CN101951879A - 多糖凝胶制剂 - Google Patents

多糖凝胶制剂 Download PDF

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CN101951879A
CN101951879A CN2008801235242A CN200880123524A CN101951879A CN 101951879 A CN101951879 A CN 101951879A CN 2008801235242 A CN2008801235242 A CN 2008801235242A CN 200880123524 A CN200880123524 A CN 200880123524A CN 101951879 A CN101951879 A CN 101951879A
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polysaccharide
preparation
inhibitor
sulfate
gel
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D·斯特姆普利斯
C·S·马德
A·泰泽尔
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Allergan Inc
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Abstract

本文描述了包含至少一种多糖降解抑制剂的多糖凝胶制剂及其制备方法。本文描述的方法涉及步骤：提供至少一种多糖，并在所述多糖中掺入至少一种降解抑制剂。在一些实施方案中，所述掺入步骤包括1)在高水合状态下将所述至少一种抑制剂与所述至少一种多糖混合，从而将所述至少一种抑制剂封装于多糖网络中，以及2)水合所述多糖网络，从而控制释放动力学或终膨胀率。在另一个实施方案中，所述掺入步骤包括1)将所述至少一种抑制剂封装至一个生物相容的或可生物降解的容器中，以及2)将所述至少一种多糖和所述容器结合成一种凝胶制剂中。本文描述的多糖凝胶制剂可用于多种美容应用中。

Description

多糖凝胶制剂
发明人
D.斯特姆普利斯、C.S.马德和A.泰泽尔
相关专利申请的交叉引用
本申请要求以2007年11月30日提交的美国临时专利申请60/991,473为优先权基础，该临时申请的整个公开文本以引用的方式纳入本文。
技术领域
整体上公开了用于增加多糖凝胶寿命的应用于美容和医疗中的制剂，以及制备其和使用其的方法。
背景技术
多糖是相对复杂的糖。多糖是由糖苷键连接在一起的许多单糖组成的聚合物。因此，多糖是较大并经常有支链的大分子。多糖(尤其是透明质酸(HA))已被应用于美容和医疗中。例如，这类聚合物已被用作软组织填充中的填充剂。
HA停留于细胞外空间，其作用是填充空间、稳定结构以及作为具有独特延展性物理性质和极好生物相容性的细胞保护分子。HA基质有极端的粘弹性，而又保持高水平的水合。在皮肤含水量和真皮组织中HA水平之间存在强相关。已知当人皮肤老化时，HA含量和代谢发生改变。随着这些改变，皮肤的机械性质有明显劣化。在年轻皮肤和细胞间基质中存在强HA网络之间似乎存在关联。
不幸地是，非交联多糖链以及交联多糖链例如HA会通过不同通路降解(如酶降解、自由基降解)；从而限制该聚合物的体内寿命。因此，开发在体内降低天然分解速率并增加产物持久性的方法和组合物是重要的。对通过抗降解而具有增加的寿命的多糖制剂仍有未被满足的需求。
发明内容
本文描述了在体内寿命增加或降解时间增加的多糖凝胶(例如透明质酸，HA)制剂。该降解时间的增加由掺入作为降解抑制剂的分子提供。此外，本发明提供了用于封装这些制剂以在体内维持延长的寿命或降解时间的方法。本发明还涉及可应用于药物或美容用的凝胶制品。
