CN101549169B - 使用点击化学法形成的生物粘合剂组合物 - Google Patents
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- CN101549169B CN101549169B CN200910130350.9A CN200910130350A CN101549169B CN 101549169 B CN101549169 B CN 101549169B CN 200910130350 A CN200910130350 A CN 200910130350A CN 101549169 B CN101549169 B CN 101549169B
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
本发明提供了在医疗和外科应用上可以用作粘合剂或密封剂的组合物。在一些实施方式中，该组合物可以通过含有至少一个叠氮基的第一组分与含有至少一个炔基的第二组分的环加成反应形成。
Description
相关申请的交叉参考
该申请要求受益于并享有于2008年4月1日提交的美国临时专利申请第61/041,303号的优先权，其全部内容在此引入作为参考。
技术领域
本发明涉及适合于包括用作组织粘合剂和/或组织密封剂的原位应用的组合物。
背景技术
近年来，人们对于用粘合剂粘结代替或者补充缝合的兴趣已经越来越浓厚。兴趣变得浓厚的原因包括：(1)可以实现修复的潜在速度；(2)粘合物质实现完全闭合的能力，从而防止渗液；和(3)在使组织不过度变形的情况下形成粘结的可能性。
然而，在这方面的研究已经显示，对于可被外科医生接受的外科粘合剂，其必须具有一系列性能。它们必须显示出较强的初始粘性(initial tack)和与活组织快速粘结的能力；粘结的强度应该足够高以至于在粘结失效之前组织衰竭；所述粘合剂应该形成桥状物，通常为可渗透的柔性的桥状物；以及所述粘合剂桥状物和/或其代谢产物不会产生局部毒害组织(localhistotoxic)或者致癌作用。
目前有几种可用作组织粘合剂或组织密封剂的材料。一种目前可用的粘合剂是氰基丙烯酸酯粘合剂。然而，氰基丙烯酸酯粘合剂可以具有较高的弯曲模量，其可能限制它们的有用性。目前另一种可用的组织密封剂使用从牛和/或人源得到的组分。例如，血纤维蛋白密封剂是可用的。然而，如所使用的任何天然材料一样，可以观察到该材料的变异性。
较理想地为提供一种柔韧的、生物相容的和无毒的完全合成的生物粘合剂或密封剂。
发明内容
本发明提供了适合在医疗或者外科应用中的用作粘合剂或者密封剂的组合物。在一些实施方式中，该组合物可以从含有至少一个叠氮基的第一组分与含有至少一个炔基的第二组分的环加成反应中形成。
本发明也提供了用这些组合物来粘结和/或密封组织的方法。在一些实施方式中，根据本发明的用于粘结和/或密封组织的方法可以包括使含有至少两个炔基的第一组分与含有至少两个叠氮基的第二组分接触，催化第一组分和第二组分的聚合反应以形成生物粘合剂组合物，并使生物粘合剂组合物与至少一个组织表面接触，从而使生物粘合剂组合物粘结到至少一个组织表面上。在一些实施方式中，可以使用本发明的组合物将例如植入物的装置粘结到组织上。在其它实施方式中，本发明的组合物可以包含生物活性剂，从而可以用来在体内释放生物活性剂。
附图说明
参照附图，下面将详细描述本发明的各种实施方式，其中：
图1为描述用于形成炔衍生物的季戊四醇加合物的图，所述炔衍生物用于形成本发明的生物粘合剂组合物；
图2为描述用于形成本发明的生物粘合剂组合物的炔衍生物的图。
具体实施方式
本发明提供了可以通过使含有至少一个叠氮基的第一组分与含有至少一个炔基的第二组分进行铜催化的环加成反应制备的组合物。在一些实施方式中，第二组分可以含有至少一个乙炔基作为至少一个炔基。实施方式中的叠氮基与炔基反应的机理参照点击化学。这里使用的“点击化学”指的是十分可靠并且自导向有机反应的集合体，包括如上所述的铜催化叠氮-炔环加成反应，其可以在水中形成高度可靠的分子连接。
在一些实施方式中，第一组分、第二组分或者两种组分，可含有用至少两个叠氮基或者至少两个炔基官能化的核，在一些实施方式中，分别为乙炔。用作核的合适的组分包括单体、低聚物、大分子单体、聚合物等，但并不限于此。在一些实施方式中，第一组分、第二组分或者两种组分可以包含至少2个官能团，在一些实施方式中包含大约3至大约15个官能团。这些官能团可以从核形成伸展的臂。这样的核可以为直链、支链、星形、树形等。
