CN111905155A - 一种封闭水凝胶及其制备方法和应用 - Google Patents
一种封闭水凝胶及其制备方法和应用 Download PDFInfo
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Abstract
本发明属于高分子材料技术领域,具体涉及一种封闭水凝胶及其制备方法和应用。制备所述封闭水凝胶的原料包括第一组分和第二组分;所述第一组分中包括化合物A和化合物B;所述化合物A为多臂聚乙二醇的衍生物,所述化合物B为缩水甘油异丙醚和乙基缩水甘油醚的多臂共聚酯;所述第二组分中包括低聚肽或其衍生物。本发明通过对凝胶组分中高分子量化合物的选择,并将第一组分和第二组分进行配合,可有效地降低水凝胶的溶胀率。
Description
技术领域
本发明属于高分子材料技术领域,具体涉及一种封闭水凝胶及其制备方法。
背景技术
基于PEG衍生物开发的水凝胶产品具有生物相容性好,无毒、无刺激,生物可降解性,临床应用中术后无需再移除,产品会随着患者的康复逐渐降解并通过肾脏代谢等优点,目前市场上已有多种基于PEG开发的水凝胶密封剂上市,用于伤口封闭、防粘连、漏液封堵等。近年来,随着脊柱翻修手术和硬脊膜粘连严重及高龄患者的增多,CSFL的发生率也有增加的趋势。正确处理脑脊液漏对于脊柱手术获得成功及防止严重的并发症有重要意义。由于临床使用中,脊柱伤口、硬脊膜或硬脑膜的封闭水凝胶因存在神经压迫的风险,要求水凝胶的溶胀率尽可能低;此外,对有炎症等其它治疗需求的患者,不仅需要对伤口封闭还需要负载药物进行治疗;另外,目前技术所用的低溶胀PEG水凝胶的酸碱性比较强,使用过程中存在对组织的不良刺激等;目前已上市的封闭水凝胶溶胀率大、不能载药或载药后影响其封闭性能。因此,急需一种可载药的低溶胀水凝胶用于脊柱、硬脑膜等的封闭。
发明内容
针对现有技术中存在的问题,本发明提供一种封闭水凝胶,制备所述封闭水凝胶的前体包括第一组分和第二组分;
所述第一组分中包括化合物A和化合物B;所述化合物A为多臂聚乙二醇的衍生物,所述化合物B为缩水甘油异丙醚和乙基缩水甘油醚的多臂共聚酯;
所述第二组分中包括低聚肽或其衍生物。
优选的,所述化合物A和化合物B中均含有如下基团:
优选的,所述化合物A的结构通式为:
n1为2-8的整数,n2为4-8的整数;PEG分子量为1250-8000,PDI≤1.02;
Y是相同或不同的连接基团,选自-O-,-O(CH2CH2)i-,-(CH2CH2)i-,-(CH2)iCONH-,-OOC(CH2)iCOO-,-OOCNH(CH2)iNHCOO-,-OOC(CH2)iCONH-中的一种或多种;i为0-20的整数;
所述化合物B的结构通式为:
n3为11-70的整数,n4为2-8的整数,n5为4-8的整数;
通式II中Y可选择的基团与通式I中Y可选择的基团相同;R为乙基或异丙基。
优选的,所述封闭水凝胶在三维方向的溶胀率大于等于-5%且小于等于5%。
优选的,所述化合物B中,每100份的所述乙基缩水甘油醚与缩水甘油异丙醚中包括乙基缩水甘油醚60-80份。
优选的,所述化合物A和化合物B的臂数相同。
优选的,所述化合物A和化合物B的分子量相同。
优选的,每100份所述化合物A和化合物B的混合物中包括化合物A40~60份。
优选的,第一组分中还含有显色剂;
进一步优选的,所述显色剂与第一组分中化合物A和化合物B的总质量之比为(0.0001-0.01):1;
更进一步优选的,所述显色剂为荧光素。
优选的,所述低聚肽及其衍生物中氨基酸的残基个数为2~6;
优选的,所述低聚肽及其衍生物为三赖氨酸或其衍生物。
优选的,所述第二组分中还包括抑菌剂;
进一步优选的,所述抑菌剂为壳聚糖衍生物,
更进一步优选的,所述壳聚糖衍生物为羧甲基壳聚糖,与所述低聚肽及其衍生物的质量比为(0.015-0.1):1。
优选的,所述第一组分和/或第二组分中添加有药物;
