CN116583304A - 具有改善的放射性造影特性的多糖 - Google Patents
具有改善的放射性造影特性的多糖 Download PDFInfo
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- CN116583304A CN116583304A CN202180083493.8A CN202180083493A CN116583304A CN 116583304 A CN116583304 A CN 116583304A CN 202180083493 A CN202180083493 A CN 202180083493A CN 116583304 A CN116583304 A CN 116583304A
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- Prior art keywords
- iodinated
- polysaccharide
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- carboxyl
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Abstract
本公开涉及包含多糖主链的碘化多糖化合物，所述多糖主链包含多个羧基和多个碘化侧基。本公开还涉及碘化多糖化合物，其中存在于含羧基多糖链中的至少一部分羧基被多个碘化侧基官能化。本公开的其它方面涉及形成碘化多糖化合物的方法、包含碘化多糖化合物的医疗组合物、包含将这种医疗组合物引入患者的组织内或组织间的医疗方法、以及包含这种医疗组合物的医疗试剂盒。
Description
优先权
本申请要求2020年12月28日提交的美国临时申请序列号63/130,950的权益，其公开内容在所有目的下通过引用全部并入本文。
技术领域
在其他方面，本公开涉及包含具有放射性造影特性的碘化多糖化合物的医疗组合物，制备这种碘化多糖化合物的方法，包含这种碘化多糖化合物的医疗组合物，以及使用这种碘化多糖化合物的医疗方法。
背景技术
可注射水凝胶是一类新兴材料，具有多种医疗用途。作为一个具体的实例，可注射水凝胶已经用于在组织之间产生或保持空间，以减少脱靶的放射治疗的副作用。在图1A和1B中示意性地示出了与前列腺放射治疗结合的间隔物材料的用途。图1A示出了包括前列腺110和直肠壁112的人类男性解剖结构的截面。当使用放射疗法治疗前列腺时，在受到高剂量辐射的前列腺附近存在较高剂量区域114，随着远离前列腺110而形成较低剂量区域116。如图1B所示，可以在前列腺110和直肠壁112之间注射间隔材料118，这可以将直肠壁从较高剂量区域114推到较低剂量区域116，从而减少对直肠壁的损伤。
然而，对于包括在放射治疗前使用可注射水凝胶作为肿瘤部位附近的间隔物在内的各种应用，该材料另外具有一些持久的放射性造影特性将是有用的。可以添加钨颗粒，但是这些颗粒不会生物降解，并且可能从水凝胶中沉淀下来，使得这不是理想的策略。碘化造影剂也可以在注射前立即加入。然而，这种方法存在三个问题：1)需要在植入后数小时内拍摄图像，否则植入物将不可见，2)后续成像将没有任何可感知的对比度，以及3)碘没有结合到水凝胶上，因此有可能成像的造影剂不是水凝胶，而是从水凝胶扩散出来的造影剂。
因此，在生物医学领域中，除了其他需求之外，还对具有放射性造影特性的新材料以及制造和使用此类材料的方法存在持续的需求。
