曲安西龙(triamcinolone))、莫米松(mometasone)、氢化可的松(hydrocortisone)等)一起溶于酸性或中性的缓冲液中。将两种溶液混合以允许在所述多糖、合成聚合物和交联剂之间形成截留所述一种或多种类固醇的水凝胶网络。类固醇通常在碱性溶液中是不可溶的,因此在将所述类固醇掺入到所述水凝胶中之前将类固醇添加到含有交联剂的中性至酸性缓冲液中起到防止或减轻类固醇从溶液中析出的作用。随后将所述水凝胶风干至恒重并进行冷冻碾磨或冷冻粉碎以产生负载有所述一种或多种类固醇的具有一定粒径分布的一批颗粒。将干燥颗粒通过一系列过滤器过筛以分离所需粒径范围,并且放入中性或酸性pH的水溶液中。可以该状态使用复水的浆液来将所述类固醇递送至目标靶解剖部位,其中类固醇的药物释放状况由类固醇从水凝胶中的扩散决定,或由碎裂水凝胶的水解或酶促降解(在用可水解和/或酶促降解键合制备的水凝胶的情况下)决定,或由两者决定。所述浆液可以进一步与另一种包含例如增稠剂的溶液混合,以产生抵抗从递送点扩散和/或迁移的负载类固醇的颗粒的粘稠溶液。
或者,将多糖和合成聚合物溶于中性或碱性的缓冲液中。将交联剂溶于适当pH的平衡缓冲液中。将两种溶液混合以允许在所述多糖、合成聚合物和交联剂之间形成水凝胶网络。随后将水凝胶风干至恒重并进行冷冻碾磨或冷冻粉碎以产生具有一定粒径分布的一批颗粒。将干燥颗粒通过一系列过滤器过筛以分离所需粒径范围,并且放入中性或酸性pH的包含一种或多种类固醇的水溶液中以进行溶胀。可以该状态使用复水的浆液来将所述一种或多种类固醇递送至目标靶解剖部位,或进一步调整以掺入其它组分,所述组分包括但不限于造影剂、防腐剂、染料、稀释剂、增韧剂、盐和或缓冲液、填充剂、软化剂、稳定剂、纳米粒子、增塑剂、生物活性剂、药物活性剂等。
在第四实施方案中,将多糖和合成聚合物溶于中性或碱性的缓冲液中。将交联剂连同麻醉剂(例如利多卡因(lidocaine)、丁哌卡因(bupivacaine)、木卡因(xylocaine)等)一起溶于酸性至中性的缓冲液中。将两种溶液混合以允许在所述多糖、合成聚合物和交联剂之间形成截留所述一种或多种类固醇的水凝胶网络。麻醉剂通常在酸性缓冲液中配制,因此向含有交联剂的中性至酸性缓冲液中添加麻醉剂符合当前的配制惯例。随后将所述水凝胶风干至恒重并进行冷冻碾磨或冷冻粉碎以产生负载有所述一种或多种类固醇的具有一定粒径分布的一批颗粒。将干燥颗粒通过一系列过滤器过筛以分离所需粒径范围,并且放入中性或酸性pH的水溶液中。可以该状态使用复水的浆液来将所述麻醉剂递送至目标靶解剖部位,其中麻醉剂的药物释放状况由类固醇从水凝胶中的扩散决定,或由碎裂水凝胶的水解或酶促降解(在用可水解和/或酶促降解键制备的水凝胶的情况下)决定,或由两者决定。所述浆液可以进一步与另一种包含例如增稠剂的溶液混合,以产生抵抗从递送点扩散和/或迁移的负载麻醉剂的颗粒的粘稠溶液。
或者,将多糖和合成聚合物溶于中性或碱性的缓冲液中。将交联剂溶于适当pH的平衡缓冲液中。将两种溶液混合以允许在所述多糖、合成聚合物和交联剂之间形成水凝胶网络。随后将水凝胶风干至恒重并进行冷冻碾磨或冷冻粉碎以产生具有一定粒径分布的一批颗粒。将干燥颗粒通过一系列过滤器过筛以分离所需粒径范围,并且放入中性或酸性pH的包含麻醉剂的水溶液中以进行溶胀。可以该状态使用复水的浆液来将所述麻醉剂递送至目标靶解剖部位中,或进一步调整以掺入其它组分,所述组分包括但不限于增稠剂、造影剂、防腐剂、染料、稀释剂、增韧剂、盐和或缓冲液、填充剂、软化剂、稳定剂、纳米粒子、增塑剂、生物活性剂、药物活性剂等。