在一个实施方案中，本文描述了一种包含至少一种多糖和至少一种多糖降解抑制剂的多糖凝胶制剂，所述多糖选自透明质酸、纤维素、壳聚糖、o-硫酸化的HA、葡聚糖、硫酸葡聚糖、硫酸软骨素、硫酸皮肤素、硫酸角蛋白、肝素、硫酸肝素和藻酸盐，所述多糖降解抑制剂选自糖胺聚糖(glycos iaminoglycan)、抗氧剂、黄酮类化合物、蛋白质、脂肪酸和它们的结合物。在一个实施方案中，所述多糖是交联的。在一个实施方案中，所述至少一种多糖为透明质酸。
在一个实施方案中，所述糖胺聚糖选自肝素、硫酸肝素、硫酸皮肤素、硫酸软骨素、o-硫酸化的透明质酸、亚麻仁苷(Linamarin)和苦杏仁苷(Amygdalin)。在另一个实施方案中，所述糖胺聚糖为硫酸软骨素，并且以约1重量％至约40重量％的浓度存在。
在一个实施方案中，抗氧剂选自抗坏血酸、褪黑激素、维生素C、维生素E和它们的结合物。
在一个实施方案中，所述黄酮类化合物选自四羟黄酮、芹菜素、福橘素、槲皮素、山萘酚、杨梅素、漆黄素、异鼠李素、藿香黄酮醇、鼠李秦素、橙皮素、柚皮素、圣草酚、高圣草素、紫杉醇、二氢槲皮素、二氢山萘酚、鞣酸、单宁、浓缩单宁、可水解单宁和它们的结合物。在另一个实施方案中，所述黄酮类化合物为鞣酸，并且以约0.0001重量％至约1重量％的浓度存在。
在一个实施方案中，所述蛋白质为血清透明质酸酶抑制剂。在另一个实施方案中，所述脂肪酸为饱和C10-22脂肪酸。
在一个实施方案中，所述制剂还包含生物相容的或可生物降解的容器(vessel)，其中所述抑制剂在所述容器之中或者是所述容器的一部分，其中所述容器为脂质体、胶束或聚合的小囊。在另一个实施方案中，所述抑制剂为所述制剂提供提高的流变性质，使得与交联的多糖凝胶制剂相比给予所述制剂需要更小的挤出力。
在一个实施方案中，本文描述了一种生产降解时间增加的多糖凝胶制剂的方法，包括步骤：提供至少一种选自透明质酸、纤维素、壳聚糖、o-酸化的HA、葡聚糖、硫酸葡聚糖、硫酸软骨素、硫酸皮肤素、硫酸角蛋白、肝素、硫酸肝素和藻酸盐的多糖，并在所述多糖中掺入至少一种选自糖胺聚糖、抗氧剂、黄酮类化合物、蛋白质和脂肪酸的多糖降解抑制剂。
在所述方法的一个实施方案中，掺入步骤包括1)在高水合状态下将所述抑制剂与所述多糖混合，从而将所述抑制剂封装于多糖网络中，以及2)使所述多糖网络脱水，从而控制释放动力学或终膨胀比。
在所述方法的另一个实施方案中，在掺入所述至少一种多糖降解抑制剂前使用交联剂交联所述至少一种多糖，所述交联剂选自1，4-丁二醇二缩水甘油醚(BDDE)、1，2-双(2，3-环氧丙氧基)乙烯、1-(2，3-环氧丙基)-2，3-环氧环己烷和它们的结合物。
在所述方法的一个实施方案中，所述掺入步骤包括1)将一种抑制剂封装至一个生物相容的或可生物降解的容器中，以及2)将所述至少一种多糖和所述容器结合至一种凝胶制剂中。
在一个实施方案中，本文描述了一种降解时间增加的多糖凝胶制剂，其包含交联的透明质酸和鞣酸，其中所述鞣酸以约0.0001％至约1％的浓度存在。
在一个实施方案中，本文描述了一种降解时间增加的多糖凝胶制剂，其包含交联的透明质酸和硫酸软骨素，其中所述硫酸软骨素以约1％至约40％的浓度存在。
本文还描述了包含多糖凝胶制剂、可药用载体和活性成分的药物组合物。在一个实施方案中，所述活性成分选自抗痒剂、抗蜂窝组织剂、抗瘢痕剂、抗炎症剂、抗氧剂、维生素、增湿剂和它们的结合物。
附图说明
图1以曲线图示出使用量热试验得到的含硫酸软骨素A(CSA)的多糖凝胶的酶降解程度。
图2以曲线图示出使用量热试验得到的含鞣酸(TA)的多糖凝胶的酶降解程度。
图3以曲线图示出使用可溶性HA试验得到的有或无CSA的多糖凝胶的酶降解程度。
图4以曲线图示出使用可溶性HA试验得到的有或无TA的多糖凝胶的酶降解程度。
图5以曲线图示出CSA对多糖凝胶的挤出力的效应。
具体实施方式
本文描述了通过掺入作为降解抑制剂的分子提供的在体内寿命增加或降解时间增加的多糖凝胶(例如透明质酸，HA)制剂。在一些实施方案中，所述多糖凝胶是交联的。此外，本发明还涉及用于封装这些制剂以在体内维持延长的寿命或降解时间的方法。本发明还涉及可应用于药物或美容用的凝胶制品。
