CN112812325A - 一种含盐立构复合型聚乳酸温敏性水凝胶及其制备方法 - Google Patents
一种含盐立构复合型聚乳酸温敏性水凝胶及其制备方法 Download PDFInfo
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Abstract
本发明涉及温敏性水凝胶领域,公开了一种含盐立构复合型聚乳酸温敏性水凝胶及其制备方法。该温敏性水凝胶按重量份计包括以下原料:1~20份组分A,1~20份组分B,60~98份盐溶液;所述组分A为聚左旋乳酸‑聚乙二醇‑聚左旋乳酸(PLLA‑PEG‑PLLA)三嵌段共聚物,所述组分B为聚右旋乳酸‑聚乙二醇‑聚右旋乳酸(PDLA‑PEG‑PDLA)三嵌段共聚物。在本发明的温敏性水凝胶中,通过改变盐的种类和浓度即可改变水凝胶的溶胶‑凝胶相转变温度和力学性能,可控性好,且制备过程简单。
Description
技术领域
本发明涉及温敏性水凝胶领域,尤其涉及一种含盐立构复合型聚乳酸温敏性水凝胶及其制备方法。
背景技术
温敏性水凝胶作为一种新型生物医用材料备受关注,在药物释放、组织工程等领域具有广阔的应用前景。其中,两亲性嵌段共聚物具有疏水-亲水平衡特性,在水溶液中自组装形成胶束,仅通过升高温度即可发生溶胶-凝胶相转变,是一种优异的可注射水凝胶材料。然而,设计和研制一种兼具良好的生物相容性、生物可降解性、力学性能及相转变行为等诸多优异特性于一体的水凝胶材料,仍是一项极具挑战性的任务,该技术的突破对推动这类材料应用具有极为重要的意义。
脂肪族聚酯类温敏性水凝胶因其生物相容性和生物可降解性得到业内广泛关注。聚乳酸(PLA)的对映体聚左旋乳酸(PLLA)与聚右旋乳酸(PDLA)分子链间可发生立构复合结晶化。在两亲性的PLLA-聚乙二醇(PEG)-PLLA和PDLA-PEG-PDLA三嵌段共聚物共混物水溶液中,PLLA/PDLA立构复合结晶可驱动水溶液的物理凝胶化(如Fujiwara T等,Macromol.Biosci.,2001,1,204-208)。当PLLA-PEG-PLLA和PDLA-PEG-PDLA水溶液以1∶1共混,随着温度变化可呈现溶液-凝胶转变。与传统的聚酯温敏性水凝胶相比,立构复合结晶提高了相应物理凝胶疏水链段间的相互作用和缔合程度,加速凝胶化,可实现力学性能的有效改善。
然而,PLLA-PEG-PLLA/PDLA-PEG-PDLA的水凝胶仍存在一些缺点,目前已报道的调控立构复合型水凝胶的温度响应行为与力学性能的方法有通过设计复杂拓扑结构(Nagahama K等,Polymer,2007,48,2649-2658)、改变嵌段链长和共聚组成(Fujiwara T等,Biomacromolecules,2012,13,1828-1836)、调整疏水链段序列(Mao H,Soft Matter,2016,12,4628-4637)等。上述方法涉及复杂的化学合成,水凝胶制备过程相对复杂,条件要求苛刻且可控性较差。
发明内容
为了解决上述技术问题,本发明提供了一种含盐立构复合型聚乳酸温敏性水凝胶及其制备方法。本发明通过改变盐的种类和浓度、组分A、B的比例和聚合物总浓度即可改变水凝胶的溶胶-凝胶相转变温度和力学性能,可控性好,制备过程简单。
本发明的具体技术方案为:
