CN1213285A - 用作伤口闭合器的单体组合物 - Google Patents
用作伤口闭合器的单体组合物 Download PDFInfo
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- CN1213285A CN1213285A CN97192705A CN97192705A CN1213285A CN 1213285 A CN1213285 A CN 1213285A CN 97192705 A CN97192705 A CN 97192705A CN 97192705 A CN97192705 A CN 97192705A CN 1213285 A CN1213285 A CN 1213285A
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- compositions
- cyanoacrylate
- tissue surface
- tissue
- monomer
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Abstract
一种生物相容单体组合物包括:(A)至少一种可形成医学上可接受的聚合物的单体;(B)至少一种增塑剂,增塑剂在组合物中的含量为0.5—15%(重量);和(C)至少一种pKa电离常数约为1—7的酸性稳定剂。组合物可施加到各种材料上,特别适于用作体内组织胶粘剂。一种合拢体内两个表面如体组织的方法,包括(a)将受伤的组织表面合在一起形成毗连的组织表面;(b)将过量组合物涂敷到毗连组织表面上,组合物包含1)至少一种形成医学上可接受的可生物降解的聚合物的单体,2)至少一种增塑剂和3)至少一种酸性稳定剂;和(c)与表面保持接触直至组合物聚合成跨接毗连组织薄膜的聚合组合物厚膜。
Description
发明领域
本发明涉及用于制成生物医学胶粘剂和密封剂的单体和聚合物组合物，以及它们的施用方法。更具体地，本发明涉及伤口闭合的单体和聚合物组合物及其在内科、外科以及其它体内用途中的应用。
背景
主要用于伤口闭合的产品是外科用缝线和钩环。缝线被认为可提供足够的伤口支撑。然而，缝线会使受伤部位产生附加的外损伤(因为要使针和缝线通过组织并且在施针时要麻醉受伤区域)，缝线耗时间，并且在表皮上会形成难看的伤口闭合痕迹。外科用钩环可加速伤口对合，并有改善的整容效果。然而，外科用钩环也形成了附加的伤口外损伤，并且需要用辅助的通常较昂贵的装置来固定和施加钩环。在儿科(患者有强烈的恐惧反应，在安置钩环时拒绝合作)和老年科(患者皮肤较脆弱，易撕裂)中，缝线和钩环均特别成问题。
或者，建议用胶粘剂作为伤口闭合器械。这种胶粘剂中的一类是单体形式的α-氰基丙烯酸酯类化合物。
对比文献可参见例如美国专利5,328,687(Leung等)、3,527,841(Wicher等)、3,722,599(Robertson等)、3,995,641(Kronenthal等)和3,940,362(Overhults)，它们公开了用作外科胶粘剂的α-氰基丙烯酸酯类化合物。所有前述对比文献均结合入本文作参考。
通常，氰基丙烯酸酯外科用胶粘剂涂敷在伤口或切口的一个或两个表面上，包括伤口的内部，而将其余多余的胶粘剂则迅速从粘结表面除去。随后，将伤口边缘被合在一起直至它们粘合。参见美国专利No.3,559,652(小Coover等)。伤口表面可涂敷两层胶粘剂涂层。然而，由于伤口部位吸留外科用胶粘剂，因此这种涂敷方法会产生显著水平的组织毒性。
另一种将氰基丙烯酸酯外科用胶粘剂涂敷到伤口或切口上的方法是在伤口部位上方形成一个跨桥(bridge)。如美国专利No.3,667,472(Halpern)所述的，将切开的组织合在一起，并保持固定位置直至在切口上敷用氰基丙烯酸酯胶粘剂并经所需长的时间形成粘合。从切口上除去多余的胶粘剂。然而，这种方法中所用的组合物有膜强度和柔韧性不足和伤口部位组织毒性高的缺点。
这些涂敷组织胶粘剂的传统方法并没有指出一种特别佳的方法，也没有提到在伤口上涂敷大于最少量的胶粘物。出于组织毒性的考虑，传统的涂敷方法力求减少对伤口涂敷多余量的组织胶粘剂。
一种商业上可获得的外用组织胶粘剂是购自德国B.Braun Melsungen AG的Histoacryl。生产商建议，这种胶粘剂只能用于较小的皮肤伤口闭合，而不能内服。而且生产商还建议，胶粘剂用量应较少，或以薄膜形式涂敷，因为厚的膜不但不会提高膜强度，而且会由于生热反应而导致周围组织坏死。而且，这种胶粘剂形成的薄膜很脆，会使伤口严重裂开。
已经在氰基丙烯酸酯外科用胶粘剂组合物中加入增塑剂。参见美国专利No.3,759,264(小Coover等)、3,667,472(Halpern)、3,559,652(Banitt)，其中主要内容结合入本文作参考。然而，在这种组合物中加入增塑剂将降低聚合材料的膜强度。因此，这种组合物只能用于伤口部位，而不能在伤口部位上方作为跨桥。
为了改善胶粘剂的固化速度和使用寿命，也已在氰基丙烯酸酯外科用胶粘剂中采用了其它添加剂。例如氰基丙烯酸酯聚合反应抑制剂或稳定剂，包括路易斯酸，如二氧化硫、氧化氮、三氟化硼和其它酸性物质，包括氢醌单甲基醚、氢醌、硝基氢醌、儿茶酚和氢醌单乙基醚。例如参见美国专利No.3,559,652(Banitt)，其主要内容结合入本文作参考。这些组合物含有大量的杂质，因此需要大量的稳定剂来抑制单体的过早聚合。
其它胶粘剂可包括增塑剂和稳定剂。例如，美国专利No.5,480,935(Greff等)描述了一种有增塑剂和聚合抑制剂的组织胶粘剂。然而，其中公开的增塑剂(即，邻苯二甲酸烷酯)有很高的毒性，不适于用作生物相容的医用胶粘剂。
发明概述
