CN106046396B - 可再水化的多糖颗粒和海绵体 - Google Patents
可再水化的多糖颗粒和海绵体 Download PDFInfo
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- CN106046396B CN106046396B CN201610369681.8A CN201610369681A CN106046396B CN 106046396 B CN106046396 B CN 106046396B CN 201610369681 A CN201610369681 A CN 201610369681A CN 106046396 B CN106046396 B CN 106046396B
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Abstract
组织和其他身体结构可用水化组合物保护，该水化组合物是由自由流动、基本无胶原质的可再水化多糖颗粒和可再水化多糖海绵体形成。在不结块的情况下颗粒的再水化可通过在生物相容水易混溶极性分散剂如乙醇中分散颗粒并将分散体与足够的颗粒水性溶剂结合从而将其转化为粘性水凝胶而进行。该水化组合物可有助于将受损的、发炎的或手术修复的表面恢复成正常状态，例如，通过一种或多种愈合机制诸如炎性应答的调节、吞噬作用、粘膜重塑、纤毛再生或其他正常功能的完全或部分恢复。
Description
本发明专利申请是国际申请号为PCT/US2009/041589，国际申请日为2009年4月23日，进入中国国家阶段的申请号为200980119930.6，名称为“可再水化的多糖颗粒和海绵体”的发明专利申请的分案申请。
发明领域
本发明涉及多糖和用于身体的材料。
背景
某些多糖材料已经用于手术修复或药物递送。关于这些材料的文献包括美国专利号5,820,608(Luzio等)、5,993,846(Friedman等)、6,123,965(Jacob等)、6,342,251B1(Illum等)、6,706,690B2(Reich 等)、6,835,389B1(Dohi等)和7,195,675B2(Okazaki等)；美国专利申请公开号US 2005/0208122A1(Al len等)；公布的PCT申请号WO 93/21906 A(Brown University Research Foundation)和Weng等，Rheological Characterizationof in Situ Crosslinkable Hydrogels Formulated from Oxidized Dextran and N-Carboxyethyl Chitosan(由氧化葡聚糖和N-羧乙基壳聚糖配制的原位可交联水凝胶的流变性表征),Biomacromolecules,8,1109-1115(2007)。多糖凝胶可以用作耳、鼻和咽喉(ENT)手术中的组织封闭剂。
发明概述
为了避免在保存期间过度降解，需要将多糖凝胶材料以干燥形式(例如，作为粉末或海绵体)包装，并且仅在使用之前再水化材料。再水化有时存在困难。一些再水化材料提供具有物理性能差的凝胶或海绵体。在一些情况下，再水化凝胶的物理性能可以经原位交联来改善，但可能增加这样的风险——过度交联的凝胶会不经意地以大块固体的形式移位(例如，吸入)至肺或其他地方。一些外部交联剂可损害组织，或可导致非常长的或难以控制的停留时间。
在一个方面，本发明提供了一种组合物，其包含基本上不含胶原的脱水热交联多糖的自由流动可再水化颗粒。在一个示例性实施方式中，所述颗粒包含纤维素例如羧甲基纤维素(CMC)，并且可以提供具有一种或多种所需性质的再水化凝胶，所述性质包括迅速、无团块的再水化；当被喷雾或注射时的触变行为；一旦固定就位后的高粘度和粘性凝胶性质；可控的生物降解性质，对过早生物降解的抵抗力和分解或移位而不产生大块固体的能力。在另一个示例性实施方式中，颗粒包括CMC和壳聚糖的混合物，并可提供具有一种或多种如公开的CMC再水化凝胶所提供的期望性质，以及一种或多种另外期望性质的再水化凝胶，另外期望性质包括固有的抗微生物(例如，杀菌)行为；止血能力或促进伤口愈合。本发明的再水化凝胶可以有助于将受损的、发炎的或手术修复的表面(例如，粘膜组织表面)恢复成正常状态，例如，通过一种或多种愈合机制诸如炎性应答的调节、吞噬作用、粘膜重塑、纤毛再生(reciliation)或其他正常功能的完全或部分恢复。
在另一个方面，本发明提供了一种可植入物品，其包含可再水化的多孔海绵体，所述多孔海绵体包含基本上不含胶原的脱水热交联多糖。所述海绵体可以被包装且是压缩形式的固体，可以被修剪成所需尺寸或形状用于在治疗部位植入，并且可以在植入之前或之后被再水化。本发明的海绵体的示例性实施方式包括由CMC制成的海绵体和由CMC以及壳聚糖的混合物制成的海绵体。
在另一个方面，本发明提供了一种制备形成多糖凝胶的组合物的方法，该方法包括提供基本上不含胶原的多糖溶液，将所述溶液干燥以形成粉末，并且将所述粉末脱水热交联以形成自由流动的颗粒，所述颗粒当被再水化时将提供多糖凝胶。本发明方法的示例性实施方式包括从CMC和从CMC与壳聚糖的混合物制备粉末的方法。
在另一个方面，本发明提供了一种制备可植入物品的方法，该方法包括提供基本上不含胶原的多糖溶液，将所述溶液冻干以形成干燥的多孔海绵体，将所述海绵体脱水热交联，并且任选地将所述海绵体压缩，从而形成可植入物品，所述可植入物品当被再水化时将形成多糖海绵体。此本发明方法的示例性实施方式包括从CMC和从CMC与壳聚糖的混合物制备海绵体的方法。
