CN1166504A - 可被吸收的聚氧杂酯 - Google Patents

可被吸收的聚氧杂酯 Download PDF

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CN1166504A
CN1166504A CN97109520A CN97109520A CN1166504A CN 1166504 A CN1166504 A CN 1166504A CN 97109520 A CN97109520 A CN 97109520A CN 97109520 A CN97109520 A CN 97109520A CN 1166504 A CN1166504 A CN 1166504A
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integer
scopes
formula
polyoxaesters
scope
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R·S·比兹维达
D·D·雅米奥科斯基
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Johnson and Johnson Medical SAS
Ethicon Inc
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Ethicon SAS
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Abstract

本发明描述一种新型脂族聚氧杂酯,它是可生物吸收的和可用于生产外科器械如缝线,与针连接的缝线,模制器械,及类似物。本发明还计划了生产这些聚酯的方法。本发明的脂族聚氧杂酯具有式I的第一种二价重复单元:[O-C(O)-C(R1)(R2)-O-(R3)-O-C(R1)(R2)-C(O)-]I和选自下列式子的第二种重复单元:II[-O-R4-]A;III[-O-R5-C(O)-]B和XI([-O-R5-C(O)]P-O-)LG及其混合物。

Description

可被吸收的聚氧杂酯
本发明是1995年11月6日申请的系列号为08/554011的部分继续,而所述申请又是1995年3月6日申请的系列号为08/366308现为US专利5464929的部分继续,现已全部转让给Ethicon,Inc.,因此本文参考引入所有这些文献。本发明涉及一种生物可吸收的聚合物材料,尤其是涉及由这样的聚合物制成的可被吸收的外科产品。
自从1920年至1930年间Carothers的早期工作以来,芳族聚酯尤其聚对苯二甲酸乙二醇酯已成为商业上最重要的聚酯。这些聚合物的用途与聚合物链中对亚苯基的变硬作用紧密相连。尤其对纤维、薄膜和一些模制品来说,聚合物链的主链中对亚苯基的存在导致高熔点和良好的机械性能。事实上,聚对苯二甲酸乙二醇酯已成为许多普通消费产品例如一升或两升软饮料容器选择的聚合物。
许多相关的聚酯树脂已描述在美国专利4440922,4552948和4963641中,它们通过用其它含亚苯基的同类二羧酸代替对苯二甲酸寻求改进聚对苯二甲酸乙二醇酯的性质。一般合成的这些聚合物降低了芳族聚酯的透气性。
还为特殊用途例如辐射稳定生物可吸收的材料开发出其它芳族聚酯。美国专利4510295,4546152和4689424描述了辐射消毒的芳族聚酯,可用它制缝合线等。这些聚合物,象聚对苯二甲酸乙二醇酯,在聚合物的主链中有亚苯基。
然而,对脂肪族聚酯的研究报导的且很少。Carothers对聚酯的初期工作之后,一般都忽视了脂族聚酯,因为确信这些材料有低熔点和高溶解度。已被广泛研究的脂族聚酯只有聚内酯例如聚交酯,聚乙交酯,聚(对二恶烷酮)和聚己内酯。这些脂族聚内酯主要用于生物可降解的外科缝合线和外科器械如U形钉。尽管聚内酯已证实在许多用途中是有用的,但它们不能满足医学界的全部需求,例如,聚交酯的膜不易透水蒸汽,因此理论上它不能用作绷带,绷带需要渗透水蒸汽。
只有最近才恢复了非内酯脂族聚酯的重要性。美国专利5349028描述了很简单的脂族聚酯的形成,它是基于二醇与二羧酸反应形成预聚物链然后将其偶合在一起。这些聚酯促进了其它纤维和模制品中的使用,因为它们被埋藏如在挖坑掩埋之后,这些聚酯是可生物降解的。然而,没有公开这些材料适合于在外科器械中使用。