本发明是基于这样一个发现，即下文描述的单体与一种增塑剂和一种酸性稳定剂的组合提供了一种外科用胶粘剂组合物，该组合物在涂敷到伤口或切口上后，可在伤口或切口部位聚合成牢固而柔韧的粘合体。而且，本发明提供了一种以跨桥结构涂敷该外科用胶粘剂组合物的方法，该跨桥结构比将聚合组合物涂敷到伤口或切口部位的传统方法有出乎意料的改善的粘合强度，这就提高了这种单体和聚合物在体内应用中的效果。
外科用胶粘剂在伤口和切口上形成了柔韧而牢固的粘合体。而且，将外科用胶粘剂涂敷到伤口或切口上的方法提供了牢固而柔韧的生物相容性粘合体。 较佳实施例详述
本发明的一个例子提供了一种伤口闭合单体组合物，该组合物包括：
A)至少一种单体，它可形成药学上接受的伤口闭合聚合物；
B)至少一种增塑剂；和
C)至少一种酸性稳定剂。
在另一个实例中，本发明涉及一种将上述单体、从其制得的共聚物和聚合物的用于生物医学目的的使用方法。
在这样一个实例中，伤口或切口的边缘被夹在一起，将过量的上述外科用胶粘剂组合物涂敷到已经夹住或毗连的相对的伤口边缘上，最好用超过一次的涂敷次数。该方法在毗连的相对的伤口边缘上形成一个柔韧而且拉伸强度高的跨桥。敷在毗连的相对的伤口边缘上的过量胶粘剂在其上形成了厚的薄膜，并且出乎意料地提高了膜强度。
例如，本发明包括一种在毗连组织表面上形成生物相容的薄膜的方法，方法包括：(a)将至少两个组织表面夹在一起形成毗连的组织表面，(b)在所述毗连的组织表面上涂敷一种生物相容的胶粘剂单体组合物，和(c)使所述组合物在所述毗连组织表面上聚合成一生物相容的薄膜，该膜的体内膜强度至少有70mmHg(引起伤口破裂所需的真空压力)，通常为70mmHg至400mmHg，以90-400mmHg为较佳，100-400mmHg为更佳。
较佳的，该单体是α-氰基丙烯酸酯。本发明的单体组合物和从其制得的聚合物可用作组织胶粘剂、用于防止出血或用于覆盖开放伤口的密封剂，以及其它生物医学应用。发现它们可用于，例如，合拢外科上切开的或外伤撕开的组织；固定折断的骨结构；阻止血液从伤口流出；和帮助活组织修复和再生长。
如上所述，传统的外科用胶粘剂组合物含有的增塑剂有减少膜强度的不利影响。与已有技术相反，在本发明中发现，当加入大量增塑剂时，在某些条件下的膜强度(如韧度)不会减少。由于胶粘剂组合物中所用的特定的酸性稳定剂和单体的纯度，加入较大量的增塑剂可提高伤口上形成的粘合体的韧度。已经发现弱酸性稳定剂不会显著影响本发明组合物中单体的聚合，并可通过增加增塑剂的用量来提高膜强度。
可用于本发明的单体可以聚合(如阴离子聚合或自由基聚合)成聚合物。这些单体包括那些形成可以(但不是必须)生物降解的聚合物的单体。例如参见美国专利No.5,328,687，其内容结合入本文作参考。如本文所定义的，“组织毒性”是指不良的组织反应，如由于组织中有毒物质存在而引起的发炎。
有用的1,1-二取代乙烯单体包括(但不局限于)有以下结构式的单体：
(Ⅰ)CHR=CXY其中X和Y分别是强吸电子基团，R是H、-CH=CH2或，如果X和Y均为氰基，则R是C1-C4烷基。
结构式(Ⅰ)范围内的单体例子包括结构式为CH2=CH′Y′的α-氰基丙烯酸酯、亚乙烯基二氰、亚乙烯基二氰的C1-C4烷基同系物、亚甲基丙二酸二烷酯类、酰基丙烯腈类、亚磺酸乙烯酯类和磺酸乙烯酯类，其中X′是-SO2R′或-SO3R′,Y′是-CN、-COOR′、-COCH3、-SO2R′或-SO3R′,R′是H或烃基。
用于本发明的结构式(Ⅰ)的较佳单体是α-氰基丙烯酸酯类。这些单体是本领域中已知的，并有结构式(Ⅱ)其中R2是氢，R3是烃基或取代的烃基、有结构式R4-O-R5-O-R6的基团，其中R4是有2-4个碳原子的1,2-亚烷基，R5是有2-4个碳原子的亚烷基，R6是有1-6个碳原子的烷基；R3或是有结构
的基团，其中R7是亚甲基、亚乙基或亚异丙基，R8是一个有机基团。
合适的烃基和取代烃基的例子包括有1-16个碳原子的直链或支链烷基；被酰氧基、卤代烷基、烷氧基、卤原子、氰基或卤代烷基取代的C1-C16直链或支链烷基基团；有2-16个碳原子的直链或支链链烯基；有2-12个碳原子的直链或支链炔基；环烷基；芳烷基；烷基芳基和芳基。
有机基团R8可以是取代或未取代的，可以是直链、支链或环状的，可以是饱和、不饱和的或芳族的。这些有机基团的例子包括C1-C8烷基、C2-C8链烯基、C2-C8炔基、C3-C12脂环族基团、芳基如苯基和取代的苯基，以及芳烷基如苄基、甲基苄基和苯乙基。其它有机基团包括取代的烃类基团，如卤素(如氯、氟和溴取代的烃)和氧基(如烷氧基取代的烃)取代的烃基团。较佳的有机基团是有1至约8个碳原子的烷基、链烯基和炔基，及其卤代衍生物。特别佳的是有4-6个碳原子的烷基。
在结构式(Ⅱ)的氰基丙烯酸酯单体中，R3宜为有1-10个碳原子的烷基基团或有结构式-AOR9的基团，其中A是有2-8个碳原子的二价直链或支链亚烷基或氧基亚烷基，R9是有1-8个碳原子的直链或支链烷基。
结构式-AOR9表示的基团的例子包括1-甲氧基-2-丙基、2-丁氧基乙基、异丙氧基乙基、2-甲氧基乙基和2-乙氧基乙基。
用于本发明的较佳的α-氰基丙烯酸酯类单体是氰基丙烯酸2-辛酯、氰基丙烯酸十二烷酯、氰基丙烯酸2-乙基己酯、氰基丙烯酸丁酯、氰基丙烯酸甲酯、氰基丙烯酸3-甲氧基丁酯、氰基丙烯酸2-丁氧基乙酯、氰基丙烯酸2-异丙氧基乙酯或氰基丙烯酸1-甲氧基-2-丙酯。
结构式(Ⅱ)的α-氰基丙烯酸酯类可通过本领域已知的方法制得。参见例如美国专利No.2,721,858和3,254,111，两者中的内容均结合入本文作参考。例如，α-氰基丙烯酸酯类可通过使氰基乙酸烷酯与甲醛在非水性有机溶剂中并在碱性催化剂存在下反应，然后在聚合抑制剂存在下热解无水的聚合物中间体来制得。制得的含水量低且基本不含杂质的α-氰基丙烯酸酯单体可特别佳地用于生物医学用途。
