CN101678151B - 用于软组织扩增的可注射型空隙填充剂 - Google Patents
用于软组织扩增的可注射型空隙填充剂 Download PDFInfo
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- CN101678151B CN101678151B CN200880016687.0A CN200880016687A CN101678151B CN 101678151 B CN101678151 B CN 101678151B CN 200880016687 A CN200880016687 A CN 200880016687A CN 101678151 B CN101678151 B CN 101678151B
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Abstract
本发明教导了微孔的、可注射的、柔弹性的、可完全再吸收的、基于纤维蛋白的组合物，其用作软组织内腔和空隙填充剂。本发明的组合物表现出的物理特征，诸如机械性质，通常在弹性体和机械稳定性方面被观察到的，优于单独的纤维蛋白。本发明组合物的多种性质可以通过调节被包含在空隙填充剂组合物中的粒子的类型和含量以及增塑剂的类型和含量进行精细调节和改变。
Description
技术领域
本发明一般地涉及微孔的、可注射的、柔弹性的、可完全再吸收的、基于纤维蛋白的组合物，其用作软组织内腔和空隙填充剂。本申请的组合物表现出的物理特征，诸如机械性质，通常在弹性体和机械稳定性方面被观察到的，优于单独的纤维蛋白。根据本发明的教导，通过调节在所述空隙填充剂组合物中所包含的粒子的类型和含量以及增塑剂的类型和含量，可以有效地精细调节所述空隙填充剂的多种性质。
发明概述
本发明的纤维蛋白组合物是天然生物材料。其是可灭菌的(stehlizable)并具有低的潜在毒性。其易于使用并且流变学允许进行注射和用于可能的具有最小侵入性的治疗的情况。纤维蛋白改性剂(增塑剂)和/或粒子组分的改变可允许精细控制吸水、溶胀、降解和生物活性分子的释放。另外，本发明是完全可再吸收。其放热量很小，并且表现出弹性体力学行为，使得其在机械性方面优于单独的纤维蛋白。
观察到，在纤维蛋白原凝固物中合并碘化造影剂和磷酸钙粒子(最大200μm)产生新的完全不同的材料。在这之后，鉴定了许多的纤维蛋白增塑剂和可供选择的粒子，并且组合物的使用随后也被扩大到包括硬组织空隙的其它适应症。
本发明试图将经过改性的纤维蛋白组合物的可能的适应症扩大到包括软组织适应症。这些包括但不限于部分或完全闭锁，扩增或填充软组织内腔和空隙。内腔被认为是管状结构诸如维管结构、生殖道和胃肠道的空腔体积。空隙被认为包括病变，裂隙，瘘和憩室(diverticulae)。这些空隙可以是生理性结果，或者是感染、手术、囊肿、肿瘤除去或跌打损伤或软组织重建的结果。
附图说明
图1显示荧光素从不含增塑剂的纤维蛋白凝固物的释放和从含碘克沙醇或甘油的纤维蛋白凝固物的释放；
图2显示了材料的弹性和具有不同浓度的造影剂的凝固物的粘度的改变；和
图3显示包含作为增塑剂的碘克沙醇和增加量的钙盐的组合物的流变学数据。
发明详述
本发明一般地涉及用于可注射型软组织空隙填充剂组合物的多组分体系，其包括：
包括纤维蛋白原的组分(a)；
包括凝血酶的组分(b)；
包括至少一种增塑剂的组分(c)；和
包括直径为约200微米或更低的粒子的组分(d)。