在一些实施方式中，用作第一组分、第二组分或者二者的合适的核可以由多羟基化合物、多胺或者多硫醇制备。在一些实施方式中，多羟基化合物可以用于形成核。在一些实施方式中，这样的多羟基化合物的例子包括聚醚、聚酯、聚醚-酯、聚链烷醇及其组合等。
可以在形成第一组分和/或第二组分的核的过程中使用的合适的聚醚为在本领域的技术人员所知的范围内，以及其包括：例如聚乙二醇、聚丙二醇、聚亚丁基二醇、聚丁二醇、聚亚己基二醇(polyhexamethylene glycol)，及其共聚物，例如环糊精-聚乙二醇、聚缩醛树脂及其组合。在一些实施方式中，合适的聚醚可以包括聚乙二醇。
可以在形成第一组分和/或第二组分的核的过程中使用的合适的聚酯为在本领域的技术人员所知的范围内，以及包括，例如，三亚甲基碳酸酯(trimethylene carbonate)、ε-己内酯、对二氧杂环己酮(p-dioxanone)、乙交酯、丙交酯、1，5-二氧杂环庚-2-酮(1，5-dioxepan-2-one)、聚己二酸亚丁酯、聚己二酸亚乙酯、聚对苯二甲酸乙二酯及其组合。
此外，如上所述，第一组分和/或第二组分可以包括聚(醚-酯)嵌段。可以使用本领域的技术人员已知范围内的任意合适的聚(醚-酯)嵌段。连接两个二羟基化合物的这些大分子单体(有时，这里称作“聚(醚-酯)大分子单体”)可以包括脂肪族二酸、芳香族二酸、脂环族二酸或者其组合。可以存在多达10个聚(醚-酯)大分子单体的重复单元。
在形成聚(醚-酯)大分子单体过程中可以使用的合适的二酸包括，例如，含有大约2～10个碳原子的二酸。合适的二酸包括：癸二酸、壬二酸、辛二酸、庚二酸、己二酸、戊二酸、丁二酸、丙二酸、乙二酸、对苯二甲酸、环己烷二羧酸及其组合，但并不限于此。
在形成聚(醚-酯)大分子单体的过程中可以使用的合适的二羟基化合物包括：例如，包括聚环氧烷、聚乙烯醇、聚己内酯二醇等的多羟基化合物。在一些实施方式中，所述二羟基化合物可以为例如聚环氧乙烷(“PEO”)、聚环氧丙烷(“PPO”)、聚环氧乙烷(“PEO”)和聚环氧丙烷(“PPO”)的嵌段或者无规共聚物以及它们的组合。
在本发明的一个实施方式中，可以将聚乙二醇(“PEG”)用作二羟基化合物。较理想地为使用分子量为大约200g/mol至大约10000g/mol的PEG，在一些实施方式中使用分子量为大约400g/mol至大约900g/mol的PEG。合适的PEG包括多种来源的市售可得的牌号为PEG 200、PEG 400、PEG 600和PEG 900的PEG。
可以使用任意方法形成聚(醚-酯)大分子单体。在一些实施方式中，通过使己二酰二氯(adipoyl chloride)与例如PEG 600的PEG和吡啶在例如四氢呋喃(THF)的合适的溶剂中结合可以形成聚(醚-酯)大分子单体。该溶液可以在从大约-70℃至大约25℃的合适的温度下保持大约4小时至大约18小时的时间，然后，可以过滤反应混合物以除去沉淀的盐酸吡啶副产物而得到聚(醚-酯)大分子单体，即，这里的PEG/己二酸酯化合物。通过醚或者石油醚的加入从溶液中可以获得所得的聚(醚-酯)大分子单体，以及通过包括过滤的合适的方法来收集。制备该大分子单体的其它合适的方法在本领域的技术人员所知的范围内。
在一些实施方式中，可以使用于形成聚(醚-酯)的组份官能化或者反应，以形成聚(醚-酯-聚氨酯)、聚(醚-酯-脲)等。
可以使用的聚(醚-酯)嵌段的其它合适的例子包括：聚乙二醇-聚己酸内酯、聚乙二醇-聚交酯、聚乙二醇-聚乙醇酸交酯以及在此所述的单独聚醚和聚酯的多种组合，但并不限于此。合适的聚(醚-酯)嵌段的另外的例子包括在美国专利第5,578,662号和美国申请第2003/0135238号中披露的那些例子，其全部内容都在此引入作为参考。
在一些实施方式中，所得的聚(醚-酯)大分子单体的通式如下：
HO-(X-A)y-X-OH (I)
其中，A为从脂肪族、芳香族或者脂环族二酸衍生中的基团；在各处的X可以相同或者不同，并且可以包含从二羟基化合物中衍生的基团；以及y可以为大约1至大约10。在一些实施方式中，A基团可以从己二酸衍生得到，并且X可以从分子量为大约200g/mol至大约1000g/mol的聚乙二醇中衍生得到，在一些实施方式中分子量为大约400g/mol至大约800g/mol，在一些实施方式中分子量为大约600g/mol。
这些化合物的分子量和粘度取决于一系列的因素，例如所使用的具体的二酸、所使用的具体的二羟基化合物和存在的重复单元的数目。一般而言，在25℃和20.25sec-1的剪切速率下这些化合物的粘度可以为大约300至大约10,000cP。