在第五实施方案中,将多糖和合成聚合物溶于中性或碱性的缓冲液中。将交联剂连同抗生素(例如庆大霉素(gentamicin)、头孢氨苄(cephalexin)、头孢克洛(cefaclore)等)一起溶于酸性至中性的缓冲液中。将两种溶液混合以允许在所述多糖、合成聚合物和交联剂之间形成截留所述一种或多种类固醇的水凝胶网络。抗生素通常在酸性缓冲液中配制,因此向含有交联剂的中性至酸性缓冲液中添加麻醉剂符合当前的配制惯例。随后将所述水凝胶风干至恒重并进行冷冻碾磨或冷冻粉碎以产生负载有所述一种或多种类固醇的具有一定粒径分布的一批颗粒。将干燥颗粒通过一系列过滤器过筛以分离所需粒径范围,并且放入中性或酸性pH的水溶液中。可以该状态使用复水的浆液来将所述抗生素递送至目标靶解剖部位,其中抗生素的药物释放状况由抗生素从水凝胶中的扩散决定,或由碎裂水凝胶的水解或酶促降解(在用可水解和/或酶促降解键制备的水凝胶的情况下)决定,或由两者决定。所述浆液可以进一步与另一种包含例如增稠剂的溶液混合,以产生抵抗从递送点扩散和/或迁移的负载抗生素的颗粒的粘稠溶液。
或者,将多糖和合成聚合物溶于中性或碱性的缓冲液中。将交联剂溶于适当pH的平衡缓冲液中。将两种溶液混合以允许在所述多糖、合成聚合物和交联剂之间形成水凝胶网络。随后将水凝胶风干至恒重并进行冷冻碾磨或冷冻粉碎以产生具有一定粒径分布的一批颗粒。将干燥颗粒通过一系列过滤器过筛以分离所需粒径范围,并且放入中性或酸性pH的包含抗生素的水溶液中以进行溶胀。可以该状态使用复水的浆液来将所述抗生素递送至目标靶解剖部位中,或进一步调整以掺入其它组分,所述组分包括但不限于增稠剂、造影剂、防腐剂、染料、稀释剂、增韧剂、盐和/或缓冲液、填充剂、软化剂、稳定剂、纳米粒子、增塑剂、生物活性剂、药物活性剂等。
在第六实施方案中,将多糖和合成聚合物溶于中性或碱性的缓冲液中。将交联剂溶于适当pH的平衡缓冲液中。将两种溶液混合以允许在所述多糖、合成聚合物和交联剂之间形成水凝胶网络。随后将水凝胶风干至恒重并进行冷冻碾磨或冷冻粉碎以产生具有一定粒径分布的一批颗粒。将干燥颗粒通过一系列过滤器过筛以分离所需粒径范围,并且用作用于富含血小板血浆(PRP)的载体。将所述干燥颗粒与PRP的溶液混合以将所述PRP吸收到所述水凝胶网络的空隙中。可以该状态使用复水的浆液来将PRP经过指定的一段时间递送至靶解剖部位,所述组织如软组织缺损(例如肌腱、韧带、疝、肩袖等)、撕裂伤或外部创面(例如压疮、糖尿病溃疡等)或硬组织缺损(例如骨)。可以向复水的浆液中加入钙、凝血酶或胶原来激活生长因子从PRP的释放。所述浆液可以进一步调整以掺入其它组分,所述组分包括但不限于增稠剂、造影剂、防腐剂、染料、稀释剂、增韧剂、盐和/或缓冲液、填充剂、软化剂、稳定剂、纳米粒子、增塑剂、生物活性剂、药物活性剂等。
应该清楚的是,将类固醇、麻醉剂、抗生素和PRP掺入到本发明的组合物中的实例可以扩展至任何药物或生物活性剂,包括但不限于天然存在的或合成制备的血浆蛋白、激素、酶、防腐剂、抗肿瘤剂、抗真菌剂、抗病毒剂、抗炎剂、人源性和非人源性生长因子、麻醉剂、细胞悬浮液、细胞毒素、细胞增殖抑制剂、纤维蛋白、纤维蛋白原、胶原和仿生剂。
在第七实施方案中,将多糖和合成聚合物溶于中性或碱性的缓冲液中。将交联剂溶于适当pH的平衡缓冲液中。将两种溶液混合以允许在所述多糖、合成聚合物和交联剂之间形成水凝胶网络。随后将水凝胶真空干燥至恒重并进行冷冻碾磨或冷冻粉碎以产生具有一定粒径分布的一批颗粒。将干燥颗粒通过一系列过滤器过筛以分离所需粒径范围并在壳聚糖的中性溶液中复水以产生流动性的浆液。所述浆液的粘度可以通过改变干燥颗粒的质量百分数或改变壳聚糖在所述复水溶液中的浓度来调节。或者,可以向所述复水溶液中加入第二种组分(例如葡聚糖)作为增稠剂。所述浆液可以进一步调整以掺入其它组分,所述组分包括但不限于造影剂、防腐剂、染料、稀释剂、增韧剂、盐和/或缓冲液、填充剂、软化剂、稳定剂、纳米粒子、增塑剂、生物活性剂、药物活性剂等。