如上所述的用于可注射型软组织空隙填充剂组合物的多组分体系还可包括任何其它的适于扩增、加强、支撑、修复、重建、痊愈、闭锁或充填软组织的组分，诸如生长因子，化疗剂或药理学试剂，生物活性剂，硬化化合物和/或粘合剂化合物和矿物质添加剂。这些化合物可被包含在本发明的多组分体系的组分(a)-(d)的任一项中，或者可作为额外的组分被包括。
根据本发明的一个实施例，上述的多组分体系的纤维蛋白原组分(a)还可包括一种或多种细胞外基质蛋白，例如，粘连蛋白，细胞相关蛋白，其它血浆由来蛋白例如凝血因子XIII(FXIII)和蛋白酶和蛋白酶抑制剂，及其混合物。本发明的纤维蛋白原溶液还可包括任何添加剂，这些添加剂在现有技术和/或市售的纤维蛋白原组合物例如市售的纤维蛋白原溶液中被包括在内。
术语“纤维蛋白原”不仅包括纤维蛋白原本身，而且包括任何凝固物形成物质，诸如纤维蛋白原的凝固物形成衍生物，诸如“fibrini”。
在多组分体系的组分(a)中纤维蛋白原的量为例如约10mg/ml到约200mg/ml，诸如约30mg/ml到约150mg/ml，或约75mg/ml到约115mg/ml。
本发明的多组分体系的凝血酶组分(b)还可包括本领域已知的另外的化合物以及组分(c)和组分(d)之一或二者，特别是增塑剂组分(c)。关于凝血酶的用量没有特别限制。在本发明的一个实施例中，在所述凝血酶组分(b)中凝血酶的量为使得其在最终凝固的组合物中为至少约1IU/ml，诸如约30IU/ml。
术语“凝血酶”不仅包括凝血酶本身，而且包括用于组分(a)的任何胶凝诱导剂或凝固诱导剂，例如，生理学可接受的碱性缓冲液体系。
本文使用的术语“增塑剂”包括用于改变最终凝固的组合物的性质例如粘度、弹性体行为或机械稳定性的任何适当的物质。在本发明的一个实施方案中，上述的多组分体系的增塑剂具有低的重量克分子渗透压浓度并且允许纤维蛋白组装在适当的程度进行。
在本发明的一个实施例中，本发明多组分体系的适当的增塑剂包括至少一种生物可降解的水溶性有机化合物。本文使用的表述“生物可降解的水溶性有机化合物”还包括在生物环境中可以降解并且至少充分地溶于在例如约10℃到约40℃的水中的所有化合物。术语“生物可降解的”还被认为包括不被降解但是例如通过排泄途径进行生物消除的增塑剂。
上述的多组分体系的增塑剂的实例选自：水溶性造影剂，聚乙二醇，多元醇诸如甘油(及其衍生物(and dehvates of))，单糖、二糖、三糖和多糖，及其任何组合。
在本发明的一个实施例中，本发明的多组分体系的适当的造影剂包括至少一种含碘的有机化合物。在本发明的另一个实施例中，可以使用包含稀土元素诸如钆的有机化合物。
本文使用的术语“含碘的有机化合物”包括包含至少一个经过物理结合或化学结合的(例如共价结合的或配位结合的)碘原子和/或碘离子的所有化合物。该相同定义加以必要的变更适用于上述的包含稀土元素的有机化合物。
造影剂的实例包括但不限于泛影酸钠(葡甲胺)，碘的可，碘克沙醇，碘拉醇，碘骨胺(iogulamide)，碘海醇，碘美普尔，碘帕醇，碘普胺，碘曲伦，碘佛醇，碘格雷(ioxaglate)和室椎影methzamide)，及其混合物。
根据本发明的一个实施例，在组分(c)中的增塑剂的量为使得其在最终凝固的组合物中为约10到约80％w/v，诸如约15到约60％w/v，或约20到约40％w/v。
术语“粒子”包括任何类型的颗粒形状或已知的形状，例如，球形，角形或中空的。