结构式(Ⅱ)中R3为有结构式R4-O-R5-O-R6的基团的α-氰基丙烯酸酯类可根据美国专利No.4,364,876(Kimura等)所公开的方法制备，其内容结合入本文作参考。在Kimura等的方法中，α-氰基丙烯酸酯类化合物的制备如下。通过用醇来酯化氰基乙酸或是用氰基乙酸烷酯和一种醇的转酯化来制得氰基乙酸酯；在摩尔比为0.5-1.5∶1(0.8-1.2∶1更佳)的催化剂存在下，使氰基乙酸酯和甲醛或多聚甲醛缩合成一种缩合物；直接或是在除去缩合催化剂后使缩合反应混合物解聚，生成粗制的氰基丙烯酸酯；然后蒸馏粗制的氰基丙烯酸酯，获得高纯度的氰基丙烯酸酯。
结构式(Ⅱ)中R3为结构式
的基团的α-氰基丙烯酸酯类化合合物可根据美国专利No.3,995,641(Kronenthal等)所述的方法制备，其内容结合入本文作参考。在Krontnthal等的方法中，这些α-氰基丙烯酸酯类单体的制备如下。使α-氰基丙烯酸的一种烷酯与环1,3-二烯反应生成狄尔斯-阿德耳加成物，然后使加成物碱水解，然后酸化生成相应的α-氰基丙烯酸加成物。α-氰基丙烯酸加成物最好用溴代乙酸烷酯来酯化，生成相应的α-氰基丙烯酸烷氧羰基甲酯加成物。或者，α-氰基丙烯酸加成物可通过与亚硫酰氯反应来转变成α-氰基烯丙酰卤加成物。然后，α-氰基烯丙酰卤代物加成物分别与羟基乙酸烷酯或甲基取代的羟基乙酸烷酯反应生成相应的α-氰基丙烯酸烷氧羰基甲酯加成物或α-氰基丙烯酸烷氧羰基烷酯加成物。最后通过在稍稍不足量的马来酐存在下加热该加成物，脱除环1,3-二烯保护基团，使α-氰基丙烯酸烷氧羰基甲酯加成物或α-氰基丙烯酸烷氧羰基烷酯加成物转变成相应的α-氰基丙烯酸烷氧羰基烷酯。
结构式(Ⅱ)的单体例子包括氰基戊二烯酸酯和结构式(Ⅲ)的α-氰基丙烯酸酯：(Ⅲ)
其中Z是-CH=CH2,R3如上所述。结构式(Ⅲ)中R3为1-10个碳原子的烷基的单体，即2-氰基戊-2,4-二烯酸酯，可通过使合适的2-氰基乙酸酯与丙烯醛在催化剂如氯化锌存在下反应来制得。这种制备2-氰基戊-2,4-二烯酸酯的方法公开在例如美国专利No.3.554,990中，其内容结合入本文作参考。
较佳的单体是α-氰基丙烯酸烷酯，更佳的是α-氰基丙烯酸辛酯，特别佳的是α-氰基丙烯酸2-辛酯。用于本发明应用中的单体应非常纯，含有很少的杂质(如外科用级)。
本发明组合物中的组分B)是至少一种能为在伤口或切口上形成的聚合的单体提供柔韧性的增塑剂。增塑剂最好含有极少的水分或不含水分，并且应当对单体的聚合没有显著影响。
合适的增塑剂例子包括乙酰柠檬酸三丁酯、癸二酸二甲酯、磷酸三乙酯、磷酸三(2-乙基己酯)、磷酸三对甲苯酯、三乙酸甘油酯、三丁酸甘油酯、癸二酸二乙酯、己二酸二辛酯、肉豆蔻酸异丙酯、硬脂酸丁酯、月桂酸、偏苯三酸三辛酯(trioctyl trimellitate)、戊二酸二辛酯及其混合物。较佳的增塑剂是柠檬酸三丁酯和乙酰柠檬酸三丁酯。
本发明的组合物中组分C)是至少一种可抑制聚合的酸性稳定剂。这些稳定剂也可包括阴离子稳定剂和自由基稳定剂的混合物。
合适的阴离子稳定剂的例子包括二氧化硫、磺酸、内酯、三氟化硼、有机酸、硫酸烷酯、亚硫酸烷酯、3-二氢噻吩烯(sulfolene)、烷基砜、烷基亚砜、硫醇和烷基硫化物及其混合物。较佳的阴离子稳定剂是有机酸酸性稳定剂如乙酸或磷酸，而乙酸是更佳的酸性稳定剂。胶粘剂组合物中二氧化硫存在的最大量应低于50ppm，较佳的应低于30ppm
合适的自由基稳定剂的例子包括氢醌、氢醌一甲基醚、儿茶酚、焦棓酚、苯醌、2-羟基苯醌、对甲氧基苯酚、叔丁基儿茶酚、丁基化的羟基茴香醚、丁基化的羟基甲苯和叔丁基氢醌。
合适的酸性稳定剂包括那些pKa电离常数为约0-7的稳定剂，以约1-6为佳，约2-5.5为更佳。例如合适的酸性稳定剂包括：硫化氢(pKa为7.0)、碳酸(pKa为6.4)、三乙酰甲烷(pKa为5.9)、乙酸(pKa为4.8)、苯甲酸(pKa为4.2)、2,4-二硝基苯酚(pKa为4.0)、甲酸(pKa为3.7)、亚硝酸(pKa为3.3)、氢氟酸(pKa为3.2)、氯乙酸(pKa为2.9)、磷酸(pKa为2.2)、二氯乙酸(pKa为1.3)、三氯乙酸(pKa为0.7)、2,4,6-三硝基苯酚(苦味酸)(pKa为0.3)、三氟乙酸(pKa为0.2)及其混合物。
当胶粘剂组合物中加入上述弱酸性稳定剂时，发现加入约0.5-16％(重量)的增塑剂(增塑剂的用量以约3-9％(重量)为佳，约5-7％(重量)为更佳)可为聚合单体提供比增塑剂和酸性稳定剂的量不在上述范围内的聚合单体更高的膜强度(如韧度)。
所用的酸性稳定剂的浓度可根据酸的强度而不同。例如，当采用乙酸时，可用80-200ppm(重量/重量)的浓度，以90-180ppm(重量/重量)为佳，100-150ppm(重量/重量)为更佳。当采用更强的酸(如磷酸)时，可采用20-80ppm(重量/重量)的浓度范围，以30-70ppm(重量/重量)为佳，40-60ppm(重量/重量)为更佳。
本发明的组合物也可包括至少一种可有效降低聚合物的体内生物降解产生的活性甲醛浓度水平的生物相容剂(这里也称为“甲醛浓度降低剂”)。较佳的，这种组分是甲醛清除剂化合物。用于本发明中的甲醛清除剂化合物例子包括亚硫酸盐、亚硫酸氢盐、亚硫酸盐和亚硫酸氢盐的混合物、亚硫酸铵盐、胺、酰胺、酰亚胺、腈、氨基甲酸盐、醇、硫醇、蛋白质；胺、酰胺和蛋白质的混合物；活泼的亚甲基化合物如环酮和有β-二羰基的化合物；以及不含羰基并有NH基团的杂环化合物，其中环由氮原子和碳原子组成，环是不饱和的，或当环与苯基稠合时环是不饱和或饱和的，NH基团与碳原子或氮原子连接，而该原子又通过双键与另一个碳原子或氮原子直接连接。
用作本发明中甲醛清除剂化合物的亚硫酸氢盐和亚硫酸盐包括碱金属盐如锂、钠和钾盐以及铵盐，例如，亚硫酸氢钠、亚硫酸氢钾、亚硫酸氢锂、亚硫酸氢铵、亚硫酸钠、亚硫酸钾、亚硫酸锂、亚硫酸铵等。
本发明中采用的胺的例子包括脂族和芳族胺类，如苯胺、联苯胺、氨基嘧啶、甲苯二胺、三亚乙基二胺、二苯胺、二氨基二苯胺、肼和酰肼。