进一步优选的,所述药物为抗炎药、止血药、止痛药、抗排异药、抗肿瘤药中的至少一种。
优选的,由如下方法制备得到:
1)将所述第一组分和第二组分与缓冲液a混合,得混合液体系;
2)将缓冲液b与所述混合液体系混合,得封闭水凝胶;
优选的,所述缓冲液a的pH为6.0~7.5;和/或,所述缓冲液b的pH为9.0~9.5。
优选的,所述混合液体系中,所述低聚肽或其衍生物的浓度为1-7mg/mL;
优选的,所述混合液体系中,化合物A和化合物B的总浓度为40-100mg/mL,优选40-75mg/mL。优选的,所述缓冲液a中含有磷酸盐、氯化钠、氯化钾、磷酸、盐酸中的一种或几种;
和/或,所述缓冲液b中含有磷酸盐、碳酸盐、硼酸盐、氢氧化钠的一种或几种。
优选的,所述缓冲液a与所述缓冲液b的体积比为1:0.8~1.2。
本发明还提供本发明所述封闭水凝胶的制备方法,包括如下步骤:
1)将所述第一组分和第二组分与缓冲液a混合,得混合液体系;
2)将缓冲液b与所述混合液体系混合,得封闭水凝胶;优选的,所述缓冲液a的pH为6.0~7.5;和/或,所述缓冲液b的pH为9.0~9.5。
本发明还提供制备本发明所述封闭水凝胶的试剂盒,所述试剂盒中设有双联注射器,所述第一组分和第二组分溶解于缓冲液a中并储存于注射器1中;所述缓冲液b储存于注射器2中。
本发明还保护本发明所述的封闭水凝胶在硬脊膜和硬脑膜封闭、其它组织的漏液封堵、伤口封闭和防粘连中的应用。
本发明具有如下有益效果:
1)本发明通过对凝胶组分中高分子量化合物的选择,并将第一组分和第二组分进行配合,可有效地降低水凝胶的溶胀率。
2)本发明所述的水凝胶在低聚合物浓度下和载药后依然具有较高的封闭强度,因此可减少降解产物,减少体内代谢产物对人体的影响,降低原料成本,同时可负载药物用于治疗。
3)本发明所述的水凝胶载药后具有较好地药物释放性能,释放速度适中,有利于对疾病进行有效地治疗。
3)本发明所述的水凝胶的缓冲液酸性和碱性小,更接近中性人体环境,刺激性小,细胞毒性低;
4)本发明所述的水凝胶具有抗菌性能,可减少抗生素的使用;
5)本发明所述的水凝胶具有显色剂荧光素,可实现水凝胶体内应用的示踪观察。
具体实施方式
下面通过以下附加技术特征对本申请进行详细说明。
本发明提供一种封闭水凝胶,制备所述封闭水凝胶的前体包括第一组分和第二组分;
所述第一组分中包括化合物A和化合物B;所述化合物A为多臂聚乙二醇的衍生物,所述化合物B为缩水甘油异丙醚和乙基缩水甘油醚的多臂共聚酯;
所述第二组分中包括低聚肽或其衍生物。
本申请所述的封闭水凝胶,通过化合物B与化合物A的配合使用,再进一步与第二组分进行组合,与现有技术中单独使用A与第二组分配合制备的水凝胶相比,可显著地降低溶胀率,得到的水凝胶的酸碱性比较弱,使用过程中不存在对组织的不良刺激,而且这种水凝胶可载药,载药后不影响水凝胶的封闭性。
根据一些优选的实施例,所述化合物A和化合物B中均含有如下基团:
根据一些优选的实施例,所述化合物A的结构通式为:
n1为2-8的整数,n2为4-8的整数;PEG分子量为1250-8000,PDI≤1.02;
Y是相同或不同的连接基团,选自-O-,-O(CH2CH2)i-,-(CH2CH2)i-,-(CH2)iCONH-,-OOC(CH2)iCOO-,-OOCNH(CH2)iNHCOO-,-OOC(CH2)iCONH-中的一种或多种;i为0-20的整数;
所述化合物B的结构通式为:
n3为11-70的整数,n4为2-8的整数,n5为4-8的整数;
通式II中Y可选择的基团与通式I中Y可选择的基团相同;R为乙基或异丙基。
根据一些优选的实施例,所述封闭水凝胶在三维方向的溶胀率大于等于-5%且小于等于5%。
本发明所述的水凝胶由于选择了上述原料,可制备得到溶胀率大于等于-5%且小于等于5%的水凝胶,可满足存在神经压迫风险的临床治疗的需求,可应用于脊柱伤口、硬脊膜或硬脑膜的封闭,具有安全性高、效果好的优点。