在本发明的一个实施方案中，本发明的多组分体系的粒子是生物可降解的和/或生物相容的，无毒的，不溶于水的，无机的和/或有机的。粒子包括例如选自以下的物质：钙盐诸如磷酸三钙，α-磷酸三钙，β-磷酸三钙，磷酸钙，磷酸钙的多晶型物，羟基磷灰石，碳酸钙，硫酸钙，聚合物化合物诸如聚丙交酯(polyactide)，聚乙交酯(polyglycolide)，聚己酸内酯，聚三亚甲基碳酸酯，聚乙二醇及其无规或有序的共聚物，生物可降解的或生物相容的玻璃和陶瓷，及其任何组合。在一个实施例中，粒子选自磷酸三钙，α-磷酸三钙，β-磷酸三钙和磷酸钙，及其混合物，具有的Ca/P比为约1.5约2。本发明的粒子还包括本领域已知的、要在组分(d)的含义范围内被使用的所有市售的化合物和/或混合物。根据另一个实施例，本发明的多组分体系的所述粒子具有小于约100微米的直径，例如，小于约50微米的直径。在本发明的一个具体实施例中，在组分(d)中的粒子的量相对于最终凝固的组合物为1到约50％w/w，诸如约10到约45％w/w，或约30到约40％w/w。
根据本发明的一个实施方案，在上述的多组分体系的组分(a)中的纤维蛋白原的量为约10到约200mg/ml，在组分(b)中的凝血酶的量为使得其在最终凝固的组合物中为至少约1IU/ml，在组分(c)中的增塑剂的量为使得其在最终凝固的组合物中为约10到约80％w/v，和在组分(d)中的粒子的量相对于最终凝固的组合物为约1到约50％w/w。
根据本发明的一个具体实施方案，在上述的多组分体系的组分(a)中的纤维蛋白原的量为约75到约115mg/ml，在组分(b)中的凝血酶的量为使得其在最终凝固的组合物中为至少约25IU/ml到约50IU/ml，在组分(c)中的增塑剂的量为使得其在最终凝固的组合物中为约30到约50％w/v，和在组分(d)中的粒子的量相对于最终凝固的组合物为约30到约40％w/w。
在本发明的另一个实施方案中，用于可注射型空隙填充剂组合物的多组分体系包括：
包括纤维蛋白原的组分(a)；
包括凝血酶的组分(b)；
包括至少一种增塑剂的组分(c)；和
包括具有约200微米或更低的直径粒子的组分(d)；
其中组分(a)-(d)中的一种或多种或全部都以固体形式存在。
本发明的多组分体系可包含溶液形式或分散体形式或固体如冻干剂形式或其任何组合的组分。另外，在所述多组分体系中的组分可存在于适于所述多组分体系的保存、运输或使用的容器中。可用于本发明多组分体系的容器不以任何方式受到限制，并且包括具有任何大小、材料或形状的容器，例如小瓶或注射器。
另外，所述多组分体系的组分可例如被包含在不同的容器中，或者可以任何组合存在于相同的容器中，例如，作为在一个容器中的组分(b)和组分(c)的组合以及各自存在于不同容器中的组分(a)和组分(d)。
根据本发明，所述容器例如可包含作为固体的一种或多种组分，以及通过位于所述容器中的分隔机构与所述组分隔开的溶剂，其中可通过破坏或除去所述分隔机构而制备一种或多种组分各自的溶液。本发明的多组分体系的组分(a)-(d)还可作为备用型(ready-to-use)混合物存在。
另外，存在于一个或多个容器中的所述组分(a)-(d)还可作为包括上述的多组分体系的试剂盒的一部分。所述试剂盒还可包括可用于本发明的多组分体系中的任何另外的化合物，例如，助剂，缓冲盐或缓冲液。上述的试剂盒还可包含用于将所述组分进行混合的机构，例如，注射器，Luer连接器，管，额外的容器等等。
本发明的另一个方面涉及可注射型空隙填充剂组合物，其包括：
包括纤维蛋白的组分(a)；
包括凝血酶的组分(b)；
包括至少一种增塑剂的组分(c)；和
包括具有约200微米或更低的直径的粒子的组分(d)。
根据本发明的一个实施例，可注射型软组织空隙填充剂组合物从上述的多组分体系制备，例如通过将所述多组分体系的各组分混合在一起和/或将所述组分进行匀化处理。可注射型软组织空隙填充剂组合物的制备可在任何适当的温度下进行，所述温度为约18℃到约37℃，例如，25℃。