因此,本发明的目的是提供一种新类型脂族聚酯,它是可生物吸收的并可用于外科器械例如缝合线,模塑器械,药物分选基质,涂料,润滑剂及类似物。
我们已发现一种新类型合成聚合物材料,它是可生物吸收的并可用于生产外科器械例如缝合线,系在针上的缝合线,模塑器械,药物分送基质,涂料,润滑剂及类似物。本发明还规划一种生产生物可吸收的聚合物和共聚物的方法。本发明的脂族聚氧杂酯是聚酯,它含有式(I)中的第一种二价重复单元:[0-C(O)-C(R1)(R2)-O-(R3)-O-C(R1)(R2)-C(O)-]                I和选自下列式子的第二重复单元:
[-O-R4-]A              II
[-O-R5-C(O)-]B         III
([-O-R5-C(O)]P-O-)LG   XI及其混合物,其中R1和R2分别是氢或含1至8个碳原子的烷基;R3是含2至12个碳原子的亚烷基单元或是下式的氧代亚烷基:
-[(CH2)C-O-]D-(CH2)E-  IV其中C是2至约5范围内的整数,D是约0至约2000范围内的整数,E是2至约5范围内的整数,只是当D是0时,此情况下E将是2至约12范围内的整数;R4是含2至8个碳原子的亚烷基单元;A是1至2000范围内的整数;R5选自基团-C(R6)(R7)-,-(CH2)3-O-,-CH2-CH2-O-CH2-,-CR8H-CH2-,-(CH2)4-,-(CH2)F-O-C(O)-和-(CH2)F-C(O)-CH2-;R6和R7分别是氢或含1至8个碳原子的烷基;R8是氢或甲基;F是2至6范围内的整数;B是1至n范围内的整数,以使式III的数均分子量小于约200000,优选小于约100000和最优选小于40000;P是1至m范围内的整数,以使式XI的数均分子量小于1000000,优选小于200000和最优选小于40000;G表示从上述含1至约200个羟基的醇的羟基中去掉1至L个氢原子的残基,及L是1至约200的整数。
本发明的脂族聚氧杂酯是脂族聚氧代羧酸与至少一种下述化合物的反应产物:二元醇(或聚二元醇),内酯(或内酯低聚物),偶联剂或其混合物。
适用于本发明的脂族α-氧代羧酸一般具有下式:HO-C(O)-C(R1)(R2)-O-(R3)-O-C(R1)(R2)-C(O)-OH   V其中R1和R2分别选自氢或含1至8个碳原子的烷基和R3是含2至12个碳原子的亚烷基或是下式的氧代亚烷基:
-[(CH2)C-O-]D-(CH2)E-    IV其中C是约2至约5范围内的整数,D是约0至约2000范围内,优选0-12范围内的整数,E是约2至约5范围内的整数。在适宜的条件下通过二醇或聚二醇与α-卤代羧酸如溴代乙酸或氯代乙酸反应可生成这些脂族α-羟基羧酸。
适用于本发明的二醇或聚二醇是二醇或含最多8个碳原子的具有下式的二醇重复单元:
H[-(OR4-)A]OH,或       VI其中R4是含2至8个亚甲基的亚烷基单元,A是1至约2000范围内和优选1至约1000范围内的整数。适宜二醇的例子包括选自下述组中的二醇,1,2-乙二醇(乙二醇),1,2-丙二醇(丙二醇),1,3-丙二醇,1,4-丁二醇,1,5-戊二醇,1,3-环戊二醇,1,6-己二醇,1,4-环己二醇,1,8-辛二醇及其混合物。优选聚二醇的例子包括选自下述组中的聚二醇:聚乙二醇(H[-O-CH2-CH2-]AOH)和聚丙二醇(H-[-O-CH2-CH(CH3)-]AOH)。
脂族二羧酸与上述二醇反应生成的聚合物将提供一般具有下式的聚合物:[-O-C(O)-C(R1)(R2)-O-(R3)-O-C(R1)(R2)-C(O)-(O-R4)A-]N    VII其中R1,R2,R3,R4,和A如上所述;N是1至约10000范围内的整数,优选在范围约10至约1000,最优选范围为约50至约200。
可在本发明中使用的适宜内酯单体一般具有式:
Figure A9710952000101
可聚合这些内酯单体以提供有以下通式的聚合物:
H[-O-R5-C(O)-]BOH        IX