发明内容
在一些方面，本公开涉及包含多糖主链的碘化多糖化合物，所述多糖主链包含多个羧基和多个碘化侧基。在某些实施方案中，多糖主链包含碘化侧基所连接的含羧基多糖链。在某些实施方案中，含羧基多糖链包含一个或多个选自葡糖醛酸残基、甘露糖醛酸残基或半乳糖醛酸残基中的一种或多种的残基。
在一些方面，本公开涉及碘化多糖化合物，其中存在于含羧基多糖链中的至少一部分羧基被多个碘化侧基官能化。在某些实施方案中，含羧基多糖链包含一个或多个选自葡糖醛酸残基、甘露糖醛酸残基或半乳糖醛酸残基的残基。
在可与前述方面和实施方案结合使用的一些实施方案中，碘化侧基可以包含碘化芳基，其中芳基的一个或多个氢被碘取代，并且芳基的一个或多个氢被亲水基团取代。在这些实施方案的一些中，芳基可以是苯基。在这些实施方案的一些中，亲水基团可以包含多羟基基团。
在可与前述方面和实施方案结合使用的一些实施方案中，碘化侧基可以包含碘化芳基和亲水基团。在这些实施方案的一些中，碘化芳香侧基可以包含单碘代苯基、二碘代苯基、三碘代苯基或四碘代苯基。在这些实施方案的一些中，亲水基团可以包含多羟基基团，例如包含含多羟基-C1-C6-烷基的基团的多羟基基团等。
在可与前述方面和实施方案结合使用的一些实施方案中，碘化侧基可以包含2,4,6-三碘代苯基，其中3位和5位上的至少一个氢被多羟基基团取代，例如包含含多羟基-C1-C6-烷基的基团的多羟基基团等。
在可与前述方面和实施方案结合使用的一些实施方案中，碘化侧基可以包含–N,N′-双(多羟基-C1-C6-烷基)-2,4,6-三碘代苯基-3,5-二羧酰胺基团。
在一些方面，本发明涉及形成根据前述方面和实施方案中任一方面或实施方案的碘化多糖化合物的方法。在一些实施方案中，所述方法包括通过偶联反应形成酰胺键，其中含氨基碘化化合物的氨基与含羧基多糖链的羧基反应。
在可与前述方面和实施方案结合使用的一些实施方案中，偶联在偶联剂存在下在水溶液中进行。例如，偶联剂可以是碳化二亚胺偶联剂等。
在可与前述方面和实施方案结合使用的一些实施方案中，含氨基碘化化合物包含芳基，其中一个或多个氢被含氨基的基团取代，一个或多个氢被碘取代，并且一个或多个氢被亲水基团取代，例如选自上述那些的亲水基团。
在一些方面，本公开涉及包含根据前述方面和实施方案中任一方面或实施方案的碘化多糖化合物的医疗组合物。
在一些实施方案中，医疗组合物为水凝胶。在这些实施方案的某些中，水凝胶是可注射水凝胶。
在一些可与前述方面和实施方案结合使用的实施方案中，医疗组合物进一步包含治疗剂。
在一些方面，本公开涉及医疗方法，其包括将根据前述方面和实施方案中任一方面或实施方案的医疗组合物引入患者的组织内或组织间。
在一些实施方案中，医疗方法进一步包括使用基于X射线的成像技术对医疗组合物进行成像。
在可与前述方面和实施方案结合使用的一些实施方案中，医疗方法选自植入包含碘化多糖化合物的基准标记物的方法、植入包含碘化多糖化合物的组织再生支架的方法、植入包含碘化多糖化合物的组织支撑物的方法、植入包含碘化多糖化合物的组织填充剂(bulking agent)的方法、植入包含碘化多糖化合物的含治疗剂的储库的方法、包含植入医疗组合物的组织增大方法、将医疗组合物引入第一组织和第二组织之间以将第一组织与第二组织隔开的方法。
在一些方面，本公开涉及医疗试剂盒，其包含在容器中的根据前述方面和实施方案中任一方面或实施方案的医疗组合物和以下一种或多种：(a)在容器中的可注射降解组合物，所述降解组合物用于分解碘化多糖化合物，(b)导管或其它递送装置，(d)针，或(e)适于注射的稀释流体(例如，注射用水或生理盐水)。