合适的蛋白质包括胶原、明胶、酪蛋白、大豆蛋白、植物蛋白、角蛋白和动物胶。本发明中所用的较佳的蛋白质是酪蛋白。
用于本发明的合适的酰胺包括脲、氨基氰、丙烯酰胺、苯甲酰胺和乙酰胺。脲是较佳的酰胺。
合适的醇包括苯酚、1,4-丁二醇、右旋山梨糖醇和聚乙烯醇。
合适的有β-二羰基的化合物例子包括丙二酸、乙酰丙酮、乙基丙酮(ethylacetone)、乙酸酯、丙二酰胺、丙二酸二乙酯或其它丙二酸酯。
用于本发明的较佳的环酮包括环己酮或环戊酮。
用作本发明中甲醛清除剂的合适的杂环化合物的例子公开在例如美国专利No.4,127,382(Perry)中，其内容结合入本文作参考。这些杂环化合物包括，例如，苯并咪唑、5-甲基苯并咪唑、2-甲基苯并咪唑、吲哚、吡咯、1,2,4-三唑、二氢吲哚、苯并三唑、二氢吲哚等。
用于本发明的较佳的甲醛清除剂是亚硫酸氢钠。
在实施本发明时，氰基丙烯酸酯中应加入有效量的甲醛浓度降低剂如甲醛清除剂化合物。“有效量”是指足以减少聚合的氰基丙烯酸酯在随后的体内生物降解时产生的甲醛量的用量。这一用量取决于活性甲醛浓度减少剂的类型，本领域技术人员很容易不需很多试验就可确定该用量。
用于本发明的甲醛浓度减少剂可以是游离形式或微囊包封形式。
当用微胶囊包封时，甲醛浓度降低剂在氰基丙烯酸酯聚合物在体内生物降解的一段时间内从微胶囊中连续释放出来。
出于本发明的目的，微囊包封形式的甲醛浓度降低剂是较佳的，因为在这一实例中通过甲醛浓度降低剂防止或大大降低了氰基丙烯酸酯单体的聚合，这就延长了使用寿命，并使得单体组合物在使用时的操作更方便。
甲醛清除剂的微胶囊化可通过许多已知的微囊化方法来实现。例如，微囊化可这样来实现，通过将一种涂料聚合物溶解在挥发性溶剂(如二氯甲烷)中至聚合物浓度约为6％(重量)；在搅拌下将颗粒形式的甲醛清除剂化合物加入涂料聚合物/溶剂溶液中至清除剂浓度为18％(重量)；在迅速搅拌下将含有表面活性剂的矿物油溶液缓慢加入聚合物溶液中；在搅拌下使挥发性溶剂蒸发；除去搅拌器；从矿物油中分离得到固体；和清洗并干燥微颗粒。微颗粒的大小在约0.001-1000微米范围内。
用于微囊包封甲醛浓度降低剂的涂料聚合物应当是这样一种聚合物，它能以等于或大于由单体形成的氰基丙烯酸酯聚合物的速度在体内受生物侵蚀，并且应当有低的固有含水量。这种“生物侵蚀”的发生是由于包封材料的物理或化学降解，例如包封材料在体液存在下由固态变为溶解物，或包封材料受到体内因素而生物降解。
可用作甲醛浓度降低剂的微胶囊的涂料聚合物例子包括聚酯，如聚乙醇酸(polyglycolic acid)、聚乳酸、聚乙醇酸和聚乳酸的共聚物、聚己酸内酯、聚-β-羟基丁酸酯、ε-己内酯和δ-戊内酯的共聚物、ε-己内酯和DL-丙交酯的共聚物、和聚酯水凝胶；聚乙烯吡咯烷酮；聚酰胺；明胶；白蛋白；蛋白质；胶原；聚(原酸酯)；聚酐；聚(烷基-2-氰基丙烯酸酯)；聚(二氢吡喃)；聚(缩醛)；聚(膦嗪)(phosphazene)；聚氨基甲酸酯；聚(二羟吲哚(dioxinone))；纤维素；和淀粉。
可加入矿物油中的表面活性剂的例子包括那些商业上可购得的名称为Tritonx-100、吐温20和吐温80的表面活性剂。
本发明的组合物中还可含有一种或多种辅助物质，如增稠剂、药剂等，以改善用于特定医学应用的单体的医学用途。
合适的增稠剂包括，例如，聚氰基丙烯酸酯、聚乳酸、聚乙醇酸、乳酸-乙醇酸共聚物、聚己酸内酯、乳酸-己内酯的共聚物、聚-3-羟基丁酸、聚原酸酯、聚丙烯酸烷酯、丙烯酸烷酯和乙酸乙烯酯的共聚物、聚甲基丙烯酸烷酯和甲基丙烯酸烷酯和丁二烯的共聚物。
为了改善本发明的组合物形成的胶粘剂的内聚强度，本发明的单体组合物中可加入双功能单体交联剂。这些交联剂是人们熟知的。参见例如美国专利No.3,940,362(Overhults)，其内容结合入变为作参考。合适的交联剂例子包括二(2-氰基丙烯酸)烷酯、异氰脲酸三烯丙酯、二丙烯酸烷二酯、二甲基丙烯酸烷二酯、三羟甲基丙烷三丙烯酸酯(trimethylol propane triacrylate)和二(2-氰基丙烯酸烷酯)。氰基丙烯酸酯单体/交联剂混合物中加入催化有效量的胺活化自由基引发剂来引发聚合。
本发明的组合物中还可含有纤维状的增强剂和着色剂，即染料和颜料。合适的纤维状增强剂的例子包括PGA微纤维、胶原微纤维、纤维素微纤维和烯属微纤维(olefinic microfibrils)。合适的着色剂例子包括1-羟基-4-(4-甲基苯基-氨基)-9,10-蒽二酮(D+C紫色第2号)；6-羟基-5-[(4-磺苯基)氧代(axo)]-2-萘-磺酸二钠(FD+C黄色第6号)；9-(o-羧苯基)-6-羟基-2,4,5,7-四碘代-3H-吨-3-酮，二钠盐，一水合物(FD+C红色第3号)；2-(1,3-二氢-3-氧代-5-硫代-2H-吲哚-2-亚基)-2,3-二氢-3-氧代-1H-吲哚-5-磺酸二钠盐(FD+C蓝色第2号)；和[酞菁(2-)]铜([phtha-1-ocyaninato(2-)]copper)。
通过将本发明的组合物涂敷到被合在一起的相对的伤口表面上，本发明的组合物可用来使两个表面闭合在一起。根据使用者的特殊需求，本发明的胶粘剂组合物可用已知的方法来涂敷，如用一玻璃搅拌棒、无菌刷或药物滴管。然而，在许多情况下，保压的气溶胶分散包是较佳的，其中胶粘剂组合物在含有相容的无水推进剂的溶液中。
在一个实例中，本发明涉及一种合拢体内两个表面的方法，方法包括(a)将伤口或切口的组织表面合在一起形成毗连的组织表面；(b)将本发明的组合物涂敷到所述毗连的组织表面上，组合物包含1)至少一种形成医学上可接受的聚合物的单体(如结构式(Ⅰ)的单体)，2)一种增塑剂和3)一种合适的酸性稳定剂；和(b)使表面保持接触直至所述组合物聚合。
如上所述，传统的外科用胶粘剂组合物是在伤口表面贴合之前以非常少的量涂敷到伤口表面上，并仔细除去多余的胶粘剂。在过去，伤口表面上形成的厚膜将增加对伤口组织的组织毒性，并会增加膜的脆性而不会增加膜强度。