(H[-O-R5-C(O)]P-O-)LG    X其中R5选自-C(R6)(R7)-,-(CH2)3-O-,-CH2-CH2-O-CH2-,-CR8H-CH2-,-(CH2)4-,-(CH2)F-O-C(O)-和-(CH2)F-C(O)-CH2-;R6和R7分别是氢或含1至8个碳原子的烷基;R8是氢或甲基;F是约2至6的整数,B是1至n的整数,以使式IX的数均分子量小于约200000,优选小于100000,最优选小于40000;P是1至m范围内的整数,以使式X的数均分子量小于1000000,优选小于200000,最优选小于40000;G表示从上述含1至约200个羟基的醇的羟基中去掉1至L个氢原子的残基;及L是1至约200的整数。在一个实施方案中,G将是二羟基醇去掉两个羟基的残基和式X的数均分子量小于约1000000,优选小于200000和最优选小于40000。在本发明的另一个实施方案中,G可以是含侧羟基的聚合物(包括聚糖)。适宜的内酯衍生的重复单元可从下述单体包括但并不限于内酯单体产生的,它们选自乙交酯,d-丙交酯,1-丙交酯,内消旋丙交酯,ε-己内酯,P-二噁烷酮,三亚甲基碳酸酯,1,4-二氧杂环庚-2-酮,1,5-氧杂环庚-2-酮及其混合物。
由上述二醇(或聚二醇)VI与脂族聚氧代羧酸V反应生成的聚合物还可在缩聚中与上述内酯聚合物IX共聚生成下述通式的聚合物:[(-C(O)-C(R1)(R2)-O-R3-O-C(R1)(R2)-C(O)-(O-R4)A-O)s(C(O)-R5-O)B]W   XII或[(-C(O)-C(R1)(R2)-O-R3-O-C(R1)(R2)-C(O)-(O-R4)A-O)s([-O-R5-C(O)]P-O-)LG]W  XIII其中S是约1至约10000范围内和优选1至约1000范围内的整数,W是1至约1000范围内的整数。可以无规共聚物或嵌段共聚物形式制成这些聚合物。可向上述的二醇,脂族聚氧代羧酸和内酯单体中加入选自下述组中的偶联剂:三官能或四官能多元醇,氧代羧酸,及多元羧酸(或其酸酐)。加偶联剂可引起长链支化,可将熔融态下的所需性能赋予给聚酯预聚物。合适多官能偶联剂的例子包括三羟甲基丙烷,甘油,季戊四醇,苹果酸,柠檬酸,酒石酸,1,3,5-苯三酸,丙烷三羧酸,环戊烷四羧酸酐及其混合物。
在凝胶发生之前待添加的偶联剂的量为所用偶联剂类型和聚氧杂酯聚合条件或被添加预聚物分子量的函数,以所存在的或合成所期望的脂族聚氧杂酯聚合物的摩尔为基准,可加入一般范围为约0.1至约10mole%的三官能或四官能的偶联剂。
优选在熔融缩聚条件下,在有机金属催化剂存在下于升高温度进行脂族聚氧杂酯的聚合反应。有机金属催化剂优选是基于锡的催化剂,例如辛酸亚锡。
存在于混合物中的催化剂优选以二醇、脂族聚氧代羧酸及任选的内酯单体与催化剂的摩尔比范围为约15000至80000/1。优选在温度不低于约120℃于减压下进行反应。较高的聚合温度可导致进一步增加共聚物的分子量,这是许多用途中所需要的。所选择的准确反应条件将取决于许多因素,包括所需聚合物的性质,反应混合物的粘度,及聚合物的玻璃化转变温度和软化温度。通过确定这些和其它因素很容易地确定温度、时间和压力的优选反应条件。
通常,反应混合物将保持在约220℃。让聚合反应在这一温度下进行,直到达到共聚物所需的分子量和转化百分率,典型地将要进行15分钟至24小时。增加反应温度一般要降低反应时间以达到特定的分子量。
在另一个实施方案中,可通过在熔融缩聚条件下形成所聚合的脂族聚氧杂酯预聚物,然后添加至少一种内酯单体或内酯预聚物来制备脂族聚氧杂酯的共聚物。然后将混合物调至所需的温度和时间条件以使预聚物与内酯单体共聚。
预聚物的分子量及其组成可随预聚物赋予共聚物的所需特性而改变。然而,优选的是,用来制备共聚物的脂族氧杂预聚物具有这样的分子量,它将提供比浓对数粘度在约0.2至约2.0每克分升(dl/g),是在25℃于0.1g/dl六氟异丙醇溶液中测量的。本领域熟练技术人员将认可,还可由一种以上二醇或二氧代羧酸的混合物制备本文所述的脂族聚氧杂酯预聚物。
由本发明方法制备的脂族聚氧杂酯的有益性能之一是酯键是水解不稳定的,因此,当暴露于潮湿体组织时易于降解成小片段,所以聚合物是生物可吸收的。在这点上,可以想象,可以向用来生成脂族聚氧杂酯预聚物的脂族二氧代羧酸和二醇的混合物中加入共反应物,优选反应混合物不含一定浓度的任何共反应物,该浓度使得随后制成的聚合物不可吸收。优选的是,如果生成的聚合物变得不可吸收,反应混合物基本不含任何这样的共反应物。