在另一个方面，本发明提供了一种治疗组织和其他身体结构的方法。该方法包括在其上施用包含再水化的基本上不含胶原的脱水热交联多糖的凝胶或海绵体。
再水化可以表现出其他困难。一些干粉物质当与水合并时易于结块。团块可能难以分散并且可堵塞注射器、套管或喷嘴。还在另一个方面，本发明提供了一种将干粉组合物转变为凝胶的方法，所述方法包括将自由流动的多糖颗粒分散在生物相容的水易混溶的极性分散剂中，以及将所得到的分散体与充足的所述颗粒的水性溶剂合并从而将它们转变为粘性水凝胶。所述多糖颗粒可以是交联的或未交联的，并且如果是交联的，则交联可以是脱水热交联或使用单独的交联剂进行的交联。所述多糖颗粒可以是基本上不含胶原的。所述多糖颗粒可以基本上是单一的多糖，或两种或更多种多糖的共混物。可以形成粘性水凝胶而没有可见的未水化多糖的团块。本发明的方法可以紧接着进行一种治疗方法，所述方法包括将所述粘性水凝胶层注射或喷雾在组织(例如，粘膜组织)或其他身体结构上的步骤。
附图简要说明
图1是显示本发明的治疗方法的示意性视图；
图2是可以在本发明的治疗方法中使用的分配工具的立体图；
图3是本发明的海绵体的立体图；和
图4是处于压缩状态的本发明海绵体的立体图。
图5是显示酸滴定三种壳聚糖悬浮液的曲线图。
图6和图7是显示在90℃和120℃时脱水热交联的壳聚糖凝胶的粘结结果的图。
在附图的各张图中类似的附图标记表示类似的元件。附图中的元件没有按比例绘制。
详述
下面的详述描述了某些实施方式，并且不能认为具有限制性的意义。本文中的所有重量、量和比率为按重量计，除非另外具体地注明。下面显示的术语具有下列的含义：
术语“粘附性”是指将身体结构或假体材料与组织粘在一起，指将组织与组织粘在一起使其紧密地接触持续延长的时间，或指形成将身体结构、假体材料或组织跨越正常开放的空间彼此连接的组织。
术语“抗微生物”是指在金黄色葡萄球菌、铜绿假单孢菌、肺炎链球菌、流感嗜血杆菌或粘膜炎莫拉菌(Moraxella catarrhalis)的一种或多种的群体中导致大于90％的数值减少(即，至少1个对数数量级的减少)的能力。
术语“附着”和“粘附”当用来提及细菌生物膜和表面时是指该生物膜建立在和至少部分地涂敷在或覆盖在该表面上，并且具有一些对从该表面上去除的抵抗力。因为此关系的性质是复杂的和理解甚少，因此这种使用并不意在有特殊的附着或粘附机制。
术语“细菌生物膜”是指附着在表面上的细菌的群落，在该群体中的生物体包含在由该细菌产生的细胞外多糖(EPS)基质中。
术语“生物相容的”当用来提及物质时是指该物质表现出对身体的不显著的有害或不良作用。
术语“生物可降解的”当用来提及物质时是指该物质在体内将降解或蚀解以形成小的化学或物理种类。此类降解过程可以是酶促的、化学的或物理的。
术语“生物可吸收的”当用来提及物质时是指该物质能够被身体吸收。
术语“粘性的”当用来提及液体或凝胶时是指当置于水平面上时该液体或凝胶将趋于(但不一定在所有情况下)粘住其自身并且形成单一团块。
术语“粉碎的”当用来提及颗粒物质时是指颗粒已经通过切割、磨碎、粉碎、捣碎或采用外部施加力量的其他颗粒破碎工艺被破碎并且尺寸减小。
术语“共形的”当用来提及施用于组织或其他身体结构的组合物时是指该组合物可以在已经施用该组合物的区域上形成基本上连续的层。
术语“分离”、“去除”和“破坏”当用于提及附着或粘附在表面上的细菌生物膜时是指至少显著量的最初存在于该表面上的生物膜不再附着或粘附于该表面。这种使用不意在有特殊的分离、去除或破坏机制。
术语“流体”当用来提及物质时是指该物质是其损耗模量(G″)大于其储能模量(G′)且损耗角正切值(tanδ)大于1的液体。
术语“凝胶”当用来提及物质时是指该物质是可变形的(即，不是固体)，G″小于G′且tanδ小于1。
术语“凝胶化”当用来提及凝胶层的形成时是指G″等于G′且tanδ等于1的时刻。
术语“止血器”是指停止血流的装置或材料。
术语“水凝胶”当用来提及凝胶时是指该凝胶是亲水的且含有水。
术语“水化的”当用来提及装置或物质时是指该装置或物质含有均匀分布的化学键合的水。“完全水化的”装置或物质不能吸收额外的水化作用的水。“部分水化的”装置或物质能够吸收额外的水化作用的水。
术语“内耳”是指半规管和耳蜗。
术语“中耳”是指由鼓膜、内部结构诸如听骨链、周围衬里和边缘结构诸如乳突限定的区域。
术语“粘膜附着剂”当用来提及装置或物质时是指该装置或物质将粘附于粘液被覆上皮。
术语“鼻腔或窦腔”是指在鼻和窦内限定正常充气通道和小室的各种组织，包括但不限于鼻孔、鼻甲(nasal concha)或鼻甲骨(turbinate)、额窦、筛窦、蝶窦和上颌窦、窦口(sinus ostia)和鼻咽(nasopharnyx)。
术语“多糖”包括多糖的衍生物和改性多糖，以及各多糖种类和改性的各多糖种类的衍生物。例如，术语“羧甲基纤维素”包括羧甲基纤维素衍生物和改性的羧甲基纤维素，术语“壳聚糖”包括壳聚糖衍生物和改性的壳聚糖，术语“淀粉”包括淀粉衍生物和改性淀粉。
术语“保护性的”当用来提及在组织或其他身体结构上的组合物层时是指该层有助于使损伤的、发炎的或手术修复的组织表面恢复至正常状态，例如，通过一种或多种愈合机制诸如炎性应答的调节、吞噬作用、粘膜重塑、纤毛再生或其他正常功能的完全或部分恢复。
术语“停留时间”当用来提及在组织或其他身体结构上的保护性凝胶层时是指在肉眼观察下凝胶层或其一部分在体内仍然就位所持续的时间期限。
术语“溶剂化”是指形成含有溶剂或其他载体的溶液或分散体，溶质溶解或悬浮在所述溶剂或载体内。
术语“基本上不含胶原的”是指含有足够低量的胶原使得不会造成传播或感染牛海绵状脑病(BSE)或变异性克雅氏病(variant Creutzfeldt-Jakob disease)(vCJD)。