在其它实施方式中，可以使用聚轮烷(polyrotaxane)作为第一组分、第二组分或者二者的核。聚轮烷材料包括环状分子、穿过环形分子的直链分子和在直链分子上的非必需的庞大端基以防止穿过去(dethreading)而使环状分子掉下来。关于轮烷，“直链分子”指的是任意的能够穿过环状分子以形成轮烷材料的合适的分子，不管是支化的或者非支化的。直链分子通常以非支化的链形式。直链分子可以发生支化，但是不能到显著影响轮烷材料的形成的程度。
合适的聚轮烷的例子包括由例如聚环氧乙烷(PEO)的直链聚合物穿过环糊精(CD)的内腔以形成具有类似项链超分子结构的包含络合物的那些聚轮烷。
除了上述的多羟基化合物以外，可以使用多胺和/或多硫醇形成核。
在一些实施方式中，例如上述的聚醚、聚酯或者聚醚-酯的多羟基化合物可以为支化的多羟基化合物。这种多羟基化合物具有可以从其中伸展出大约3至大约12臂的核，在各臂的自由末端具有羟基。因此，例如，4臂的多羟基化合物具有如下的结构：
在一些实施方式中，例如如上所述的聚醚、聚酯或者聚醚-酯的多羟基化合物可以用官能团封端。使多羟基化合物封端以提供活性端基的方法在本领域的技术人员已知的范围内。在一些实施方式中，第一组分可以用至少两个叠氮基封端，以及第二组分可以用至少两个炔基封端。其中，用两个基团使其中一个组分封端，另外的组分用3个或者更多的基团封端。
4臂炔烃的例子包括如下通式的炔烃：
其中，X可以为O、NH、S、SO2及其组合等。
可以使上述通式III的炔烃与多叠氮化物(polyazide)反应。合适的叠氮化物包括，例如：
N-((2S，3R，4S，5S，6S)-4，5-二叠氮基-6-(叠氮基甲基)-2-(苯甲氧基)-四氢-2H-吡喃-3-基)乙酰胺
4，4′-二叠氮基-2，2′-茋二磺酸二钠盐水合物
(3R，4R，5S，6S)-4-叠氮基-6-(叠氮基甲基)四氢-2H-吡喃-2，3，5-三醇
4，4′-氧二(叠氮基苯)
4，4′-磺酰基二(叠氮基苯)
二[2-(4-叠氮基水杨基酰氨基)乙基]二硫化物
1，17-二叠氮基-3，6，9，12，15-五氧杂十七烷
(2E，6E)-2，6-二(4-叠氮基亚苄基)环己酮
四叠氮基-季戊四醇乙氧基化物
七-6-叠氮基-6-脱氧-β-环糊精及其组合等。使用铜催化剂可以使通式III的炔烃与叠氮化物反应产生具有如下结构的本发明的化合物：
其中，X如前述的通式III所限定，并且R可以为多叠氮组分的剩余部分，即，多叠氮分子的片段，其中，通过烷基、脂环基、芳香基及其组合等将所述叠氮基与余下的分子相连。
在其它实施方式中，支链炔基可以为如下的通式：
其它支链炔烃包括，例如，
其中，X可以为脂肪族、脂环族、芳香族或者其组合，以及R可以为脂肪族、脂环族、芳香族或者其组合；
其中，Y可以为脂肪族、脂环族、芳香族或者其组合，以及其中，R可以为脂肪族、脂环族、芳香族或者其组合；和
其中，R可以为脂肪族、脂环族、芳香族或者其组合，以及在上述的任一通式中，n可以为大约0至112，在一些实施方式中n为大约1至大约100，在其它实施方式中n大约3至大约56的数值。
支化的叠氮化物可以具有大约3至大约12个臂，在一些实施方式中，其具有大约4至大约6个臂。示例性的4-臂叠氮化物可以具有如下通式：
在铜催化剂的存在下，可以使结构式V的炔烃与结构式VI的叠氮化物反应以制备如下化合物：
铜催化剂、在一些实施方式中的Cu(I)催化剂的使用，使叠氮化物和炔烃对于可能存在于体内的大量的大多数官能团和条件(conditions)保持惰性的同时通过使因子达到107而可以加速反应过程。可以使用的合适的铜催化剂包括：硫酸铜、碘化亚铜、与抗坏血酸组合的硫酸铜(II)及其组合等，但并不限于此。在一些实施方式中，铜催化剂可以包括硫酸铜，在一些实施方式中，铜催化剂为CuSO4·5H2O。
需要催化剂的量取决于使用的初始材料及其官能度。在一些实施方式中，催化剂合适的量可以为大约1wt％至10wt％，在一些实施方式中为大约2wt％至大约5wt％。
在一些实施方式中，缓冲盐可以与上述催化剂组合。这种缓冲盐包括：醋酸盐、柠檬酸盐、丙二酸盐、酒石酸盐、琥珀酸盐、苯甲酸盐、抗坏血酸盐、磷酸盐、硫酸盐、硝酸盐、碳酸氢盐、碳酸盐及其组合等，但并不限于此。在一些实施方式中，例如抗坏血酸钠、抗坏血酸钙、抗坏血酸亚铁(II)等的抗坏血酸盐及其组合可以与催化剂一起使用。
从上述铜催化反应制备的化合物，其为唑类(azole)，可以用作形成本发明的生物粘合剂。
