CN114369354A - 用于血管栓塞的可注射水凝胶 - Google Patents
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Abstract
本发明公开了一种用于血管栓塞的可注射水凝胶,由醛基封端的星形多臂聚乙二醇、聚乙烯亚胺和聚赖氨酸原位交联而成,醛基与聚乙烯亚胺中的氨基的摩尔比为1:0.6~5,醛基与聚赖氨酸中的氨基的摩尔比为1:0~5。本发明所述水凝胶体外成胶时间等于或者小于8秒在8s,能够快速栓塞血管造成目标器官或组织的坏死。
Description
技术领域
本发明属于生物医药技术领域,具体涉及一种用于血管栓塞的可注射水凝胶,可作为血管栓塞剂用于阻塞患病或受伤的血管。
背景技术
血管栓塞是指使用栓塞剂有意地阻塞患病或受伤的血管的一种治疗方法,可用于治疗许多血管疾病,包括出血,动脉瘤,血管畸形和血供丰富的肿瘤。目前在临床中使用不同类型的栓塞剂,包括弹簧圈,微球和液体栓塞等。
高分子聚合物多用于制备液体型血管栓塞剂。文献报道了一种液体栓塞产品,将高分子聚合物溶解于有机溶剂DMSO中,将高分子溶液注入血管后随着聚合物的沉淀形成固体的栓塞(张海霞等,以二甲基亚砜为溶剂的液体栓塞剂在脑血管性疾病栓塞治疗中的应用,介入放射学杂志,2002,Vol.11,No.3)。然而,DMSO本身具有一定的毒性,而且聚合物DMSO溶液的粘度较高,无法有效分散到小血管内,并不能满足临床实际需要。
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,并减少了病人的痛苦。
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。
由于血液中含有血细胞、蛋白质以及多种电解质和有机化合物,成分复杂且具有流动性,这与现有PEG水凝胶研究中使用的液体成胶环境存在很大的差异。因此即使水凝胶材料具有良好的可注射性,但是需要在血流速度较快的血管内原位形成凝胶并维持一定时间的栓塞效果仍然面临巨大的挑战。
中国专利文献CN109646723A公开了一种医用水凝胶,采用醛基封端的多臂聚乙二醇与聚乙烯亚胺和聚赖氨酸的混合物形成凝胶。该水凝胶制备时采用A/B双组分经注射器和混合头混合后形成凝胶,具有良好的可注射性。虽然该凝胶在体外环境成胶快,在水溶液中具有长期稳定性,然而该水凝胶只能满足作为医用放疗防护垫片用于辐射防护的要求,是否能够在血管内形成稳定的凝胶并保持稳定栓塞效果是尚未可知的。
发明内容
本发明在现有医用水凝胶的研究基础上,提供了一种新型的聚乙二醇水凝胶栓塞剂,具有良好的可注射性和血管内原位形成凝胶的能力。动物实验结果证实本发明所述水凝胶能够较长时间的栓塞目标血管,并引起目标器官或者组织的供血不足和坏死。
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、聚乙烯亚胺和聚赖氨酸原位交联而成。
本发明所述医用水凝胶能够在血管内原位成胶,体外成胶时间等于或者小于8秒.本发明所述的医用水凝胶,优选醛基与聚乙烯亚胺中的氨基的摩尔比为1:0.6~5,醛基与聚赖氨酸中的氨基的摩尔比为1:0~5。更优选醛基与聚乙烯亚胺中的氨基的摩尔比为1:0.9~2,醛基与聚赖氨酸中的氨基的摩尔比为1:0.4~5(更优选1:0.4~4)。
优选的,所述醛基与星形多臂聚乙二醇之间以酯键、醚键、酰胺键、氨酯键、亚胺键或脲键化学键连接。更优选的,所述醛基与星形多臂聚乙二醇之间以酰胺键或酯键连接。
优选的,星形多臂聚乙二醇的臂数为2-8,更优选4-8,单臂分子量1000-5000Da。更优选的,星形多臂聚乙二醇为8臂,总分子量为15kDa~20kDa。凝胶中星形多臂聚乙二醇的浓度为10~20%。
优选的,所述醛基选自芳香醛基、烷基醛基中的一种或几种。
本发明另一目的在于提供本发明所述医用水凝胶作为血管栓塞剂在血管栓塞领域中的应用。
本发明另一目的在于提供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,配制醛基封端的星形多臂聚乙二醇溶液;将聚乙烯亚胺和聚赖氨酸溶解在pH4-10缓冲液中,配置溶液;将两者混合得到医用水凝胶。
上述pH4-10缓冲液优选pH4-10的磷酸盐或硼酸盐缓冲液。