术语“薄的”当用来提及在组织或其他身体结构上的保护层时是指具有小于约2毫米的平均厚度。
参照图1，本发明的治疗方法可以在患者的鼻腔或窦腔100中进行，窦腔包括上颌窦110a、110b和额窦112a、112b,它们都可以通过鼻孔114a、114b进入。应当注意，患者的外部特征，包括鼻孔114a、114b以虚线显示。当患者患有例如慢性鼻炎及鼻窦炎时，与上颌窦110a相关的一个或多个治疗部位诸如治疗部位116可以经医疗或如果需要经手术治疗。治疗部位116包括上颌窦110a的纤毛上皮并且可以包括栖息在相关的生物膜中的细菌的相关层(在图1中未显示)。治疗部位不必限于自然组织并且可以包括人工结构(在图1中未显示)诸如窦填塞材料或支架，其也可以至少部分地用细菌生物膜层覆盖。如果存在，生物膜可以使用溶剂化系统(例如美国专利申请公开号US 2007/0264310 A1中所述的溶剂化系统)去除，该系统可以使用带有含有灌洗管(隐藏在图1中)的活节式(articulatable)输送管122的导引器120来施用至治疗部位116，通过所述输送管122，溶剂化系统可以流动至导引器120的远端处的喷嘴124并且因此流动至治疗部位。溶剂化系统和生物膜的残留物可以从治疗部位经吸引管(隐藏在图1中)被去除。本发明的可再水化凝胶组合物可以同样地使用导引器120中的相同或不同的灌洗管在治疗部位处施用。本领域技术人员要理解，该可再水化凝胶(和如果使用，溶剂化系统)可以使用其他方法或装置施用至治疗部位。示例性的其他方法包括动力喷雾或其他喷涂法、灌洗、喷雾(misting)、涂抹(mopping)、芯吸(wicking)、滴落(dripping)和环钻术，并且示例性的其他装置包括喷雾嘴(例如，单个元件或多个元件的喷雾嘴)和注射器(例如，单管或多管玻璃或塑料注射器和冲洗球)。治疗方法还可以在其他身体部分中进行。治疗方法特别地用于非血管应用，包括治疗耳、鼻或咽喉中或附近的组织(例如粘膜组织)或结构和肢体或脊柱中的开口、隐窝、通道或关节。
图2显示示例性的工具200，其可以用于本发明的治疗方法中。工具200包括手柄202和导引器222，其远端224(总体参考)包括喷嘴、灌洗和吸引管(在图2中未单独编号)。工具200可以任选地进一步包括第一致动器组件226(总体参考)和第二致动器组件228(总体参考)。第一致动器组件226中的导轮230可以由用户操作以实现导引器222的弯曲，并且第二致动器组件228中的导轮232可以由用户操作以实现从导引器222的远端224喷出的液体相对于导引器222的移动或旋转。手柄202通常用作工具200的各种其他元件的外壳并且作为导引器222的支撑。手柄202可以具有手枪柄样的形状，限定把手部234和机头236。把手部234的大小和形状制成为适于用户的手抓握，而机头236则适于与导引器222连接。扳机238和相关的传感器和阀门(图2中未显示)可以用来控制本发明的可再水化凝胶(和如果使用，公开的溶剂化系统)通过灌洗管240和然后通过远端224的喷嘴并到所需的治疗部位上的流动。扳机238可以设置以多向运动范围并且与一个或多个附加的传感器和阀门(图2中未显示)相关联以控制溶剂化系统、生物膜残留物和其他碎片从治疗部位通过远端224的吸引管去除并且从此进入至吸引管242中。扳机238还可以用来控制本发明的可再水化凝胶通过灌洗管240中的独立腔的流动并且从此通过远端224的喷嘴流动至所需治疗部位上。
施用的可再水化凝胶可以填充治疗部位(例如，鼻腔或窦腔，或一部分肢体或脊柱中的开口、隐窝、通道或关节)，在此情况下，本发明的凝胶层可以是非常厚的，并且不接触空气或其他附近的气体，并且在整个层上具有不同的厚度。本发明的可再水化凝胶还可以作为薄膜或其他共形涂层施用，在此情况下本发明的凝胶层可以是相对薄的，并且暴露于空气或其他附近的气体，并且在整个层上具有基本上均一的厚度。可再水化凝胶组合物提供保护层，该保护层可以是粘性的、弹性的或粘弹性的。该保护层理想地粘附于治疗部位处的粘膜或其他天然组织(例如，软骨或骨)并且抵抗分离或其他破坏直至凝胶层发生天然的降解或吸收，例如，在1天至几天(例如，2、3、或4天)、几周或几个月的体内停留时间后。同时细菌再建群(recolonization)或再感染可以显著地减少或避免，并且可以发生改善的愈合和纤毛再生(reciliation)。保护性凝胶层可以提供多种治疗优势，包括但不限于抵抗细菌粘附、抗感染特性、局部免疫调节、组织保护、减少或消除疼痛或出血、减少炎症、优化纤毛再生环境、减少与重要解剖结构的粘附等等。这些优势可以由多种机制引起，包括a)杀死细菌，b)抑制细菌建群，c)抑制细菌与组织的粘附，d)减少组织发病或脓肿形成，e)减少或防止疾病复发(例如，特别是减少与细菌毒素和EPS相关的慢性炎症),f)在愈合期间涂敷和保护组织，诸如通过保持湿润的伤口，从而促进血小板聚集，或通过闭合干性伤口而不会形成过度粗糙的结构，g)止血，h)优化粘膜纤毛再生的环境，i)加速纤毛的生长或再生和j)将一种或多种治疗剂递送至治疗部位。理想地保护性凝胶层将粘附于一部分粘膜，而使未粘附部分中的纤毛游离以经历自然的有节律的纤毛运动(即，纤毛摆动)，如果需要也将抗微生物剂或其他的治疗剂递送至治疗部位，并且理想地将阻碍或阻止细菌粘附于治疗部位。
图3显示了处于非压缩状态的本发明的海绵体的实例30，且图4显示处于压缩状态的本发明的海绵体的实例40。在再水化前的非压缩形式中，海绵体30提供基本上无水的多孔硫醇化多糖基质。压缩的海绵体诸如海绵体40可以施用多种技术在脱水热交联之前或之后形成，所述技术包括用相对的滚筒挤压、压延辊、接受外部气压或内部真空的塑料袋和本领域普通技术人员可以想到的其他压缩技术。海绵体的压缩或非压缩形式的任一种均可以用于医疗过程中。在治疗部位中放置海绵体诸如海绵体30或海绵体40之前，海绵体可以被修剪成所需大小或形状(例如，如果在制造场所完成，修剪使用合适的凸凹模，或如果在放置时完成修剪则使用剪刀或外科手术刀)。然后未修剪的或修剪的海绵体可以再水化。如果先前被压缩，则可以允许海绵体在插入至治疗部位之前、期间或之后膨胀。安放的海绵体可以提供各种治疗优势，如上面结合保护性凝胶层所述的那些。