在一些实施方式中，第一组分、第二组分或者二者可以结合另外的官能团。这种另外的官能团包括：氨基、烷氧基、羧酸基、羧酸酯基、酮基、醚基、酰胺基、砜基、氨磺酰基及其组合等，但是并不限于此。在一些实施方式中，使用也含有胺官能度(functionality)的第一或第二组分是有益的，因为胺通过提供有利于制备Cu-乙炔化物的中间产物的碱性环境而使胺有利于铜催化过程。胺也促进与金属核强烈的螯合作用，例如，胺可以提供重要组分，即Cu(I)的三唑基胺配体，至少一个作用是在溶液相反应中提高了催化效率。
在一些实施方式中，在形成本发明的生物粘合剂组合物的叠氮化物和炔烃的比率为大约1∶2至大约1∶1，在一些实施方式中为大约1∶1。
在一些实施方式中，第一组分、第二组分、催化剂或者其任意组合可以在稀溶液中。可以用来形成稀溶液的合适的溶剂包括本领域技术人员已知的范围内的任意的生物可相容溶剂，其将不会干涉第一组分的叠氮基与第二组分的炔基的反应。可以使用的合适的溶剂包括，例如，极性溶剂，如水，乙醇，三甘醇，二甲亚砜(DMSO)，甘醇二甲醚类(例如二甘醇二甲醚、三甘醇二甲醚、四甘醇二甲醚等)，聚乙二醇，甲氧基聚乙二醇，二甲基甲酰胺，二甲基乙酰胺，γ-丁酸内酯，N-甲基吡咯烷酮(NMP)，酮类，如甲乙酮、环己酮的酮类，二乙二醇单乙醚乙酸酯，二乙二醇单丁基醚乙酸酯，二乙二醇单甲基醚，二乙二醇单乙基醚，二乙二醇单丁基醚，二乙二醇单异丁基醚，二异丁基酮，双丙酮醇，乙基戊基酮，乳酸乙酯等。在其它实施方式中，可以使用例如四氢呋喃、乙酸乙酯、乙酸异丙酯、乙酸丁酯、异丙醇、丁醇、丙酮等溶剂。在一些实施方式中，可以使用任意的前述溶剂的组合形成稀释溶剂。
可以使溶剂与第一组分、第二组分、催化剂或者其组合混合。可以使溶剂与第一组分混合以便使第一组分的浓度为稀溶液的大约5重量百分比至大约50重量百分比，在一些实施方式中为稀溶液的大约8重量百分比至大约20重量百分比。可以将溶剂与第二组分混合以便第二组分的浓度为稀溶液的大约5重量百分比至大约50重量百分比，在一些实施方式中为稀溶液的大约8重量百分比至大约20重量百分比。可以将溶剂与催化剂混合以便催化剂的浓度为稀溶液的大约10重量百分比至大约80重量百分比，在一些实施方式中为稀溶液的大约30重量百分比至大约50重量百分比。
第一组分、第二组分、催化剂与这里所述的任意的溶剂的混合物可以形成乳液或者稀溶液。所得乳液或者溶液的粘度可以为大约1cP至大约50cP，在其它实施方式中为大约2cP至大约10cP，在另外的实施方式中为大约3cP至大约5cP。
使用的溶剂的量取决于多个因素，包括所采用的具体的第一组分、第二组分、催化剂或者其组合和该组合物的预期的最终用途。
根据本发明，本发明的组合物的固化的速率可以通过控制第一组分、第二组分、催化剂或者任意的组合的浓度来调节。一般而言，在第一或者第二组分或者催化剂中任一个具有较高的浓度下观察到的固化速率比相同组分在较低浓度下观察到的固化速率快。在本发明的组合物的两种组分与催化剂接触并涂敷到组织上之后，大约1秒至大约5分钟可以固化，在一些实施方式中，在接触大约30秒至大约2.5分钟后固化。
也可以向本发明的组合物中加入多种非必需的成分，其包括：表面活性剂、抗微生物剂、着色剂、防腐剂、例如碘或硫酸钡或氟的显像剂、药剂，但并不限于此。在一些实施方式中，该组合物可以非必需地包含一种或多种生物活性剂。在这里使用的术语“生物活性剂”以其最广泛的含义被使用，并且包含具有临床用途的任意的物质或物质的混合物。因此，生物活性剂本身可以具有或者不具有药理学活性，例如染料。或者，生物活性剂可以为能提供治疗或者预防效果的任意的试剂，影响或者参与了组织生长、细胞生长和/或细胞分化的化合物，能够引起例如免疫反应的生物反应或者能够在一个或者多个生物过程起作用的化合物。
可以使用的根据本发明的生物活性剂的种类的例子包括抗菌类、镇痛药类、退热药类、麻醉剂类、抗癫痫药类、抗组胺剂类(antihistamines)、消炎药类、心血管药物类、诊断用药类、拟交感神经药类、拟胆碱药物类、抗毒蕈碱类(antimuscarinics)、镇痉剂类、激素类、生长因子类、肌松剂类、肾上腺素能神经元阻滞剂类、抗瘤剂类、免疫剂类、免疫抑制剂、胃肠药类、利尿剂、类固醇、脂质类、脂多糖类、多糖类和酶类。同样预期可以使用生物活性剂的组合。