然而，本发明涉及一种通过将本发明的组合物涂敷到已经毗连的伤口或切口组织表面上来使体内两种组织表面合拢的方法，其中最好是多次涂敷或涂布在毗连的组织表面，从而在毗连的组织表面上提供过量的胶粘剂组合物。直接涂敷在毗连组织表面上或伤口或切口附近的任何多余的胶粘剂最好不要除去，但是涂敷在不靠近伤口区域的周围组织上的多余物可以除去。
后一次涂敷可在前次涂敷后立即进行，或是在前次涂敷物完全聚合后进行。较佳的，在下次涂敷或施用附加的单体组合物前，应使涂敷到毗连组织表面上的单体组合物至少部分聚合。单体与第一次或前次涂敷的单体不同的本发明胶粘剂组合物的涂敷可作为第二次或下次涂敷。由于加入了增塑剂和酸性稳定剂，毗连组织表面上形成的聚合物有足够的粘合强度和柔韧性，甚至对于厚度相当大的薄膜或涂层也是如此。合适的膜厚度在0.1mm至0.2或0.3mm或更高，以0.2-1.5mm为佳，0.4-0.8mm为更佳。
在另一个实例中，本发明直接涉及一种通过用各种涂药器来涂敷本发明的胶粘剂组合物以使体内两个组织表面合拢的方法。这些涂药器包括可挤压的刷笔式涂药器、有不同分散喷嘴或喷头的注射器或小瓶。
例如，注射头可从盛有可聚合和/或可交联的物料的涂药器容器上拆卸下来。为了防止涂药器容器中未涂敷材料过早聚合或交联，这种涂药头(applicator tip)在使用前可以与涂药器容器相连，在使用后可从涂药器容器上拆下。此时可以弃去涂药头，并将一新的涂药头与涂药器容器相连以便以后使用，或是涂药头可重复使用。
或者，本发明的涂药头可包括多个部分，其中至少一个部分包含引发剂。例如，含有引发剂的部分可与涂药头的其它部分分开，并在与涂药器容器连接之前组装起来。
涂药头也可采用喷嘴形式，以使液态的可聚合和/或可交联的物料雾化。锥形、扁平形喷洒器或压缩流喷嘴(condensed stream nozzle)是合适的。
本发明的涂药头可用于各种器具中。例如人工涂药的方法可包括用手持型器具如注射器、胶粘剂枪、滴管、眼药滴管等。
涂药头和涂药器容器也可以是一个整体组件。该组件可预先形成为单件并装入可聚合的和/或可交联的物料。在从涂药器容器中涂敷物料后，该器件可以丢弃。另外，这种涂药头/涂药器容器的整体组件可制成能够在组件中加入新的物料，以用作多次使用的组件。
涂药头可由多种材料的任何一种组成，材料包括聚合材料如塑料、泡沫塑料、橡胶、热固性物质、薄层或膜。另外，涂药头可由材料如金属、玻璃、纸张、陶瓷、硬卡纸等组成。涂药头材料可以是多孔的、吸收或吸附性质的，以有助于或使引发剂更多地装载在涂药头上或涂药头中。例如，涂药头可以由有不规则孔隙、织物状结构的材料、蜂窝形材料等组成。空隙度取决于所用的材料。
当本发明的涂药头与涂药器容器相连时，它可有伸出的管状部分，而混合的聚合和/或交联材料从中排出。为了避免突然的压强下降以及为了保证恒定的混合比曲线，涂药头紧接涂药器容器的下游部分最好是多孔的。该结构最好可以捕获用来隔离涂药器容器内多种组分的隔离物或材料。
引发材料的聚合和/或交联的引发剂可以施加到涂药头表面的一部分或整个表面上，包括涂药头的内部和外部。或者，可以将引发剂只涂布到涂药头的内表面。较佳的是，只有涂药头内部的一部分被引发剂涂布。
涂药头上的引发剂可以是固态的，如粉末或固体膜，或是液态的，如粘稠或糊状材料。引发剂也可包括各种添加剂如表面活性剂或乳化剂。较佳的，引发剂可溶于可聚合和/或可交联材料中，和/或包含或含有至少一种表面活性剂，该表面活性剂在实例中有助于引发剂和可聚合和/或可交联材料共同流出。在实例中，表面活性剂有助于引发剂溶解在可聚合和/或可交联的材料中。
对于特定的体系，本领域技术人员无需大量试验就可容易选出特定的引发剂。合适的引发剂包括(但不局限于)，洗涤剂组合物；表面活性剂例如是非离子表面活性剂，如聚山梨酸酯20(如吐温20TM)、聚山梨酸酯80(如吐温80TM)和泊洛沙姆，阳离子表面活性剂如氯化苯甲烃铵和四丁铵溴化物，阴离子表面活性剂如四癸基硫酸钠，和两性表面活性剂如十二烷基二甲基(3-磺基丙基)氢氧化铵、内盐；胺类、亚胺类和酰胺类，如咪唑、色胺、脲、精氨酸和聚乙烯吡咯酮碘；膦、亚磷酸盐和鏻盐如三苯基膦和亚磷酸三乙酯；醇如乙二醇、棓酸甲酯、抗坏血酸、单宁和单宁酸；无机碱和盐，如亚硫酸氢钠、氢氧化镁、硫酸钙和硅酸钠；含硫化合物如硫脲和多硫化物；聚合环醚如莫能菌素、无活菌素、冠醚、杯芳烃(calixarene)和聚合环氧化物；环状和无环碳酸酯，如碳酸二乙酯；相转移催化剂如Aliquat 336；有机金属化合物如环烷酸钴和乙酰丙酮镁；和自由基引发剂和自由基，如过氧化二叔丁基和偶氮二异丁腈。在涂药头中，可聚合和/或可交联的材料也可含有一种直至被一种催化剂或促进剂激活才有活性的引发剂(包括在本文所用的“引发剂”范围内)。通过刺激如热和/或光(如紫外光或可见光)激活的引发剂也是适用的，如果涂药头和/或涂药器适当地受这种刺激的话。
引发剂可施加在涂药头表面上，或是浸润或掺混入涂药头的基质或内部。例如，引发剂可通过用含有引发剂的液态介质喷洒、浸泡或刷涂涂药头来施加到涂药头上。液态介质可包括非水性溶剂，如乙醚、丙酮、乙醇、戊烷或其混合物；或可包括水性溶液。较佳的，液态基质是低沸点溶剂。
用于涂敷本发明胶粘剂的合适的涂药器包括那些在待审查申请No.08/488,411中描述的涂药器，其内容结合入本文作参考。较佳的涂药器是可挤压的刷笔式涂药器。
使用本发明胶粘剂组合物的具体方法包括修复受伤的活组织以防止体液从其中流出的方法，该方法是将受伤的组织边缘贴合成毗连的关系，向毗连组织涂敷本发明的单体组合物，并使组合物聚合；还包括防止血液从血管中流出的方法，方法是将受伤的血管区域合在一起，向受伤的区域涂敷本发明的单体组合物并使组合物聚合；以及粘合骨组织以愈合衰弱或折断的骨组织的方法，该方法包括将受伤的骨组织合在一起，向受伤的组织涂敷本发明组合物，并使组合物聚合。