大量多糖可以用于本发明的可再水化凝胶组合物和本发明的海绵体中。除了纤维素和壳聚糖，示例性的多糖包括琼脂、藻酸盐、角叉菜胶、几丁质、硫酸软骨素、葡聚糖、半乳甘露聚糖、糖原、透明质酸、淀粉和其他能够形成水凝胶或自支撑海绵体的生物相容的多糖。还可以使用多糖的衍生物(包括氧化的多糖盐)和混合物(包括衍生物)。含有多糖的混合物的组合物特别理想地用于形成水凝胶和海绵体，使用单一的多糖不能提供其特性。例如，含有CMC和壳聚糖的组合物可以提供特别合意的一组特性。其他合意的组合物包括含有壳聚糖以及藻酸盐、透明质酸或硫酸软骨素的那些。选择的一种或多种多糖理想地可以经如下面详述的脱水热缩合反应来交联，并且可以如此地交联多糖混合物中的一种或所有多糖。所选择的一种或多种多糖还理想地是水溶性的或可以例如，通过适当的酸化作用而变得是水溶性的。
多种纤维素可用于公开的可再水化凝胶和公开的海绵体中，包括CMC、甲基纤维素、乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素和半纤维素，以及其衍生物，包括氧化的纤维素。示例性的纤维素材料可从多个商业来源获得，包括Dow WolffCellulosics公司(例如，羧甲基纤维素钠产品的WALOCELTMCRT系列)、Hercules公司(例如，纤维素胶和羧甲基纤维素产品的AQUALONTM系列)和Sigma-Aldrich公司(例如，No.C4021微粒纤维素)。纤维素材料理想是以颗粒形式获得，例如，为自由流动颗粒，其平均颗粒直径小于约1mm，小于约100μm，约1到约80μm，或小于1μm。
1.多种壳聚糖可用于公开的可再水化凝胶和公开的海绵体中。示例性的未修饰壳聚糖及其盐(包括柠檬酸盐、硝酸盐、乳酸盐、磷酸盐、氯化物和谷氨酸盐)可从多个商业来源获得，包括KitoZyme S.A.、Fluka Chemie AG、FMC BioPolymer AS的NovaMatrix部门和Sigma-Aldrich公司。壳聚糖也可以通过水解使几丁质(聚-N-乙酰基-D-葡糖胺)脱乙酰化以去除氮原子上的乙酰基来合成。生成的聚合物具有多个重复单位(例如，约30-约3000个重复单位，约60-约600个重复单位，或对于所选择的终端用途可能需要的此类其他量)，它们的一些或全部含有脱乙酰化氨基(例如，全部重复单位的约30-约100％或约60-约95％)，剩余的重复单位(如果有的话)含有乙酰化氨基。聚合物是阳离子的并且可以被认为由葡萄胺单体组成。壳聚糖可以具有多种数均分子量，例如，约5-约2000kDa，约10-约500kDa，或约10-约100kDa。壳聚糖可以是例如，数均分子量小于约50kDa的超低分子量物质，数均分子量为约50-约200kDa的低分子量物质，数均分子量为约200-约500kDa的中分子量物质或数均分子量大于约500kDa的高分子量物质。壳聚糖衍生物还可以采用，例如，其中一个或多个羟基或氨基已经被修饰以改变衍生物的溶解度或粘膜粘附特性的衍生物。示例性的衍生物包括硫醇化壳聚糖，以及非硫醇化壳聚糖衍生物，例如乙酰化、烷基化或磺化壳聚糖(例如，O-烷基醚，O-酰基酯，阳离子化三甲基壳聚糖和用聚乙二醇改性的壳聚糖)。壳聚糖衍生物可从多种来源获得。例如，硫醇化壳聚糖可从ThioMatrix Forschungs Beratungs公司和Mucobiomer Biotechnologische Forschungs-und Entwicklungs公司获得，或通过壳聚糖与合适的硫醇化试剂反应制备，如公开的PCT申请WO 03/020771A1以及Roldo等人的Mucoadhesive thiolated chitosans as platforms for oral controlled drugdelivery:synthesis and in vitro evaluation,European Journal of Pharmaceuticsand Biopharmaceutics，57，115–121(2004)；Krauland等人,Viscoelastic Properties ofa New in situ Gelling Thiolated Chitosan Conjugate，Drug Development AndIndustrial Pharmacy,31,885-893(2005),Bernkop-Schnürch，Thiomers:A newgeneration of mucoadhesive polymers，Advanced Drug Delivery Reviews，57，1569-1582(2005)；和Bernkop-Schnürch等人，Thiomers:Preparation and in vitroevaluation of a mucoadhesive nanoparticulate drug delivery system，International journal of Pharmaceutics,317,76-81(2006)中所述。硫醇化壳聚糖理想地以颗粒形式获得，例如，作为自由流动的颗粒，其平均粒径小于约1mm，小于约100μm，约1-约80μm，或小于1μm。其他类型多糖(例如，琼脂、藻酸盐、角叉菜胶、几丁质、硫酸软骨素、葡聚糖、半乳甘露聚糖、糖原、透明质酸、淀粉)的来源可以由本领域技术人员基于与上面对纤维素和壳聚糖所给出的那些类似的选择特性来选择。