本发明的一个方面涉及包含至少一种多糖和至少一种多糖降解抑制剂的多糖凝胶制剂。本发明还涉及通过掺入降解抑制剂增加多糖凝胶的降解时间。“多糖”是指超过两个单糖分子的聚合物，其中所述单糖可以相同或不同。本发明的多糖可以是交联的或非交联的。本文使用的多糖可以为，但不限于HA、纤维素、壳聚糖、o-硫酸化的HA、葡聚糖、硫酸葡聚糖、硫酸软骨素、硫酸皮肤素、硫酸角蛋白、肝素、硫酸肝素和藻酸盐。
抑制剂为通过靶向并中和具体降解机制如酶降解和自由基降解发挥作用的分子。呈现抑制活性的分子包括但不限于糖胺聚糖(GAG)(例如肝素、硫酸肝素、硫酸皮肤素、硫酸软骨素、o-硫酸化的HA、亚麻仁苷和苦杏仁苷)、抗氧剂(例如抗坏血酸、褪黑激素、维生素C和维生素E)、蛋白质(例如血清透明质酸酶抑制剂)和脂肪酸(例如饱和C10-C22脂肪酸)。
抑制剂的分子量一般比交联的多糖聚合物具有更小的数量级。由于抑制剂大小较小且扩散性较高，它们在体内倾向于快速吸收，这有可能限制其性能。一种在体内增加这类分子的局部半衰期的方法是，将它们化学接枝于所述多糖聚合物网络并且将它们同时递送。该方法的一个缺点是，结合的分子可呈现比未结合的分子显著更低的活性。在本发明的多糖凝胶制剂中，所述抑制剂的浓度可以是约0.0001重量％-约99重量％，约0.001重量％-约75重量％，约0.01重量％-约60重量％，约1重量％-约50重量％，约1重量％-约40重量％，约1重量％-约30重量％，约1重量％-约20重量％，约10重量％-约20重量％，约20重量％-约30重量％，0.0001重量％-约0.01重量％，约0.0001重量％-约0.1重量％，约0.0001重量％-约1重量％，约0.001重量％-约1重量％，约0.01重量％-约1重量％，约1重量％-约10重量％。
本发明的另一方面涉及一种生产降解减少的多糖凝胶制剂的方法，包括提供一种多糖，并在所述多糖中封装一种降解抑制剂。
非交联多糖链以及交联多糖链会通过不同途径降解(如酶降解、自由基降解)，这经常会限制该聚合物在体内的寿命。因此，开发在组织中降低天然分解速率并增加产物持久性的方法是重要的。
获得多糖持续时间增加的一种方法是，将抑制剂分子封装于多糖聚合物网络本身中或者至所述网络中的大容器中，这将使得降解抑制剂被局部(注入部位)、持续且可控的释放。这还将能够避免天然降解机制。本发明的封装方法可在数周的时间向所述多糖聚合物网络持续供应降解抑制剂。在另一些实施方案中，在数月的时间提供降解抑制剂的持续供应。一种封装方法是，通过吸附或者通过封装过程将所述降解抑制剂封装于所述多糖聚合物网络中。在后一种情况中，所述抑制剂被允许以高水合状态与所述多糖网络混合，然后对所述网络脱水以控制所述释放动力学(例如所述聚合物的终膨胀率)。高水合状态对应于低于约20mg/ml的HA浓度。
可通过调节pH或者使所述多糖网络部分脱水而控制所述终膨胀率。可将所述收缩的网络的大小调节成颗粒，与所述多糖凝胶混合并递送至所述注入部位。所述装载抑制剂的多糖颗粒的缓慢再水合可提供其活性内容物的持续且可控的递送。
本发明的另一方面涉及一种包含多糖和多糖降解抑制剂的多糖凝胶制剂，所述多糖凝胶制剂还包含生物相容的或可生物降解的容器，其中所述抑制剂在所述容器之中或者是所述容器的一部分。这类容器可以由非共价或共价连接的自组装分子例如脂质体、胶束和聚合化小囊组成。
脂质体是一种由一个或多个双层膜组成的小囊，所述双层膜由含混合脂质链的天然来源的磷脂(例如卵磷脂酰乙醇胺)形成，或者由纯表面活性物质组分如二油酰磷脂酰乙醇胺(DOPE)形成。脂质体(通常但非限定性地)包含一个水性溶液核心；包含非水性材料的脂质结构称为胶束。胶束是分散于胶体流体中的表面活性分子的聚集体。水性溶液中的典型胶束可形成聚集体，具有与周围溶剂接触的亲水“头部”区域，隔离所述胶束中央的疏水“尾部”区域。这种类型的胶束被称为正相胶束(水包油胶束)。逆胶束的头部基团在中央，尾部伸展向外(油包水胶束)。胶束通常近似球形，然而，还有可能为椭圆体、圆筒和双层。胶束的形状和大小随其表面活性分子的分子几何结构以及溶液条件例如表面活性物质浓度、温度、pH和离子强度变化。胶束的形成过程被称为胶粒形成，并根据脂质的多态性形成多种脂质相性质的一部分。
