CN109939065B - 医用水凝胶 - Google Patents
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Abstract
本发明公开了一种医用水凝胶,由醛基封端的星形多臂聚乙二醇和多氨基化合物原位交联而成,所述醛基与星形多臂聚乙二醇之间以醚键、酰胺键、氨酯键、亚胺键或脲键化学键连接。本发明利用多臂聚乙二醇端部的醛基和多氨基化合物的氨基反应生成schiff碱从而产生交联,形成医用可注射凝胶。所制得的凝胶成胶时间短,具有理想的凝胶胀破强度,并且在水溶液中稳定性好,相较于现有医用凝胶具有更好的应用价值。
Description
技术领域
本发明属于生物医药技术领域,具体涉及一种医用水凝胶,可用于术后组织密封与防渗漏、防组织黏连、组织填充剂、组织修复、皮肤敷料和药物释放等领域。
背景技术
水凝胶是一种由亲水性聚合物交联得到的含有大量水分的软材料。水凝胶具有优良的理化性能和生物学特性,如高含水量、高弹性、柔软、具有生物相容性等特点,在药物转运、组织工程等生物医学研究领域有着重要的应用价值。可注射水凝胶是指具有一定流动性的、能够通过注射的方法应用的一类水凝胶,对于外界刺激(温度,温度/pH等变化)呈现出溶胶与凝胶间的相转变,在注射入人体之前呈液态或是具有剪切变稀性质的半固态,在注射入人体内之后能原位成胶,因而不需要侵入性手术,这有效地避免了感染的风险,并减捏了病人的痛苦。目前已发展的各种可注射的PEG水凝胶包括PEG为亲水段的两亲性聚酯/聚肽水凝胶、超分子作用制备的PEG水凝胶以及通过温和化学反应制备的PEG水凝胶。
聚乙二醇(polyethylene glycol,PEG)是一类非离子型聚合物,由于其本身有较好的生物相容性和安全性,是获美国食品和药品管理局(FDA)许可的可应用在人类临床的一类合成聚合物。PEG既可以作为药用辅料,又可以使用含有末端活泼官能团的PEG对药物进行修饰(聚乙二醇化)。聚乙二醇化技术具有较多的优点,尤其是在修饰蛋白和多肽类药物方面:具有延长其体内循环时间、增强生物活性、避免蛋白水解和降低免疫反应的特点。可通过连接活性末端官能团,如氨基、硫醇基、叠氮、炔基和醛基等制备聚乙二醇偶联物来提高聚乙二醇的性能。
CN105963792A公开了一种医用水凝胶组合物,包括第一组分和第二组分,所述第一组分包括聚赖氨酸和聚乙烯亚胺;所述第二组分包括四臂-聚乙二醇-琥珀酰亚胺戊二酸酯、四臂-聚乙二醇-琥珀酰亚胺丁二酸酯、四臂-聚乙二醇-琥珀酰亚胺碳酸酯中的一种或几种。使用时将第一组分的亲核试剂(聚赖氨酸和聚乙烯亚胺)与第二组分的亲电试剂(四臂-聚乙二醇-琥珀酰亚胺戊二酸酯、四臂-聚乙二醇-琥珀酰亚胺丁二酸酯、四臂-聚乙二醇-琥珀酰亚胺碳酸酯中的一种或几种)发生迈克尔加成反应,可以快速成胶具有低溶胀的优良性质。然而,琥珀酰亚胺有机酸酯封端的聚乙二醇材料在水中半衰期很短,极易水解,需要特别的技术才能以粉末的形式在室温长期保存,且在溶解之后很短时间内(一般为1个小时)使用,便利性较低。