当在混合物中合并时，每种多糖的量可以广泛地变化以获得所需的性质组合。例如，通过改变共混物中两种多糖的比率，可以改变该共混物的生物可降解或生物可吸收特性和停留时间。两种多糖的混合物可以例如含有约99-约1％的第一种多糖和约1-约99％的第二种多糖，或约80-约20％的第一种多糖和约20-约80％的第二种多糖，或约60-约40％的第一种多糖和约40-约60％的第二种多糖。通过适当地选择混合物中多糖的类型和量，可以获得具有可调性质的可再水化凝胶和海绵体。例如，CMC和壳聚糖的共混物可由于具有壳聚糖而具有良好的抑菌性能，和由于具有CMC而具有可控的、持续的和可调的降解速率，而单独使用壳聚糖可形成具有固有的较差的机械和再吸收性能的凝胶或海绵体，并且单独使用CMC可形成不具有杀菌性能的凝胶或海绵体。
本发明的可再水化凝胶组合物和海绵体基本上不含胶原。理想地可再水化凝胶组合物和海绵体充分地不含有胶原(例如，根本不含有胶原)，从而适于在全球范围内销售而在人类中没有限制地使用。
本发明的可再水化凝胶组合物和海绵体任选地在被包装和发送至终端用户之前进行交联。交联优选地使用脱水热交联工艺进行。对于本发明的可再水化凝胶，这优选地通过将自由流动的可再水化多糖颗粒脱水热交联以形成自由流动的可再水化交联多糖颗粒来完成。换句话说，颗粒优选地是本身单独地被交联，而仍然是自由流动的并且能够以后快速地溶解和再水化。对于本发明的海绵体，交联优选地通过将成形的多孔物品脱水热交联来完成，所述物品已经通过将所需多糖的溶液放置在合适的模具中并且将所述溶液冻干以形成具有与所需的非压缩的海绵体形状相对应的形状的多孔固体而制成。换句话说，海绵体优选地在交联之前成形和制备成多孔的。
脱水热交联实际上是一种固体状态交联工艺，其中材料暴露于热和减压的一种或两种，从而导致初步脱水，紧接着经分子间或分子内缩合过程丢失额外的水并且形成交联键。没有必要加入外来的交联剂，并且在本发明的颗粒的情况下，所述试剂的存在可能使得难以保持其自由流动性。脱水热交联理想地包括将待交联的产物脱水至小于约1％的含水量，并且使用充足的额外热量或真空以达到所需的交联密度。例如，在缺少真空的条件下，可以采用约80℃之上，约90℃之上，约100℃之上或约120℃之上的温度，较高的温度通常提供较快的反应速率。多糖理想地不加热至足以导致褐变的程度，并且相应地优选小于160℃或小于150℃的温度。在环境压力下可能需要相当长的加热时间，例如，在140-150℃下约40小时加上用于加热和冷却的约总计20小时。当使用减压时，可以采用较低的温度，并且优选至多约1mm Hg，和优选至多约10-3mm Hg的压力。因此，温度越高，所需的真空越低或达到指定的交联密度所需的加热时间越少，且反之亦然。因此难以规定确切的加热时间或加热时间的范围，尽管可以采用至少约10小时，至少约20小时，至少约30小时或约40-约60小时(不计算加热和冷却所需的时间)的时间。在许多情况下，足以用经验来确定加热时间、温度和压力，例如通过使用实施例中所示的凝胶保留时间测试(Gel Retention Time test)来评价是否已经获得了适当的交联度。对于未交联的样品，凝胶保留时间可以为例如，1天或更少，而通过使用适当程度的脱水热交联，凝胶保留时间例如可以延长至至少2天和优选约3-约7天。与其脱水热交联形式相比，未交联的样品还可以倾向于不太快速地再水化，吸收较多的水或形成更为粘性的凝胶或糊。与研磨成粉末形式的常规交联材料相比，脱水热交联的颗粒可以是未粉碎的，可以由缩合反应(例如，导致失水的脱水反应，或导致丢失其他小分子诸如氯化氢、甲醇或乙酸的反应)而交联，而不由其他交联反应(例如，包括加聚反应(例如，乙烯基的加聚反应)的反应、离子反应或包括硫化物或胺基的反应)而交联。与研磨成粉末形式的常规交联材料相比，脱水热交联颗粒还可以具有较窄的多分散指数，较低的数均分子量，经历更多交联的能力，较低的生产成本和较低的制造资本需求。
当两种或更多种多糖用来制备本发明的再水化凝胶时，在掺合颗粒之前脱水热交联过程可以对一种或多于一种的多糖进行。这容许通过改变一些性质包括用于每种多糖组分的交联时间、温度或真空，然后在对个别的共混组分完成一个或多个脱水热交联反应后将交联的(或如果需要，未交联的)组分共混来对下述的性质进行定制，所述性质诸如胶凝行为、胶凝时间和植入后的降解时间。如果需要，得到的共混物可以进行额外的脱水热交联反应。颗粒还可以保持分开的状态，并且以后由终端用户混合，尽管这与在制造场所形成混合物相比通常会不太便利。
用于本发明的海绵体的脱水热交联条件类似于可以用于多糖种类的那些。当两种或更多种多糖用来制备本发明的海绵体时，多糖的混合物可以在溶液中形成、冻干和脱水热交联。作为另一种方式，所述混合物中的一种或多种多糖可以是脱水热交联的，并且所述混合物中剩余的一种或多种多糖可以吸收进脱水热交联的聚合物中，并且得到的膨胀的物品可以被冻干以形成海绵体。这些和其他相关的方法可以容许改变性质定制的程度。
本发明的可再水化凝胶组合物和海绵体典型地将进行灭菌和置于合适的密封包装(例如，合适材料制成的注射器、瓶子或袋子)中，然后装运给终端用户。可以通过使用灭菌方法诸如γ辐射或电子束(E-Beam)加工以导致可控的断链来进行额外的性质定制。冷电离辐射灭菌(例如，冷E-Beam灭菌)可以用来限制断链程度，如尚未批准的以与本申请同一日申请的PCT申请(代理人案卷号P0035142.00和151-P-35142WO01)中所讨论的那样。