一种含盐立构复合型聚乳酸温敏性水凝胶,按重量份计包括以下原料:1~20份组分A,1~20份组分B,60~98份盐溶液;所述组分A为聚左旋乳酸-聚乙二醇-聚左旋乳酸(PLLA-PEG-PLLA)三嵌段共聚物,所述组分B为聚右旋乳酸-聚乙二醇-聚右旋乳酸(PDLA-PEG-PDLA)三嵌段共聚物;所述盐溶液的浓度为0.01~10wt%,所述盐溶液中的溶质为金属卤化盐或金属硫酸盐中的至少一种。
本发明在现有的PLLA-PEG-PLLA/PDLA-PEG-PDLA温敏性水凝胶的基础上,添加盐类构成盐/立构复合型聚乳酸温敏性水凝胶,利用盐效应和水-PEG的配位相互作用使溶液中胶束的疏水性增加的原理,通过调节盐的种类和浓度,即可调控体系的立构复合结晶及微观结构,进而调节温敏性水凝胶的溶胶-凝胶相转变温度和力学性能;随着盐浓度的增加,溶胶-凝胶相转变温度显著降低,力学性能显著增加。
本发明的温敏性水凝胶保留了PLLA-PEG-PLLA/PDLA-PEG-PDLA水凝胶较好的生物相容性和生物可降解性,能被人体代谢,可用于药物载体、组织工程等生物医用领域。并且,相较于现有技术中通过改变内在因素(拓扑结构、共聚组成、分子量大小及分布等)调控PLLA-PEG-PLLA/PDLA-PEG-PDLA温敏性水凝胶的溶胶-凝胶相转变温度和力学性能而言,本发明通过改变盐的种类和浓度即可实现这种调控,具有水凝胶制备过程简单、溶胶-凝胶相转变温度和力学性能可控性好的优点。
作为优选,所述盐溶液中的溶质为氯化钠、氯化镁、硫酸钠、硫酸镁中的至少一种。
作为优选,所述盐溶液的浓度为0.5~3wt%。
作为优选,所述组分A或组分B中,聚乙二醇嵌段的数均分子量为500~5000,单个聚左旋乳酸或聚右旋乳酸嵌段的数均分子量为500~2000。
作为优选,所述组分A或组分B的制备方法如下:以双端羟基封端的聚乙二醇为引发剂,辛酸亚锡为催化剂,分别以L-丙交酯或D-丙交酯为单体,进行开环聚合反应后,分离出反应产物,获得组分A或组分B。
一种制备所述温敏性水凝胶的方法,包括以下步骤:
(1)将组分A和组分B分别溶于盐溶液中,制得组分A溶液和组分B溶液;
(2)将组分A溶液和组分B溶液混合,制得混合溶液;
(3)将混合溶液升温至形成凝胶,获得含盐立构复合型聚乳酸温敏性水凝胶。
在以上制备过程中,通过调节步骤(1)中组分A溶液和组分B溶液的浓度,以及步骤(2)中两者的比例,也可以调节温敏性水凝胶的溶胶-凝胶相转变温度。
作为优选,步骤(1)中,所述组分A溶液中,组分A的质量分数为1~20wt%;所述组分B溶液中,组分B的质量分数为1~20wt%。
作为优选,步骤(2)中,所述组分A溶液与组分B溶液的质量比为1∶9~9∶1。
作为优选,步骤(3)中,所述升温的具体过程如下:每次升高1~5℃,每个温度下维持5~30min。
作为优选,步骤(3)中,所述升温的起始温度为0~5℃。
与现有技术相比,本发明具有以下优点:
(1)目前,对可立构复合的两亲性高分子水溶液的热致凝胶化的调控方法复杂、条件苛刻且可控性差。本发明通过改变无机盐的种类和浓度、组分A、B的比例和聚合物总浓度即可改变水凝胶的溶胶-凝胶相转变温度和力学性能,可控性好,且制备过程简单;
(2)本发明通过盐效应和水-PEG的配位相互作用,使溶液中胶束的疏水性增加的原理调控体系的立构复合结晶及微观结构,进一步调控体系的溶胶-凝胶相转变温度。
(3)本发明水凝胶的生物相容性好,且具有生物可降解性,能被人体代谢,可用于药物载体、组织工程等生物医用领域。
附图说明
图1为实施例4和对比例2所测得的广角X散射衍射图;
图2为实施例4和对比例2室温下的所测得的储能模量与损耗模量随着温度的变化示意图。
具体实施方式