CN107693838A公开了一种医用可注射凝胶及其制备方法,将浓度为2-20%(w/v)醛基封端超支化聚合物HP-PEG-CHO溶液与浓度为2-20%(w/v)多氨基化合物溶液通过双组份注射器混合后喷涂,利用醛基和氨基反应生成西弗碱从而产生交联,形成医用可注射凝胶。醛基封端超支化聚合物HP-PEG-CHO中的醛基以酯键与聚合物连接,在水溶液中的长期稳定性较低,另外超支化聚合物分子量分布较宽,可能含有较高分子量的聚合物,不利于人体排出。
发明内容
本发明针对现有技术不足,提供了一种水溶液可长期稳定保存、基于多臂星形聚乙二醇的医用水凝胶。
本发明具体技术方案如下:
一种医用水凝胶,由醛基封端的星形多臂聚乙二醇和多氨基化合物原位交联而成,所述醛基与星形多臂聚乙二醇之间以醚键、酰胺键、氨酯键、亚胺键或脲键等不易水解键连接。
所述多氨基化合物选自聚乙烯亚胺和聚赖氨酸中的一种或多种。
所述醛基封端的多臂聚乙二醇为臂数不小于2,分子量不小于2000的多臂聚乙二醇。
所述醛基封端的多臂聚乙二醇的臂数为2-8,优选为8。
所述醛基选自芳香醛、烷基醛中的一种或几种,优选为苯醛基。
本发明另一目的在于提供所述医用水凝胶在术后组织密封与防渗漏、防组织黏连、组织填充剂、组织修复、皮肤敷料和药物制剂中的应用。
本发明另一目的在于提供所述医用水凝胶的制备方法,将醛基封端的星形多臂聚乙二醇溶解在pH4-10缓冲液中,配置醛基封端的星形多臂聚乙二醇溶液;将多氨基化合物溶解在pH4-10缓冲液中,配置多氨基化合物溶液;将两者混合得到医用水凝胶。
本发明所用的醛基封端的星形多臂聚乙二醇可以通过商业途径购买。
上述pH4-10缓冲液优选pH4-10的磷酸盐或硼酸盐缓冲液。
所述醛基封端的星形多臂聚乙二醇溶液的终浓度为2-30%(w/v),优选为10-20%(w/v);所述多氨基化合物溶液浓度为0.5-20%,优选为1-5%(w/v)
所述醛基封端的星形多臂聚乙二醇中醛基与多氨基化合物中氨基物质的量比例为0.01-5:1。
本发明在具体应用时先制备成双组份水凝胶,为包含亲核官能团的第一组分和包含亲电官能团的第二组分,所述第一组分为醛基封端的亲水性化合物,其中臂的个数不低于两个,亲水性化合物为醛基封端的星形多臂聚乙二醇,优选为八臂聚乙二醇(分子量5000-20000),醛基为芳香醛、烷基醛中的一种或几种,优选为苯醛基。醛基与聚合物之间可以以醚键、酰胺键等不易水解的化学键连接。
所述第二组分可以选择包含多氨基的化合物,包括聚赖氨酸(包括ε-聚赖氨酸和多聚赖氨酸)和聚乙烯亚胺中的一种或几种的混合组分。
酰胺键连接苯醛基封端八臂聚乙二醇、醚键连接苯醛基封端八臂聚乙二醇、醚键连接丙醛基封端八臂聚乙二醇的化学结构如下所示。
由于醛基和氨基在水溶液中的稳定性,以上两组分均可以以水溶液或粉末形式提供。使用时将两组分分别溶解于缓冲液中,然后混合组分即得到水凝胶。可将水凝胶两组分分别存储在双管注射器中,使用时两个组分经混合头喷出或者注射到指定部位形成凝胶。
本发明利用多臂聚乙二醇端部的醛基和多氨基化合物的氨基反应生成schiff碱从而产生交联,形成医用可注射凝胶。所制得的凝胶成胶时间短,具有理想的凝胶胀破强度,并且在水溶液中稳定性好,相较于现有医用凝胶具有更好的应用价值。
附图说明
图1为醚键连接、酰胺键连接和酯键连接的醛基封端聚乙二醇成胶稳定性考察结果。
具体实施方式
以下通过实施例说明本发明的具体步骤,但不受实施例限制。