本发明的另一方面涉及一种制备降解减少的多糖凝胶制剂的方法，包括步骤：1)提供一种多糖，2)将一种抑制剂掺入至一种生物相容的或可生物降解的容器中，以及3)将所述多糖和容器结合成一种凝胶制剂中。该封装方法因此将所述抑制剂掺入至生物相容的和可生物降解的容器中，所述容器可与所述多糖同时递送。这类容器可由非共价或共价连接的自组装分子(例如胶束、脂质体和聚合的小囊)组成。本文使用的术语自组装描述这样的过程，即其中已存在组分的无序体系形成一个有组织的结构或模式，无外部指导的情况下在所述组分自身中形成特定的局部相互作用。
所提出的制剂的另一优点是所述终产品流变性质的调整能力的增加。交联多糖凝胶一般具有高粘度，需要相当大的力挤压通过细针。非交联多糖通常被用作润滑剂，以有利于该挤压过程。然而，尤其在HA皮肤填充剂中，非交联HA对所述终产物在体内的持久性没有贡献。事实上，越多交联HA被非交联HA替换以调整所述皮肤填充剂的流变性质(为获得固定的总HA浓度)，所述产品的降解抗性将会越低。另外，根据所提出的制剂，亦为降解抑制剂的非交联GAG(例如硫酸软骨素、o-硫酸化的透明质酸)可用于延长所述终产物的寿命并改善其流变性质。
本文描述的多糖可以是交联的或非交联的。交联剂可用于交联本说明书的多糖。所述交联剂可以是已知适合于多糖或其衍生物经由羟基交联的任意试剂。合适的交联剂包括但不限于，例如1，4-丁二醇二缩水甘油醚(或者1，4-双(2，3-环氧丙氧基)丁烷或1，4-双缩水甘油氧丁烷，它们通常都被称为BDDE)、1，2-双(2，3-环氧丙氧基)乙烯和1-(2，3-环氧丙基)-2，3-环氧环己烷。本发明的范围还涵盖使用不止一种交联剂或不同交联剂。在一个实施方案中，所述交联剂包含BDDE或者由BDDE组成。
皮肤填充剂可用于治疗轻度至重度面部皱纹和褶皱如法令纹(那些从鼻子扩展至嘴角的细纹)。皮肤填充剂可以为包括HA的凝胶植入物，HA是一种增强皮肤弹性的天然复合糖，提供一种平滑且柔软的外表。它是生物相容的，可补充身体的天然HA——其随衰老而耗尽。
皮肤凝胶可经注射器注入至面部的真皮中部至深处。真皮是表皮之下的皮肤层，含结缔组织、神经末梢、汗腺和油脂腺、以及血管。皮肤填充剂可通过提升及增加治疗区域的皱纹和褶皱的体积而改善皮肤外表。
本发明的另一方面涉及一种美容用的组合物，包含本发明的多糖凝胶制剂、美容用的载体和活性成分。所述美容用的活性成分可包括但不限于抗氧剂、维生素和增湿剂。
本文使用的形容词“美容用的”是指改善表皮外表或者遮盖缺陷。一般而言，美容用的组合物可用于提高表皮的美观，而不是提高表皮的功能方面。更通常地，美容用的组合物被配制用途健康和美学处理法，或者用于改变身体如角质表面的个性化外表，例如皮肤、毛发、指甲等。
本文使用的“可美容用载体”是指适合应用于角质表面或身体其他区域的物质。在应用时，可美容用载体与皮肤和其他角膜表面基本上无不良反应。例如，美容用载体可采取以下形式：脂肪乳剂或非脂肪乳剂、乳状悬液、油包乳剂或水包油型、洗剂、凝胶或胶冻剂、胶状或非胶状水性溶液剂或油溶液剂、糊剂、气溶胶、可溶解片剂或者棒剂。
本文使用的“制剂”和“组合物”可互换使用，是指在一块呈现给定目的的成分的结合物。这类术语是本领域普通技术人员公知的。
本文使用的“载体”、“惰性载体”和“可用的载体”可互换使用，是指可以与本发明公开的多糖凝胶结合以提供所需组合物的载体。本领域普通技术人员应了解许多熟知的载体可用于制备具体的治疗性药物和/或美容用组合物。
本发明的另一方面涉及一种药物组合物，所述药物组合物包含所述多糖凝胶制剂、药用载体和活性成分。本文使用的活性成分包括但不限于药物。药物一般可定义为用于疾病的治疗、治愈、预防或诊断的或者用于另外增强身体健康或精神健康的化学物质。
可以包括在本发明药物组合物中的活性成分的实例有抗痒剂、抗蜂窝组织剂、抗瘢痕剂、抗炎症剂。抗痒剂可包括甲基磺酰甲烷、碳酸氢钠、炉甘石、尿囊素、高岭土、薄荷油、茶树油和它们的结合物。抗蜂窝组织剂可包括福斯高林(forskolin)、黄嘌呤化合物，例如但不限于咖啡因、茶碱、可可碱、氨茶碱和它们的结合物。抗瘢痕剂可包括IFN-γ、氟尿嘧啶、乳酸/羟基乙酸共聚物、甲基化的聚乙二醇、聚乳酸、聚乙二醇和它们的结合物。抗炎症剂可包括地塞米松、泼尼松龙、皮质酮、布地奈德、雌激素、柳氮磺吡啶、美沙拉嗪和它们的结合物。