可以作为生物活性剂包含在本组合物中的合适的抗菌剂包括三氯生，也称作2，4，4′-三氯-2′-羟基二苯醚，双氯苯双胍己烷及其盐，其包括醋酸洗必太、葡萄糖酸洗必太、盐酸洗必太和硫酸洗必太，银及其盐，其包括醋酸银、苯甲酸银、碳酸银、柠檬酸银、碘酸银、碘化银、乳酸银、月桂酸银、硝酸银、氧化银、棕榈酸银、蛋白银和磺胺嘧啶银，多粘菌素，四环素，氨基糖甙类，例如托普霉素和庆大霉素，利福平，杆菌肽，新霉素，氯霉素，咪康唑，喹诺酮类，例如奥索利酸、氟哌酸、萘啶酸、萘啶酸、依诺沙星和环丙沙星，青霉素类，例如苯唑西林和哌拉西林钠，壬苯醇醚9(nonoxynol 9)，夫西地酸，先锋霉素类及其组合。此外，例如牛或猕猴(rh-)的乳铁蛋白和乳铁蛋白B的抗微生物蛋白质和肽作为生物活性剂可以包含在本发明的组合物中。
可以包含在在该组合物中作为生物活性剂的其它生物活性剂包括：局部麻醉药；非类固醇类的抗生育剂；拟副交感神经药；精神治疗药物；安定药；解充血药；镇静催眠药；类固醇；磺胺类药物；拟交感神经药；疫苗；维生素；抗疟药；抗偏头痛药；例如左旋多巴的抗震颤麻痹药；镇痉剂；抗胆碱能药物(奥昔布宁)；镇咳药；支气管扩张剂；例如冠脉扩张药和硝化甘油的心血管药；生物碱类；镇痛药；例如可待因、双氢可待因酮、派替啶、吗啡等的麻醉药；例如水杨酸盐、阿斯匹林、扑热息痛、d-丙氧芬(d-propoxyphene)等的非麻醉药；例如环丙甲羟二羟码啡酮和纳洛酮的阿片受体拮抗剂；抗癌剂；抗惊厥剂；抗催吐药；抗组胺类；例如激素、氢化可的松、泼尼松龙、泼尼松、非激素剂(non-hormonal agent)、别嘌醇、吲哚美辛、保泰松等的抗炎剂；前列腺素和细胞毒类药物；雌激素；抗菌药物；抗生素；抗真菌药；抗病毒剂(anti-virals)；抗凝血剂；抗惊厥药；抗抑郁药；抗组胺类；和免疫剂。
可以包括在该组合物中的合适的生物活性剂的其它例子包括细胞、肽、多肽和蛋白质，其类似物，突变蛋白质及其活性片段，例如免疫球蛋白类，抗体，细胞活素类(例如淋巴因子、单核因子、化学增活素)，凝血因子类，造血因子类，白细胞介素(IL-2、IL-3、IL-4、IL-6)，干扰素类(β-IFN、α-IFN和γ-IFN)，红细胞生成素，核酸酶，肿瘤坏死因子，集落刺激因子(例如GCSF、GM-CSF、MCSF)，胰岛素，抗(肿)瘤剂和肿瘤抑制基因，血蛋白，促性腺激素类(例如FSH、LH、CG等)，激素类和类激素类(例如生长激素)，疫苗(例如肿瘤、细菌和病毒抗原)；生长激素抑制素；抗原类；凝血因子；生长因子(例如神经生长因子、胰岛素样生长因子)；蛋白质抑制剂、蛋白质拮抗药(protein antagonist)和蛋白质促效剂(protein agonist)；例如反义分子，DNA和RNA的核酸；寡核苷酸；和核酶。
天然产生的高分子，包括例如胶原的蛋白质和例如葡萄糖胺聚糖天然产生的多糖的衍生物作为生物活性剂可以非必需地包含在本发明的组合物中。
在该组合物中可以使用的单个的生物活性剂，在替换的实施方式中，在该组合物中可以使用生物活性剂的任意组合。
所述第一组分上的叠氮基与所述第二组分上的炔基使本发明的组合物交联以形成凝胶基体，在将其给药到组织上之后，该基体起到优异的组织粘合剂或者密封剂的作用。一般而言，在大约20℃至大约40℃的温度下可以进行交联反应，在一些实施方式中为大约25℃至大约37℃。实现本发明的组合物的交联反应的确切条件取决于多个因素，其包括：组分的官能度、封端的程度、官能作用的程度、所选择的催化剂及其用量、具体的溶剂(如果有)等。
本发明中的组合物打算用来传输药物或者蛋白质，可以调节第一和第二组分的量以促进在生物粘合剂组合物的药物或聚合物的初期保留(initialretention)及其后续的释放。进行调节的方法和手段对于本领域的技术人员将会是显而易见的。
通过使用本领域的技术人员已知的方法使组分结合，可以使用第一组分(非必需地在溶液中)、第二组分(非必需地也在溶液中)和催化剂(非必需地也在溶液中)形成本发明的粘合剂和/或密封剂，在此有时称作生物粘合剂组合物，所述使组分结合的方法包括：混合(mixing)、掺和(blending)、滴加(dripping)、刷涂(brushing)等，或者其它在组织表面上直接处理组合物的方法，或者将该组合物喷雾在表面上。在开放式外科手术中，通过手、镊子等进行涂敷。在内镜手术中，通过本领域已知的任意的装置经由套管针的套管传输所述组合物并涂敷在接受部位。
例如，在一些实施方式中，使用例如压舌板的简单装置使用混合的方法使稀溶液中的含有叠氮基的第一组分与含有炔基的第二组分在催化剂的存在下结合。在其它的实施方式中，通过简单地将两种组分置入第一注射器中，并将第一注射器的内含物排出至第二注射器中，接着将第二注射器的内含物排出至第一注射器中，并在两个注射器之间重复该步骤直到组分混合，这样可以使第一组分与第二组分在稀溶液中结合。在这种实施方式中，催化剂可以包含在第一注射器、第二注射器或者二者中。