本发明的可再水化凝胶组合物和海绵体可以在放置于或插入在治疗部位中之前被再水化，或可以以干燥状态放置，然后原位再水化(例如，经由加入外部提供的再水化流体，通过摄取内源性流体，或两者)。再水化海绵体通常是直接进行的，并可以通过将海绵体用水或含有任何其他所需成分的水溶液浸泡或饱和来进行。例如，生理盐水可以是优选的并且是容易地获得的再水化溶液，如果需要可以使用其他的物质诸如磷酸缓冲盐水(PBS)。再水化可再水化凝胶颗粒可以如上所述表现出其他困难，其原因是一些干粉物质当与水合并时倾向于形成团块。然而，通过将可再水化凝胶颗粒分散在生物相容的水易混溶的极性分散剂中，然后将分散体与充足的水性颗粒溶剂(即颗粒的水基溶剂)混合来将所述颗粒转变为粘性水凝胶来避免结块。分散剂因此是颗粒的足够差的溶剂，使得颗粒和分散剂的混合物将不会形成真溶液。在颗粒和分散剂已经通过例如将它们漩涡在一起而搅拌后，所述分散体中的颗粒理想地为充分地小，使得该分散体是稳定的或准稳定的(例如，胶态分散体或适度持久的悬浮液)。不受理论的限制，水性颗粒溶剂的加入被认为容许在每个悬浮的颗粒的表面处经由周围的分散剂溶解至该水性颗粒溶剂相中而几乎同时地发生再水化，从而容许形成粘性水凝胶，而不形成可见的未水化多糖的团块。以此方式，分散的多糖可以与水或水溶液合并以形成无团块的水凝胶，即使干粉状多糖通常不会那样。在许多情况下，本发明的方法可以用来使用两个注射器之间的通道、温和的搅动或其他简单的混合技术而不需要使用机械搅拌器，制备令人满意的无团块的凝胶。本发明的混合方法还可以容许形成非常浓缩的水凝胶，其不能通过仅将粉末状多糖与水或酸化水混合来获得。多糖浓度典型地取决于选择的分子量，并且例如可以是再水化凝胶的约1-约20％，约1-约10％或约1-约5％。凝胶可以理想地在小于30分钟、小于20分钟、小于10分钟、小于5分钟、小于1分钟内或甚至在再水化后基本上立即形成。对于没有立即再水化的多糖，可以理想地在多糖已经变得太粘而不能喷雾或另外通过小的孔口分配之前将粉末饱和并将其注射。
分散剂和水性颗粒溶剂的选择可以取决于选择的多糖。对于例如在纯水中溶解度相对差但当水被酸化时变得可溶的壳聚糖的多糖，去离子水可以用作分散剂并且酸化水可以用作水性颗粒溶剂。还可以使用分散剂和水性溶剂的其他组合。例如，乙醇、异丙醇或丙酮可以用作许多多糖(包括壳聚糖和含壳聚糖的混合物)的分散剂，且去离子水、生理盐水或PBS可以用作水性颗粒溶剂。
本发明的可再水化凝胶颗粒可以如上所述是交联的或未交联的，并且如果是交联的则交联可以是脱水热交联或使用单独的交联剂(例如，京尼平(genipin)、氧化多糖或戊二醛)进行的交联。当使用单独的交联剂交联时，得到的聚合物可以任选地被冻干，并且如果需要，被分散以提供自由流动的颗粒。
本发明的可再水化凝胶组合物和海绵体可以在再水化之前或之后任选地包括多种其他组分。示例性的其他成分包括其他溶剂、酸、碱、缓冲剂、抗微生物剂、治疗剂和其他辅剂。酸、碱或缓冲剂可以例如将凝胶保持在用于接触人类组织的适当pH，例如，大于5的pH，接近中性的pH，或小于8.5的pH。示例性的缓冲剂包括巴比妥钠、甘氨酰胺、甘氨酸、氯化钾、磷酸钾、邻苯二甲酸氢钾、乙酸钠、柠檬酸钠、磷酸钠和它们的共轭酸。
本发明的可再水化凝胶组合物和海绵体理想地是固有的抗微生物剂，而不需要加入单独的抗微生物剂。如果需要可以采用单独的抗微生物剂。所述抗微生物剂的有用的列举可以参见，例如，上面提到的美国专利申请公开号US 2007/0264310 A1。
可以用于本发明的可再水化凝胶组合物和海绵体中的示例性治疗剂包括适合用于目标治疗部位处的任何物质，包括止痛剂、抗胆碱能药、抗真菌剂、抗组胺剂、甾体或非甾体抗炎剂、抗寄生虫剂、抗病毒剂、生物抑菌组合物(biostatic compositions)、化疗/抗肿瘤剂、细胞因子、减充血剂、止血剂(例如凝血酶)、免疫抑制剂、粘液溶解剂、核酸、肽类、蛋白质、类固醇、血管收缩剂、维生素、它们的混合物和本领域技术人员知晓的其他治疗性物质。所述治疗剂的有用的列举可以参见，例如，上面提到的美国专利申请公开号US 2007/0264310 A1中。
可以包含在本发明的可再水化凝胶组合物和海绵体中的其他辅剂包括染料、颜料或其他着色剂(例如，FD&C 3号红、FD&C 20号红、FD&C 6号黄、FD&C 2号蓝、D&C 5号绿、D&C4号橙、D&C 8号红、焦糖、二氧化钛、水果或蔬菜着色剂诸如甜菜粉或β-胡萝卜素、姜黄根、红辣椒和本领域技术人员知晓的其他物质)；指示剂；调味剂或甜味剂包括但不限于茴香油、樱桃、肉桂油、柠檬油(例如，柠檬油、黎莓油或橙油)、可可、桉树、草药芳香剂(例如丁香油、鼠尾草油或肉桂油)、乳糖、麦芽糖、薄荷醇、薄荷油、糖精、环拉酸钠、薄荷油(留兰香油)、山梨醇、蔗糖、香草醛、冬青油、木糖醇和它们的混合物；抗氧化剂；消泡剂；和流变学改性剂包括增稠剂和触变胶。本发明的可再水化凝胶组合物和海绵体理想地不含有可能潜在地损害患者组织或结构例如鼻腔或窦腔中的粘膜组织的成分。
在需要从组织中去除水，例如，以从息肉或水肿组织中去除流体的那些情况下，高渗剂可以用于本发明的可再水化凝胶组合物和海绵体中。示例性的高渗剂包括呋塞米、氯化钠凝胶和可以从组织或物质中抽出水的其他盐制剂，它们直接或间接地改变粘膜层的渗透压量(osmolar content)。当需要治疗剂的持续释放或延迟释放时，还可以包括释放剂改性剂。