受伤组织的修复(如控制出血)的方法通常包括用海绵擦去表面的体液，将受伤的组织表面贴合成毗连的关系，然后向暴露的毗连组织涂敷本发明的胶粘剂组合物。当组合物与毗连的组织表面接触时，组合物聚合成聚合物薄膜。没有出血或被体液包覆的组织不需预先用海绵擦洗。毗连的组织表面上可涂敷一次以上的单体组合物。
单体很容易聚合成加成型(addition-type)的聚合物和共聚物，其通常是透光的(如薄膜)。
在用本发明组合物的大多数粘合应用中，单体的聚合反应由粘合物表面上的少量水分来催化；因此所需的组织粘合或止血可在血液和其它体液存在下很好地进行。形成的粘合体是足够柔韧的，并有足够的抵抗正常组织运动的强度。另外，在自然伤口愈合进行时始终维持粘合强度。
本发明所用的组合物最好可用传统方法灭菌，这些传统的灭菌方法包括，但不局限于，高压消毒或无菌过滤方法。实施例Ⅰ-Ⅵ
本发明的组合物用常规混合设备来制备。例如，方法可按如下步骤进行：
在圆底烧瓶中，在外科用级氰基丙烯酸酯中加入本文所述的增塑剂、酸性稳定剂和其它制剂组分。机械搅拌得到的混合物直至均匀。
本发明将进一步通过下列非限制性的实施例来描述。
在下列实施例中，在本发明胶粘剂组合物中采用不同量的增塑剂(即乙酰柠檬酸三丁酯)，以描述其对胶粘剂形成的粘合体的强度效果。
表Ⅰ所示数据通常用下列方法来获得：
1．在5 1/2″×5 1/2″胶乳片上切一道2″的切口(1/16″深)。
2．用有引发聚合的涂药头的可挤压刷笔式涂药器将胶粘剂组合物(即氰基丙烯酸2-辛酯)涂敷到切口的外表面上。切口的内表面必须没有被无意地涂胶。
3．在固化一个小时后，将片固定在两片有机玻璃上。下面一片装有压力传感器和气体入口。上面一片玻璃在中间有3 5/8″的孔。将测试片的涂有胶粘剂的一侧朝有3 5/8″的孔的上片有机玻璃放置。
4．打开控制气流的阀门，对试样进行加压。增大压力直至试样破裂。
5．由传感器记录压力峰值并记录在图纸记录仪中。每一试样进行10次测试。
结果如下：
表Ⅰ
实施例Ⅶ-Ⅹ
| 实施例 | 增塑剂浓度(重量/重量％) | 破裂压力(psi) |
| Ⅰ | 0.0 | 3.9 |
| Ⅱ | 5.7 | 3.9 |
| Ⅲ | 9.1 | 3.7 |
| Ⅳ | 15.2 | 3.2 |
| Ⅴ | 20.0 | 2.6 |
| Ⅵ | 25.9 | 2.1 |
为了证明本发明的胶粘剂组合物及其施用方法可提供出人意料的体内膜强度的优越性，评价用于伤口闭合和各种外科用伤口闭合器件的外用给药的各种方法和材料(实施例Ⅶ-Ⅹ)。体内强度由引起伤口破裂所需的最终压力的数值(即，暴露伤口所需的真空压力)来客观地确定。用Dimensional Analysis Systems(DAS)(DIMENTIONAL ANALYSIS SYSTEMS,LEONIA,NEW JERSEY)来进行生物力学分析。这种方法具体设计成用于测试线形切开的伤口的客观体内生物力学表征。与已有的生物力学分析方法(如单轴向表面张力计)相反，DAS对伤口施加多轴向应力，该应力与临床条件下遇到的应力更为相似。而且，在测试前，DAS不需要试样组织操作或破坏性切开。因此，在愈合的早期阶段就可对易破碎伤口进行灵敏、可靠而再现性好的测定。而且，DAS还消除了由切除方法引起的人为误差和试验变化(如非存活组织试样、试样尺寸反复变化和切除组织边缘破裂)。
选择雄性Sprague Dawley大鼠用于动物模型，由于大鼠的遗传纯和性、容易操作和供宿，整个种群可用作线形切割伤口模型，因此可以与其它类似研究进行比较。这种模型广泛用于切割伤口研究中，其内容在文献中有详细记载。
在测试中采用购自Harlan sprague Dawley,Inc(Indianapolis,Indiana)的雄性Sprague Dawley大鼠。在测试前将所有动物放置7天以使其饮食和行为稳定。在相同条件下测试四组大鼠(组A-D)，每组采用不同的伤口闭合方法和/或外科用胶粘剂。在线形切割伤口闭合一小时后测试每一试样的膜强度。
实施例Ⅶ
在第一组大鼠中(称为组A)，采用一次性涂敷组织胶粘剂的方法。用有刷笔式涂药头的可压缩安瓿瓶来涂敷α-氰基丙烯酸2-辛酯中含有约6％(重量)的增塑剂以乙酸为酸性稳定剂(pKa=4.8)的本发明的胶粘剂，使胶粘剂沿相对的伤口边缘以一次性的方式通过来进行外表面给药。
实施例Ⅷ
在第二组大鼠中(称为组B)，用多次涂覆方法、相同的胶粘剂来闭合线形切割伤口。胶粘剂用可压缩的安瓿瓶来涂敷，其以“多次涂覆”方式多次沿相对的伤口边缘通过，获得2-3种不同的胶粘剂涂敷。
实施例Ⅸ
在第三组大鼠中(称为组C)，用最小表面暴露方法和相同的胶粘剂来使线形切割伤口闭合。用UniJectTM注射器(购自Horizon,Santa Ana,CA,USA)滴加约3-4滴胶粘剂，以试图限制暴露在皮肤表面的胶粘剂的量，从而使胶粘剂只对相对的伤口边缘给药。
实施例Ⅹ
在第四组大鼠中(称为组D)，用实施例Ⅸ的涂敷方法和HistoacrylTM(一种购自德国B.Braun Melsungen AG的外科用胶粘剂)来使线形切割伤口闭合。
体内生物力学测定结果列于下表Ⅱ中。如表Ⅱ所示，发现在研究的一小时期间所有组之间均有明显的不同。与组A或组C相比，组B(多次涂敷方法)表明最终压力有显著提高。该数据表明，增加涂敷的胶粘剂量可获得更高的体内强度。而组D与所有评价的组相比，表现出体内强度有显著下降。
表Ⅱ
揭示了涂敷后1小时时本发明各种方法
和其它方法的统计结果的直接比较
| 组 | 切口数 | 体内强度(mmHg) |
| A：一次涂敷 | 10 | 110.30 |
| B：多次涂敷 | 10 | 214.57 |
| C：最小表面暴露 | 10 | 94.36 |
| D:Histoacryl(最小表面暴露) | 10 | 62.80 |
实施例Ⅺ
在猪模型中测试相同的本发明胶粘剂使皮肤切口闭合的效果。用组织胶粘剂HistoacrylTM作为对照。