因此，在一些实施方式中，在给药之前，在稀溶液中的第一组分和第二组分可以与催化剂结合，在一些实施方式中所述催化剂为铜催化剂。这有利于本发明的组合物用作空腔的填充物或者密封剂用于填充动物体内的缺陷，从而更精确地控制条件和交联的程度。例如，较理想地为在用来填充动物组织的空腔之前部分交联该组合物。在这种情况下，可以将本发明的生物粘合剂组合物应用于空腔或缺陷并使其固化，因此填充了空腔或缺陷。
在其它的实施方式中，非必需地在稀溶液中，在给药时，第一组分可以与第二组分和催化剂结合。一个实施例包括使第一组分和第二组分分开，并向相同的位置以连续的方式喷雾单独的成分和催化剂，因此，使两种成分和催化剂混合并原位形成键。在该实施例中，催化剂可以与两种组分分开、可以与第一组分分开、可以与第二组分分开或者与两种组分分开，并在催化剂与两种组分应用之后催化第一组分和第二组分的反应。
另外的实施例包括：使第一组分与第二组分分开，并通过例如喷雾器或者喷嘴的相同的装置同时喷雾两种成分和催化剂，因此在将它们喷雾至组织上时使成分混合，同时它们将原位形成键。
在给药时使两种组分与催化剂结合的方法在本领域的技术人员已知的范围内，以及其包括，例如，从常规的粘合剂分配器(dispenser)中调配两种组分和催化剂，其在置入分配器之前通常提供与催化剂混合的第一和第二组分。例如，在美国专利第4,978,336号、第4,361,055号、第4,979,942号、第4,359,049号、第4,874,368号、第5,368,563号和第6,527,749号公开的这些分配器，上述各自公开的内容在此全部引入作为参考。
本发明的组合物可以用于一系列不同人类或者动物的医疗应用，其包括：伤口的愈合(包括外科切口和其它伤口)，但并不限于此。粘合剂或者作为代替物或者作为补充物与缝合线、肘钉(staple)、夹子(clamps)、扎带、绷带等一起用于粘结组织。使用该组合物可以避免或者大量减少目前行医中通常所需要的缝合线的量，并避免了移去肘钉和某种类型的缝合线的后续的需求。这里所描述的组合物可以因此适合于脆弱的组织，在这些组织中，缝合、夹子或其它常规的组织愈合机制可以引起进一步的组织损伤。例如，本发明的组合物可以用于同时密封或粘结脆弱组织，例如肺组织，代替可能引起机械应力的常规的器械。该组合物也可以用于在组织中密封空气和/或液漏，和预防手术后的粘合以及填充组织中的空腔和/或缺陷。
为了使两组织的边缘完成结合，该两边缘可以相互紧靠，以及可以将本发明的组合物应用到两相互紧靠的边缘上。在一些实施方式中，第一组分、第二组分和催化剂可以首先结合以形成可以应用到组织上的生物粘合剂组合物。然后，第二组织表面可以与具有生物粘合剂组合物的组织接触以便其粘结至上面。在其它实施方式中，第一组分、第二组分和催化剂可以分别应用到组织的表面，然后第二组织表面可以与第一组织表面接触，然后生物粘合剂组合物可以使两组织表面粘结。在其它的实施方式中，第一组分、第二组分和催化剂可以分别应用于至少两个组织的表面上，然后，该组织表面可以相互接触以便本发明的生物粘合剂组合物在体内形成以使组织表面粘结。
本发明的生物粘合剂组合物交联得很快，通常需要少于一分钟。本发明的组合因而可以应用于伤口上并使其固化，因此使伤口闭合。
这里所述的组合物也可以用作密封剂。当用作密封剂时，本发明的组合物可以用于外科手术中以在手术操作过程中或之后防止或抑制流血或液漏(fluid leakage)。也可以应用它防止肺部手术的漏气。可以将这里所述的组合物以足够密封组织的任意的缺陷和密封任意液体或气体流动的至少的量直接施用至所需的区域。该组合物也可以用于防止或控制血液或其它液体在缝合处或肘钉线处的渗漏。
该组合物也可以在整形外科中用于粘结皮肤植片和安置组织皮瓣(tissue flaps)。或者，该组合物可以用于牙周症手术中使组织皮瓣闭合。
在另一实施方式中，本发明说明了用于使用本发明的组合物将医疗装置粘结至组织上的方法。合适的医疗装置包括植入物。其它医疗装置包括：起搏器、支架、分流器等，但是并不限于此。通常而言，对于将装置粘结至动物组织的表面上，可以将本发明的组合物应用到装置上，组织的表面上或者二者上。然后，使装置和组织的表面通过位于二者间的本发明的组合物开始接触。在其它实施方式中，可以将第一组分应用到装置上或组织的表面上，并将第二组分应用到另一个上。使装置与组织的表面开始相互接触，以便第一组分和第二组分相互接触。催化剂的应用将导致形成本发明的组合物。一旦该组合物交联和固化，该装置和组织表面相互有效地粘结在一起。