本发明的可再水化凝胶组合物和海绵体可以理想地用作多步骤治疗方案的一部分，其破坏细菌生物膜并且阻碍其复发。例如，可以进行一系列步骤，其可以广义地分类为清洁/破坏、杀死、充气、保护/涂覆和愈合。清洗/破坏步骤可以通过结合图1和图2施用如上讨论的溶剂化系统来进行。杀死步骤可以通过将适当的抗微生物剂应用于治疗部位来进行。这可以例如通过将抗微生物剂包含在溶剂化系统中作为单独应用的组合物，或包含在溶剂化系统和单独应用的组合物两者中来实现。抗微生物剂还可以在操作后应用或施用。充气步骤可以通过开放闭塞的或部分闭塞的通道，例如，对于鼻部应用的窦或窦口，从而向被治疗组织提供空气通道或改善空气通道来进行。这可以例如通过手术去除阻塞性组织结构或手工地将所述结构移位来实现。保护/涂覆步骤可以通过用本发明的凝胶组合物涂覆由此治疗的组织的至少一部分，或通过用本发明的海绵体覆盖由此治疗的组织的至少一部分来进行。愈合步骤可以通过允许清洗的、保护的和封闭的组织表面经历恢复至正常状态的过程来进行，例如，通过一种或多种愈合机制诸如炎性应答的调节、吞噬作用、粘膜重塑、纤毛再生或正常功能的完全或部分恢复。多步骤治疗方案可以包括或紧接着清除步骤，在该步骤中凝胶组合物或海绵体是充分生物可降解的或生物可再吸收的，从而在所需的时间期限内从治疗部位消失，所述时间期限，例如，超过1天、超过3天，或约4-约7天，并且理想地不脱落大的固体块。本发明的方法可以有利地在无需手术的条件下实现，例如，通过普通的吸入/吸出技术应用和去除任选的溶剂化系统，或通过简单地冲洗受感染组织紧接着应用本发明的凝胶组合物或海绵体。等同的一系列步骤可以在一部分中耳或内耳中以多步骤治疗方案进行。关于所述治疗方案的更多细节可以参见美国专利申请公开号2007/0264310A1。
本发明进一步在下面的非限制性实施例中进行阐明。
实施例1
脱水热交联的CMC
粉末状羧甲基纤维素钠(Emerging Technologies公司的CMC 52MSC)与1％的二氧化钛混合，并通过10小时加热到140℃、在150-160℃加热40小时和10小时冷却到环境温度进行脱水热交联。获得平均颗粒直径约为40微米的自由流动白色粉末。将粉末以1.5克包装在聚氨酯袋中并在30kGy进行电子束灭菌。
实施例2
注射器再水化和分配
将0.7g实施例1的CMC粉末与3mL去离子水在10mL LUER-LOKTM注射器(Becton，Dickinson公司)中混合。注射器用LUERTM连接器(Becton，Dickinson公司)连接到第二个这样的10mL注射器，且交替地将注射器柱塞下压以再水化粉末。获得含许多块体的混合不良的物质，且块体堵塞注射器之间的通道。在第二试验中，将0.7g实施例1的CMC粉末与0.5mL乙醇组合并摇荡，得到明显稳定的悬浮液。第二注射器中3mL的去离子水被加入到悬浮液中，然后注射器柱塞交替下压以混合成分，导致逐渐形成清澈、均质水凝胶，该水凝胶完全没有可见的未水化的CMC颗粒。该水凝胶可易于通过2.7mm内径、10cm长的套管注入到目标表面，形成浓稠、高粘性、无明显颗粒的均匀凝胶。凝胶看起来有点像无定形海绵体。
实施例3
粘性
实施例2中凝胶样品被放置在MTS张力测试机(MTS Systems公司)中胶原涂覆的销钉之间，且在25.4mm/min的分离速度下评估，以确定凝胶-胶原键合的张力粘结强度。获得约55kPa的值，然而用未交联CMC粉末制成的凝胶，仅获得约35kPa。
实施例4
凝胶保留时间
再水化1.5g实施例1粉末以用实施例2的方法形成无块体凝胶。将凝胶浸入200mLPBS，然后倒入150μm筛网，使其排水并称重。将凝胶返回到收集的PBS溶液中，存放过夜，筛分和再称重过程重复共三次，此时凝胶消失。最终3天测试持续时间被记录为凝胶保留时间。未脱水热交联的实施例1CMC粉末的凝胶的凝胶保留时间小于1天。
实施例5
壳聚糖悬浮液和凝胶
从螃蟹壳获得的高分子量粉末状壳聚糖(Sigma-Aldrich公司的高粘壳聚糖BIOCHEMICATM)被悬浮在去离子水中，添加水平为10、25和50g/L。以1M HCl滴定搅拌的50毫升每种悬浮液。如图5所示，其中10、25和50g/L悬浮液被分别标为曲线A、B和C，pH值随酸加入而逐渐减小。pH值在约pH6和酸加入少于1mL时通过拐点，相应于可观察的凝胶形成的开始。高粘度凝胶在pH值通过另一个拐点时获得，pH约4.5，对于曲线A、B和C酸加入分别为约2、3或5mL。在更低pH值时，壳聚糖然后完全水化且额外的酸进一步酸化水和稀释凝胶。
在单独的实验中，高分子量壳聚糖的1％溶液通过加入壳聚糖粉末到含1％醋酸的去离子水中形成。用装配了CP-52锥锭的BROOKFIELDTMDV-I I+Pro锥板粘度计，在37℃评估时溶液具有453cP的粘度。类似制备的低分子量壳聚糖的1％溶液(来自Sigma-Aldrich公司的BIOCHEMICA低粘度壳聚糖)具有185cP粘度。
实施例6
脱水热交联的壳聚糖粘性
使用实施例1中方法，将低分子量和高分子量粉末状壳聚糖在90℃脱水热交联10小时，或在120℃脱水热交联20小时，加到不同量的1M HCl中，形成凝胶，并用实施例3的方法评估粘性。图6示出在90℃交联的壳聚糖的粘性结果，图7示出在120℃交联的壳聚糖的粘性结果。
在单独的试验中，中等分子量的壳聚糖在120℃用实施例1中方法脱水热交联40小时，并用实施例2中方法评估粘性。获得约65kPa的值，然而用未交联CMC粉末形成的凝胶仅获得约41kPa的值。
实施例7
多糖混合物