在第八实施方案中,将多糖和合成聚合物溶于中性或碱性的缓冲液中。所述交联剂包含与水接触时降解的水解区域,并且将其溶于酸性缓冲液。将两种溶液混合以允许在所述多糖、合成聚合物和交联剂之间形成水凝胶网络。随后将水凝胶真空干燥至恒重并进行冷冻碾磨或冷冻粉碎以产生具有一定粒径分布的一批颗粒。将干燥颗粒通过一系列过滤器过筛以分离所需粒径范围并且在酸性溶液中复水以在使用之前减缓或停止交联剂的水解和水凝胶的相关降解。所述浆液的粘度可以通过改变干燥颗粒的质量百分数或通过掺入作为增稠剂的第二种组分(例如葡聚糖)来调节。所述浆液可以进一步调整以掺入其它组分,所述组分包括但不限于造影剂、防腐剂、染料、稀释剂、增韧剂、盐和/或缓冲液、填充剂、软化剂、稳定剂、纳米粒子、增塑剂、生物活性剂、药物活性剂等。
效用
本文中描述的组合物可以兼备如以下描述的多种效用。例如,所述水凝胶可以用作用于动脉瘤闭合的栓塞。所述组合物可以用于神经血管和/或周围动脉瘤的封闭或输卵管和/或精囊的封闭来灭菌。本发明组合物的其它应用是在美国专利第7,670,592号中教导的静脉曲张栓塞、子宫肌瘤栓塞、高度血管化肿瘤的栓塞、动静脉畸形的栓塞、脑膜瘤栓塞、副神经节肿瘤栓塞和转移性肿瘤栓塞,所述专利以引用的方式整体并入本文。肿瘤的治疗可以包括或不包括作为所述水凝胶的组分的化学治疗剂。
所述组合物可以用作止血剂。本发明的一个应用是管理破裂、灼烧或划破的粘膜内层,如扁桃体切除术后的扁桃体、增殖腺切除术后的增殖腺,拔牙之后,用于治疗牙齿干槽症,治疗鼻出血或治疗需要控制流血的任何其它粘膜表面的破裂。如在美国专利第5,080,655号、第5,741,223号、第5,725,498号和第6,071,301号中教导的,在肝脏、肺、肾、乳房、软组织和淋巴结活检中为了活检目的经受组织去除后,所述组合物可以用于提供止血控制。在前段中列举的所有专利均以引用的方式整体并入本文。
所述组合物可以用来作为治疗糖尿病足溃疡、静脉瘀血性溃疡、压疮或需要高级创伤处理的任何类型的溃疡和撕裂伤。如在美国专利第4,963,489号、第5,266,480号和第5,443,950号中教导的,这些材料的目的是为了提供湿润环境以覆盖和保护露出的组织,有时是为了促进最佳的愈合。在前段中列举的所有专利均以引用的方式整体并入本文。
所述组合物可以在全身性、妇科和ENT手术应用中用作粘连屏障以降低术后粘连的发生率、范围和严重程度。粘连是一种在通常在身体内是分离的两种器官或表面之间形成连接的疤痕组织。据推测由手术产生的自由血液和血浆可以在组织之间急剧地形成纤维蛋白链;这些链可以在几天的时间跨度内成熟为永久组织带,它可影响正常器官功能并引起其它严重的临床并发症。如在美国专利第5,852,024号、第6,551,610号和第5,652,347号中教导的,它们有时与子宫内膜异位和盆腔炎性疾病相关并且已知往往在腹部、骨盆或窦房手术之后形成。进行这种类型手术操作的超过90%的患者都可能形成粘连。所述组合物可以形成为在所述组合物内保留有内腔以使空气流动(即在窦房手术之后的应用期间)或液体排泄能够进行。所述组合物还可以用作保持组织之间的间隔的支架。在另一个实例中,所述组合物可以用作筛窦隔片以在手术之后保持通向所述筛窦的开口。在前段中列举的所有专利均以引用的方式整体并入本文。