优选的,所述醛基封端的星形多臂聚乙二醇溶液的终浓度为2-40%(w/v),优选为10-30%(w/v);所述聚乙烯亚胺和聚赖氨酸溶液浓度为0.5-20%,优选为0.5-5%(w/v)。
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8臂、6臂和4臂聚乙二醇(单臂分子量1000-5000Da),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稳定或可水解的化学键连接。
所述第二组分为包括聚赖氨酸(包括ε-聚赖氨酸和多聚赖氨酸)和聚乙烯亚胺的混合组分。
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。
本发明优点:
本发明以动物以及模拟血液为环境,分别从血管内成胶能力、血管内凝胶溶胀率、凝胶在血液中的稳定性、凝胶分数凝胶及血管栓塞效果多个方面对水凝胶组成对性能的影响进行了研究和优化。所得到的水凝胶能够较长时间的栓塞目标血管,并引起目标器官或者组织的供血不足和坏死。
附图说明
图1.注射到大鼠肾动脉内原位形成的凝胶。
图2.经凝胶栓塞9天后新西兰大白兔的肾坏死情况。
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。
实施例1水凝胶中醛基与氨基的比例对的血管内成胶能力的影响为了测试不同水凝胶配方的血管内形成凝胶的能力,本实施例使用双联注射器将双组分水凝胶注射到大鼠动脉血管内,双组分水凝胶由A液和B液经双联注射器混合形成。首先,将200mg的酯键连接的苯醛基封端的8臂聚乙二醇(分子量15kDa)溶解在1mL的磷酸盐缓冲液中(pH5.6),作为A液。根据表1所示不同的摩尔比配置不同含量聚赖氨酸和聚乙烯亚胺(M.W.1.8K)的硼砂缓冲液(pH9.2)溶液,作为B溶液。将A和B溶液混合注射得到水凝胶,将不同配方的水凝胶前驱体注射到大鼠肾动脉内测试血管内形成凝胶的能力,同时研究A和B溶液在体外环境的成胶时间作为辅助研究。
表1
验结果表明,只有在聚乙烯亚胺的氨基与醛基摩尔比超过0.9:1时,才能在血管内形成凝胶。
实施例2水凝胶中醛基与氨基的比例以及PEG浓度对凝胶的血管溶胀率的影响凝胶在血液中的溶胀率对有效的血管栓塞非常重要,溶胀率过低(负溶胀)的水凝胶会在成胶后发生收缩,导致水凝胶无法充满血管并形成有效栓塞。本实施例考察水凝胶在模拟血液中的溶胀率,满足栓塞条件的凝胶溶胀率应大于0。
根据表2所示不同的聚乙二醇终浓度,将不同质量的酯键连接的苯醛基封端的8臂聚乙二醇(分子量15kDa)溶解在1mL的磷酸盐缓冲液中(pH5.6),作为A液。根据表2所示不同的摩尔比配置不同含量聚赖氨酸和聚乙烯亚胺(M.W.1.8K)的硼砂缓冲液(pH9.2)溶液,作为B溶液。将A和B溶液混合注射得到水凝胶。将不同配方的水凝胶置入37度模拟血液(购自于北京汇智泰康公司)中,测试2小时后的溶胀变化。
表2
实验结果表明,水凝胶中聚乙二醇的浓度和聚乙烯亚胺均对溶胀率产生影响,其中聚乙二醇浓度对凝胶溶胀率影响显著,当聚乙二醇浓度为15%和10%时,水凝胶的溶胀率为负值,不适合用作血管栓塞。
实施例3
凝胶在血液中的稳定性对有效的血管栓塞非常重要,栓塞需要持续一段时间才能达到良好的效果。当凝胶稳定时间过短时,形成有效栓塞的时间过短,导致效果不佳。发明人早期研究发现表明聚赖氨酸的氨基与聚乙二醇的醛基的摩尔比影响水凝胶的稳定性(体外水溶液环境下聚赖氨酸的氨基与8-PEG-amide-BA醛基的摩尔比大于等于0.4时,水凝胶稳定性超过一个月),本实施例考察水凝胶在模拟血液中的稳定性。首先,将200mg酯键连接的苯醛基封端的8臂聚乙二醇(分子量15kDa)溶解在1mL的磷酸盐缓冲液中(pH5.6),作为A液。根据表3所示不同的摩尔比配置不同含量聚赖氨酸和聚乙烯亚胺(M.W.1.8K)的硼砂缓冲液(pH9.2)溶液,作为B溶液。将A和B溶液混合注射得到水凝胶。将不同配方的水凝胶置入37度模拟血液中,测试水凝胶的稳定性。
表3
聚乙二醇的醛基与聚乙烯亚胺氨基以及聚赖氨酸氨基的摩尔比 | 模拟血液中凝胶稳定性 |
1:4:0.4 | 小于3天 |
1:4:1 | 小于3天 |