下面结合实施例对本发明作进一步的描述。
以下实施例可以使本专业的专业技术人员更全面地理解本发明,但不以任何方式限制本发明。本发明制备水凝胶所用的试剂、药品:PEG购自aladdin公司;丙交酯购自普拉克公司,备用;催化剂辛酸亚锡购自Sigma公司;溶剂甲苯为国药分析纯,用金属钠蒸馏除去水分,备用。
实施例1
通过以下方法制备一种含盐立构复合型聚乳酸温敏性水凝胶,并确定其溶胶-凝胶相转变温度:
(1)组分A和组分B的制备:
组分A的合成参考文献Bhatia,S.R.等,Macromolecules,2007,40,7864-7873进行。在希丁克管中加入摩尔比为1∶1的双端羟基封端PEG和L-丙交酯,抽真空后充入氩气,气体置换3次,加入用量为PEG质量4倍的干燥甲苯。加热至130℃共沸蒸馏出1/3甲苯,以去除体系中残留的水分,加入辛酸亚锡,辛酸亚锡用量为PEG质量的0.2wt%,反应12小时。将反应混合物按1∶1的体积比加入至乙醚/正己烷(50/50v/v)沉淀剂中沉淀,抽滤分离后所得固体即为组分A,25℃条件下真空干燥12h,备用。组分B的制备方法相同,仅将L-丙交酯换成D-丙交酯。
产物分子量通过核磁共振(1H-NMR)测定,分子量分布指数(PDI)由凝胶渗透色谱仪(GPC)测定,具体方法如下:
NMR测试:利用核磁核磁共振仪(Bruker公司,400MHz)测试嵌段共聚物的1H NMR谱图,进而计算其Mn。测试温度为室温,溶剂为氘代氯仿,化学位移(δ)由溶剂峰校正。分子量计算说明:根据1H-NMR图谱上δ=3.6ppm化学位移峰面积与δ=1.5ppm处化学位移分面积的比值以及PEG链段的理论分子量计算嵌段共聚物的Mn,以及其中聚乳酸嵌段的Mn。分子量分布测试:共聚物分子量分布采用GPC(型号Waters 1525/2414)测试,测试温度为30℃,流动相为四氢呋喃,标准样品为单分散聚苯乙烯。
步骤(1)制得的组分A和组分B的具体结构特征如表1。
表1:组分A和B的制备与结构特性
(2)盐溶液的制备:
将氯化钠溶解于去离子水中,搅拌均匀得到浓度为0.5wt%的盐溶液。
(3)含盐立构复合型聚乳酸温敏性水凝胶的制备:
将步骤(1)制得的组分A溶解于步骤(2)制得的盐溶液中,获得组分A的浓度为5wt%的组分A溶液;将步骤(1)制得的组分B溶解于步骤(2)制得的盐溶液中,获得组分B的浓度为5wt%的组分B溶液;将组分A和组分B等质量比混合至瓶内并置于水浴中,从5℃梯次逐渐升温到70℃,每次升温2℃,每个间隔温度恒温15分钟,然后采用试管倒置法测试是否形成凝胶。所述的试管倒置法,即将样品瓶在垂直方向倒置,观察样品在10秒内是否发生流动,如不流动就认为其已经凝胶化,如流动则视为溶液。
实施例2~7、对比例1~3
实施例2~7和对比例1~3与实施例1的区别在于,根据表2,改变步骤(2)中的盐溶液浓度,以及步骤(3)中的组分A溶液浓度和组分B溶液浓度,其余制备过程均相同。
测试例
(1)溶胶-凝胶相转变温度:
实施例1~7和对比例1~3中的组分A溶液浓度、组分B溶液浓度、盐溶液浓度及混合后溶胶-凝胶相转变温度如表2所示。
表2:实施例1~7和对比例1~3的制备条件和溶胶-凝胶相转变温度
由表2可知,水凝胶的溶胶-凝胶相转变温度受组分A和组分B的浓度以及盐浓度的影响:
①根据对比例1~3,可知:组分A溶液和组分B溶液浓度为5~11wt%的共混溶液表现出溶胶-凝胶相转变,且溶胶-凝胶相转变温度随着组分A和组分B浓度的增大而降低。