本文中描述的组合物可以用作医疗器械或组织上的表面涂层以防止生物膜和细菌或真菌菌落的形成。选择强阳离子多糖(例如壳聚糖)作为所述水凝胶网络的组分允许在提供对生物膜沉积的阻碍的植入物和一次性医疗器械上的连续表面涂层(Carlson,R.P.等,Anti-bioflm properties of chitosan coated surfaces.Journal of PolymerScience,Polymer Edition,19(8):ppl035-1046,2008)。作用机理可能有两方面,所述多糖的物理结构可能起破坏细菌细胞壁的作用,或所述多糖的阳离子性质可能用于与阴离子抗生素剂结合。或者,可以用非多糖组分或添加剂来提供类似的抗微生物、抗菌或抗真菌性质(例如银)。提供感染控制的表面涂层的一个重要应用是预防或治疗骨髓炎。骨髓炎是由致热细菌(pyrogenic bacteria)引起的具有进展倾向的骨或骨髓感染。由于医源性原因如关节代替物、骨折内固定术或根管牙,可以观察到骨髓炎的表象。本发明的水凝胶组合物可以允许局部持续性抗生素治疗。此外,可以将所述组合物设计成能防止或减轻细菌或真菌感染,减少或避免对长期全身抗生素治疗的需求,如美国专利第5,250,020号、第5,618,622号、第5,609,629号和第5,690,955号中所教导。在前段中列举的所有专利均以引用的方式整体并入本文。
本文中描述的组合物可以有效地用于形成有利于细胞接种和组织工程应用的受控微结构的多孔和无孔支架。孔径大小和结构的控制方法包括以下:冷冻干燥(冻干)、盐萃取、使用发泡剂如过氧化氢和本领域熟知的其它方法。多种细胞系具有使用这些多孔和无孔支架实来现复杂组织生长和修复的现时意义,如用于形成组织工程胰腺、神经再生、软骨再生和修复、骨生长和修复和连接和软组织修复(腹部和腹股沟疝、骨盆底再建、阴道吊带、肩袖、肌腱等)的血管、上皮组织、胰岛细胞。
本发明的水凝胶组合物可以在治疗剂或缓和剂的受控递送或施用中使用。所述组合物可以包括作为所述治疗剂或缓和剂的载体或储库的合成组分。所述药剂可以与所述水凝胶基质的结构共价结合或以物理方式截留在所述水凝胶基质内。所述治疗剂或缓和剂的释放速率可以通过调整本发明的组合物来控制。具有现时意义的靶包括以下:用于治疗肿瘤的紫杉醇、用于治疗糖尿病的胰岛素、用于治疗疼痛的镇痛剂或麻醉剂、用于控制血压的血管收缩剂如安非他明(amphetamines)、抗组胺药、伪麻黄碱和咖啡因、用于控制血压的血管扩张剂如α阻滞剂、一氧化氮诱导剂和罂栗碱、降低胆固醇药如他汀类(例如洛伐他汀(lovostatin))、用于控制凝结的促凝血剂如硫酸鱼精蛋白、凝血酶、纤维蛋白和胶原、用于控制凝结的抗凝血剂如肝素、香豆定(Coumadin)、糖蛋白2-β-3-α、华法林(warfarin)、阿昔单抗(abciximab)和硫酸氯吡格雷(clopidogrel bisulfate),和选择性血清素再吸收抑制剂如氟西汀(fluoxetine),以提供抑郁症、强迫症、食欲过盛、食欲不振、恐慌症和月经前焦虑障碍的缓和治疗,和单胺氧化酶抑制剂,如用于抑郁症的缓和治疗的苯乙肼。所述水凝胶组合物可以用作用于合成的和基于人的骨再生长剂如重组人骨形态发生蛋白以及可用于该指征的仿生材料的载体,所述仿生材料如来自Bio Surfaces Engineering Technology的B2A、F2A、PBA、LAI、VA5、PBA、LAI、VA5、B7A、F9A、F5A和F20A,如在美国专利第7,528,105中教导的杂二聚链合成肝素-结合生长因子类似物,如在美国专利第7,482,427号和第7,414,028号中教导的骨形态发生蛋白-2的正调节剂,如在美国专利第7,414,028号中教导的生长因子类似物和如在美国专利第7,166,574号中教导的合成肝素-结合生长因子类似物,所有专利均以引用的方式整体并入本文。