多糖例如HA天然出现在身体的多种组织中，例如但不限于皮肤、软骨和玻璃体液。因此，它十分适合于靶向这些组织的生物医学应用。HA可用于眼科手术中(即角膜移植、白内障手术、青光眼手术和修复视网膜脱离的手术)。HA还可用于治疗膝的骨关节炎。这类治疗被称为黏弹性补充疗法，以注入膝关节中的过程给予，被认为可补充关节液的粘度，从而润滑关节，缓冲关节并产生镇痛效应。还已经提出，HA对软骨细胞具有积极的生物化学效应。最近提出可口服HA，但需证明其有效性。现如今，有一些初步的临床研究表明，口服HA对骨性关节炎有积极效应。
由于HA的高生物相容性极普遍存在于组织的细胞外基质中，它可在组织工程研究中用作生物材料支架。在一些癌症中，HA水平与恶性和预后不良很好地相关。因此，HA经常被用作前列腺和乳腺癌的肿瘤标记物。它还可以被用于监视疾病的进展。HA还可在手术后使用，以诱导组织愈合，特别是在白内障手术后。现在的伤口愈合模型提出，更大的HA聚合物出现于愈合的早期阶段以物理地为白细胞腾出空间，所述白血病介导免疫反应。
药物组合物可任选地包含一种或多种试剂，例如但不限于乳化剂、湿润剂、甜味剂或风味剂、渗透佐剂、防腐剂、缓冲剂、抗氧剂、黄酮类化合物。可用于本发明的药物组合物中的渗透佐剂包括但不限于盐，例如乙酸钠、氯化纳、氯化钾；甘露醇或甘油；以及其他可药用的渗透佐剂。可用于本文公开的药物组合物中的防腐剂包括但不限于苯扎氯铵、三氯叔丁醇、硫柳汞、乙酸苯汞和硝酸苯汞。用于调节pH的多种缓冲剂和方法可用于制备药物组合物，包括但不限于乙酸盐缓冲物、柠檬酸盐缓冲物、磷酸盐缓冲物和硼酸盐缓冲物。类似地，可用于药物组合物中的抗氧剂是本领域中熟知的，包括例如焦亚硫酸钠、硫代硫酸钠、乙酰半胱氨酸、丁羟茴醚和丁羟甲苯。黄酮类化合物是植物中出现的化合物，已知它们具有不同的有利生物化学和抗氧剂效应。黄酮类化合物的亚类包括：黄酮、黄酮醇、黄烷酮和黄烷酮醇。黄酮类化合物的实例包括：四羟黄酮、芹菜素、福橘素、槲皮素、山奈酚、杨梅素、漆黄素、异鼠李素、藿香黄酮醇、鼠李秦素、橙皮素、柚皮素、圣草酚、高圣草素、紫杉醇、二氢槲皮素、二氢山奈酚、鞣酸、单宁、浓缩单宁和可水解单宁。应理解，药理学领域中已知的这些和其他物质可包括在本发明的药物组合物中。参见，例如Remington’s Pharmaceutical Sciences Mac Publishing Company，Easton，PA，第16版，1980。
在下文使用实施例描述了本发明的一些优点，这些实施例记载了依照本文描述的方法制备HA填充凝胶剂，依照现有技术制备HA填充凝胶剂以及针对这些样品进行的降解试验。
本文中使用的分子量(Mw)是指一个分子中原子的原子总重量。例如，甲烷(CH4)的分子量是16.043g/mol，原子量为碳＝12.011g/mol，氢＝1.008g/mol。道尔顿(Da)是重量单位，等于120重量的1/12，1百万Da可记作1MDa。
实施例1
依照本发明公开的内容制备HA填充凝胶剂
将HA浓度为24mg/mL、交联度为约6％且G’为约180的1-5克多糖填充物(
Figure BPA00001174741300091
24HV，(Allergan Inc.，Irvine，California))与补充有10-200mg硫酸软骨素A(CSA-Mw＝5,000-120,000Da)的1000μl磷酸盐缓冲盐水(PBS)溶液(pH约7)混合。将所述混合物进行机械匀化。
实施例2
通过现有技术的方法制备HA填充凝胶剂
将HA浓度为24mg/mL、交联度为约6％且G’为约180的1-5克多糖填充物(
Figure BPA00001174741300092
24HV)与1000μl的PBS混合，使终HA浓度与实施例1中的相同。将所述混合物进行机械匀化。
实施例3
依照本发明公开的内容制备另一种透明质酸填充凝胶剂