在本发明中使用的术语,除非另有说明,一般具有本领域普通技术人员通常理解的含义。
下面结合具体实施例并参照数据进一步详细描述本发明,应理解,这些实施例只是为了举例说明本发明,而非以任何方式限制本发明的范围。
在以下实施例中,未详细描述的各种过程和方法是本领域中公知的常规方法。
下面结合具体实施例对本发明进行进一步描述,但本发明的保护范围并不仅限于此。
实施例1
将600mg的醚键连接苯醛基封端8臂聚乙二醇8-PEG-O-BA(M.W.10K)溶解在2mL的磷酸盐缓冲液中(pH7.4),作为A溶液;配置聚乙烯亚胺2.2%(w/v)的磷酸盐缓冲液溶液,作为B溶液;将A、B溶液等体积混合即获得具有粘性的水凝胶,成胶时间为21秒,凝胶胀破强度为16kPa。
实施例2
将600mg的醚键连接苯醛基封端8臂聚乙二醇8-PEG-O-BA(M.W.13.5K)溶解在2mL的磷酸盐缓冲液中(pH7.4),作为A溶液;配置聚乙烯亚胺1.67%(w/v)的磷酸盐缓冲液溶液,作为B溶液;将A、B溶液等体积混合即获得具有粘性的水凝胶,成胶时间为22秒,凝胶胀破强度为11kPa。
实施例3
将400mg酰胺键连接苯醛基封端8臂聚乙二醇8-PEG-amide-BA(M.W.10K)溶解在2mL的磷酸盐缓冲液中(pH7.4),作为A溶液;配置聚乙烯亚胺1.48%(w/v)的磷酸盐缓冲液溶液,作为B溶液;将A、B溶液等体积混合即获得具有粘性的水凝胶,成胶时间为2秒,凝胶胀破强度为13kPa。
实施例4
将600mg酰胺键连接苯醛基封端4臂聚乙二醇4-PEG-amide-BA(M.W.10K)溶解在2mL的磷酸盐缓冲液中(pH7.4),作为A溶液;配置聚乙烯亚胺2.2%(w/v)的磷酸盐缓冲液溶液,作为B溶液;将A、B溶液等体积混合即获得具有粘性的水凝胶,成胶时间为20秒,凝胶胀破强度为11kPa。
实施例5
将400mg酰胺键连接苯醛基封端8臂聚乙二醇8-PEG-amide-BA(M.W.10K)溶解在2mL的磷酸盐缓冲液中(pH7.4),作为A溶液;配置聚赖氨酸2.44%(w/v)的磷酸盐缓冲液溶液,作为B溶液;将A、B溶液等体积混合即获得具有粘性的水凝胶,成胶时间为5秒,凝胶胀破强度为21kPa。
实施例6
将400mg酰胺键连接苯醛基封端8臂聚乙二醇8-PEG-amide-BA(M.W.10K)溶解在2mL的磷酸盐缓冲液中(pH7.4),作为A溶液;配置聚赖氨酸3.66%(w/v)的磷酸盐缓冲液溶液,作为B溶液;将A、B溶液等体积混合即获得具有粘性的水凝胶,成胶时间为5秒,凝胶胀破强度为25kPa。
实施例7
将600mg的醚键连接丙醛基封端8臂聚乙二醇8-PEG-O-PA(M.W.10K)溶解在2mL的磷酸盐缓冲液中(pH7.4),作为A溶液;配置聚乙烯亚胺1.48%(w/v)的磷酸盐缓冲液溶液,作为B溶液;将A、B溶液等体积混合即获得具有粘性的水凝胶,成胶时间为15秒,凝胶胀破强度8kPa。
实施例8
将600mg的醚键连接苯醛基封端8臂聚乙二醇8-PEG-O-BA(M.W.13.5K)溶解在2mL的磷酸盐缓冲液中(pH7.4),作为A溶液;配置聚赖氨酸2.75%(w/v)的磷酸盐缓冲液溶液,作为B溶液;将A、B溶液等体积混合即获得具有粘性的水凝胶,成胶时间小于5分钟,凝胶胀破强度为2kPa。