在这些猪的背上每一侧上用消毒手术刀切成深度一定的切口。用测试物或对照物使切口闭合。将加入涂药器的本发明相同的胶粘剂涂敷到相对的毗连的伤口边缘上直至胶粘剂聚合(即胶粘剂摸上去不再有粘性)。涂药器是有吸收涂药头(可挤压的刷笔)的柔软的透明塑料圆筒。圆筒内有含有胶粘剂的玻璃小瓶，小瓶可通过挤压圆筒而破碎。当涂药器倒置时，胶粘剂从圆筒中挤出进入涂药器然后涂敷到皮肤上。Histoacryl也用一种涂药器来涂敷，该涂药器是有狭窄瓶颈的密封塑料安瓿瓶。安瓿瓶与27号计量皮下注射器相连。将安瓿瓶倒转，通过挤压安瓿瓶，使小液滴从针末端滴到相对的切口边缘上来涂敷胶粘剂。注意不要使针尖碰到皮肤。涂敷Histoacryl的方法已由J.Quinn和J.Kissick(1994，“用于运动时撕伤修复的组织胶粘剂(Tissue adhesibes for laceration repair during sportingevents”,Clin.J.Sport Med4:245-248)描述。
在痊愈阶段经常进行观察，在手术后约4小时、以及随后每天记录观察结果，以确定是否任何切口部分或完全分开(裂开)，以及是否有任何不良组织反应。如果伤口在观察期间分开，不再将其合拢。
表Ⅲ
猪表皮切口的裂开情况
| 本发明胶粘剂 | HistoacrylTM | |
| 1号猪切口数部分或完全裂开数 | 40 | 41 |
| 2号猪切口数部分或完全裂开数 | 40 | 44 |
| 3号猪切口数部分或完全裂开数 | 40 | 42 |
观察猪伤口裂开情况10天。在用本发明胶粘剂闭合的任一切口中没有发现有裂开。而用HietoacrylTM闭合的12个切口中发现有7个切口部分或完全裂开。没有发现有如感染或坏死的并发症。
Claims (23)
1．一种生物相容单体组合物，包括：
(A)至少一种形成医学上可接受的聚合物的单体；
(B)至少一种增塑剂，增塑剂在组合物中的含量为组合物的0.5-16％重量；和
(C)至少一种pKa电离常数约为0-7的酸性稳定剂。
2．根据权利要求1所述的组合物，其中所述至少一种增塑剂的含量为所述组合物的3-9％重量。
3．根据权利要求1所述的组合物，其中所述至少一种增塑剂的含量为所述组合物的4-7％重量。
4．根据权利要求1所述的组合物，其中所述至少一种酸性稳定剂的pKa约为1-7。
5．根据权利要求1所述的组合物，其中所述至少一种增塑剂的含量为所述组合物的3-9％重量，所述至少一种酸性稳定剂的pKa约为1-6。
6．根据权利要求1所述的组合物，其中所述至少一种增塑剂的含量为所述组合物的5-7％重量，所述至少一种酸性稳定剂的pKa约为2-5.5。
7．根据权利要求1所述的组合物，其中所述增塑剂选自乙酰柠檬酸三丁酯、柠檬酸三丁酯及其混合物。
8．根据权利要求1所述的组合物，其中所述酸性稳定剂是乙酸。
9．根据权利要求1所述的组合物，其中所述单体是氰基丙烯酸2-辛酯、氰基丙烯酸十二烷酯、氰基丙烯酸2-乙基己酯、氰基丙烯酸丁酯、氰基丙烯酸甲酯、氰基丙烯酸3-甲氧基丁酯、氰基丙烯酸2-丁氧基乙酯、氰基丙烯酸2-异丙氧基乙酯或氰基丙烯酸1-甲氧基-2-丙酯。
10．根据权利要求1所述的组合物，其中所述组合物包含至少两种不同的单体。
11．一种合拢体内活组织表面的方法，包括：
(a)将至少两个组织表面合在一起形成毗连的组织表面；
(b)向所述毗连的组织表面施用过量的胶粘剂组合物，该组合物含有至少一种形成医学上可接受的聚合物的单体；和
(c)与所述组织表面保持体内接触直至所述组合物在所述毗连组织表面上聚合形成聚合组合物的厚膜。
12．根据权利要求11所述的方法，其中所述至少一种增塑剂的含量为所述组合物的3-9％重量，所述至少一种酸性稳定剂的pKa约为1-5。
13．根据权利要求11所述的方法，其中沿所述毗连组织表面多次涂敷所述胶粘剂组合物。
14．根据权利要求13所述的方法，其中在下一次涂敷或施用所述胶粘剂组合物前在所述毗连组织表面上涂敷的所述胶粘剂组合物可至少部分聚合。
15．根据权利要求13所述的方法，其中含有与前次涂敷的单体不同的单体的胶粘剂组合物用作下一次涂敷。
16．根据权利要求11所述的方法，其中所述胶粘剂组合物沿所述毗连组织表面聚合成一跨桥。
17．根据权利要求11所述的方法，其中所述厚膜的厚度为0.1-3.0mm。
18．根据权利要求11所述的方法，其中所述胶粘剂组合物用可挤压刷笔式涂药器来涂敷。
19．一种将权利要求1所述的胶粘剂组合物涂敷到活组织上的方法，方法包括将至少两个组织表面合在一起形成毗连的组织表面，沿所述毗连组织表面涂敷所述胶粘剂组合物并使所述组合物聚合。
20．一种用权利要求12所述的方法制得的沿毗连组织表面形成的体内膜。
21．一种沿毗连组织表面形成生物相容薄膜的方法，方法包括：
(a)将至少两个组织表面合在一起形成毗连的组织表面，
(b)沿所述毗连组织表面涂敷一种胶粘性生物相容单体组合物，和
(c)使所述组合物在所述毗连组织表面上聚合形成一层生物相容的薄膜，薄膜体内膜强度至少有引起伤口破裂所需的70mmHg的真空压力。
22．根据权利要求12所述的方法，其中所述体内膜强度至少有引起伤口破裂所需的90mmHg的真空压力。
23．根据权利要求12所述的方法，其中所述体内膜强度至少有引起伤口破裂所需的100mmHg的真空压力。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/609,921 | 1996-02-29 | ||
| US08/609,921 US5981621A (en) | 1996-02-29 | 1996-02-29 | Monomeric compositions effective as wound closure devices |