可用许多方法熔融加工本发明的聚合物以制备许许多多有用的器械。可将这些聚合物注塑或压塑制成可植入的医疗或外科器械,尤其伤口闭合器械。优选的伤口闭合器械是外科夹,U形钉和缝线。
此外,可将脂族聚氧杂酯挤出制成纤维。如此制成的丝可制成缝线或结扎线,接到外科针上,用已知技术包装和消毒。本发明的聚合物可以纺成多丝纱和纺织或针织形成海绵或纱布,(或可制成无纺片)或用于与其它塑压结构结合作为人或动物体内的假体器械,其中需要有高抗拉强度和所需的柔性和/或韧性水平。有用的例子包括动脉、静脉或肠修复的导管,包括支化导管,神经缝接,腱缝接,定型和支撑损坏的表面擦伤体的片料,尤其较大擦伤,或皮和皮下组织被损坏或外科移除的区域用的片料。
另外,该聚合物可模塑制成膜,消毒时可用作粘合防护载体阻隔体。本发明聚合物的另一种选择加工技术包括溶剂流延,尤其在需要药物分送基质用途时更是如此。
更详尽地,本发明的丝、膜及模制品的外科和医疗用途包括但不必限于此:a.烧伤敷料b.疝帖c.药制敷料d.筋膜代用品e.用于肝脏止血的纱布,织物,单子,毡子或海绵f.纱布绷带g.动脉移植物或代用品h.表皮用绷带i.结夹缝线j.矫形外科针或钉、夹、螺钉和板k.夹(例如静脉腔用)l.U形钉m.钩,钮和夹n.骨头替代品(例如假颚骨)o.宫内节育器(例如杀精子器)p.引流或测试管或毛细管q.外科仪器r.血管植入物或支撑物s.脊椎盘t.肾脏和人工心肺机的体外导管u.人造皮或其它物v.工程细胞垫。
在另一个实施方案中,脂族聚氧杂酯用于涂敷外科制品的表面以增加被涂表面的润滑性。聚合物可用常规技术用作涂料,例如,在易挥发有机溶剂的稀溶液中溶解该聚合物,溶剂的例子有丙酮,甲醇,乙酸乙酯或甲苯,然后将制品浸入溶液以涂其表面,一旦表面被涂敷,可从溶液中取出外科物品,可在升温下干燥直到除去溶剂和任何残留反应物。
在涂料用途使用中,脂族聚氧杂酯将有以在每分升六氟异丙醇(HFIP)0.1g中测量的比浓对数粘度在约0.05至约2.0dl/g,优选约0.10至约0.80dl/g。如果比浓对数粘度小于约0.05dl/g,那么聚合物不具有为各种外科和医疗物品的表面制备表面或涂层所必需的完整性。另一方面,尽管可以使用比浓对数粘度大于2.0dl/g的聚合物,但做起来非常困难。
尽管期望可用本发明的聚合物涂敷许多外科物品(包括但并不限于内窥仪器)以改进用品的表面性质,但优选的外科用品是外科缝线和针。最优选的外科用品是缝线,最优选地接到针上。优选地,缝线是合成可吸收的缝线。这些缝线例如可由内酯单体如乙交酯,丙交酯,G-己内酯,1、4-二恶烷酮和三亚甲基碳酸酯的均聚物和共聚物制成。优选的缝线是由聚乙交酯或聚(乙交酯共丙交酯)构成的编织多丝缝线。
在编织缝线的表面上施用的涂敷聚合物的量可由实验很容易地确定,并将取决于所选的特定共聚物和缝线。理想地,施于缝线表面的涂敷共聚物的量为被涂敷缝线重量的约0.5至约30%(重量),优选约1.0至约20%(重量),最优选1至约5%(重量)范围内。如果在缝线上涂敷的量大于约30%(重量),可能会增加当缝线经过组织时涂料剥落的危险。
由于其有更滑的感觉,所以用本发明的聚合物涂敷的缝线是所需求的,如此使外科医生更易于滑动缝线下的节到外科创伤的位置。另外,缝线是很柔韧的,因此外科医生在使用中更易于手术。与没有用本发明聚合物涂表面的缝线相比更能体现出这些优点。
在本发明的另一个实施方案中,当物品是外科针时,施于物品表面涂料的量是在针上生成的层厚度优选在约2至约20微米,更优选约4至约8微米。如果针上涂料量使得涂层厚度大于约20微米,或是如果厚度小于2微米,那么在针通过组织时达不到所需针的性质。
在本发明另一种实施方案中,可以使用脂族聚氧杂酯在药物运送基质中作药物载体。为形成该基质,可将聚氧杂酯与治疗剂混合形成基质。可与本发明的脂族聚氧杂酯结合使用的不同治疗剂的种类是很多的,通常,可借用本发明的治疗制剂施用的治疗剂包括但不限于:抗感染药例如抗生素和抗病毒剂;镇痛剂和镇痛合剂;抗厌食(anorexics)药;抗蠕虫剂;抗关节炎药;抗哮嚅剂;抗惊阙;抗抑郁药;抗利尿剂;抗腹泻;抗组胺剂;抗炎剂;抗偏头痛制剂;止吐剂;抗肿瘤剂;抗帕金森氏症药;止痒药;抗精神病药;解热药;抗痉挛药;抗胆碱能药;拟交感神精药;黄嘌呤衍生物;心血管制剂包括钙血管堵塞和β-堵塞如心得乐和抗心律失常;抗高血压;利尿剂;包括通常冠状的、外周的和大脑的血管舒张药;中枢神精系统刺激剂;咳嗽和感冒制剂,包括减充血剂,激素如雌烷二醇和其它类固醇,包括皮质类固醇;安眠药;免疫抑制剂;肌肉松驰剂;抗副交感神精药;神精刺激剂;镇静剂;和安定药;及天然衍生或基因工程蛋白质,多糖,糖蛋白,或脂蛋白。
