CN109010912B - 一种改性的玻尿酸可注射填充材料及其制备方法 - Google Patents
一种改性的玻尿酸可注射填充材料及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种改性的玻尿酸可注射填充材料及其制备方法,包括自由透明玻尿酸凝胶、交联玻尿酸凝胶、水溶性维生素,缓冲溶液,其中所述的玻尿酸‑聚乙二醇改性材料具有如下结构:
Description
技术领域
本发明涉及美容领域,特别是涉及一种由聚乙二醇交联的改性玻尿酸可注射填充材料领域。
背景技术
玻尿酸(透明质酸)是一种广泛存在于人和动物体内,由双糖单位(葡萄糖醛酸-N-乙硫氨基葡糖组成的直链高分子多糖),其结构式为:
广泛的存在于脊椎动物的***、粘液组织以及细菌夹膜中,在表皮、真皮、脐带、关节骨液和软骨组织中的含量也较高。自从1934年,美国Meyer等首先从牛眼玻璃体中分离出玻尿酸以来,逐渐被人民发现具有良好的生物相容性、高度粘弹性、可塑性和渗透性等重要性能。从而在医疗、美容和生物工程等领域得到了广泛的应用。在整形美容领域,玻尿酸主要用于填充面部凹陷、除皱、隆鼻等方面。
近10年来,玻尿酸作为皮肤填充剂广泛应用于医学美容领域,注入真皮下可以使皮下组织直接容积增大,起到“垫”的作用,同时还可以吸收周围组织的水分,以达到扩张体积的作用,使松弛、凹陷的皮肤重新饱满起来,这种注射疗法已经广泛地应用于修复与老化相关的皮肤皱褶和一些先天或后天的疾病引起的凹陷。
然而,由于人体透明质酸酶、自由基降解等原因,导致外援的透明质酸在体内维持存在的时间较短,限制了玻尿酸在皮下组织填充或者皮肤等方面的应用。因此,如何通过改性加工工艺来提高透明质酸在体内的降解周期是亟需解决的技术问题。
专利文献CN105131348B公开了一种由交联透明质酸凝胶与自由透明质酸溶液,其中交联剂为1,4-丁二醇缩水甘油醚形成的无菌可注射填充材料,尽管可以提高降解周期,稳定性能有所改善,但是仍无法满足产业上的需要。
专利文献CN104870479B公开了一种由透明质酸化合物与葡甘露聚糖经由至少一个酯键合衍生自交联剂的基团键合形成的聚合物,所形成的球和聚合物具有较高的水捕获能力,胀起更好、更快,可以用于改善皮肤或粘膜水合。然而,由于葡甘露聚糖价格较高,从而增加了应用的成本。
聚乙二醇是一种非离子型的水溶性聚合物,由于聚乙二醇兼有很多优良的性质:水溶性、不挥发性、生理惰性、温和性,被广泛的应用于医用高分子材料表面改性中。
现有技术中没有公开通过将玻尿酸与聚乙二醇通过酯键键合形成凝胶而应用于皮下填充材料的文献。
发明内容
本发明提供了一种含有由玻尿酸与聚乙二醇通过酯键键合形成的交联玻尿酸凝胶的可注射填充材料。
解决本发明的技术问题是通过以下技术方案来实现的:
一种改性的玻尿酸可注射填充材料,其特征在于:包括自由透明玻尿酸凝胶、交联玻尿酸凝胶、水溶性维生素,缓冲溶液,其中,所述的自由透明玻尿酸凝胶与交联玻尿酸凝胶的质量比为2:10-40:1;其中所述的自由透明玻尿酸凝胶的分子量为5K-200KDa,优选为10K-100KDa,更优选为50K-80KDa;其中所述的交联玻尿酸凝胶具有如下结构I:
其中n选自10-5000,m选自100-5000;其中所述的水溶性维生素选自维生素B、维生素C、维生素E或其各自的衍生物中的一种或其任意组合。
在本发明的优选技术方案中,其中所述的缓冲溶液维持组合物的pH在5与8.5之间,更优选的为6.8与8之间,最优选的为7.0与8之间,其中,合适的缓冲溶液可以选自磷酸盐缓冲溶液,例如,NaH2PO4-NaHPO4,乙酸盐缓冲溶液、苯甲酸盐缓冲溶液、柠檬酸盐缓冲溶液、马来酸盐缓冲溶液、酒石酸盐缓冲溶液;
在本发明的优选技术方案中,其中所述的自由透明玻尿酸凝胶的分子量为50K-80KDa;