在系列试验中，粉末状壳聚糖(超低分子量壳聚糖低聚糖乳酸盐，或BIOCHEMICATM低粘度或中等粘度螃蟹壳壳聚糖，这些都来自Sigma-Aldrich公司)是以其本身、壳聚糖混合物或以与实施例1粉末状CMC的混合物使用的，并与用不同量的HCl或醋酸酸化的水混合。形成的混合物用动力型搅拌器搅动5分钟。这样做使得能够进行下述抗微生物测试，但如果要求在手术前进行则非常不便利。评估搅拌的溶液以确定所形成凝胶对大肠杆菌(E.Coli)、金黄色葡萄球菌(S.Aureus)、绿脓杆菌(P.Aeruginosa)，以及某些情形中对肺炎链球菌(S.Pneumoniae)的抗微生物活性。抗微生物活性评估使用抑菌板方法的改进抑菌圈(modified zone)，其中少量凝胶跨琼脂平板划线，该琼脂平板已经以所需的微生物新划线。与抑菌测试中传统抑菌圈不同——其中抗生素浸泡的纸盘是贴着琼脂表面设置的且抗生素经琼脂向外扩散，凝胶的粘性阻止了这样的扩散。因此结果在本质上符合Boolean逻辑，且主要提供是否发生抑菌的指示。结果在下面表1中示出。
表1中的结果表明，壳聚糖和壳聚糖与多糖羧甲基纤维素的混合物可被再水化以提供具有固有抗微生物性的凝胶层。
实施例8
自由流动交联的粉末可通过在水中溶解干燥粉末状多糖聚合物如羧甲基壳聚糖以产生含约5wt.％聚合物的粘性溶液进行制备。通过将每种溶液装入10mL LUER-LOKTM注射器(Becton，Dickinson公司)，用LUERTM连接器(Becton，Dickinson公司)连接该注射器与另一注射器，并交替地下压注射器柱塞以在两个注射器之间交换流体数次，将含10wt.％双醛淀粉或0.1wt.％戊二醛的交联剂溶液与聚合物溶液快速混合。停顿短时间后——该时间内发生交联，应获得粘性凝胶。通过冷冻和冻干已冻的凝胶，然后研磨冻干产品，凝胶可转化为颗粒。
实施例9
自由流动交联的粉末也可通过在非溶剂化液体交联剂或非溶剂化交联剂溶液中浸泡干燥的粉末状多糖聚合物而制备。实施例8中使用的干燥粉末状羧甲基壳聚糖原料可被浸泡在乙二醇二缩水甘油醚(如Sigma-Aldrich的E27203乙二醇二缩水甘油醚)中足够长时间，以允许交联发生。形成的自由流动的、交联颗粒的物质以甲醇洗涤，除去残余交联剂并微热干燥。取决于所选多糖，可采用多种交联剂。例如，乙二醇二缩水甘油醚可以用六亚甲基二缩水甘油醚或与羟基或氨基反应的其他缩水甘油基交联剂代替。如果多糖含伯胺基，则可采用适当反应性的交联剂，如双醛淀粉、氧化的甲基纤维素或戊二醛。
实施例10
用类似于实施例8所述的10mL注射器的两个3mL注射器，快速混合等体积的2.5wt.％的羧甲基壳聚糖在PBS中的溶液和10wt.％的双醛淀粉。得到的粘性水凝胶从注射器后面挤出以提供保持形状的物质。
实施例11
等体积的5wt.％的羧甲基壳聚糖在PBS中的溶液在冷冻和室温下经电子束辐射交联。将得到的水凝胶冻干为可容易粉末化的海绵体。当放入PBS中时，海绵体保持三到七天。
尽管在本文中已经阐明并且描述了具体的实施方式，用于说明优选的实施方式，但本领域普通技术人员要理解的是预期达到相同目的的大量可替代的或等价的实现方式可以代替所示和所述的具体实施方式，而不背离本发明的范围。本申请意在涵盖本文所讨论的优选实施方式的任何改动或变型。因此，显然，本发明旨在仅由权利要求及其等同形式来限制。
Claims (23)
1.一种将干粉组合物转变为凝胶的方法，所述方法包括：
a)将自由流动的多糖颗粒分散在生物相容的水易混溶的极性分散剂中，其中所述的生物相容的水易混溶的极性分散剂是所述颗粒的足够差的溶剂，使得颗粒和分散剂的混合物将不会形成真溶液，但在所述颗粒和所述生物相容的水易混溶的极性分散剂搅拌后会形成胶态分散体或适度持久的悬浮液，以及
b)将所得到的分散体与充足的所述颗粒的水性溶剂合并从而将它们转变为粘性水凝胶，
其中所述的生物相容的水易混溶的极性分散剂包含水、乙醇、异丙醇或丙酮。
2.根据权利要求1所述的方法，其中所述水易混溶的极性分散剂是水，以及所述颗粒的水性溶剂是酸化水。
3.根据权利要求1所述的方法，其中所述水易混溶的极性分散剂包括乙醇。
4.根据权利要求1所述的方法，其中所述水易混溶的极性分散剂包括异丙醇或丙酮。
5.根据权利要求1所述的方法，其中所述多糖颗粒已被交联。
6.根据权利要求1所述的方法，其中所述多糖颗粒已被脱水热交联，其中所述脱水热交联是一种固体状态交联工艺，其中材料暴露于热和减压的一种或两种，从而导致初步脱水，紧接着经分子间或分子内缩合过程丢失额外的水并且形成交联键。
7.根据权利要求1所述的方法，其中所述多糖颗粒已经用单独的交联剂交联。
8.根据权利要求1所述的方法，其中所述多糖颗粒是未交联的。
9.根据权利要求1所述的方法，其中所述多糖颗粒是不含胶原的。
10.根据权利要求1所述的方法，其中所述多糖颗粒是单一的多糖。
11.根据权利要求1所述的方法，其中所述多糖颗粒是两种或更多种多糖的混合物。
12.根据权利要求1所述的方法，其中所述多糖包括纤维素、壳聚糖、琼脂、藻酸盐、角叉菜胶、几丁质、硫酸软骨素、葡聚糖、半乳甘露聚糖、糖原质、透明质酸、淀粉及其混合物。
13.根据权利要求1所述的方法，其中所述多糖包括氧化的多糖或盐。
14.根据权利要求1所述的方法，其中所述多糖包括羧甲基纤维素。
15.根据权利要求1所述的方法，其中所述多糖只是羧甲基纤维素。
16.根据权利要求1所述的方法，其中所述多糖包括壳聚糖。
17.根据权利要求16所述的方法，其中所述壳聚糖是未修饰的。
18.根据权利要求1所述的方法，其中所述多糖包括壳聚糖和另一种多糖的混合物。
19.根据权利要求1所述的方法，其中所述多糖包括羧甲基纤维素和壳聚糖的混合物。
20.根据权利要求1所述的方法，其包括形成粘性水凝胶，而没有可见的未水化多糖的团块。
21.根据权利要求1所述的方法，其中所述粘性水凝胶是在目标表面上的层形式。
22.根据权利要求1所述的方法，其中所述粘性水凝胶被施加到目标表面上。
23.根据权利要求1所述的方法，其中所述粘性水凝胶通过冷冻和冻干已冻的凝胶，然后研磨所述的冻干产品从而转化为颗粒。
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