可以用任何适用的剂形施用药物输送基质,例如口服、肠胃外,皮下作为移植物,阴道内或作为栓剂。可以通过将一种或多种治疗剂与聚氧杂酯混合制成含脂族聚氧杂酯的基质制剂。治疗剂可以以液体,细分散固体,或以任何其他物理形式存在。典型地但任选地,基质将包括一种或多种添加剂,例如,无毒辅助物质例如稀释剂,载体,赋形剂,稳定剂或类似物。其它适宜的添加剂可以与聚氧杂酯或药物活性剂或化合物配合,然而,如果使用水则在施用前应立刻加入。
治疗剂的量将取决于所用的特定药物和治疗的病情。典型地,药物的量相当于基质的约0.001%至约70%,更常用约0.001%至约50%,最常用约0.001%至约20%(重量)。
掺入到非肠道药中的聚氧杂酯的量和类型将根据所用药的所需释放曲线和量变化。产品可以含有聚氧杂酯的掺混物以便为给定的配制料提供所需的释放曲线和浓度。
当与体液包括血液或类似液接触时,聚氧杂酯经逐步降解(主要经水解)同时持续和延长期地释放分散的药物(与从等渗盐水溶液的释放比较)。这可能导致药物有效量(比如说,0.0001mg/kg/小时至10mg/kg/小时)的延长输送(经过比如说1至2000小时,优选2至800小时)。需要时这种剂形可根据治疗目的,害病程度,规定医生的判断等服用。
药物和聚氧杂酯的各配制剂可在适宜的试管内和体内模式中试验以达到所需的药物释放曲线。例如,药物可与聚氧杂酯配合并给动物口服。然后可通过适当的方法例如在特定时间取血样并分析样品的药物浓度来监测药物释放曲线,在这一过程或类似过程之后,本领域熟练技术人员能够配制各种配制剂。
本发明的聚合物、共聚物和掺混物可以交联以改变机械性能。可通过添加交联增强剂和/或辐射(如γ照射)完成交联。尤其是,可以使用交联以控制所说发明物的水溶胀性。
在本发明的进一步实施方案中,可在组织工程应用中使用该聚合物或这些聚合物的掺混物作为细胞支撑体。合适组织骨架结构在本领域中是已知的,例如在以US5306311中所述的假肢关节软骨,WO94/25079中所述的多孔生物可降解的骨架,和WO93/08850中所述的预形成血管植入物(由此本文参考引入这些文献)。本领域还已知在组织骨架中接种和/或培养细胞的方法,例如在EPO422209B1,  WO88/03785,WO90/12604和WO95/33821中公开的那些方法(由此本文参考引入这些文献)。
下述给定的实施例仅用于说明目的,无意以任何方式限制本发明的权利要求范围。在本发明范围和精神内许多其它方案对本领域熟练技术人员来说将成为显而易见的。
               实施例13,6-二氧杂辛二酸二甲基酯的制备
通过三甘醇的氧化合成二酸,3、6-二氧杂辛二酸,在一装有温度计、加料漏斗、气体吸收管和磁力旋转棒的500ml三颈圆底烧瓶中进行氧化。在磁搅拌时将反应烧瓶下降至静放在磁力搅拌器上的油浴中。向反应烧瓶中加157.3ml 60%的硝酸溶液。加37.0g三甘醇到加料漏斗中,
Figure A9710952000171
将烧瓶的物料加热到78-80℃,将含有0.5g乙二醇和1ml浓硝酸的试管在水溶中温热至到出现褐色烟雾,然后将该物料加到反应烧瓶中。混合物搅拌几分钟,此后仔细加乙二醇。应非常仔细地注意添加速度以保持在受控条件下反应,添加速度低到足以使放热反应混合物保持在78-82℃。添加完成(80分钟)后,反应混合物的温度在78-80℃另外保持1小时。在继续保持该温度范围的同时,减压水泵抽吸蒸出过量的硝酸和水,冷却浆状剩余物,出现一些固体。反应产物具有预期为二羧酸的IR和NMR光谱,粗产品本身可用于酯化。
如下完成粗制3、6-二氧杂辛二酸的酯化:向含有36g粗制二酸的反应烧瓶中加110ml甲醇。在室温搅拌3天,之后加入15g碳酸氢钠和搅拌一夜过滤混合物除去固体,向液体中另加10g碳酸氢钠,该混合物再搅拌一夜,分馏液体。
酯化产物的NMR分析表明三乙醇酸二甲基酯(78.4mol%)和三乙醇酸单酯(21.6mole%)的混合物,未观察到显著的二酸缩合物。
                   实施例2由3,6-二氧杂辛二酸的甲基酯和乙二醇制备聚氧杂酯