在本发明的技术方案中,基于自由透明玻尿酸凝胶的重量,其中所述的水溶性维生素的重量百分比为1.0%-5%,优选为2.5%;
在本发明的技术方案中,还包括山梨糖醇,其中基于自由透明玻尿酸凝胶的重量,山梨糖醇的质量分数可以小于3%,优选为1%;
在本发明的技术方案中,其中所述的玻尿酸可注射填充材料在使用前需经无菌处理。
在本发明的技术方案中,其中无菌处理可以为高温灭菌、紫外线辐照灭菌。
在本发明的技术方案中,其中所述的改性玻尿酸可注射填充材料可应用于软组织填充、修复及外科手术,例如可用于除皱纹、隆鼻、隆胸,也可以用于医疗外科手术用的防粘连和骨科关节的润滑。
本发明还提供了一种改性玻尿酸可注射填充材料的制备方法,其包括如下步骤:
步骤(1)交联玻尿酸凝胶的制备:将聚乙二醇结构上的羟基与玻尿酸骨架上一个或多个羧基进行键合的步骤,其反应过程如下所示:
在优选的实施例中,其中包括如下步骤a.将玻尿酸溶液、聚乙二醇溶液、交联剂混合,并不断搅拌;b.维持反应体系的pH=4-6;
c.控制反应温度为60-80℃,充分搅拌12h;d.将反应产物经透析处理,经干燥处理后得到玻尿酸-聚乙二醇接枝交联聚合物;
在步骤(1)的优选技术方案中,其中玻尿酸与聚乙二醇的重量百分比为10:1-1:40;优选为5:1;
在步骤(1)的优选技术方案中,其中所述的玻尿酸溶液与聚乙二醇溶液的溶剂为水,步骤b的pH值优选为5;
在步骤(1)的优选技术方案中,其中所述的交联剂选自EDC或者HOBt,或者其组合;
步骤(2):按照比例称取自由透明玻尿酸凝胶水溶液,加入至步骤(1)所制备得到的交联玻尿酸凝胶的制备,并于室温下充分混合搅拌;
步骤(3):按照比例称取水溶性维生素及山梨糖醇,溶解于水中充分搅拌后加入至步骤(2)所得的自由透明玻尿酸凝胶与交联玻尿酸凝胶混合液中;并加入缓冲溶液,保持体系的pH为6-6.8;
步骤(4):将上述混合物经透析处理,经干燥处理后得到本发明的改性的玻尿酸可注射填充材料。
本发明所提供的改性的玻尿酸可注射填充材料具有以下优点:
1、可注射性能好:本发明改性的玻尿酸可注射填充材料具有较好的流动性;
2、良好的生物相容性:本发明所提供的改性的玻尿酸可注射填充材料具有良好的生物相容性,在植入体内后不会导致受试者产生发炎反应或者免疫反应;
3、稳定性能好:本发明所提供的由玻尿酸与聚乙二醇通过共价键键合形成稳定的交联玻尿酸材料,在体内代谢稳定,不易被降解。
具体实施方式
实施例1
步骤(1)交联玻尿酸凝胶的制备:
a.按照一定比例称取玻尿酸/聚乙二醇/HOBc/EDC(玻尿酸/聚乙二醇/HOBt/EDC=1g/0.5g/0.1/0.1,w/w),分别溶解于50mL的去离子水中充分搅拌使之混合均匀;
b.向反应体系中加入NaH2PO4-NaHPO4,控制反应体系的pH值=5,;
c.控制反应温度为60-80℃,充分搅拌12h;
d.将反应产物经透析处理,得到交联玻尿酸凝胶。
步骤(2):按照比例称取自由透明玻尿酸凝胶水溶液(分子量为50KDa)(自由透明玻尿酸凝胶:交联玻尿酸凝胶=0.8g/1g,w/w),加入至步骤(1)所制备得到的交联玻尿酸凝胶的制备,并于室温下充分混合搅拌;
步骤(3):按照比例称取水溶性维生素E(水溶性维生素E:自由透明玻尿酸凝胶=0.02g:1g,w/w)及山梨糖醇(山梨糖醇:自由透明玻尿酸凝胶=0.02g:1g,w/w),溶解于水中充分搅拌后加入至步骤(2)所得的自由透明玻尿酸凝胶与交联玻尿酸凝胶混合液中;并加入缓冲溶液,保持体系的pH为6.8;
步骤(4):将上述混合物经透析处理,经干燥处理后得到本发明的改性的玻尿酸可注射填充材料。
实施例2
步骤(1)交联玻尿酸凝胶的制备:
a.按照一定比例称取玻尿酸/聚乙二醇/HOBc/EDC(玻尿酸/聚乙二醇/HOBt/EDC=1g/1g/0.1/0.1,w/w),分别溶解于50mL的去离子水中充分搅拌使之混合均匀;
b.向反应体系中加入NaH2PO4-NaHPO4,控制反应体系的pH值=5,;
c.控制反应温度为60-80℃,充分搅拌12h;
d.将反应产物经透析处理,得到交联玻尿酸凝胶。
步骤(2):按照比例称取自由透明玻尿酸凝胶水溶液(分子量为50KDa)(自由透明玻尿酸凝胶:交联玻尿酸凝胶=0.5g/1g,w/w),加入至步骤(1)所制备得到的交联玻尿酸凝胶的制备,并于室温下充分混合搅拌;
步骤(3):按照比例称取水溶性维生素E(水溶性维生素E:自由透明玻尿酸凝胶=0.02g:1g,w/w)及山梨糖醇(山梨糖醇:自由透明玻尿酸凝胶=0.02g:1g,w/w),溶解于水中充分搅拌后加入至步骤(2)所得的自由透明玻尿酸凝胶与交联玻尿酸凝胶混合液中;并加入缓冲溶液,保持体系的pH为6.8;
步骤(4):将上述混合物经透析处理,经干燥处理后得到本发明的改性的玻尿酸可注射填充材料。
实施例3
步骤(1)交联玻尿酸凝胶的制备:
a.按照一定比例称取玻尿酸/聚乙二醇/HOBc/EDC(玻尿酸/聚乙二醇/HOBt/EDC=0.5g/1/0.1/0.1,w/w),分别溶解于50mL的去离子水中充分搅拌使之混合均匀;b.向反应体系中加入NaH2PO4-NaHPO4,控制反应体系的pH值=5;
c.控制反应温度为60-80℃,充分搅拌12h;
d.将反应产物经透析处理,得到交联玻尿酸凝胶。
步骤(2):按照比例称取自由透明玻尿酸凝胶水溶液(分子量为50KDa)(自由透明玻尿酸凝胶:交联玻尿酸凝胶=0.5g/1g,w/w),加入至步骤(1)所制备得到的交联玻尿酸凝胶的制备,并于室温下充分混合搅拌;
步骤(3):按照比例称取水溶性维生素E(水溶性维生素E:自由透明玻尿酸凝胶=0.02g:1g,w/w)及山梨糖醇(山梨糖醇:自由透明玻尿酸凝胶=0.02g:1g,w/w),溶解于水中充分搅拌后加入至步骤(2)所得的自由透明玻尿酸凝胶与交联玻尿酸凝胶混合液中;并加入缓冲溶液,保持体系的pH为6.8;
步骤(4):将上述混合物经透析处理,经干燥处理后得到本发明的改性的玻尿酸可注射填充材料。
对照例1
步骤(1):按照比例称取自由透明玻尿酸凝胶水溶液(分子量为50KDa),水溶性维生素E(水溶性维生素E:自由透明玻尿酸凝胶=0.02g:1g,w/w)及山梨糖醇(山梨糖醇:自由透明玻尿酸凝胶=0.02g:1g,w/w),溶解于水中充分搅拌;
步骤(2):加入缓冲溶液,保持体系的pH为6.8;
步骤(3):将上述混合物经透析处理,经干燥处理后得到本发明的改性的玻尿酸可注射填充材料。
实施例4:红外光谱分析
对实施例1-实施例3所得到的玻尿酸-聚乙二醇改性材料进行红外光谱表征。其中聚乙二醇和玻尿酸-聚乙二醇在1092、1136、1186cm-1波数处出现了酯基醚键的强振动吸收峰,同时,聚乙二醇在3500cm-1附近有游离的-OH的振动吸收,但是与玻尿酸发生作用后,该处振动吸收峰消失,说明在修饰过程中,聚乙二醇的羟基也参与了化学反应。
实施例5流变性能分析
以流变仪分析实施例1-3所得到的玻尿酸-聚乙二醇改性材料的流变性能,具体试验方法是使用30mm平盘、温度梯度模式,温度范围为10-50℃,升温速率为2℃/min。
流变学分析结果可以得出对于玻尿酸-聚乙二醇改性材料而言,所得到的材料具有良好的感温性。例如,实施例1的改性材料在25℃下储存模量(G’)为452Pa,损失模量(G”)为218Pa;实施例2的改性材料在25℃下储存模量(G’)为446Pa,损失模量(G”)为202Pa;实施例3的改性材料在25℃下储存模量(G’)为468Pa,损失模量(G”)为176Pa。