本发明的组合物具有多种用途,特别是在美容手术和皮肤科领域。如在美国专利第5,827,937号、第5,278,201号和第5,278,204号中所教导,可将有韧性的流动性组合物制备为可注射的制剂,并且适于表层至深层皮肤的扩大,例如用来矫正、填充和支撑皮肤的皱纹、皱痕和皱褶以及嘴唇。如在美国专利第6,418,934号中所教导,可以构思较大体积的注射用于乳房、阴茎阴茎头和在身体内的其它解剖部位的扩大;所有列举的专利均以引用的方式整体并入本文。为了美容和重建的目的,涵盖塑身方法,包括乳房扩大。阴茎的阴茎头的扩大用于治疗早泄。在历史上,用于早泄的医学治疗的主要限制是停药之后的复发。使用本发明的可注射组合物的阴茎头扩大通过阻断触觉刺激对神经受体的可及性促进早泄的治疗。本发明的组合物还可以用作用于括约肌扩大的可注射填充剂来控制失禁。在该应用中,将所述材料直接注射到括约肌组织中以改善并扩大组织结构,从而可以恢复括约肌控制。如在美国公开专利申请2006/0241777中所教导,本发明的组合物还可以用作乳房植入物的填充剂,以及用作可吸收植入物的填充剂,如用于紧靠骨放置和用于填充空隙(如在骨骼之间的)的那些,所述专利以引用的方式整体并入本文。
本文中描述的组合物可以用作空间填充剂和能量屏障以减弱现有的基于能量的过程并降低相邻组织中的当前的剂量限制的发病问题。本发明的水凝胶组合物在非患病组织和肿瘤靶标之间起过渡缓冲液的作用。该方法的有益效果有两方面;所述制剂的空间填充性质将并生组织以物理方式移动远离被施加能量的目标肿瘤,此外,所述组合物可以配制为包括减弱所施加的辐射或其它能量的强度的添加剂。例如,所述组合物可以在放射治疗过程期间用于降低前列腺的辐射损伤。本文中描述的使肿瘤移位远离健康组织还适用于头部和颈部癌症、骨盆、胸部、乳房和软组织肉瘤。该组合物在放射治疗和手术肿瘤去除过程中的另一种用途是使用所述组合物作为描绘肿瘤边界的标记系统。
本发明的组合物可以用于填充组织中的空隙。潜在的用途包括骨骼中的空隙(承重的和非承重的)的治疗、关节软骨中的空隙或缺口、由活检操作引起的空隙和心脏的间隔缺损的治疗。这些空隙的治疗可以通过在所述水凝胶制剂中包含生物活性剂和生物激活剂来增强。例如,可以将重组人骨形态发生蛋白或同种异体人源性骨骼材料,或脱矿质骨基质,或合成仿生材料掺入所述组合物,以帮助骨骼空隙的治疗。
当前环境下的组合物可用作合成滑膜液或其它类型的润滑剂。通过掺入高亲水性的合成聚合物,这些材料可以在如肌腱或韧带修复和胸部手术领域得到应用。已进行手术修复的撕裂肌腱与腱鞘的粘连降低了损伤指趾或四肢的活动范围并且增加了达到其余活动范围需要的动力。在手术修复的肌腱和腱鞘之间设置所述水凝胶组合物的流动性浆液可以起到减少摩擦的作用并且能够使用于所述损伤肌腱伸展动力降低。在胸外科手术中,可以在胸部干预之后形成粘连。引入本文中描述的水凝胶可以防止或减少胸膜之间粘连的形成,并且此外提供相邻组织经过彼此移动的润滑剂。
试剂盒
还提供了用于实施所述主题方法的试剂盒,其中所述试剂盒通常包括在运送给使用者之前就已经固化的水凝胶制剂。容器应理解为是指可以容纳或包裹本发明的水凝胶组合物的组分的任何结构;示例性的容器包括注射器、小瓶、小袋、胶囊、卡普耳(carpule)、安瓿、药筒等。容器可以通过使用其它部件(例如包裹注射器的箔片小袋)或通过选择容器本身的材料性质(例如棕色玻璃小瓶或不透明注射器)来屏蔽可见、紫外或红外辐射。
所述主题试剂盒还可以包括递送装置(其它可以包括或不包括混合元件),如导管装置(例如具有相同或不同大小和形状的一个或多个管腔并具有不同几何形状、尺寸和位置的出口端的管子)、具有类似或不同直径和体积、喷雾元件、单向阀、柱塞、Y型连接器、放气元件的注射器(例如允许在向患者递送之前从液体溶液去除空气的膜)、用于引导加压气体流的入口或腔、允许水凝胶组合物的长时间沉积的一次性药筒,施用器或涂布器,在递送本发明的组合物中用于实现机械优点的组件,保护并包含上述部件的腔室或套管等。