1:3:0.4 | 小于3天 |
1:3:1 | 小于3天 |
1:2:0.4 | 超过2周 |
1:2:1 | 超过2周 |
1:1:0.4 | 超过2周 |
1:1:0.2 | 小于3天 |
实验结果表明,当聚乙烯亚胺和醛基摩尔比为3:1和4:1时,凝胶的稳定性小于3天;而当聚乙烯亚胺和醛基摩尔比保持1:1,同时将聚赖氨酸的氨基和醛基摩尔比下降至0.2:1时,凝胶稳定性同样小于3天。只有在聚乙烯亚胺和醛基摩尔比在小于等于2:1,且赖氨酸的氨基和醛基摩尔比大于等于0.4:1时,模拟血液中凝胶稳定性超过两周。
实施例4水凝胶在模拟血液中的凝胶分数测试
双组份溶液混合形成的凝胶有可能存在一定的不均匀性,导致局部的溶液比例偏离预设比例,局部无法形成凝胶。这种局部不均匀性会导致过多的凝胶预聚溶液进入血管,进而影响栓塞效果,并可能引起毒性。凝胶在模拟血液中的凝胶分数测试过程如下。首先,根据表4将不同质量的酯键连接的苯醛基封端的8臂聚乙二醇(分子量15kDa)溶解在1mL的磷酸盐缓冲液中(pH5.6),作为A液。根据表4所示不同的摩尔比配置不同含量聚赖氨酸和聚乙烯亚胺(M.W.1.8K)的硼砂缓冲液(pH9.2)溶液,作为B溶液。将A和B溶液混合注射得到水凝胶。将上述凝胶直接冻干后记录凝胶的干重(w0);另外制备同样的一批凝胶,将凝胶置于模拟血液中37度放置2小时,然后将凝胶取出冻干记录凝胶干重(w);计算放置2小时候的干重与初始干重的比值,为凝胶分数。
表4
实验结果表明,当A液聚乙二醇终浓度为60%(凝胶中聚乙二醇终浓度为30%)时,凝胶分数小于90%,表明聚乙二醇浓度过高会导致凝胶存在较大的不均匀性,可能影响栓塞效果和凝胶毒性。
实施例5凝胶血管内稳定性及栓塞效果验证
为了验证聚乙二醇水凝胶栓塞剂的栓塞效果,本实施例将200mg苯醛基封端的8臂聚乙二醇(分子量15kDa)溶解在1mL的磷酸盐缓冲液中(pH5.6),作为A液。根据表5所示不同的摩尔比配置不同含量聚赖氨酸和聚乙烯亚胺(M.W.1.8K)的硼砂缓冲液(pH9.2)溶液,作为B溶液。将A和B溶液混合注射得到水凝胶。将双组分水凝胶注射到兔右肾动脉内,观察一段时间后血管内凝胶的稳定性以及右肾的坏死情况。
表5
聚乙二醇的醛基与聚乙烯亚胺氨基以及聚赖氨酸氨基的摩尔比为1:1.5:1的凝胶注射到大鼠肾动脉内原位形成的凝胶实物图如图1所示。图中显示了不同粗细的血管中的凝胶栓塞物。图2为上述配方凝胶栓塞9天后新西兰大白兔的肾坏死情况。
Claims (10)
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、聚乙烯亚胺和聚赖氨酸原位交联而成。
2.根据权利要求1所述医用水凝胶,其特征在于水凝胶能够在血管内原位成胶,体外成胶时间等于或者小于8秒。
3.根据权利要求2所述医用水凝胶,其特征在于醛基与聚乙烯亚胺中的氨基的摩尔比为1:0.6~5,醛基与聚赖氨酸中的氨基的摩尔比为1:0~5。
4.根据权利要求3所述医用水凝胶,其特征在于醛基与聚乙烯亚胺中的氨基的摩尔比为1:0.9~2,醛基与聚赖氨酸中的氨基的摩尔比为1:0.4~5。
5.根据权利要求3所述医用水凝胶,其特征在于星形多臂聚乙二醇的臂数为2-8,单臂分子量1000-5000Da,凝胶中星形多臂聚乙二醇的浓度为10~20%。
6.根据权利要求1所述医用水凝胶,其特征在于所述醛基与星形多臂聚乙二醇之间以酰胺键或酯键连接。
7.根据权利要求5所述医用水凝胶,其特征在于所述星形多臂聚乙二醇的臂数为4-8。
8.根据权利要求1所述医用水凝胶,其特征在于所述醛基选自芳香醛基、烷基醛基中的一种或几种。
9.根据权利要求1-8任一项所述医用水凝胶在制备血管栓塞剂中的应用。
10.根据权利要求1-8任一项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,配制醛基封端的星形多臂聚乙二醇溶液;将聚乙烯亚胺和聚赖氨酸溶解在pH4-10缓冲液中,配置溶液;将两者混合得到医用水凝胶,所述醛基封端的星形多臂聚乙二醇溶液的终浓度为2-40%,w/v,所述聚乙烯亚胺和聚赖氨酸溶液浓度为0.5-20%,w/v。
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