实施例6可注射性能分析
方法:制备重量百分比为10-20%的实施例1-3所制备材料的水溶液,充分搅拌使之完全溶解,将试样转移至针筒中,使用27号针头进行试验。从试验结果可以看出,实施例1-实施例3的改性玻尿酸填充材料均可以在室温下轻易通过27号针头,从而表明该材料具有较好的可注射性。
实施例7体外降解性能
本实施例比较了实施例1-3所获得的玻尿酸-聚乙二醇改性材料(试验组1-3)与未经改性的玻尿酸(对照组1)以及瑞兰2(Restylance)(对照组2)的体外降解性能,具体测试方法是:
将1g样品装入1mL离心管中,离心甩平管内液面,然后向各测试管中加入50μL透明质酸酶溶液,使得透明质酸酶的作用浓度达到100IU/mL。在37℃下恒温保持12小时,反应后将各管倒立,将液体样品用纸吸收,测定残留在管底部的样品重量。各试验组的样品重量以及理论残留样品百分率(%)的结果如表1所示:
组别 | 玻尿酸浓度(mg/mL) | 百分比 |
实施例1 | 34.2 | 84.2±0.2% |
实施例2 | 32.6 | 82.4±0.2% |
实施例3 | 31.4 | 80.6±0.2% |
对照组1 | 24.2 | 64.1±0.2% |
对照组2 | 18.6 | 50.4±0.2% |
从表1的结果可以看出,本发明的经改性的玻尿酸可注射填充材料与未经改性的玻尿酸或者瑞兰2号相比,其降解周期明显改善。
以上所述为本发明的优选实施例而已,并不用于限制本发明,尽管参照前述实施例对本发明进行了详细的说明,对于本领域的技术人员来说,其依然可以对前述各实施例记载的技术方案进行修改,或者对其中部分技术特征进行等同替换。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (4)
1.一种改性的玻尿酸可注射填充材料的制备方法,其特征在于,包括如下步骤:步骤(1)交联玻尿酸凝胶的制备:将聚乙二醇结构上的羟基与玻尿酸骨架上一个或多个羧基进行键合的步骤,其反应过程如下所示:
其中包括如下步骤:a.将玻尿酸溶液、聚乙二醇溶液、交联剂混合,并不断搅拌;b.维持反应体系的pH=4-6;c.控制反应温度为60-80℃,充分搅拌12h;d.将反应产物经透析处理,经干燥处理后得到玻尿酸-聚乙二醇接枝交联聚合物,其中,在步骤(a)中,其中玻尿酸与聚乙二醇的重量百分比为10:1-1:40;其中,在步骤(1)中,所述的玻尿酸溶液与聚乙二醇溶液的溶剂为水,步骤(b)的pH值为5;其中所述的交联剂选自EDC或者HOBt,或者其组合;
步骤(2):按照比例称取自由透明玻尿酸凝胶水溶液,加入至步骤(1)所制备得到的交联玻尿酸凝胶的制备,并于室温下充分混合搅拌;其中所述的自由透明玻尿酸凝胶与交联玻尿酸凝胶的质量比为2:10-40:1;其中所述的自由透明玻尿酸凝胶的分子量为5K-200KDa;
步骤(3):按照比例称取水溶性维生素及山梨糖醇,溶解于水中充分搅拌后加入至步骤(2)所得的自由透明玻尿酸凝胶与交联玻尿酸凝胶混合液中;并加入缓冲溶液,保持体系的pH为6-6.8;所述的水溶性维生素的占所述自由透明玻尿酸凝胶的重量百分比为1.0%-5%;所述的山梨糖醇占所述自由透明玻尿酸凝胶的重量百分比小于3%;
步骤(4):将上述混合物经透析处理,经干燥处理后得到所述的玻尿酸可注射填充材料。
2.如权利要求1所述的方法,所述的玻尿酸与聚乙二醇的重量百分比为5:1。
3.如权利要求1所述的方法,所述的水溶性维生素的占所述自由透明玻尿酸凝胶的重量百分比为2.5%。
4.如权利要求1所述的方法,所述的山梨糖醇占所述自由透明玻尿酸凝胶的重量百分比为1%。
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