实施例9
将600mg的醚键连接苯醛基封端8臂聚乙二醇8-PEG-O-BA(M.W.13.5K)溶解在2mL的磷酸盐缓冲液中(pH7.4),作为A溶液;配置含聚赖氨酸2.75%(w/v)和聚乙烯亚胺(M.W.1.8K)1%(w/v)的磷酸盐缓冲液溶液,作为B溶液;将A、B溶液等体积混合即获得具有粘性的水凝胶,成胶时间35秒,凝胶胀破强度为22kPa。
实施例10
将400mg酯键连接苯醛基封端8臂聚乙二醇8-PEG-amide-BA(M.W.10K)溶解在2mL的磷酸盐缓冲液中(pH7.4),作为A溶液;配置聚乙烯亚胺(M.W.1.8K)1.48%(w/v)的磷酸盐缓冲液溶液,作为B溶液;将A、B溶液等体积混合即获得具有粘性的水凝胶,成胶时间为5秒,凝胶胀破强度为13kPa。
实施例11
比较醚键连接、酰胺键连接和酯键连接的苯醛基封端聚乙二醇在水溶液中的长期稳定性,为了缩短试验时间,选择碱性硼酸盐缓冲液作为溶剂,比较不同时间点成胶时间的变化。分别将400mg的醚键连接、酰胺键连接和酯键连接苯醛基封端8臂聚乙二醇(M.W.10K)溶解在2mL的0.1M硼酸盐缓冲液(pH9.2),作为A溶液;配置含聚乙烯亚胺(M.W.1.8K)1.48%(w/v)的磷酸盐缓冲液溶液,作为B溶液;将A、B溶液等体积混合即获得具有粘性的水凝胶,初始成胶时间分别为25秒、2秒和5秒。将三种A液置于37℃烘箱1、2、4、16、24和40小时,再分别测定与B液混合后的成胶时间与初始成胶时间的变化(如图1所示)。结果显示,酯键连接的聚乙二醇在40小时后失去成胶能力,而醚键连接和酰胺键连接苯醛基封端8臂聚乙二醇成胶时间基本保持不变。
Claims (6)
1.一种医用水凝胶,其特征在于由醛基封端的星形多臂聚乙二醇和多氨基化合物原位交联 而成,所述醛基与星形多臂聚乙二醇之间以醚键或酰胺键连接,所述多氨基化合物选自聚乙烯亚胺和聚赖氨酸中的一种或多种,所述醛基封端的星形多臂聚乙二醇为臂数为2-8,分子量不小于2000的多臂聚乙二醇,所述醛基选自芳香醛、烷基醛中的一种或几种。
2.根据权利要求1所述医用水凝胶在制备术后组织密封、防渗漏、防组织黏连、组织填充、组织修复、皮肤敷料的材料或药物制剂中的应用。
3.根据权利要求1所述医用水凝胶的制备方法,其特征在于将醛基封端的星形多臂聚乙二醇溶解在 pH4-10 缓冲液中,配置醛基封端的星形多臂聚乙二醇溶液;将多氨基化合物溶解在 pH4-10 缓冲液中,配置多氨基化合物溶液;将两者混合得到医用水凝胶。
4.根据权利要求3所述医用可注射凝胶制备方法,其特征在于所述醛基封端的星形多臂聚乙二醇溶液的终浓度为 2-30 %,所述多氨基化合物溶液浓度为0.5-20% 。
5.根据权利要求3所述医用可注射凝胶制备方法,其特征在于所述醛基封端多臂的星形聚乙二醇溶液的终浓度为10 ~ 20%,所述多氨基化合物溶液浓度为1-5% 。
6.根据权利要求3所述医用可注射凝胶制备方法,其特征在于所述醛基封端的星形多臂聚乙二醇中醛基与多氨基化合物中氨基物质的量比例为0.01- 5:1。
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