CN110330623A - 具有pH响应性的聚氨酯微球及其制备方法 - Google Patents
具有pH响应性的聚氨酯微球及其制备方法 Download PDFInfo
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- CN110330623A CN110330623A CN201910464630.7A CN201910464630A CN110330623A CN 110330623 A CN110330623 A CN 110330623A CN 201910464630 A CN201910464630 A CN 201910464630A CN 110330623 A CN110330623 A CN 110330623A
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Classifications
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Abstract
本发明涉及一种具有pH响应性的聚氨酯微球，由以下质量分数的原料制成，20～30％的低聚物二元醇、45～55％的二异氰酸酯、3～5％的羧甲基纤维素钠、3～5％的酸性核单元、5～15％的扩链剂、10～15％的中和剂以及0.01～0.05％的催化剂，其中，低聚物二元醇为摩尔比为1:1～2:1的聚乙二醇和聚己内酯二元醇的混合物。发明的合成方法简单，得到的产品在碱性环境中有良好的pH响应性，而在酸性环境中相对稳定，可以作为定向给药的pH响应型聚氨酯微球药物载体。
Description
技术领域
本发明涉及功能性高分子材料技术领域，尤其涉及一种具有pH响应性的聚氨酯微球及其制备方法。
背景技术
医疗水平的不断提高离不开医学材料的快速发展，自20世纪70年代将药物制剂通过微型包覆技术应用于微胶囊领域以来，使用生物高分子材料制备的微胶囊在生物医药和基因工程等领域获得迅速发展和广泛的应用。微胶囊是一种具有核-壳结构的封闭微型容器，其具有胶囊的释放机理：将药物包覆其中，通过扩散或载体的降解来释放药物。用来制作微胶囊的材料分为天然高分子以及合成高分子两大类：天然高分子主要包括胶原质、明胶、海藻酸盐、壳聚糖等；合成高分子主要包括聚氧化乙烯、聚丙烯酸、聚乙烯醇、聚N-异丙基丙烯酰胺等。
刺激响应型微胶囊，因其可以模拟活体***的响应过程，因此受到了广泛关注。这种微胶囊能够对环境的微小变化做出响应，发生物理化学性能包括结构、极性、相结构和化学组成等的明显改变。根据刺激不同，刺激响应型微胶囊微分温度、pH、光、电以及复合响应微胶囊。由于人体消化***的pH存在明显差异，因此pH响应性高分子微胶囊有广泛的应用前景。例如胰岛素会在胃中被蛋白水解酶分解为缩氨酸，而通过pH响应型高分子载体就可以有效的保护胰岛素及其他蛋白类药物免受胃中酶的消化，然后将药物释放到pH为中性的小肠中。对于pH响应型微胶囊，还可以用于癌症的治疗中，因为正常组织和血液中的pH为中性，而在一些肿瘤中，pH为0.5-1.0，远远低于正常值。因此具有可生物降解、pH响应性的微胶囊能够实现：(1)药物缓释，降低药物毒副作用，延长药物生物活性；(2)降解吸收，不会使人体产生免疫性；(3)在特定pH环境下释放药物；(4)在人体器官或组织靶向释放等功能。