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| CN1213285A true CN1213285A (zh) | 1999-04-07 |
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| EP (1) | EP0886507B2 (zh) |
| JP (2) | JP2000503574A (zh) |
| CN (1) | CN1213285A (zh) |
| AT (1) | ATE374006T1 (zh) |
| AU (1) | AU724710B2 (zh) |
| BR (1) | BR9707794A (zh) |
| CA (1) | CA2247906C (zh) |
| DE (1) | DE69738164T3 (zh) |
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| ES (1) | ES2294794T5 (zh) |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102596268A (zh) * | 2009-11-20 | 2012-07-18 | 三井化学株式会社 | 软组织用粘合剂组合物、创伤被覆用粘合剂组合物或创伤被覆剂组合物 |
| CN102596269A (zh) * | 2009-11-20 | 2012-07-18 | 三井化学株式会社 | 硬组织修补用组合物 |
| US8946317B2 (en) | 2009-11-20 | 2015-02-03 | Mitsui Chemicals. Inc. | Composition for hard tissue repair |
| CN102596269B (zh) * | 2009-11-20 | 2015-02-11 | 三井化学株式会社 | 硬组织修补用组合物 |
| TWI494139B (zh) * | 2009-11-20 | 2015-08-01 | Mitsui Chemicals Inc | Adhesive composition for soft tissue, adhesive composition for wound dressing, or wound composition |
| TWI496596B (zh) * | 2009-11-20 | 2015-08-21 | Mitsui Chemicals Inc | Hard tissue repair composition |
| CN102596268B (zh) * | 2009-11-20 | 2015-09-02 | 三井化学株式会社 | 软组织用粘合剂组合物、创伤被覆用粘合剂组合物或创伤被覆剂组合物 |
| CN103533966A (zh) * | 2011-05-19 | 2014-01-22 | 三井化学株式会社 | 软组织用粘合剂组合物、创伤被覆用粘合剂组合物或创伤被覆材料组合物 |
| CN107922840A (zh) * | 2015-08-17 | 2018-04-17 | 提克纳有限责任公司 | 用于摄像模组的液晶聚合物组合物 |
| CN107922840B (zh) * | 2015-08-17 | 2021-11-05 | 提克纳有限责任公司 | 用于摄像模组的液晶聚合物组合物 |
| CN112480830A (zh) * | 2020-12-09 | 2021-03-12 | 山东禹王和天下新材料有限公司 | 一种透明美甲胶及其制备方法与应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2247906A1 (en) | 1997-09-04 |
| AU724710B2 (en) | 2000-09-28 |
| DE69738164T3 (de) | 2013-08-01 |
| ATE374006T1 (de) | 2007-10-15 |
| BR9707794A (pt) | 1999-07-27 |
| AU1981497A (en) | 1997-09-16 |
| DK0886507T3 (da) | 2007-11-05 |
| ES2294794T5 (es) | 2013-05-06 |
| US5981621A (en) | 1999-11-09 |
| US20030202956A1 (en) | 2003-10-30 |
| JP2000503574A (ja) | 2000-03-28 |
| JP5646520B2 (ja) | 2014-12-24 |
| DE69738164T2 (de) | 2008-06-26 |
| PT886507E (pt) | 2007-11-21 |
| WO1997031598A1 (en) | 1997-09-04 |
| EP0886507A1 (en) | 1998-12-30 |
| JP2012106018A (ja) | 2012-06-07 |
| DE69738164D1 (de) | 2007-11-08 |
| CA2247906C (en) | 2006-11-21 |
| DK0886507T4 (da) | 2013-06-03 |
| EP0886507B1 (en) | 2007-09-26 |
| US6565840B1 (en) | 2003-05-20 |
| ES2294794T3 (es) | 2008-04-01 |
| EP0886507A4 (en) | 2001-11-28 |
| EP0886507B2 (en) | 2013-03-06 |
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