根据一些优选的实施例,所述化合物B中,每100份的所述乙基缩水甘油醚与缩水甘油异丙醚中包括乙基缩水甘油醚60-80份,化合物B中的基团在上述范围内,所得凝胶具有较小的溶胀率。
根据一些优选的实施例,所述化合物A和化合物B的臂数相同。在上述条件下所得凝胶具有较小的溶胀率。
根据一些优选的实施例,所述化合物A和化合物B的分子量相同。在上述条件下所得凝胶具有较小的溶胀率。
根据一些优选的实施例,每100份所述化合物A和化合物B的混合物中包括化合物A40~60份。在上述条件下所得凝胶具有较小的溶胀率。
本发明所述的水凝胶在满足上述条件的情况下,有利于进一步降低凝胶的溶胀率,在三维方向的溶胀率甚至可达到2~3%左右。
根据一些优选的实施例,所述化合物A为四臂-聚乙二醇琥珀酰亚胺丁二酸酯(分子量5000-32000Da)、四臂-聚乙二醇琥珀酰亚胺戊二酸酯(分子量5000-32000Da、四臂-聚乙二醇琥珀酰亚胺己二酸酯(分子量5000-32000Da)、四臂-聚乙二醇琥珀酰亚胺庚二酸酯(分子量5000-32000Da)、四臂-聚乙二醇琥珀酰亚胺癸二酸酯(分子量5000-32000Da)、六臂-聚乙二醇琥珀酰亚胺丁二酸酯(分子量5000-32000Da)、六臂-聚乙二醇琥珀酰亚胺戊二酸酯(分子量5000-32000Da)、六臂-聚乙二醇琥珀酰亚胺己二酸酯(分子量5000-32000Da)、六臂-聚乙二醇琥珀酰亚胺庚二酸酯(分子量5000-32000Da)、六臂-聚乙二醇琥珀酰亚胺癸二酸酯(分子量5000-32000Da)、八臂-聚乙二醇琥珀酰亚胺丁二酸酯(分子量5000-32000Da)、八臂-聚乙二醇琥珀酰亚胺戊二酸酯(分子量5000-32000Da)、八臂-聚乙二醇琥珀酰亚胺己二酸酯(分子量5000-32000Da)、八臂-聚乙二醇琥珀酰亚胺庚二酸酯(分子量5000-32000Da)、八臂-聚乙二醇琥珀酰亚胺癸二酸酯(分子量5000-32000Da)中的一种或几种。
根据一些优选的实施例,所述化合物B为四臂-共聚醚琥珀酰亚胺丁二酸酯(分子量5000-32000Da)、四臂-共聚醚琥珀酰亚胺戊二酸酯(分子量5000-32000Da、四臂-共聚醚琥珀酰亚胺己二酸酯(分子量5000-32000Da)、四臂-共聚醚琥珀酰亚胺庚二酸酯(分子量5000-32000Da)、四臂-共聚醚琥珀酰亚胺癸二酸酯(分子量5000-32000Da)、六臂-共聚醚琥珀酰亚胺丁二酸酯(分子量5000-32000Da)、六臂-共聚醚琥珀酰亚胺戊二酸酯(分子量5000-32000Da)、六臂-共聚醚琥珀酰亚胺己二酸酯(分子量5000-32000Da)、六臂-共聚醚琥珀酰亚胺庚二酸酯(分子量5000-32000Da)、六臂-共聚醚琥珀酰亚胺癸二酸酯(分子量5000-32000Da)、八臂-共聚醚琥珀酰亚胺丁二酸酯(分子量5000-32000Da)、八臂-共聚醚琥珀酰亚胺戊二酸酯(分子量5000-32000Da)、八臂-共聚醚琥珀酰亚胺己二酸酯(分子量5000-32000Da)、八臂-共聚醚琥珀酰亚胺庚二酸酯(分子量5000-32000Da)、八臂-共聚醚琥珀酰亚胺癸二酸酯(分子量5000-32000Da);
根据一些优选的实施例,所述化合物A为四臂-聚乙二醇琥珀酰亚胺己二酸酯或八臂-聚乙二醇琥珀酰亚胺丁二酸酯,所述化合物B为四臂-共聚醚琥珀酰亚胺己二酸酯、八臂-共聚醚琥珀酰亚胺丁二酸酯或四臂-共聚醚琥珀酰亚胺戊二酸酯。
根据一些优选的实施例,第一组分中还含有显色剂;
进一步优选的,所述显色剂与第一组分中化合物A和化合物B的总质量之比为(0.0001-0.01):1;
更进一步优选的,所述显色剂为荧光素。本发明所述的第一化合物可与荧光素较好地结合,进而制备得到具有荧光特性的水凝胶。
根据一些优选的实施例,所述低聚肽及其衍生物中氨基酸的残基个数为2~6,上述选择可保证制备的凝胶具有较小的溶胀率及较快的成胶时间。