另外，所述的可注射型软组织空隙填充剂组合物还可包括任何其它的适于扩增、加强、支撑、修复、重建、痊愈、闭锁或充填空隙的组分，诸如生长因子，化疗剂或药理学试剂，生物活性剂，硬化化合物和/或粘合剂化合物和矿物质添加剂。这些化合物和/或试剂可化学连接于基质，被吸附到粒子组分例如含钙盐的粒子上，被截留在纤维蛋白基质中或作为游离的分子/药物粒子例如粉末被包含。
本发明的可注射型软组织空隙填充剂组合物的组分(b)-(d)与上述表征的多组分体系的定义相同。
术语“纤维蛋白”不仅是指完全凝固的纤维蛋白原，而且还包括在使用凝血酶从纤维蛋白原形成纤维蛋白期间可形成的纤维蛋白和纤维蛋白原的混合物，因此，可包括以任何比率存在的纤维蛋白原/纤维蛋白和可想得到的任何程度的胶凝和/或凝固，只要其对被注射到空隙内的最终组合物没有不利影响即可。本发明的可注射型空隙填充剂组合物的纤维蛋白组分(a)还包括仅具有少量纤维蛋白原的纤维蛋白或在所述纤维蛋白中没有任何纤维蛋白原残留。另外，术语“纤维蛋白”还包括上述的组分(a)的任何的发生部分或完全胶凝或凝固的形式。
根据本发明的一个实施例，在上述的可注射型空隙填充剂组合物的所述纤维蛋白组分(a)中的纤维蛋白的量在最终凝固的组合物中为约5到约100mg/ml，诸如约15到65mg/ml，或约30到65mg/ml。
根据另一个实施方案，在本发明的可注射型空隙填充剂组合物的所述纤维蛋白组分(a)中的纤维蛋白的量在最终凝固的组合物中为约5到约100mg/ml，在组分(b)中的凝血酶的量在最终凝固的组合物中为至少约1IU/ml，在组分(c)中分增塑剂的量在最终凝固的组合物中为约10到约80％w/v，和在组分(d)中的粒子的量相对于最终凝固的组合物为约1到约50％w/w。
根据本发明，上述的可注射型空隙填充剂组合物为胶凝或凝固状态，并具有适于注射进软组织空隙内的粘度。
本文使用的术语“胶凝”是指当与初始状态相比时粘度有所升高的任何状态。这可以在例如从纤维蛋白原形成纤维蛋白期间被观察到，或者在至少一个固相在至少一个液相中的细分散体系诸如胶体中被观察到。另外，术语“胶凝”包括本领域已知的所有的胶凝状态。
术语“凝固”是指例如包含包括纤维蛋白的凝胶并包括本领域已知的任何种类的凝聚状态。
提供了以下的实施例作为材料如何被用于闭锁、扩增或充填软组织内腔和空隙的指导，其不被认为以任何方式限制本发明。
材料：
纤维蛋白封闭溶 用抑肽酶溶液进行重构的冷冻干燥纤维蛋白原粉末，得到91mg/ml
液 的总的可凝固蛋白质浓度。
碘克沙醇 5-[乙酰基-[3-[乙酰基-[3，5-二(2，3-二羟基丙基氨甲酰基)-2，4，6-三碘-
苯基]-氨基]-2-羟基-丙基]-氨基]-N，N′-二(2，3-二羟基丙基)-2，4，6-三
碘-苯-1，3-二甲酰胺
碘海醇 5-(乙酰基-(2，3-二羟基-丙基)-氨基)-N，N′-二(2，3-二羟基丙基)-2，4，6-
三碘-苯-1，3-二甲酰胺
荧光素 2-(6-羟基-3-氧代-氧杂蒽-9-基)苯甲酸
粒子 磷酸三钙粒子(TCP)，35μm，球形(Plasma Biotal，Derby UK)
来自磨细的MBCP 60％HA/40％ TCP的羟基磷灰石(HA)粒子，
Biomatlante，France。
磷酸盐缓冲液 用磷酸盐缓冲的NaCl(0.85％盐水)，被缓冲到pH 7.2
凝血酶 用5毫升凝血酶缓冲液进行重构的500IU/ml冷冻干燥的凝血酶粉
末，达到500IU/ml的浓度。
凝血酶缓冲液 40mM CaCl2，在H2O中
实施例I：瘘治疗用空隙填充剂组合物的制备(包括纤维蛋白、增塑剂和候选药物)
在本实施例中，所述组合物被计划用于注射进其中需要充填和局部药物递送的软组织空隙内。这种需要的一个实例是在其中空隙可用抗生素释放材料填充的瘘的治疗中。纤维蛋白起生物基质的作用，其允许成纤维细胞附着/渗透和发生自然痊愈(Brown等人，1993)。另外，使用造影剂作为增塑剂允许目视观察和控制施用。