除上述内容外，通过阅读以下详细说明，本公开的进一步的方面和实施方案将变得显而易见。
附图说明
图1A和1B示意性示出了注射间隔物材料前后，包括前列腺和直肠壁的人类男性解剖结构的截面。
图2示意性示出了根据本公开实施方案形成不透射线的多糖化合物的方法。
具体实施方式
在各种方面，本公开提供了包含多糖主链的碘化多糖化合物，所述多糖主链包含多个羧基和多个碘化侧基。在各种实施方案中，多糖主链包含碘化侧基所连接的含羧基多糖链。在各种方面，本公开提供了碘化多糖化合物，其中存在于含羧基多糖链中的至少一部分羧基被多个碘化侧基官能化。
通过将碘化侧基连接到多糖链上，赋予多糖链不透射线性，使碘化多糖化合物可用于例如放射性造影设置中。
含羧基多糖链通常可以是天然来源、合成来源或其组合的任何含羧基多糖。含羧基多糖链的具体实例包括下列：含有葡糖醛酸残基的聚合物，其包括聚葡糖醛酸均聚物和聚葡糖醛酸共聚物，例如透明质酸(其包括D-葡糖醛酸残基和N-乙酰基-D-葡糖胺残基)和各种含羧基的树胶(gums)，包括具有葡糖醛酸残基的树胶，例如结冷胶(其包括D-葡糖醛酸残基、D-葡萄糖残基和L-鼠李糖残基)和黄原胶(其包括D-葡糖醛酸残基、D-葡萄糖残基和D-甘露糖残基)；含有甘露糖醛酸残基的聚合物，其包括聚甘露糖醛酸均聚物和聚甘露糖醛酸共聚物，例如海藻酸(其包括D-甘露糖醛酸残基和L-葡糖醛酸残基)；以及含有半乳糖醛酸残基的聚合物，其包括聚半乳糖醛酸均聚物和包括果胶家族成员的聚半乳糖醛酸共聚物，所述果胶家族除了D-半乳糖醛酸残基之外，还可以包括D-葡糖醛酸残基和一种或多种选自D-木糖残基(例如，木半乳糖醛酸聚糖)、D-芹菜糖残基(例如，芹菜半乳糖醛酸聚糖)、α-L-鼠李糖残基(鼠李半乳糖醛酸聚糖果胶)、D-半乳糖醛酸残基、D-半乳糖残基、L-阿拉伯糖残基和D-木糖残基)的其他残基。含羧基多糖链的其它具体实例包括羧化纤维素、羧甲基纤维素、羧化淀粉、羧甲基淀粉、N-羧甲基壳聚糖或N,O-羧甲基壳聚糖。
在各种实施方案中，碘化多糖化合物的碘化侧基包含碘化芳基，其中芳基的一个或多个氢被碘取代，并且芳基的一个或多个氢被亲水基团取代。在这些实施方案中，芳基可选自苯基或萘等。
在各种实施方案中，碘化侧基包含碘化芳基和至少一个亲水基团。在这些实施方案中，碘化芳基可选自碘化苯基或碘化萘基等。在具体的实施方案中，碘化芳基可以包含单碘代苯基、二碘代苯基、三碘代苯基或四碘代苯基。在某些实施方案中，碘化侧基可以包含2,4,6-三碘代苯基基团，其中3位和5位上的至少一个氢被亲水基团取代。
所述至少一个亲水基团可选自，例如，多羟基基团等。例如，所述至少一个多羟基基团可以包含例如含多羟基-C1-C6-烷基的基团，或多羟基-C1-C6-烷基-羧酰胺基团。
在某些实施方案中，碘化侧基可以包含—N,N′-双(多羟基-C1-C6-烷基)-2,4,6-三碘代苯基-3,5-二羧酰胺基团，其中—N,N′-双(2,3-二羟基丙基)-2,4,6-三碘代苯基-3,5-二羧酰胺是一个实例。
本公开的其它方面涉及形成碘化多糖化合物的方法，例如上述那些。在一些实施方案中，这些方法包括通过偶联反应形成酰胺键，该酰胺键将碘化侧基连接到多糖主链上，在该偶联反应中，含氨基碘化化合物的氨基与含羧基多糖链的羧基反应。通过将含氨基碘化化合物与多糖偶联，赋予多糖不透射线性。