进一步优选的,所述低聚肽及其衍生物为三赖氨酸或其衍生物。
根据一些优选的实施例,所述第二组分中还包括抑菌剂;本发明所述的第二组分可理想地与抑菌剂结合,进而使得所得凝胶具有一定的抑菌作用。
进一步优选的,所述抑菌剂为壳聚糖衍生物。上述抑菌剂既有抑菌作用,又可满足体内植入的安全性。
更进一步优选的,所述壳聚糖衍生物为羧甲基壳聚糖,与所述低聚肽及其衍生物的质量比为(0.015-0.1):1。
本发明在第一组分中添加显色剂,在第二组分中添加抑菌剂,不会影响凝胶反应,有利于凝胶的形成。
根据一些优选的实施例,所述第一组分和/或第二组分中添加有药物;
根据一些优选的实施例,所述药物为抗炎药、止血药、止痛药、抗排异药、抗肿瘤药中的至少一种。
根据一些优选的实施例,本发明所述低聚肽由包括如下步骤的方法制备得到:
1)将所述第一组分和第二组分与缓冲液a混合,得混合液体系;
2)将缓冲液b与所述混合液体系混合,得封闭水凝胶;为制备得到效果良好的封闭水凝胶,本发明在选定原料的基础上进一步对制备水凝胶的方法进行了上述优化,采用上述步骤制备水凝胶,可有效地提高最终所得水凝胶的性能。
根据一些优选的实施例,所述缓冲液a的pH为6.0~7.5,所述缓冲液b的pH为9.0~9.5。缓冲液的pH在上述范围,既可保证水凝胶的成型特性,还不会对组织细胞造成伤害。
根据一些优选的实施例,所述混合体系a中,所述低聚肽或其衍生物的浓度为1-7mg/mL;
根据一些优选的实施例,所述混合体系a中,化合物A和化合物B的总浓度为40-100mg/mL,优选40-75mg/mL。
第一组分和第二组分中的有效成分在上述范围内,可保证凝胶的溶胀率和密封强度在理想的范围内。
根据一些优选的实施例,所述缓冲液a与所述缓冲液b的体积比为1:0.8~1.2。
根据一些优选的实施例,所述缓冲液a中含有磷酸盐、氯化钠、氯化钾、磷酸、盐酸中的一种或几种;
根据一些优选的实施例,所述缓冲液b中含有磷酸盐、碳酸盐、硼酸盐、氢氧化钠的一种或几种。
本发明还保护本发明所述水凝胶的制备方法,包括如下步骤:
1)将所述第一组分和第二组分与缓冲液a混合,得混合液体系;
2)将缓冲液b与所述混合液体系混合,得封闭水凝胶。
本发明还保护制备本发明所述封闭水凝胶的试剂盒,所述试剂盒中设有双联注射器,所述第一组分和第二组分溶解于缓冲液a中并储存于注射器1中;所述缓冲液b储存于注射器2中。
根据一些优选的实施例,本发明所述的试剂盒在使用的过程中,药物可以添加于溶液a或溶液b中,对于偏酸性或中性的药物加入a溶液中,碱性条件稳定的药物加入溶液b中。
本发明还保护本发明所述的封闭水凝胶在硬脊膜和硬脑膜封闭、其它组织的漏液封堵、伤口封闭和防粘连中的应用。
下面通过实施例对本申请进行进一步地详细说明,具体见表1:
表1
对上述实施例中水凝胶的性能进行表征,结果见表2:
表2
由以上实施例和对比例可以看出,本发明通过对制备水凝胶的原料进行选择,尤其是选择了化合物B,确实可降低材料的溶胀率,进一步的,通过优化合物B的选择,化合物A与化合物B的相对用量,分子量和臂数以及第一组分和第二组分中官能团的比例,以及缓冲液的pH等条件,可进一步降低溶胀率,提高整体性能,最终得到一种溶胀率低,密封强度高,细胞生长理想的水凝胶。
对上述实施例的载药性能进行测试,结果如表3:
载药:各组分比例同实施例8
表3
载药检测结果
实验例1的甲强龙的负载量为市售单瓶用量,实验例2为提高甲强龙负载量3倍,后检测结果,从溶胀率和密封强度来看提高负载量后无明显降低。实验例4为负载市售得宝松注射液一支的效果,从结果来看,负载得宝松后对凝胶本身性能无明显影响,而且本发明所述的封闭水凝胶的药物释放周期短。
虽然,上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
Claims (20)
1.一种封闭水凝胶,其特征在于,制备所述封闭水凝胶的前体包括第一组分和第二组分;