在本实施例中，术语抗生素意在描述可产生所需治疗效果的任何抗微生物剂。其包括选自氨基糖苷类、碳头孢烯类、碳青霉烯类、头孢菌素类、糖肽类、大环内酯类、单环内酰胺类、青霉素类、多肽类、磺酰胺类和四环素类(可溶于水或有机溶剂)的“典型”抗生素，和新被鉴定的抗微生物剂诸如粒状/胶性银或铋硫醇。
术语瘘在本环境下是指选自(但不限于)肛瘘，肛门-直肠瘘，动静脉瘘，胃瘘，肠瘘，阴道瘘和支气管-食道瘘的无分支的单纯瘘。组合物在混合后的“流动性”历时一定时段，从而可允许更好地填充更复杂的瘘(当治疗更复杂的瘘时)并增加成功率(与普通的纤维蛋白相比)。然而，需要进行进一步的调查以对此进行说明。
方法：
将组合物作为液体注射进空隙(模子)中。在1小时后，将凝固的组合物转移到磷酸盐缓冲盐水溶液中并测量荧光素释放。
在凝血酶稀释缓冲液(40mM CaCl2，在重蒸馏水中)中，制备了含有甘油的凝固物：40％增塑剂(甘油)和10IU/ml的凝血酶溶液。然后将溶液匀化。将该溶液离心以除去气泡并过滤通过0.22微米过滤器进行灭菌处理。将纤维蛋白原与1∶1比率的凝血酶/增塑剂混合(因此，在胶凝的凝固物中增塑剂浓度减少)。
为此，将1ml的甘油/凝血酶溶液转移到5ml注射器中。将1ml的纤维蛋白原(91mg/ml)转移到单独的5ml注射器中。将粒子(干粉荧光素0.05g)称重并置于另一个5ml注射器中。
将包含粒子的注射器和包含凝血酶的注射器通过Luer连接器连接并通过使内容物在注射器之间进行彻底地转移来将凝血酶/甘油和粒子进行匀化。
将包含凝血酶/甘油/粒子的注射器与包含纤维蛋白原的注射器通过Luer连接器连接并将内容物进行匀化。
材料仍然保持液体历时约1-5分钟。在此期间可以将其注射进缺损中，或者在几分钟后可以将其作为预形成的凝胶进行递送。
在凝血酶稀释缓冲液(40mM CaCl2，在重蒸馏水中)中，制备了含有碘克沙醇的凝固物：60％增塑剂(碘克沙醇)和75IU/ml的凝血酶溶液。然后将溶液匀化。将溶液离心以除去气泡并过滤通过0.22微米过滤器进行灭菌处理。将纤维蛋白原与1∶1比率的凝血酶/增塑剂混合(因此，在胶凝的凝固物中增塑剂浓度被减少到30％)。
为此，将2ml的凝血酶/造影剂溶液转移到5ml注射器中。将1ml的纤维蛋白原(91mg/ml)转移到单独的5ml注射器中。将粒子(干粉荧光素0.05g)称重并置于另一个5ml注射器中。
将包含粒子的注射器和包含凝血酶的注射器通过Luer连接器连接并通过使内容物在注射器之间进行彻底地转移来将凝血酶/CA和粒子进行匀化。
将包含凝血酶/CA/粒子的注射器与包含纤维蛋白原的注射器通过Luer连接器连接并将内容物进行匀化处理。材料仍然保持液体历时约1分钟。在此期间可以将其注射进空隙中，或者在几分钟后可以将其作为预形成的凝胶进行递送。
荧光素从不含增塑剂的纤维蛋白凝固物的释放和从含碘克沙醇或甘油的纤维蛋白凝固物的释放可以参见图1。增塑剂的存在，除了改变材料的性质之外，还改变了候选药物的释放，允许更快或更延长的/持续的释放，从而允许调节抗微生物活性。
实施例II：尿压力性尿失禁治疗用的组合物，其作为填充剂包含纤维蛋白、造影剂和磷酸钙
在1994年，注射胶原蛋白以隆起尿道括约肌得到了FDA的批准，用于治疗女性的与固有括约肌缺陷(ISD)有关的压力性尿失禁和男性的前列腺切除术后尿失禁。牛胶原蛋白仍然是金标准，尽管存在诸如变态反应和由于生物降解导致失败的问题(Achtari等人，2006)。尽管文献确实暗示了胶原蛋白的失败更多地与胶原蛋白沉积物变平有关，而与胶原蛋白的再吸收无关(Barth等人，2005)。在许多正被研究的新的填充剂在寻求使用不可降解的材料时，它们也设法使用粘性和弹性更接近天然组织的粘性和弹性的那些材料。