所述试剂盒可以进一步包括其它部件,例如干燥剂或保持对试剂盒中含水量的控制的其它构件;氧气洗涤器或保持对试剂盒内氧含量的控制的其它构件;惰性气氛(例如氮气或氩气);传达所述试剂盒经受的最高温度的指示器;传达对灭菌辐射、环氧乙烷高压灭菌器条件等的暴露情况的指示器;防止对部件破坏的保持或定位结构(例如托盘或包装卡),其需要在运输和储存期间使产品保持良好的状态。以下实例是非限制性的并且旨在证实将所述水凝胶制剂制成试剂盒的可能性。
在一个实施方案中,提供装有所述固化、干燥和碎裂水凝胶制剂的容器。提供包含适于将所述粉末复水的缓冲液的注射器。将注射器与所述碎裂水凝胶容器连接,并且将缓冲液引入所述容器以使所述碎裂水凝胶复水。将复水的水凝胶制剂抽取到注射器中,使用者可以在该点将其与先前列举的任何示例性装置元件连接。
在第二实施方案中,将所述固化、干燥和碎裂水凝胶制剂和适当的缓冲溶液均在双腔注射器中提供。使用者通过按压注射器柱塞并使缓冲溶液与干燥水凝胶碎片混合来将干燥水凝胶碎片复水。使用者随后可以将注射器与先前列举的任何示例性装置元件连接。
在第三实施方案中,将所述固化、干燥和碎裂水凝胶制剂在注射器中以复水的状态提供。使用者随后可以将注射器与先前已经列举的任何示例性装置元件连接。
在第四实施方案中,将所述固化、干燥和碎裂水凝胶制剂在用于直接对靶部位应用的小袋或容器中提供。
除了上述部件之外,所述主题试剂盒通常进一步包括用于使用所述试剂盒的部件来实施所述主题方法的说明书。用于实施所述主题方法的说明书通常记录在合适的记录介质上。例如,所述说明书可以打印在基底上,如纸或塑料等。因而,可将所述说明书在所述试剂盒中作为包装说明书呈现,在所述试剂盒或其部件(即与包装或分包装相关)的容器的标签中呈现,等等。在其它实施方案中,所述说明书作为在合适的计算机可读存储介质(例如CD-ROM、磁盘等)上提供的电子存储数据文件呈现。在又一些其它实施方案中,实际的说明书不在试剂盒中提供,而是提供从远程来源(例如通过因特网)获得说明书的方法。该实施方案的一个实例是包括网址的试剂盒,可以从该网址查看和/或下载说明书。如同说明书一样,用于获得说明书的这种方法记录在合适的载体上。
实施例
提出以下实施例是为了向普通技术人员提供如何制备和使用本发明的完全公开和说明,不意欲限制本发明人看待其发明的范围,也不意欲表示以下试验是进行的全部或仅有的试验。已经努力确保使用的数值(例如量、温度等)的准确性,但是应说明一些实验误差和偏差。除非另外指出,否则份数是重量份,分子量是重均分子量,温度是摄氏度并且压力是大气压或接近大气压。
实施例1
将具有胺活性基团的多臂聚乙二醇与壳聚糖以聚乙二醇:壳聚糖为10:1的比例在硼酸钠缓冲液中混合。将在硼酸钠缓冲液中以聚乙二醇酯:聚乙二醇胺为2:1的比例复原的具有酯活性基团的等体积多臂聚乙二醇与所述壳聚糖溶液混合。经过一个小时之后,形成坚硬、透明的水凝胶(图4)。
实施例2
将实施例1的样品在环境温度和压力下干燥,直至水凝胶的含水量与环境达到平衡(通过测量质量确定)。随后利用冷冻/碾磨将样品碎裂以获得精细碾磨的粉末(图5)。
实施例3
随后为了显像的目的将实施例2的干燥粉末在含有蓝紫色染料的盐水溶液中复水以得到固化、水化颗粒的浆液。使所述浆液充分地流动以允许用最小压力通过18G针头挤出。
实施例4
将具有胺活性基团的多臂聚乙二醇与壳聚糖以聚乙二醇:壳聚糖为4:1的比例在硼酸钠缓冲液中混合。将在硼酸钠缓冲液中以聚乙二醇酯:聚乙二醇胺为2:1的比例复原的具有酯活性基团的等体积多臂聚乙二醇与所述壳聚糖溶液混合。经过一个小时之后,形成坚硬、透明的水凝胶。将该样品切成片并装入注射器。将两端母鲁尔接头(female-female luer connector)和第二注射器与最初的注射器连接以实现注射器到注射器的混合(图6)。将所述水凝胶制剂进行总共10次流通,从而产生能从18G针头挤出的浆液(图7)。