Figure A9710952000181
向火焰干燥的机械搅拌的50ml适于缩聚反应的玻璃反应器加入20.62g(约0.1mole)实施例1的3,6-二氧杂辛二酸的甲基酯,18.62g(0.3mole)蒸馏的乙二醇,和0.0606ml 0.33M辛酸亚锡在甲苯中的溶液。用氮气吹扫反应器并抽空后,在26小时的时间内逐渐将温度升至180℃,然后将180℃温度再保持另外20小时,所有这加热过程是在一个大气压的氮气氛中进行的,收集生成的甲醇。使反应烧瓶冷却到室温,然后在减压(0.015-1.0mm)下经约32小时的时间缓慢加热到160℃,在该时间内收集附加蒸留物,160℃温度保持4小时,之后取几克量的所生成的聚合物样品。测得样品的比浓对数粘度(I.V.)为0.28dl/g,在六氟异丙醇(HFIP)中于25℃以0.1g/dl浓度测量。在减压下继续聚合,同时,经约16小时将温度从160℃升到180℃;将180℃温度再保持另外8小时,此时取聚合物样品,测得I.V.为0.34dl/g。在减压下于180℃继续另8小时的反应。生成的聚合物具有比浓对数粘度为0.40dl/g,在HFIP中于25℃以0.1g/dl浓度测量。
               实施例3用3,6,9-三氧杂十一烷二酸和乙二醇制备聚氧杂酯
向火焰干燥的机械搅拌的250ml适于缩聚反应的玻璃反应器中加入44.44g(0.2mole)3,6,9-三氧杂十一烷二酸,62.07(1.0mole)蒸馏的乙二醇和9.96毫克氧化二丁锡。用氮气吹扫反应器并排气后,在一大气压氮气下,在约32小时中,将反应燃瓶的物料逐渐加热
Figure A9710952000191
到180℃,其间收集生成的水。将反应的物质冷却到室温,然后在减压下(0.015-1mm),加热反应物质在约40小时内将温度提高至180℃℃,其间收集其它蒸馏出物。在减压下继续聚合,同时保持180℃另/6个小时。所得到的聚合物的比浓对数粘度为0.63dl/g,在HFIP于25℃℃以0.1g/dl浓度测量。
                    实施例4用聚乙二醇二酸和乙二醇制备聚氧杂酯
向火焰干燥的机械搅拌的500ml适于缩聚反应的玻璃反应器加入123.8g(0.2mole)聚乙二醇二酸(分子量约619),62.07g(1.0mole)蒸馏的乙二醇和9.96毫克氧化二丁基锡。用氮气吹扫反应器并排气后,在一大气压氮气下在约32小时内加热反应烧瓶内的物料逐渐提高到200℃;其间收集生成的水。在减压下(0.015-1.0mm)经约24小时内加热反应烧瓶从室温升至140℃,其间收集其它馏出物,在这一阶段取约10克聚合物样品,在HFIP中于25℃下以浓度0.1g/dl测得I.V.为0.14dl/g。减压下继续进行聚合反应,同时在8小时从140℃加热至180℃,然后在180℃再保持8小时。再取聚合样品测得I.V.为0.17dl/g。此后反应温度升至190℃并在减压下再保持8小时。在HFIP于25℃以0.1g/dl测量,所生成聚合物被测得比浓对数粘度为0.70dl/g。
               实施例5以5/5/5重量比的聚氧杂酯/己内酯/三亚甲基碳酸酯共聚物
向火焰干燥的50ml圆底单颈烧瓶中加入5克具有I.V.0.14dl/g的实施例4的聚氧杂酯等分试样中,5.0g(0.0438mole)ε-己内酯,5.0g(0.0490mole)三亚甲基碳酸酯和0.0094ml辛酸亚锡在甲苯中的0.33摩尔溶液。烧瓶装有磁力搅拌棒,在用氮气排空之前用氮气吹扫反应器三次,反应混合物加热到160℃并在该温度下保持约6小时。在真空(0.1mmHg)80℃下干燥共聚物约16小时以除去任何未反应的单体。共聚物具有比浓对数粘度为0.34dl/g,在HFIP中于25℃以0.1g/dl浓度测量。在室温下共聚物是粘性液体。由NMR分析测得聚氧杂酯/PCL/PTMC的摩尔比是47.83/23.73/28.45。
                 实施例6重量比为6/8.1/0.9的聚氧杂酯/己内酯/乙交酯的共聚物
向火焰干燥的25ml圆底单颈烧瓶中加入6g具有I.V.0.17dl/g的实施例4的聚氧杂酯,8.1g(0.0731mole)ε-己交酯,0.9g(0.008mole)乙交酯和0.0080ml 0.33摩尔浓度辛酸亚锡在甲苯中的溶液。烧瓶装有磁力搅拌棒,用氮气排空前用氮气吹扫反应器三次,反应混合物加热到160℃并在该温度保持约18小时。在HFIP中于25℃以0.1g/dl浓度测量共聚物具有比浓对数粘度0.26dl/g。在室温下共聚物是固体,由NMR分析测得聚氧杂酯/PCL/PGA/己内酯的摩尔比为56.54/37.73/3.79/1.94。