在本实施例中的纤维蛋白/造影剂/羟基磷灰石组合物可代替胶原蛋白被使用。所述组合物与单独的纤维蛋白相比是更好地适合于该应用的柔弹性材料，其以类似于胶原蛋白的方式发生塌陷。
上述的纤维蛋白/造影剂/羟基磷灰石组合物还可包含任何其它的适于促进天然组织修复的组分。这种分子的实例是BMP-2。对于优选的生长因子/生物活性剂的更广泛的描述在已转让的专利US 5752974中有详细描述，该文献作为参考被并入本文。这些化合物和/或试剂可化学连接于基质，被吸附到粒子组分例如含钙盐的粒子上，被截留在纤维蛋白基质中或作为游离的分子/药物粒子例如粉末被包含。
方法：
在凝血酶稀释缓冲液(40mM CaCl2，在重蒸馏水中)中，制备了80％或60％的增塑剂(造影剂碘克沙醇或碘海醇)和75IU/ml凝血酶溶液。然后将该溶液匀化。将溶液离心以除去气泡并过滤通过0.22微米过滤器进行灭菌。将纤维蛋白原与1∶1比率的凝血酶/造影剂(CA)混合(从而在胶凝的凝固物中的增塑剂浓度被减少到40％或30％)。
为此，将2ml的凝血酶/造影剂溶液转移到5ml注射器中。将2ml的纤维蛋白原(91mg/ml)转移到单独的5ml注射器中。将磷酸钙粒子(约35微米)以作为最终凝固物体积的重量百分数(w/v)被并入。将它们称重并置于另一个5ml的注射器中。
将包含粒子的注射器和包含凝血酶的注射器通过Luer连接器连接并通过使内容物在注射器之间进行彻底地转移来将凝血酶/CA和粒子进行匀化。将包含凝血酶/CA/粒子的注射器与包含纤维蛋白原的注射器通过Luer连接器连接并将内容物进行匀化处理。材料仍然保持液体历时约1分钟。在此期间可以将其注射进缺损中，或者在几分钟后可以将其作为预形成的凝胶进行递送。
附图说明了为什么本发明的组合物代表了胶原蛋白的良好代用品。材料的弹性和调节具有不同浓度的造影剂和TCP的各自的凝固物的粘性的能力可参见图2。包含作为增塑剂的碘克沙醇和增加量的钙盐的组合物的流变学数据可参见图3。
该组合物还可被认为在治疗胃食管反流病(GERD)中用作食管下端括约肌的填充剂。尽管用这种方法治疗GERD已被发现既是可行的又是安全的(Zhi等人，2005)，但是可能存在X-射线遮光剂，以允许进行所述过程的实时监督并且防止注射穿过食管壁。诸如此类的并发症可以在过程期间不被发觉并且可导致有害作用。
实施例III：组织闭锁
闭锁装置通常是可膨胀材料。一些增塑剂赋予本发明组合物以这一性质。这主要是由于大的增塑剂分子被截留在组合物中并且不能迅速地从基质扩散。最后结果是材料吸水和溶胀以平衡渗透压。
骨塞是本领域公知的(专利US6607535，US 5861043，其作为参考被并入本文)并且被用来约束或预防骨水泥在髋关节置换术期间流入髓管内。在美国专利6605294中，引入了迅速水合的水凝胶塞以闭锁股管。这些水凝胶骨塞是非荷重的，但是被预期比担当植入物的一部分的不可降解的聚乙烯塞具有显著的益处。包含碘克沙醇和磷酸三钙的可注射纤维蛋白组合物还可用作骨塞。实施例2中的组合物是迅速水合的基质，其溶胀接触流体，确保在本发明的组合物和股管之间的紧密配合。使用本发明组合物的另外的优点是其可以最小的侵入性进行递送并且该递送可以由于X-射线遮光剂的存在得以被监控。