使用偶联剂可在水性和非水性溶液中促进这种偶联。例如，合适的偶联剂可以选自以下：(a)碳化二亚胺，例如1-乙基-3-(3-二甲基-氨丙基)碳化二亚胺盐酸盐(EDC)、二环己基碳化二亚胺(DCC)、二异丙基碳化二亚胺(DIC)、1-环己基-3-(2-吗啉基-4-乙基)碳化二亚胺甲基对甲苯磺酸盐(CMC)或1-环己基-3-(2-吗啉乙基)碳化二亚胺甲基-4-甲苯磺酸盐(CDI)，(b)鏻试剂，例如BOP(苯并三唑-1-基氧基-三(二甲氨基)-鏻六氟磷酸盐)、PyBOPR(苯并三唑-1-基氧基-三吡咯烷基-鏻六氟磷酸盐)、PyBrOPR(溴-三吡咯烷基-鏻六氟磷酸盐)、PyAOP(7-氮杂-苯并三唑-1-基氧基-三吡咯烷基鏻六氟磷酸盐)、PyOxim(乙基氰基(羟基亚氨基)醋酸乙酯基-O2)-三-(1-吡咯烷基)-鏻六氟磷酸盐)。DEPBT(3-(二乙氧基-磷酰氧基)-1,2,3-苯并[d]三嗪-4(3H)-酮)，(c)铵/脲-亚胺试剂，例如2-(1H-苯并三唑-1-基)-N,N,N′,N′-四甲基铵四氟硼酸盐/六氟磷酸盐(TBTU，BF4 -阴离子)/HBTU，PF6 -阴离子)、HCTU(2-(6-氯-1H-苯并三唑-1-基)-N,N,N′,N′-四甲基铵六氟磷酸盐)、HDMC(N-[(5-氯-1H-苯并三唑-1-基)-二甲氨基-吗啉代]-脲六氟磷酸盐N-氧化物)、2-(7-氮杂-1H-苯并三唑-1-基)-N,N,N′,N′-四甲基铵四氟硼酸盐/六氟磷酸盐(TATU，BF4 -阴离子/HATU，PF6 -阴离子)、COMU(1-[1-(氰基-2-乙氧基-2-氧代亚乙基氨基氧基)-二甲基氨基-吗啉代]-六氟磷酸脲)、TOTT(2-(1-氧基-吡啶-2-基)-1,1,3,3-四甲基异硫脲四氟硼酸盐)、TFFH(四甲基氟代脲六氟磷酸酯)，(d)其他偶联剂，例如EEDQ(N-乙氧羰基-2-乙氧基-1,2-二氢喹啉)、T3P(2-丙基磷酸酐)、DMTMM和相关化合物(4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基吗啉盐)、BTC(双三氯甲基碳酸酯或“三光气”)和CDI(1,1'-羰基二咪唑)。添加剂通常用于与碳化二亚胺形成酰胺键，以提高反应性并减少差向异构体和N-酰基脲的形成。添加剂包括HOBt(1-羟基苯并三唑)、HOBt-6-磺酰氨基甲基树脂·HCl(1-羟基苯并三唑-6-磺酰胺甲基树脂·HCl)、HOOBt(HODhbt)(羟基-3,4-二氢-4-氧代-1,2,3-苯并三嗪)、HOSu(N-羟基琥珀酰亚胺)、HOAt(1-羟基-7-氮杂-1H-苯并三唑)、Oxyma Pure(2-氰基-2-(肟基)乙酸乙酯)、DMAP(4-(N,N-二甲基氨基)吡啶)。前述偶联剂和添加剂可从例如供应商处获得，例如BachemAmericas,Inc.,Torrance,CA,美国。
用于这种偶联方法的含羧基多糖化合物可选自如上所述的聚葡糖醛酸均聚物和共聚物、聚甘露糖醛酸均聚物和共聚物、聚半乳糖醛酸均聚物和共聚物、羧化纤维素、羧甲基纤维素、羧化淀粉、羧甲基淀粉、N-羧甲基壳聚糖或N,O-羧甲基壳聚糖。
在各种实施方案中，含氨基碘化化合物可以是水溶性的。
在各种实施方案中，含氨基碘化化合物可以是水溶性碘化芳香胺，例如，被一个或多个亲水基团取代的碘化芳香胺。
在各种实施方案中，含氨基碘化化合物可以包含芳基，其中一个或多个氢被含氨基的基团取代，一个或多个氢被碘取代，并且一个或多个氢被亲水基团取代。例如，含氨基碘化化合物可以包含苯基，其中至少一个氢被含氨基的基团取代，至少一个氢被碘基团取代，并且至少一个氢被亲水基团取代。