将HA浓度为24mg/mL、交联度为约6％且G’为约170的1-5克基于HA的多糖填充物(30)与补充有1-20mg鞣酸(TA-Mw＝800-4,000Da)的50μl的PBS溶液(pH约7)混合。将所述混合物进行机械匀化。
实施例4
通过现有技术的方法制备另一种透明质酸填充凝胶剂将HA浓度为24mg/mL、交联度为约6％且G’为约170的1-5克基于HA的多糖填充物(
Figure BPA00001174741300094
30)与50μl的PBS混合，使终HA浓度与实施例3中的相同。将所述混合物进行机械匀化。
实施例5
依照本发明公开的内容制备透明质酸填充凝胶剂
将1克透明质酸钠纤维(NaHA，Mw＝0.5-3MDa)与5-10g的1％氢氧化钠溶液混合，并放置所述混合物1-5小时以进行水合。
将50-200毫克1，4-丁二醇二缩水甘油醚(BDDE)加入至NaHA凝胶剂中，并将所述混合物进行机械匀化。
然后，将所述混合物至于40-70℃的烤箱中1-4小时。
将所形成的交联水凝胶用当量的氢氯酸(HCl)中和并在PBS(pH≈7)中膨胀。
加入10-200毫克CSA(Mw＝5,000-120,000Da)，并将所述水凝胶进行机械匀化。
实施例6
依照现有技术的方法制备透明质酸(HA)填充凝胶剂
将1克NaHA(Mw＝0.5-3MDa)与5-10g的1％氢氧化钠溶液混合，并放置所述混合物1-5小时以进行水合。
将50-200毫克BDDE(与实施例5中HA：交联剂摩尔比相同)加入至NaHA凝胶剂中，并将所述混合物进行机械匀化。
然后，将所述混合物至于40-70℃的烤箱中1-4小时。
将所形成的交联水凝胶用当量的氢氯酸(HCl)中和并在PBS(pH≈7)中膨胀，使得终HA浓度与实施例5中的相同。将所得到的水凝胶进行机械匀化。
实施例7
酶降解研究(量热试验)
使用Morgan-Elson量热测定评估实施例1和2中制备的HA填充凝胶剂对酶降解的抗性。将该测定用于在酶降解之前和之后估计HA链的平均分子量。
将透明质酸酶(0.1-10mg)加入至HA样品中，在37℃下维持10-250分钟，然后加入0.1ml的0.8M四硼酸钾溶液并在100℃下加热10分钟。将所述样品补充3ml的10重量％对二甲氨基苯甲醛的乙酸溶液，并在37℃下孵育10-120分钟。将降解之后和之前585nm下光密度(OD)的变化用于对每个样品中的降解程度进行定量。
显示于图1的在依照本发明的方法和依照现有技术制备的填充凝胶剂上进行的测量结果(酶降解试验结果(量热测定))表明，通过本发明公开的方法制备的凝胶剂的OD值(实施例1：0.774-25.184mg/ml CSA)低于通过现有技术的方法制备的凝胶剂的OD值(实施例2：0mg/ml CSA)。再者，OD值的降低与CSA浓度成比例。由于OD值代表了降解的程度，这些结果表明依照本发明的方法制备的凝胶剂呈现比依照现有技术方法制备的凝胶剂高3-75％的酶降解抗性。
类似于补充CSA的凝胶剂的情况，如图2中所示，通过本发明的方法制备的补充有TA的凝胶剂的OD值(实施例3：0.063-1.000mg/mL TA)低于通过现有技术的方法制备的凝胶剂的OD值(实施例4：0mg/mL TA)。再者，OD值的降低与TA浓度成比例。由于OD值代表了降解的程度，这些结果表明依照本发明的方法制备的凝胶剂呈现比依照现有技术方法制备的凝胶剂高15-90％的酶降解抗性。还可以看出，TA具有比CSA更高的抑制活性，这是因为TA以低1个数量级的量获得与CSA相同的抑制。
实施例8
酶降解研究(可溶性HA测定)
为了进一步评估实施例1和2中制备的HA填充凝胶剂对酶降解的抗性，使用了基于SEC-MALS(体积排阻多角度光散射)的可溶性HA测定。可使用该测定通过评估每个样品中含有的可溶性HA的百分数(定义为可通过0.2-1.0μm滤器的凝胶部分)对降解进行定量。降解之前和之后可溶性HA的量变化可用于定量每个样品中的降解程度。