可逆的灭菌：可注射型纤维蛋白组合物可以通过导管被递送，用于预防妊娠，如已转让的专利US 5752974中所述。通过该方法，将该组合物进行注射，使得输卵管被填充/阻塞。组合物的快速水合和溶胀防止卵子和/或精子穿过或通过组合物。纤维蛋白则起生物基质的作用，其允许自然痊愈和纤维性瘢痕组织形成(Brown等人，1993)。生物活性分子(诸如表皮生长因子(EGF)，转化生长因子-α(TGF-[α])，转化生长因子-β(TGF-[β])，人内皮细胞生长因子(ECGF)，粒细胞巨噬细胞集落刺激因子(GM-CSF)，骨形态发生蛋白(BMP)，神经生长因子(NGF)，血管内皮细胞生长因子(VEGF)，成纤维细胞生长因子(FGF)，胰岛素样生长因子(IGF)，和/或血小板衍生生长因子(PDGF))还可被并入到基质中，以进一步支撑/促进组织形成。可以这种方式进行递送的治疗剂的完整描述列于列于已转让的专利WO 2005086697中，该文献作为参考被并入本文。该过程可通过切除被阻塞部分和进行管的重接被逆转。
牙齿闭锁：本发明的组合物还可用于在牙科手术后对牙龈线进行闭锁和密封。允许该组合物进行水合，溶胀和闭锁，提供了对抗口腔流体/食物材料和细菌的障碍物。可吸收的组合物将被降解并被天然组织替代。
血管闭锁：可用于在外科手术期间或在病理生理学治疗期间限制或阻断血管内的血流。这种病理生理学的实例可以是限制血液流动到肿瘤或动脉瘤。递送治疗剂的能力连同组合物一起可进一步增加组合物的适合性。在动脉瘤的情况中，限制了流到变弱血管的血流，并且被并入的血管活性分子允许进行变弱血管周围的血管的重建。本发明组合物的优点是溶胀以确保在组合物和血管之间的良好配合。纤维蛋白增塑剂的改变可允许精细控制吸水、溶胀、降解和治疗剂的释放。
实施例IV：局部药物递送
使用组合物作为局部药物递送媒介物，用于治疗患病状态诸如心血管疾病、变性疾病、出血性胃溃疡或治疗肿瘤。该组合物可作为液体或预形成的凝胶形式被注射进受影响的组织内/附近或远端。材料的位置特异性递送将避免对高系统剂量的要求，即可实现在组织中的有效剂量水平。因此，降低了毒性的可能性。除了释放治疗剂之外，组合物还可能在机械方面起作用。例如，在出血性消化性溃疡中，本发明的组合物可被注射到溃疡附近，其中该组合物在机械方面起作用以约束血液流到所述区域。这一效果可通过局部递送血管收缩剂肾上腺素得以增强。类似地，可采用该制剂来在变性的椎间盘修复中提供机械支持，并且同时递送抗炎药或甾族药剂。
细胞毒素和/或抗体，镇痛药，抗凝血药，抗炎化合物，抗微生物组合物，细胞因子，药物，生长因子，干扰素，激素，脂类，去矿化骨蛋白或骨形态发生蛋白，软骨诱导因子，低聚核苷酸，聚合物，多糖，多肽，蛋白酶抑制剂，血管收缩剂，血管扩张剂，维生素和矿物质(专利RE39192)，本发明的增强的材料性质和调节释放速率的能力(图1)使得其更适合用作局部药物递送媒介物。适当的治疗剂类别包括但不限于血管活性剂，神经活性剂，激素，生长因子，细胞因子，麻醉药和肌肉松弛药，甾族化合物，抗生素，抗凝血药，抗炎药，抗增殖药，抗溃疡药，抗病毒药，免疫调节剂，胞毒剂，预防剂，抗原和抗体。可以这种方式进行递送的治疗剂的完整描述列于已转让的专利WO 2005086697和US专利6605294，其作为参考全文被并入本文。
Claims (25)
1.组合物用于制备软组织内腔或空隙填充剂的应用，所述组合物包含：
包括纤维蛋白原的组分(a)；
包括凝血酶、用于组分(a)的胶凝诱导剂或凝固诱导剂的组分(b)；
包括至少一种增塑剂的组分(c)；和
包括平均直径为0.01-200微米的微粒子的组分(d)，
其中微粒子的量为总组合物的10-45%w/w。
2.权利要求1的应用，其中微粒子是含钙的微粒子。
3.权利要求1或2的应用，其中增塑剂包含选自X-射线造影剂、CT造影剂和MRI造影剂的造影剂。
4.权利要求1的应用，还包括选自生长因子，化疗剂，药理学试剂和生物活性剂的另外的组分。