在各种实施方案中，含氨基碘化化合物可以包含碘化芳基，其中一个或多个氢被含氨基的基团取代，并且一个或多个氢被亲水基团取代。例如，含氨基碘化化合物可以包含碘化苯基，其中至少一个氢被含氨基的基团取代，并且至少一个氢被亲水基团取代。在某些实施方案中，含氨基碘化化合物可以包含2,4,6-三碘代苯基，其中1、3和5位上的至少一个氢被含氨基的基团取代，并且1、3和5位上的至少一个氢被亲水基团取代。
亲水基团的实例包括多羟基基团等。
特定的含氨基碘化化合物包括5-氨基-N,N′-双(多羟基-C1-C6-烷基)-2,4,6-三碘代苯基-1,3-二羧酰胺化合物，其中5-氨基-N,N′-双(2,3-二羟基丙基)-2,4,6-三碘代苯基-1,3-二羧酰胺是一个实例。
现在将描述形成根据本公开的碘化多糖的方法的具体实例，其中存在于含透明质酸的多糖链中的至少一部分羧基用碘化侧基官能化，以赋予多糖链不透射线性。在一个有益的实施方案中，非动物稳定的透明质酸(NASHA)的羧基用碘化侧基官能化。在足够高的浓度下，NASHA溶液形成物理交联的水凝胶，其适于注射并具有良好的生物相容性。此外，NASHA水凝胶具有额外的吸引人的特征，即通过施用透明质酸酶来催化其水解，它们可以在温和的条件下容易地溶解。NASHA聚合物用水溶性碘化侧基官能化。参考图2，化合物5-氨基-N,N’-双(2,3-二羟基丙基)-2,4,6-三碘代间苯二甲酰胺(CAS#76801-93-9)的可用氨基可以与NASHA的D-葡糖醛酸亚基的羧基偶联，提供水溶性的、不透射线的部分。这种偶联可以在水溶液中用合适的偶联剂如EDC来促进。
本公开的其它方面涉及包含本公开的碘化多糖化合物的组合物。包含本公开的碘化多糖化合物的组合物可用于多种生物医学应用，包括用于注射剂、植入物和医疗器械。
此类组合物包括水凝胶组合物，其包含本公开的碘化多糖化合物和水。根据本公开的水凝胶可以是物理或化学(例如共价)交联的。在一些实施方案中，根据本公开的水凝胶可以形成光滑的涂层。在一些实施方案中，根据本公开的水凝胶可以是可注射的水凝胶。
如前所述，通过将碘化侧基连接到含羧基多糖链上，赋予多糖链不透射线性，从而产生可用于放射性造影设置的碘化多糖化合物。
在一些实施方案中，包含本公开的碘化多糖化合物的组合物可以包含一种或多种治疗剂，例如小分子药物、细胞、蛋白质和生物活性分子。
在一些实施方案中，治疗剂可选自以下：麻醉剂；镇痛剂，选自对乙酰氨基酚、布洛芬、氟比洛芬、酮洛芬、非那西丁和水杨酰胺；抗炎剂，选自萘普生和吲哚美辛；抗组胺剂，选自马来酸氯苯那敏、酒石酸苯茚胺、马来酸吡拉明、琥珀酸多西拉敏、柠檬酸苯托洛沙敏、盐酸苯海拉明、异丙嗪、马来酸溴苯那敏、马来酸右旋溴苯那敏、富马酸氯马斯汀和曲普利啶；镇咳药，选自氢溴酸右美沙芬和愈创甘油醚；祛痰剂；减充血剂，选自盐酸去氧肾上腺素、盐酸苯丙醇胺、盐酸伪麻黄碱和麻黄碱；抗生素，选自抗阿米巴药(广谱和中等谱)、真菌药物、单内酰胺和病毒剂；支气管扩张剂，选自茶碱、沙丁胺醇和特布他林；心血管制剂，选自地尔硫卓、普萘洛尔、硝苯地平、可乐定、α肾上腺素受体激动剂、α受体阻断剂、α和β受体阻断剂、血管紧张素转换酶抑制剂、β阻断剂、钙通道阻断剂和强心苷；中枢神经系统药物，选自甲硫哒嗪、地西泮、氯苯甲嗪、麦角酰甲磺酸酯、氯丙嗪、卡比多巴和左旋多巴；金属盐，选自氯化钾和碳酸锂；矿物质，选自由铁、铬、钼和钾组成的组；免疫调节剂；