本发明的组合物也可以用于防止手术后的粘连(adhesions)。在该应用中，可以应用并固化本发明的组合物以在体内的组织表面形成一层，从而防止在康复过程中手术部位的粘连。
所得的生物粘合剂组合物具有一系列的优点。该生物粘合剂组合物安全、对组织具有提高的粘结性、是生物可降解的、具有提高的止血性能、成本低和容易制备和使用。通过改变选择使用形成生物粘合剂组合物的化合物，可以控制该生物粘合剂组合物的强度和弹性以及胶凝时间。
用本发明的生物粘合剂组合物形成的粘合剂和/或密封剂具有优异的强度和类似的物理性能。这里所述的组合物快速形成适应的凝胶基体(compliant gel matrix)，其确保组织边缘或者在所需的位置植入医疗装置的固定位置并减少了全部所需的手术/应用时间。该组合物形成强烈的粘结结合性。其显示出优异的机械性能和强度，同时保持粘结至活组织上的必要的柔软性。该强度和柔软性在不移动手术组织的边缘的情况下允许组织一定程度的移动。
下面提出的实施例用来说明本发明的实施方式。这些实施例仅用来用于说明而不是用于限制本发明的范围。而且，除非特别声明，份数和百分比为重量份数和重量百分比。
实施例1
制备用于合成叠氮化物的甲苯磺酸酯。将大约10mL的四氢呋喃(THF)加入到大约3.6克的季戊四醇乙氧基化物(大约5毫摩尔)和1.45克氢氧化钠(大约36毫摩尔)的10mL的水溶液中。季戊四醇乙氧基化物(这里有时称作季戊四醇-EO)，其具有如下结构：
其中，n为大约3至大约60，在一些实施方式中为大约4至大约8。
然后，在室温下(大约21±5℃)和氮气氛围下在大约24小时内将大约4.31克的固体对甲苯磺酰氯(p-Tos-Cl)(大约23毫摩尔)加入到上述的溶液中。然后用30mL的水稀释反应混合物，并用40mL的乙酸乙酯萃取4次。用硫酸镁、过滤、蒸发和在高真空下干燥进行有机相的干燥。将所得的产物在重氢氯仿中由质子NMR分析。用三氯乙酰基异氰酸酯处理的NMR样品显示出最终产物具有大约16％的游离羟基。
因而制备了多磺酸酯(polysulfonate)，其在这里称作季戊四醇甲苯磺酸酯(季戊四醇-Tos)，如下所示：
其中，n为大约3至大约60的数值，在一些实施方式中为大约4至大约8。
实施例2
用聚乙炔制备用于点击反应的4臂叠氮化物。使大约2.76克的在上面的实施例1中制备的季戊四醇-Tos多磺酸酯(大约2毫摩尔)与大约0.57克的叠氮化钠(NaN3)(大约9毫摩尔)在大约10mL的二甲基甲酰胺中反应。在氮气氛围中在大约60℃下搅拌该反应混合物。该反应混合物被分成大约15mL的水和40mL的醚。分开两相并用大约25mL的醚萃取水相。用硫酸镁、过滤和蒸发来干燥化合的有机相。用NMR分析残余物。NMR光谱证实甲苯磺酸酯基的取代。
因而制备了4臂的叠氮化物如下：
其中，n为大约3只大约60的数值，在一些实施方式中为大约4至大约8。
实施例3
制备在点击反应的中使用的炔衍生物。在室温下(大约21±5℃)将大约15.75克的季戊四醇丙氧基化物(大约25毫摩尔)慢慢地加入到大约21.81克(大约125毫摩尔)的2，4-甲苯二异氰酸酯(TDI)中。然后，加热该混合物至大约65℃大约18小时。该反应混合物用石油醚洗涤7次。对于每次洗涤，加入大约45mL的石油醚并在大约65℃下搅拌该反应混合物大约10分钟至大约15分钟的时间。倾斜该混合物并用移液管移出浮于上层的石油醚。重复该步骤六次；在真空下干燥所得的材料以提供季戊四醇丙氧基化物-TDI加合物。该材料具有大约13.49％的游离异氰酸酯的含量，其是通过滴定法测定的。该季戊四醇丙氧基化物-TDI加合物的通式如图1所示，其中n为大约1至大约15。
使大约3.46克的季戊四醇丙氧基化物-TDI加合物(大约13.49％的游离NCO)与大约3.83克的4-戊炔-1-醇(大约45毫摩尔)在6mL的THF中结合。在氮气氛围下升温该混合物至65℃并保持大约20小时。
因而制备如图2所描述的炔的衍生物，其中，n为大约1至大约15。
实施例4
使实施例2的4臂叠氮化物与实施例3的炔衍生物化合以制备本发明如下的组合物。将大约100毫克的实施例3的炔衍生物(大约68微摩尔)与大约1.7毫克的五水合硫酸铜(CuSO4·5H20)(大约68微摩尔)溶解在THF和水的混合物(各为0.25mL)中，并与包含大约68.6毫克的实施例2的4臂叠氮化物(大约68微摩尔)的溶液和溶解在THF和水(各为0.25mL)中的大约5.4毫克的抗坏血酸钠混合。将所得的混合物在漩涡漏斗(Vortex)上震荡以制备本发明的组合物。