②根据实施例1~3与对比例1,实施例4~5与对比例2,实施例6~7与对比例3,可知:氯化钠的加入会使体系的溶胶-凝胶相转变温度降低,且随着氯化钠浓度的增大,溶胶-凝胶相转变温度降低。
(2)广角X散射衍射图:
为进一步确认本发明水凝胶的溶胶-凝胶相转变温度与PLLA和PDLA之间的立构复合结晶相关,对实施例4与对比例2制得的水凝胶在上海光源进行同步辐射X射线衍射分析,所用波长为0.124nm。结果如图1所示,其中,SC代表PLLA/PDLA的立构复合结晶,HC代表PLLA或PDLA的同质结晶。由图1可知:体系中存在氯化钠可促进PLLA与PDLA间立构复合结晶的形成。
(3)储能模量与损耗模量随着温度的变化:
为表征本发明水凝胶的力学特性,采用RS6000流变仪(Thermo-Fisher公司)测定了实施例4及对比例2在不同温度下的储能模量(G′)和损耗模量(G″),测试结果如图2所示。由图2可知:在不添加氯化钠的情况下,60℃时的G′数值为4.2Pa;而添加氯化钠后,浓度为1wt%的G′值提高到15.9Pa,表明添加氯化钠可有效提高水凝胶的力学性能。
最后,需要注意的是,以上列举的仅是本发明的具体实施例。显然,本发明不限于以上实施例,还可以有很多变形。本领域的普通技术人员能从本发明公开的内容中直接导出或联想到的所有变形,均应认为是本发明的保护范围。
Claims (10)
1.一种含盐立构复合型聚乳酸温敏性水凝胶,其特征在于,按重量份计包括以下原料:1~20份组分A,1~20份组分B,60~98份盐溶液;所述组分A为聚左旋乳酸-聚乙二醇-聚左旋乳酸三嵌段共聚物,所述组分B为聚右旋乳酸-聚乙二醇-聚右旋乳酸三嵌段共聚物;所述盐溶液的浓度为0.01~10 wt%;所述盐溶液中的溶质为金属卤化盐或金属硫酸盐中的至少一种。
2.如权利要求1所述的温敏性水凝胶,其特征在于,所述盐溶液中的溶质为氯化钠、氯化镁、硫酸钠、硫酸镁中的至少一种。
3.如权利要求1所述的温敏性水凝胶,其特征在于,所述盐溶液的浓度为0.5~3wt%。
4.如权利要求1所述的温敏性水凝胶,其特征在于,所述组分A或组分B中,聚乙二醇嵌段的数均分子量为500~5000,单个聚左旋乳酸或聚右旋乳酸嵌段的数均分子量为500~2000。
5.如权利要求1或4所述的温敏性水凝胶,其特征在于,所述组分A或组分B的制备方法如下:以双端羟基封端的聚乙二醇为引发剂,辛酸亚锡为催化剂,分别以L-丙交酯或D-丙交酯为单体,进行开环聚合反应后,分离出反应产物,获得组分A或组分B。
6.一种制备如权利要求1~5之一所述温敏性水凝胶的方法,其特征在于,包括以下步骤:
(1)将组分A和组分B分别溶于盐溶液中,制得组分A溶液和组分B溶液;
(2)将组分A溶液和组分B溶液混合,制得混合溶液;
(3)将混合溶液升温至形成凝胶,获得含盐立构复合型聚乳酸温敏性水凝胶。
7.如权利要求6所述的方法,其特征在于,步骤(1)中,所述组分A溶液中,组分A的质量分数为1~20 wt%;所述组分B溶液中,组分B的质量分数为1~20 wt%。
8.如权利要求6或7所述的方法,其特征在于,步骤(2)中,所述组分A溶液与组分B溶液的质量比为1:9~9:1。
9.如权利要求6所述的方法,其特征在于,步骤(3)中,所述升温的具体过程如下:每次升高1~5 ℃,每个温度下维持5~30 min。
10.如权利要求6或9所述的方法,其特征在于,步骤(3)中,所述升温的起始温度为0~5℃。
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