5.权利要求1的应用，还包括选自以下的可溶于水和可溶于有机溶剂的抗生素：氨基糖苷类，碳头孢烯类，碳青霉烯类，头孢菌素类，糖肽类，大环内酯类，单环内酰胺类，青霉素类，多肽类，磺酰胺类和四环素类，和粒状/胶性银或铋硫醇；选自以下的生长因子和生物活性剂：表皮生长因子(EGF)，转化生长因子-α(TGF-[α])，转化生长因子-β(TGF-[β])，人内皮细胞生长因子(ECGF)，粒细胞巨噬细胞集落刺激因子(GM-CSF)，骨形态发生蛋白(BMP)，神经生长因子(NGF)，血管内皮细胞生长因子(VEGF)，成纤维细胞生长因子(FGF)，胰岛素样生长因子(IGF)，和/或血小板衍生生长因子(PDGF)；选自以下的治疗剂：细胞毒素，抗体，镇痛药，抗凝血药，抗炎化合物，抗微生物组合物，细胞因子，干扰素，激素，脂类，去矿化骨蛋白，软骨诱导因子，低聚核苷酸，聚合物，蛋白酶抑制剂，血管收缩剂，血管扩张剂，维生素和矿物质，血管活性剂，神经活性剂，麻醉药，肌肉松弛药，甾族化合物，抗凝血药，抗炎药，抗增殖药，抗溃疡药，抗病毒药，免疫调节剂，胞毒剂，预防剂，抗原和抗体。
6.权利要求5的应用，其中所述治疗剂是多糖或多肽。
7.权利要求1的应用，其中另外的组分可被包含在纤维蛋白原、凝血酶或用于组分(a)的胶凝诱导剂或凝固诱导剂、增塑剂或微粒子中。
8.权利要求1的应用，其中纤维蛋白原组分包含一种或多种选自以下的蛋白：粘连蛋白和血浆由来蛋白。
9.权利要求1的应用，其中纤维蛋白原组分包含至少一种选自以下的蛋白：因子XIII，蛋白酶，蛋白酶抑制剂或其混合物。
10.权利要求1或2的应用，其中组分(b)包含微粒子。
11.权利要求10的应用，其中微粒子是磷酸钙微粒子。
12.权利要求3的应用，其中造影剂是含碘的有机化合物。
13.权利要求12的应用，其中有机化合物包含稀土元素。
14.权利要求13的应用，其中有机化合物包含钆。
15.权利要求3的应用，其中造影剂选自：泛影酸钠，碘的可，碘克沙醇，碘拉醇，碘骨胺，碘海醇，碘美普尔，碘帕醇，碘普胺，碘曲伦，碘佛醇，碘克沙酸和甲泛葡胺，及其混合物。
16.权利要求1的应用，其中在组合物中增塑剂的量为最终制剂的10-80%w/v。
17.权利要求16的应用，其中在组合物中增塑剂的量为最终制剂的15-60%w/v。
18.权利要求17的应用，其中在组合物中增塑剂的量为最终制剂的20-40%w/v。
19.权利要求2的应用，其中含钙的粒子选自：磷酸三钙，磷酸钙，羟基磷灰石，碳酸钙，硫酸钙及其混合物。
20.权利要求2的应用，其中含钙的粒子选自：α磷酸三钙、β磷酸三钙和磷酸钙的多晶型物。
21.权利要求1或2的应用，其中微粒子具有0.01微米-100微米的平均直径。
22.权利要求21的应用，其中微粒子具有0.01微米-50微米的平均直径。
23.权利要求1或2的应用，其中微粒子的量为总组合物的30-40%w/w。
24.权利要求1的应用，其中在组合物中纤维蛋白原的量为10-200mg/ml。
25.权利要求1的应用，其中在组合物中纤维蛋白原的量为25mg/ml-50mg/ml。
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| PT2136852E (pt) | 2012-02-08 |
| BRPI0809383B1 (pt) | 2018-10-30 |
| ES2381448T3 (es) | 2012-05-28 |
| BRPI0809383B8 (pt) | 2021-06-22 |
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