应该理解到可以对在此公开的实施方式进行多种改进。因此，上述的描述不能认为是限制，而仅仅是典型的实施方式的示例。在所附的权利要求的范围和实质内本领域的技术人员将可构思多种改进。
Claims (13)
1.一种生物粘合剂组合物，其特征在于：
使含有至少两个炔基的第一组分与含有至少两个叠氮基的第二组分接触；
催化第一组分与第二组分的聚合反应以形成生物粘合剂组合物；和
使该生物粘合剂组合物与至少一个组织的表面接触以使生物粘合剂组合物粘结到至少一个组织的表面上，
其中，所述第一组分的通式选自：
其中，X选自O、NH、S、SO2及其组合，并且n为1至15的数值。
2.根据权利要求1所述的生物粘合剂组合物，其中，所述第二组分选自N-((2S,3R,4S,5S,6S)-4,5-二叠氮基-6-(叠氮基甲基)-2-(苯甲氧基)-四氢-2H-吡喃-3-基)乙酰胺、4,4'-二叠氮基-2,2'-茋二磺酸二钠盐水合物、(3R,4R,5S,6S)-4-叠氮基-6-(叠氮基甲基)四氢-2H-吡喃-2,3,5-三醇、4,4'-氧二(叠氮基苯)、4,4'-磺酰基二(叠氮基苯)、二[2-(4-叠氮基水杨基酰氨基)乙基]二硫化物、1,17-二叠氮基-3,6,9,12,15-五氧杂十七烷、(2E,6E)-2,6-二(4-叠氮基亚苄基)环己酮、四叠氮基-季戊四醇乙氧基化物、七-6-叠氮基-6-脱氧-β-环糊精及其组合。
3.根据权利要求1所述的生物粘合剂组合物，其中，所述第一组分与第二组分的聚合反应通过铜催化剂催化，该铜催化剂选自硫酸铜、碘化亚铜及其组合。
4.根据权利要求3所述的生物粘合剂组合物，其中，使所述铜催化剂与缓冲盐接触，该缓冲盐选自醋酸盐、柠檬酸盐、丙二酸盐、酒石酸盐、琥珀酸盐、苯甲酸盐、抗坏血酸盐、磷酸盐、硫酸盐、硝酸盐、碳酸氢盐、碳酸盐及其组合。
5.根据权利要求1所述的生物粘合剂组合物，其中，所述第一组分和非必需的第二组分含有另外的官能团，该官能团选自氨基、烷氧基、羧酸基、羧酸酯基、酮基、醚基、酰胺基、砜基、氨磺酰基及其组合。
6.根据权利要求1所述的生物粘合剂组合物，其中，所述第二组分的叠氮基与第一组分的炔基的比为1:2。
7.根据权利要求3所述的生物粘合剂组合物，其中，所述第一组分，非必需的第二组分以及非必需的催化剂在溶液中。
8.根据权利要求1所述的生物粘合剂组合物，其中，在施用至组织之前形成所述生物粘合剂组合物。
9.根据权利要求1所述的生物粘合剂组合物，其中，所述生物粘合剂组合物在体内形成。
10.根据权利要求1所述的生物粘合剂组合物，其中，所述生物粘合剂组合物为如下通式所示：
其中，X选自O、NH、S、SO2及其组合，以及R包含含有至少两个叠氮基的第二组分的剩余部分。
11.根据权利要求1所述的生物粘合剂组合物，其中，所述生物粘合剂组合物进一步包含至少一种生物活性剂。
12.根据权利要求1所述的生物粘合剂组合物，其进一步包括使所述生物粘合剂组合物与第二组织表面接触。
13.根据权利要求1所述的生物粘合剂组合物，其进一步包括使所述生物粘合剂组合物与植入物接触。
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Also Published As
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| AU2009201045B2 (en) | 2014-07-31 |
| US20090247651A1 (en) | 2009-10-01 |
| CN101549169A (zh) | 2009-10-07 |
| EP2106809A3 (en) | 2012-08-22 |
| EP2106809A2 (en) | 2009-10-07 |
| US8034396B2 (en) | 2011-10-11 |
| JP2009247896A (ja) | 2009-10-29 |
| CA2658439A1 (en) | 2009-10-01 |
| AU2009201045A1 (en) | 2009-10-15 |
| JP5613382B2 (ja) | 2014-10-22 |
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