              实施例7
               体外水解
例3的聚氧杂酯在50℃和在回流温度下试验体外水解。100mg聚氧杂酯试样置于100ml磷酸盐缓冲液(0.2M磷酸盐,PH7.27)中,在50℃约7天完全水解,而在回流时则在约16小时内完全水解。
              实施例8
                体外水解
例2的聚氧杂酯在50℃和在回流温度下试验体外水解,100mg聚氧杂酯试样置于100ml缓冲液(PH7.27)中,于50℃在约25天内完全水解,而在回流时则在约16小时内完全水解。

Claims (10)

1一种脂族聚氧杂酯,它含有式(I)的第一种二价重复单元:[O-C(O)-C(R1)(R2)-O-(R3)-O-C(R1)(R2)-C(O)-]    I和选自下列式子的第二种重复单元:
[-O-R4-]A                 II
[-O-R5-C(O)-]B和      III
([-O-R5-C(O)]P-O-)LG  XI及其混合物,其中R1和R2分别是氢或含1至8个碳原子的烷基;R3是含2至12个碳原子的亚烷基或是下式的氧代亚烷基:
-[(CH2)C-O-]D-(CH2)E- IV其中C是2至约15范围内的整数;D是约0至约2000范围内的整数;E是约2至约5范围内的整数;只是当D是0时,在此情况下E将是2至12的整数;R4是含2至8个碳原子的亚烷基单元;A是1至2000范围内的整数;R5选自基团C(R6)(R7)-,-(CH2)3)-O-,-CH2-CH2-O-CH2-,-CR8H-CH2-,-(CH2)4-,-(CH2)F-O-C(O)-和-(CH2)F-C(O)-CH2-;R6和R7分别是氢或含1至8个碳原子的烷基;R8是氢或甲基;F是2至6范围内的整数;B是1至n范围内的整数,以使式III的数均分子量小于约200000;P是1至m范围内的整数,以使式XI的数均分子量小于约1000000;G表示从上述含1至约200个羟基的醇的羟基中去掉1至L个氢原子的残基;及L是约1至200的整数。
2权利要求1的脂族聚氧杂酯,其中聚合物具有式:[-O-C(O)-(C(R1)(R2)-O-(R3)-O-C(R1)(R2)C(O)-O(R4)A-]N其中N是约1至约10000范围内的整数。
3权利要求1的脂族聚氧杂酯,其中聚合物具有式:[(-C(O)-C(R1)(R2)-O-R3-O-C(R1)(R2)-C(O)-(O-R4)A-O)s(C(O)-R5-O)B]W其中S是约1至约10000范围内的整数和W是约1至约1000范围内的整数。
4权利要求1的脂族聚氧杂酯,其中聚合物具有式[(-C(O)-C(R1)(R2)-O-R3-O-C(R1)(R2)-C(O)-(OR4)A-O)s([-O-R5-C(O)]P-O-)LG]W其中S是1至约10000范围内的整数和W是1至约1000范围内的整数。
5由脂族聚氧杂酯制成的器械,其中聚氧杂酯含有式I的第一种二价重复单元;[O-C(O)-C(R1)(R2)-O-(R3)-O-C(R1)(R2)-C(O)-]    I和选自下列式子的第二种重复单元:
-[O-R4-]A              II
[-O-R5-C(O)-]B和            III
([-O-R5-C(O)]P-O-)LG        XI及其混合物,其中R1和R2分别是氢或含1至8个碳原子的烷基;R3是含2至12个碳原子的亚烷基单元或是下式的氧代亚烷基:
-[(CH2)C-O-]D-(CH2)E-       IV其中C是2至约5范围内的整数,D是约0至约2000的整数,和E是约2至约5范围内的整数,只是当D是0时,此情况下E将是2至12的整数;R4是含2至8个碳原子的亚烷基单元;A是1至2000范围内的整数;R5选自基团:-C(R6)(R7)-,-(CH2)3-O-,-CH2-CH2-O-CH2-,CR8H-CH2-,-(CH2)4-,-(CH2)F-O-C(O)-和-(CH2)F-C(O)-(CH2)-;R6和R7分别是氢或含1至8个碳原子的烷基,R8是氢或甲基;F是2至6范围内的整数;B是1至n范围内的整数,以使式III的数均分子量小于200000;P是1至m范围内的整数,以使式XI的数均分子量小于约1000000;G表示从上述含1至约200个羟基的醇的羟基中去掉1至L个氢原子的残基,及L是约1至约200的整数。