使用装配有Wyatt光散射和折射指数单元的Agilent体积排阻色谱系统进行SEC-MALS试验。将透明质酸酶(0.1-10mg)加入至HA样品中，在37℃下维持10-250分钟，然后加入0.1ml 0.8M四硼酸钾溶液并在100℃下加热10分钟。将所述样品于PBS中稀释，过滤通过0.2-1.0μm滤器并注入至SEC-MALS系统中。酶解之前和之后可溶性HA含量以及它们的差显示于图3中。
显示于图3中的结果(酶降解试验结果(SEC-MALS测定))表明，不含CSA的样品的酶降解后的可溶性HA含量显著更高。CSA和非CSA样品之间可溶性HA增加的这种差异与量热降解测定中得到的结果一致，并表明依照本发明的方法制备的凝胶剂显示比依照现有技术制备的凝胶剂更高的降解抗性。
类似于补充CSA的凝胶剂的情况，通过本说明书的方法制备的补充TA的凝胶剂的可溶性HA含量(实施例3：0.063-1.000mg/mL TA)低于通过现有技术的方法制备的凝胶剂的可溶性HA含量(实施例4：0mg/mL TA)。这些结果与总结于图4中的量热方法相符。再者，还可以看出，TA的抑制活性比CSA高1个数量级。
实施例9
连续挤压力试验
为了评估实施例5和6中制备的透明质酸填充凝胶剂的流变性质，在每个样品上进行了连续挤压力试验。挤压力试验可用于确定CSA是否可通过作为润滑剂而有利于所述挤压过程。
使用带有30G针头的5ml注射器在Ins tron仪器上进行挤压力试验。将0.5ml每个样品以50mm/分钟的恒定速率挤出。所记录的力的峰值是挤压容易程度的定量。两个样品的压力与压缩伸长的函数绘于图5中。
图5中的结果表明，对通过本文描述的方法制备的凝胶剂记录到的挤压力低于对通过现有技术的方法制备的凝胶剂的记录到的挤压力。挤压力的这种差异是流动时的凝胶硬度差异的特征，并且表明通过本文描述的方法制备的凝胶剂中含有的CSA发挥有利于流动的润滑剂的功能。
除非另有指出，在说明书及权利要求书中使用的表示成分数量、性质例如分子量、反应条件等的所有数值，应理解为在所有情形中都以词语“约”进行修饰。因而，除非另有指明，说明书及所附权利要求书中所提到的数值参数均为约数，其可随本发明想要获得的所需性质而变。至少，并不试图限制将等同原则用于解释权利要求书的范围，每个数值参数至少应根据所报道的有意义的数字的值，并应用常规的近似方法来理解。尽管陈述本发明的宽泛范围的数值范围和参数为约数，但对具体实施例中提到的数值作尽可能精确的报道。但是，任何数值都内在地包含一定的由它们各自的测试过程所存在的标准偏差而必然导致的误差。
在描述本发明时(尤其是在所附的权利要求书中)使用的词语“一”、“一个”、“该”以及类似的指代，应理解为包括单个和多个，除非文中另有指出，或与上下文意思明显相悖。文中引述值的范围仅意在作为一种对落在所述范围内的每个单独值各个提及的简便方法。除非文中另有指出，每个单独值均被纳入说明书中，如同单独引述一般。文中所述的所有方法可以任何合适的顺序实施，除非文中另有指出或与上下文意思明显相悖。文中使用的任何及所有实例，或示例性语言(如，“例如”)仅意在更好地阐明本发明，并不对本发明所要求保护的范围进行限制。说明书中任何语言均不应被理解为表示对于实施本发明所必需但不要求保护的要素。
文中所公开的发明的可选择要素或实施方案的分组不应被理解为限制性的。每个组要素可单个被提及和被要求，或者与该组内的其它要素或文中出现的其它要素的任意组合的形式被提及和被要求。可以预见，出于简便和/或可专利性的原因，一个或多个要素可被囊括于组内，或自组内删除。当出现任何这类囊括或删除时，说明书应被认为包含所修改的组，从而满足随附权利要求书中使用的所有马库什组的书面说明。
本发明的某些实施方案在文中作了描述，包括发明人已知的实施本发明的最佳方式。当然，所述实施方案的变型对本领域技术人员而言，在其阅读前面的说明后将会变得很清楚。发明人预期本领域技术人员可以适当地使用所述变型，并且发明人也想使本发明以与文中所具体描述的不同的方式来实施。因此，本发明包括适用的法律所许可的所附权利要求中记载的主题的所有变化及等同方式。此外，上述要素在其所有可能的变型中的任意组合均涵盖于本发明之内，除非文中另有指出或与上下文含义明显相悖。
此外，说明书通篇提到了多篇专利及出版物文献。上述文献及出版物中的每一篇的全文均通过引用的方式纳入本说明书。