前述内容仅说明本发明的原理。应理解的是,本领域的技术人员将能够设计出实施本发明的原理的各种方案,虽然本文中没有明确地描述或展示这些方案,但是这些方案包括在本发明的精神和范围之内。此外,本文中叙述的所有实施例和条件性语言主要是希望帮助读者理解本发明的原理和本发明人为了促进本项技术而贡献的理念,并且应理解为不受限于这些明确叙述的实施例和条件。此外,本文中叙述本发明的原理、方面和实施方案及其特定实施例的所有陈述均旨在同时涵盖其结构和官能的等价物。此外,希望这些等价物同时包括目前已知的等价物和未来开发的等价物,即开发的执行相同功能的任何要素,而与结构无关。因此,不希望本发明的范围局限于本文中展示和描述的示例性实施方案。相反地,本发明的范围和精神由所附权利要求来体现。

Claims (42)

1.一种水凝胶组合物,其包含
具有160道尔顿至80,300道尔顿的分子量并且包含至少两个反应性亲核基团的多糖基质或其衍生物;
具有200道尔顿至100000道尔顿的分子量并且包含至少两个亲核反应性基团的合成亲水聚合物;和
交联剂。
2.根据权利要求1所述的组合物,其中所述多糖基质是壳聚糖、羧甲基纤维素、羧甲基壳聚糖或其衍生物。
3.根据权利要求1所述的组合物,其中所述合成亲水聚合物基质是具有至少两个亲核活性基团的聚乙二醇。
4.根据权利要求1所述的组合物,其中所述交联剂是具有至少两个亲电活性基团的聚乙二醇。
5.根据权利要求1所述的组合物,其中所述交联剂是醛。
6.根据权利要求1所述的组合物,其中所述交联剂是戊二醛。
7.根据权利要求1所述的组合物,其中所述交联剂是经热处理的戊二醛。
8.根据权利要求1所述的组合物,其中所述组合物包含增稠剂。
9.根据权利要求1所述的组合物,其中所述组合物包含发泡剂。
10.根据权利要求1所述的组合物,其中所述组合物包含生物活性剂和或药物活性剂。
11.根据权利要求1所述的组合物,其中所述组合物包含显像剂和/或造影剂。
12.根据权利要求1所述的组合物,其中所述多糖基质可溶于碱性水溶液。
13.根据权利要求1所述的组合物,其中所述多糖基质可溶于浓度为至少30mM的水溶液。
14.一种制备碎裂水凝胶组合物的方法,其包括:
在溶液中混合根据权利要求1所述的水凝胶组合物的组分;
使所述溶液固化足够长的时间以形成固化的水凝胶组合物;以及
使所述固化的水凝胶组合物碎裂以形成碎裂水凝胶组合物。
15.根据权利要求14所述的方法,其中碎裂包括冷冻碾磨和/或冷冻粉碎。
16.根据权利要求14所述的方法,其中所述水凝胶组合物在完全或部分固化之后进行干燥。
17.根据权利要求16所述的方法,其中所述水凝胶组合物在干燥之后进行碎裂。
18.根据权利要求14所述的方法,其中所述碎裂水凝胶组合物通过大小分离。
19.根据权利要求18所述的方法,其中从所述碎裂水凝胶颗粒中选择特定的粒径范围。
20.根据权利要求17所述的方法,其进一步包括在使用之前使所述碎裂水凝胶组合物复水。
21.一种减少受试者伤口流血的方法,其包括:
将权利要求1所述的碎裂水凝胶组合物放置在所述伤口的至少一部分上,其中所述碎裂水凝胶组合物的放置与没有所述碎裂水凝胶组合物相比减少所述伤口的流血。
22.一种填充组织中的空隙的方法,其包括:
将权利要求1所述的碎裂水凝胶组合物放置在所述空隙中,其中所述碎裂水凝胶组合物的放置部分或完全地填充所述空隙。
23.一种减少两种或两种以上相邻组织之间的粘附或摩擦的方法,其包括:
将权利要求1所述的碎裂水凝胶组合物放置在所述两种或两种以上相邻组织之间,其中所述碎裂水凝胶组合物的放置与没有所述碎裂水凝胶组合物相比减少所述两种或两种以上相邻组织之间的粘附或摩擦。
24.一种向受试者递送治疗剂或缓和剂的方法,其包括:
对受试者施用权利要求1所述的碎裂水凝胶组合物,其中所述施用向所述受试者提供所述治疗剂或缓和剂的递送。
25.一种扩大现有靶组织的方法,其包括:
对现有靶组织施用权利要求1所述的碎裂水凝胶组合物,其中所述施用与没有所述碎裂水凝胶组合物相比提供所述现有靶组织的扩大。
26.一种减少通过缝合线、吻合口或切口渗漏的方法,其包括:
将权利要求1所述的碎裂水凝胶组合物放置在所述缝合线、吻合口或切口的至少一部分上,其中所述碎裂水凝胶组合物的放置与没有所述碎裂水凝胶组合物相比减少通过所述缝合线、吻合口或切口的液体的渗漏。
27.一种填充或封闭靶向血管或动脉瘤的方法;其包括:
将权利要求1所述的碎裂水凝胶组合物沉积在所述靶向血管或动脉瘤内,其中所述碎裂水凝胶组合物的沉积填充或封闭所述靶向血管或动脉瘤。
28.一种提供覆盖并保护受试者的裸露表面组织的湿润环境的方法,其包括:
将权利要求1所述的碎裂水凝胶组合物放置在所述裸露表面组织的至少一部分上,其中所述碎裂水凝胶组合物的放置与没有所述碎裂水凝胶组合物相比提供覆盖并保护所述裸露表面组织的湿润环境。
29.一种向医学植入物应用碎裂水凝胶组合物的方法,其包括:
将权利要求1所述的碎裂水凝胶组合物沉积在医学植入物上。
30.根据权利要求29所述的方法,其中所述医学植入物的表面涂有所述碎裂水凝胶组合物。
31.根据权利要求29所述的方法,其中在所述医学植入物中的凹处、空隙或管腔涂有或填充有所述碎裂水凝胶组合物。
32.一种形成组织支架的方法,其包括:
将权利要求1所述的碎裂水凝胶组合物形成用于组织工程或再生的支架,其中所述组织支架进一步任选地包含哺乳动物细胞。
33.一种在靶组织和相邻组织之间形成能量屏障的方法,其包括:
将权利要求1所述的碎裂水凝胶组合物放置在靶组织和相邻组织之间,其中所述碎裂水凝胶组合物的放置与没有所述碎裂水凝胶组合物相比减少从所述靶组织向所述相邻组织的能量传递。
34.一种将两种或两种以上组织彼此粘合的方法,其包括:
将权利要求1所述的碎裂水凝胶组合物放置在至少两种组织之间,其中所述碎裂水凝胶组合物的放置与没有所述碎裂水凝胶组合物相比提供所述两种组织彼此的粘合。
35.一种试剂盒,其包含:
权利要求1所述的碎裂水凝胶组合物,和
用于提供向靶区域或靶组织递送所述碎裂水凝胶的递送装置。
36.根据权利要求35所述的试剂盒,其中所述碎裂水凝胶组合物在第一容器中提供并且缓冲溶液在第二容器中提供。
37.根据权利要求36所述的试剂盒,其中用于所述碎裂水凝胶组合物的容器包含第一注射器并且用于所述缓冲溶液的容器包含第二注射器。
38.根据权利要求36所述的试剂盒,其中用于所述碎裂水凝胶组合物的容器包含小袋并且用于所述缓冲溶液的容器包含注射器。
39.根据权利要求35所述的试剂盒,其中所述碎裂水凝胶组合物和缓冲溶液在单个注射器中提供。
40.根据权利要求39所述的试剂盒,其中所述注射器是双腔注射器,并且其中所述碎裂水凝胶组合物在所述注射器的第一腔中提供并且所述缓冲溶液在所述注射器的第二腔中提供。
41.根据权利要求35所述的试剂盒,其中所述碎裂水凝胶组合物作为干燥颗粒在容器中提供。
42.根据权利要求35所述的试剂盒,其中所述碎裂水凝胶组合物作为半水合或全水合颗粒在容器中提供。
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US10159742B2 (en) 2018-12-25

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