6权利要求5的器械,其中该器械是可吸收的外科器械。
7权利要求6的可吸收的外科器械,其中该可吸收的外科器械选自烧伤敷料,疝帖,药制敷料,筋膜代用品,纱布,织物,单子,毡子,海绵,纱布绷带,动脉移植物,表皮用绷带,节夹缝线,针或钉,夹,螺钉,板,夹,U形钉,钩,钮,夹,骨头替代品,宫内节育品,导管,外科仪器,血管移植物,血管支撑物,脊椎盘,和人造皮。
8权利要求6的可吸收外科器械,其中该器械是丝。
9用可吸收的涂料涂敷的器械,该涂料包含脂族聚氧杂酯,该酯具有式I的第一种二价重复单元:[O-C(O)-C(R1)(R2)-O-(R3)-O-C(R1)(R2)-C(O)-]      I和选自下列式子的第二种重复单元:
[-O-R4-]A              II
[-O-R5C(O)-]B和       III
([-O-R5-C(O)]P-O-)LG   XI及其混合物,其中R1和R2分别是氢或含1至8个碳原子的烷基;R3是含2至12个碳原子的亚烷基单元或是下式的氧代亚烷基:
-[(CH2)C-O]D-(CH2)E-   IV其中C是2至约5的整数,D是约0至约2000范围内的整数,和E是约2至约5范围内的整数,只是当D是0时,此情况下E将是2至12的整数;R4是含2至8个碳原子的亚烷基单元;A是1至2000范围内的整数,R5选自基团:C(R6)(R7)-,-(CH2)3-O-,-CH2-CH2-O-CH2-,-CR8H-CH2-,-(CH2)4-,-(CH2)F-O-C(O)-和-(CH2)F-C(O)-CH2-;R6和R7分别是氢或含1至8个碳原子的烷基;R8是氢或甲基;F是2至6范围内的整数;B是1至n范围内的整数,以使式III的数均分子量小于约200000;P是1至m范围内的整数,以使式XI的数均分子量小于约1000000;G表示从上述含1至约200个羟基的醇的羟基中去掉1至L个氢原子的残基;及L是约1至约200的整数;其中,在0.1g/dl六氟异丙醇(HFIP)的溶液中于25℃测量,聚氧杂酯的比浓对数粘度为约0.05至约2.0dl/g。
10一种药物分配基质,它含有药物和脂族聚氧杂酯,该聚氧杂酯具有式I的第一种二价重复单元:[O-C(O)-C(R1)(R2)-O-(R3)-O-C(R1)(R2)-C(O)-]                      I和选自下列式子的第二种重复单元:
[-O-R4-]A                II
[-O-R5-C(O)-]B和         III
([-O-R5-C(O)]P-O-)LG     XI及其混合物,其中R1和R2分别是氢或含1至8个碳原子的烷基;R3是含2至12个碳原子的亚烷基单元或是下式的氧代亚烷基:
-[(CH2)C-O-]D-(CH2)E-    IV其中C是2至约5范围内的整数,D是约0至约200范围内的整数,和E是约2至约5范围内的整数,只是当D是0时,此情况下E将是2至12的整数;R4是含2至8个碳原子的亚烷基单元;A是1至2000范围内的整数;R5选自基团;-C(R6)(R7)-,-(CH2)3-O-,-(CH2-CH2-O-CH2-,-CR8H-CH2-,-(CH2)4-,-(CH2)F-O-C(O)-和-[CH2)F-C(O)-CH2-;R6和R7分别是氢或含1至8个碳原子的烷基;R8是氢或甲基;F是2至6范围内的整数;B是1至n范围内的整数,以使式III的数均分子量小于约200000;P是1至m范围内的整数,以使式XI的数均分子量小于约1000000;G表示从上述含1至约200个羟基的醇的羟基中去掉1至L个氢原子的残基;和L是约1至约200的整数。
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US5618552A (en) 1997-04-08
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