免疫抑制剂，选自米诺环素、环孢菌素A；甲状腺制剂，选自合成的甲状腺激素和甲状腺素钠；肽和糖蛋白激素以及类似物，选自人绒毛膜促性腺激素(HCG)、促肾上腺皮质激素、人生长激素(HGH-生长激素)、红细胞生成素(EPO)、碱性成纤维细胞生长因子(FGF)(包括FGF1和FGF2)、血管内皮生长因子(VEGF)、血小板衍生生长因子(PDGF)、血管生成素1和血管生成素2；类固醇和激素，选自ACTH、合成类固醇(anabolics)、雄激素和雌激素组合物、雄激素、皮质激素和镇痛药、雌激素、糖皮质激素、促性腺激素、促性腺激素释放、低血钙、促生育素、甲状旁腺激素、孕酮、孕激素、孕激素和雌激素组合物、生长抑素样化合物、尿促卵泡素、血管加压素、甲基泼尼松龙、GM1神经节苷脂、cAMP等；维生素，选自水溶性维生素和兽医制剂；生长因子，选自EGF、FGF2和神经营养蛋白；肽、肽模拟物和其他蛋白质制剂；DNA；以及小干扰RNA。
可使用根据本公开的可注射水凝胶的设置的实例包括用于提供组织间间隔的注射、用于提供基准标记物的注射(例如，以气泡的形式)、用于组织增大或再生的注射、作为软组织的填充物或替代物的注射、为受损组织提供机械支撑的注射、作为支架的注射、作为疾病和癌症治疗以及组织的修复和再生中的治疗剂载体的注射等。
本发明包括与各种医疗方法相结合的本公开组合物的各种施用方式。除其他因素外，本领域技术人员还可以根据治疗的类型和患者的病况来确定施用组合物的最理想方式。施用方法包括例如经皮技术以及其他有效的施用途径。例如，本发明的组合物可以通过注射器或导管(例如微导管)递送，其可以在导丝、可操纵的微导管或流动导向的微导管等装置上前进。
在各种方面，提供了医疗方法，其中将包含本公开的碘化多糖化合物的医疗组合物插入患者的组织内或组织间。在各种实施方案中，然后使用外部或内部成像技术对注射的医疗组合物进行成像。通常，成像技术是基于X射线的成像技术，例如计算机断层扫描或X射线透视。
在某些实施方案中，医疗方法可为以下方法之一：植入包含碘化多糖的基准标记物的方法、植入包含碘化多糖的组织再生支架的方法、植入包含碘化多糖的组织支撑物的方法、植入包含碘化多糖的组织填充剂的方法、植入包含碘化多糖的含治疗剂的储库的方法、包含植入医疗组合物的组织增大方法、将医疗组合物引入第一组织和第二组织之间以将第一组织与第二组织隔开的方法。
根据本公开的组合物(例如水凝胶)可以在各种医疗方法中在不同部位注射，包括以下：用于直肠癌放射治疗中为保持间隔在前列腺或阴道和直肠之间注射，用于前列腺癌放射治疗中为保持间隔在直肠和前列腺之间注射，用于前列腺癌姑息治疗的皮下注射，用于女性压力性尿失禁的经尿道或粘膜下注射，用于尿失禁的膀胱内注射，用于阿舍曼综合征(Asherman's syndrome)的宫腔注射，用于肛门失禁的粘膜下注射，用于心力衰竭的经皮注射，用于心力衰竭和扩张型心肌病的心肌内注射，用于心肌梗死的经心内膜注射，用于骨关节炎的关节内注射，用于脊柱融合以及脊柱、口腔颌面和整形外科创伤手术的脊柱注射，用于后外侧腰椎融合的脊柱注射，用于退行性椎间盘疾病的椎间盘内注射，用于胰腺癌成像的胰腺和十二指肠间注射，用于口咽癌成像的切除床注射，用于膀胱癌成像的肿瘤床周围注射，用于胃肠肿瘤和息肉的粘膜下注射，用于肺活检的脏层胸膜注射，用于2型糖尿病和慢性肾病的肾注射，用于先天性肾脏和泌尿道异常引起的慢性肾脏疾病的肾皮质注射，用于新生血管年龄相关性黄斑变性的玻璃体内注射，用于感觉神经性听力损失的鼓室内注射，用于矫正皱纹(wrinkle)、皱痕(crease)和褶皱(fold)、面部脂肪减少、体积减少的迹象、由浅至深的轮廓缺陷、凹陷皮肤疤痕的矫正、口周皱纹、丰唇、面部脂肪萎缩、刺激天然胶原产生的真皮注射。