最后，应理解的是，文中所公开的发明的实施方案是本发明原理的示例说明。可使用的其它变化方案也在本发明的范围内。因此，例如，但不限于，可根据本文教导而使用本发明的替代构型。因而，本发明不限于具体示出及描述的方案。
本文公开的具体实施方案可使用语言“由......组成”或“基本由......组成”在权利要求书中进一步进行限制。当用于权利要求中时，不管是初始提交或者是后加的每次修改时，及物术语“由......组成”不包括权利要求中未指定的任何要素、步骤或成分。及物术语“基本由......组成”将权利要求的范围限制到指定的物质或步骤，以及那些不重大影响基本特征和新特征的物质或步骤。所要求的本发明的实施方案在本文中固有地或明确地被记载或实现。

Claims (20)

1.一种包含至少一种多糖和至少一种多糖降解抑制剂的多糖凝胶制剂，所述多糖选自透明质酸、纤维素、壳聚糖、o-硫酸化的HA、葡聚糖、硫酸葡聚糖、硫酸软骨素、硫酸皮肤素、硫酸角蛋白、肝素、硫酸肝素和藻酸盐，所述多糖降解抑制剂选自糖胺聚糖、抗氧剂、黄酮类化合物、蛋白质、脂肪酸和它们的结合物。
2.权利要求1的制剂，其中所述多糖是交联的。
3.权利要求1的制剂，其中所述至少一种多糖为透明质酸。
4.权利要求1的制剂，其中所述糖胺聚糖选自肝素、硫酸肝素、硫酸皮肤素、硫酸软骨素、o-硫酸化的透明质酸、亚麻仁苷和苦杏仁苷。
5.权利要求4的制剂，其中所述糖胺聚糖为硫酸软骨素。
6.权利要求5的制剂，其中所述硫酸软骨素以约1重量％至约40重量％的浓度存在。
7.权利要求1的制剂，其中所述抗氧剂选自抗坏血酸、褪黑激素、维生素C、维生素E和它们的结合物。
8.权利要求1的制剂，其中所述黄酮类化合物选自四羟黄酮、芹菜素、福橘素、槲皮素、山萘酚、杨梅素、漆黄素、异鼠李素、藿香黄酮醇、鼠李秦素、橙皮素、柚皮素、圣草酚、高圣草素、紫杉醇、二氢槲皮素、二氢山萘酚、鞣酸、单宁、浓缩单宁、可水解单宁和它们的结合物。
9.权利要求8的制剂，其中所述黄酮类化合物为鞣酸。
10.权利要求9的制剂，其中所述鞣酸以约0.0001至约1重量％的浓度存在。
11.权利要求1的制剂，其中所述蛋白质为血清透明质酸酶抑制剂。
12.权利要求1的制剂，其中所述脂肪酸为饱和C10-22脂肪酸。
13.权利要求1的制剂，还包含生物相容的或可生物降解的容器，其中所述抑制剂在所述容器之中或者是所述容器的一部分，其中所述容器为脂质体、胶束或聚合的小囊。
14.权利要求1的制剂，其中所述抑制剂为所述制剂提供提高的流变性质，使得与交联的多糖凝胶制剂相比给予所述制剂需要更小的挤出力。
15.一种制备降解时间增加的多糖凝胶制剂的方法，包括步骤：
提供至少一种选自透明质酸、纤维素、壳糖、o-硫酸化的HA、葡聚糖、硫酸葡聚糖、硫酸软骨素、硫酸皮肤素、硫酸角蛋白、肝素、硫酸肝素和藻酸盐的多糖，并在所述多糖中掺入至少一种选自糖胺聚糖、抗氧剂、黄酮类化合物、蛋白质和脂肪酸多糖降解的抑制剂。
16.权利要求15的方法，其中所述掺入步骤包括1)在高水合状态下将所述至少一种抑制剂与所述至少一种多糖混合，从而将所述至少一种抑制剂封装于多糖网络中，以及2)水合所述多糖网络，从而控制释放动力学或终膨胀率。
17.权利要求15的方法，其中在掺入所述至少一种多糖降解抑制剂前使用交联剂交联所述至少一种多糖，所述交联剂选自1，4-丁二醇二缩水甘油醚(BDDE)、1，2-双(2，3-环氧丙氧基)乙烯、1-(2，3-环氧丙基)-2，3-环氧环己烷和它们的结合物。
18.权利要求15的方法，其中所述掺入步骤包括1)将所述至少一种抑制剂封装至一个生物相容的或可生物降解的容器中，以及2)将所述至少一种多糖和所述容器结合成一种凝胶制剂中。
19.一种降解时间增加的多糖凝胶制剂，包含交联的透明质酸和鞣酸，其中所述鞣酸以约0.0001％至约1％的浓度存在。
20.一种降解时间增加的多糖凝胶制剂，包含交联的透明质酸和硫酸软骨素，其中所述硫酸软骨素以约1％至约40％的浓度存在。
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