所述第一组分中包括化合物A和化合物B;所述化合物A为多臂聚乙二醇的衍生物,所述化合物B为缩水甘油异丙醚和乙基缩水甘油醚的多臂共聚酯;
所述第二组分中包括低聚肽或其衍生物。
4.根据权利要求1~3任一项所述的封闭水凝胶,其特征在于,所述封闭水凝胶在三维方向的溶胀率大于等于-5%且小于等于5%。
5.根据权利要求1所述的封闭水凝胶,其特征在于,所述化合物B中,每100份的乙基缩水甘油醚与缩水甘油异丙醚中包括乙基缩水甘油醚60-80份。
6.根据权利要求1所述的封闭水凝胶,其特征在于,所述化合物A和化合物B的臂数相同。
7.根据权利要求1所述的封闭水凝胶,其特征在于,所述化合物A和化合物B的分子量相同。
8.根据权利要求1所述的封闭水凝胶,其特征在于,每100份所述化合物A和化合物B的混合物中包括化合物A 40~60份。
10.根据权利要求1所述的封闭水凝胶,其特征在于,第一组分中还含有显色剂,优选的,所述显色剂与第一组分中化合物A和化合物B的总质量之比为(0.0001~0.01):1;进一步优选的,所述显色剂为荧光素。
11.根据权利要求1所述的封闭水凝胶,其特征在于,所述低聚肽及其衍生物中氨基酸的残基个数为2~6;
优选的,所述低聚肽及其衍生物为三赖氨酸或其衍生物。
12.根据权利要求1或10所述的封闭水凝胶,其特征在于,所述第二组分中还包括抑菌剂;优选的,所述抑菌剂为壳聚糖衍生物,所述抑菌剂与所述低聚肽及其衍生物的质量比为(0.015-0.1):1;进一步优选的,所述壳聚糖衍生物为羧甲基壳聚糖。
13.根据权利要求1所述的封闭水凝胶,其特征在于,所述第一组分和/或第二组分中添加有药物;优选的,所述药物为抗炎药、止血药、止痛药、抗排异药、抗肿瘤药中的至少一种。
14.根据权利要求1~13任一项所述的封闭水凝胶,其特征在于,由如下方法制备得到:
1)将所述第一组分和第二组分与缓冲液a混合,得混合液体系;
2)将缓冲液b与所述混合液体系混合,得封闭水凝胶;优选的,所述缓冲液a的pH为6.0~7.5;和/或,所述缓冲液b的pH为9.0~9.5。
15.根据权利要求14所述的封闭水凝胶,其特征在于,所述混合液体系中,所述低聚肽或其衍生物的浓度为1-7mg/mL;
和/或,所述混合液体系中,化合物A和化合物B的总浓度为40-100mg/mL,优选40-75mg/mL。
16.根据权利要求14或15所述的封闭水凝胶,其特征在于,所述缓冲液a中含有磷酸盐、氯化钠、氯化钾、磷酸、盐酸中的一种或几种;
和/或,所述缓冲液b中含有磷酸盐、碳酸盐、硼酸盐、氢氧化钠的一种或几种。
17.根据权利要求14~16任一项所述的封闭水凝胶,其特征在于,所述缓冲液a与所述缓冲液b的体积比为1:0.8~1.2。
18.权利要求1~17任一项所述封闭水凝胶的制备方法,其特征在于,包括如下步骤:
1)将所述第一组分和第二组分与缓冲液a混合,得混合液体系;
2)将缓冲液b与所述混合液体系混合,得封闭水凝胶;
优选的,所述缓冲液a的pH为6.0~7.5;和/或,所述缓冲液b的pH为9.0~9.5。
19.一种制备权利要求1~17任一项所述封闭水凝胶的试剂盒,所述试剂盒中设有双联注射器,所述第一组分和第二组分溶解于缓冲液a中并储存于注射器1中;所述缓冲液b储存于注射器2中。
20.权利要求1~17任一项所述的封闭水凝胶在硬脊膜和硬脑膜封闭、其它组织的漏液封堵、伤口封闭和防粘连中的应用。
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CN113521376A (zh) * | 2021-07-22 | 2021-10-22 | 赛克赛斯生物科技股份有限公司 | 一种外科密封剂试剂盒及其在脑、脊柱外科手术中的应用 |
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