在其它方面，本公开涉及包含在合适容器中的组合物的医疗试剂盒，所述组合物包含根据本公开的碘化多糖化合物。包含碘化多糖的组合物可以是干燥形式(例如干燥颗粒形式)或预制水凝胶形式。包含碘化多糖的组合物的容器可以是例如小瓶或注射器筒。注射器筒可具有开口，以在其近端接收柱塞，并在其远端具有配件(例如，鲁尔接口(luer)配件或另一种合适的配件)，用于与注射针或导管直接或间接接合，使得注射器筒的内部与注射针或导管的内部流体连通。筒还可以在其近端设置有凸缘，以便于接合，以及用于确定筒内剩余流体体积的刻度。合适注射器体积的范围可以是例如从5cc或更少到50cc或更多，通常从5cc到15cc。除了包含碘化多糖的组合物之外，医疗试剂盒还可以包含一种或多种以下各项：(a)在容器中的可注射的可降解组合物(例如，以干燥形式或以准备注射的形式)，该可降解组合物是分解碘化多糖的组合物(例如，用于含多糖的透明质酸的透明质酸酶)，(b)导管或其它递送装置，(b)针，或(d)适于注射的稀释流体(例如，注射用水或生理盐水)。
Claims (15)
1.一种碘化多糖化合物，其包含多糖主链，所述多糖主链包含多个羧基和多个碘化侧基。
2.根据权利要求1所述的碘化多糖化合物，其中所述多糖主链包含碘化侧基所连接的含羧基多糖链，所述含羧基多糖链包含一个或多个选自葡糖醛酸残基、甘露糖醛酸残基或半乳糖醛酸残基中的一种或多种的残基。
3.一种碘化多糖化合物，其中存在于含羧基多糖链中的至少一部分羧基被多个碘化侧基官能化。
4.根据权利要求3所述的碘化多糖化合物，其中所述含羧基多糖链包含一个或多个选自葡糖醛酸残基、甘露糖醛酸残基或半乳糖醛酸残基的残基。
5.根据权利要求1至4中任一项所述的碘化多糖化合物，其中所述碘化侧基包含碘化芳基，其中芳基的一个或多个氢被碘取代，并且芳基的一个或多个氢被亲水基团取代。
6.根据权利要求5所述的碘化多糖化合物，其中所述芳基是苯基。
7.根据权利要求1至4中任一项所述的碘化多糖化合物，其中所述碘化侧基包含碘化芳基和亲水基团。
8.根据权利要求7所述的碘化多糖化合物，其中所述碘化芳香侧基包含单碘代苯基、二碘代苯基、三碘代苯基或四碘代苯基。
9.根据权利要求5至8中任一项所述的碘化多糖化合物，其中所述亲水基团包含多羟基基团。
10.根据权利要求1至4中任一项所述的碘化多糖化合物，其中所述碘化侧基包含2,4,6-三碘代苯基，其中3位和5位上的至少一个氢被多羟基基团取代。
11.根据权利要求9或10所述的碘化多糖化合物，其中所述多羟基基团包含含多羟基-C1-C6-烷基的基团。
12.根据权利要求1至4中任一项所述的碘化多糖化合物，其中所述碘化侧基包含–N,N′-双(多羟基-C1-C6-烷基)-2,4,6-三碘代苯基-3,5-二羧酰胺基团。
13.一种形成根据权利要求1至12中任一项所述的碘化多糖化合物的方法，其包括通过偶联反应形成酰胺键，其中含氨基碘化化合物的氨基与含羧基多糖链的羧基反应。
14.一种医疗组合物，其包含根据权利要求1至12中任一项所述的碘化多糖化合物。
15.一种医疗方法，其包含将根据权利要求14所述的医疗组合物引入患者的组织内或组织间。
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