聚氨酯作为一种合成高分子，可作为植入人体的生物材料，具有优良的生物性能和力学性能，在药物释放方面获得了广泛研究。如刘育红等以2,4-甲苯二异氰酸酯、二苯基甲烷二异氰酸酯和木质素为原料，制备了聚氨酯微胶囊，并以硝苯地平为模拟药物研究了影响药物释放的因素；林松以聚乙二醇、聚己内酯、异佛尔酮二异氰酸酯等为原料，以二羟甲基丙酸为扩链剂，合成了聚氨酯微胶囊，研究了其可降解性。Mohajnlnad等以二苯基甲烷二异氰酸酯和多官能团的聚氨酯多元醇为原料，PVP为分散剂，乙二胺为扩链剂，改变原料与扩链剂的比例，合成了一系列不同粒径的聚氨酯微球。目前还没有一种在碱性环境中有良好的pH响应性，而在酸性环境中相对稳定的聚氨酯微球。
发明内容
本发明的目的在于提供一种具有pH响应性的聚氨酯微球，其具有在碱性环境中有良好的pH响应性，而在酸性环境中相对稳定的特点。
本发明的另一目的在于提供一种具有pH响应性的聚氨酯微球的制备方法。
为实现上述目的，本发明提供一种具有pH响应性的聚氨酯微球，由以下质量分数的原料制成，20～30％的低聚物二元醇、45～55％的二异氰酸酯、3～5％的羧甲基纤维素钠、3～5％的酸性核单元、5～15％的扩链剂、10～15％的中和剂以及0.01～0.05％的催化剂，其中，所述低聚物二元醇为摩尔比为1:1～2:1的聚乙二醇和聚己内酯二元醇的混合物。
优选的，所述聚乙二醇的分子量为200～800，所述聚己内酯二元醇的分子量为1500～2500。
优选的，所述二异氰酸酯为异佛尔酮二异氰酸酯。
优选的，所述羧甲基纤维素钠的取代度为0.7～1.2。
优选的，所述扩链剂为摩尔比为1:4～1:1二羟甲基丙酸和1,4-丁二醇的混合物。
优选的，所述酸性核单元为N-烷基化的苏氨酸。
优选的，所述中和剂为三乙醇胺、三乙胺、N-甲基二乙醇胺和乙二胺中的至少一种。
优选的，所述催化剂为辛酸亚锡或二月桂酸二辛基锡。
为实现上述目的，本发明还提供一种具有pH响应性的聚氨酯微球的制备方法，包括以下步骤：
预聚合反应，将二异氰酸酯和乙酸乙酯加入到反应釜中，开启搅拌，然后加入低聚物二元醇、羧甲基纤维素钠和酸性核单元，最后加入催化剂，控制反应体系温度为80℃～100℃，反应2～3h；
扩链反应，将反应体系温度降低至50～70℃，加入扩链剂，反应2～3h；
中和反应，将反应体系温度降低至40～45℃，加入中和剂，反应0.5～1h；
乳化反应，将反应体系温度降低至25～30℃，加入去离子水，搅拌2～3h。
优选的，还包括后处理步骤：乳化反应完成后，对乳液进行减压蒸馏，体系温度控制在80～90℃，去除乙酸乙酯后进行真空干燥，得到粉末状固体产物。
本发明的有益效果是：
本发明采用低聚物二元醇、二异氰酸酯为主要原材料，在反应过程中将羧甲基纤维素钠及酸性核单元引入到聚氨酯的分子结构中，合成了一种对人体基本无毒的具有pH响应性且可降解的聚氨酯微球。该发明的合成方法简单，得到的产品在碱性环境中有良好的pH响应性，而在酸性环境中相对稳定，可以作为定向给药的pH响应型聚氨酯微球药物载体。
具体实施方式
为了使本发明所要解决的技术问题、技术方案及有益效果更加清楚明白，以下结合实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
一种具有pH响应性的聚氨酯微球，由以下质量分数的原料制成，20～30％的低聚物二元醇、45～55％的二异氰酸酯、3～5％的羧甲基纤维素钠、3～5％的酸性核单元、5～15％的扩链剂、10～15％的中和剂以及0.01～0.05％的催化剂，其中，所述低聚物二元醇为摩尔比为1:1～2:1的聚乙二醇和聚己内酯二元醇的混合物。
本发明将羧甲基纤维素钠引入到聚氨酯中，羧甲基纤维素钠是一种水溶性纤维素醚，在日化、石油、轻工、地质、视频、医药等工业中领域有着广泛应用，经过严格的生物学、毒理学研究和试验后，其已被批准用于食品，是一种毒性非常小的钠盐。
本发明利用带电荷的酸性核单元对聚氨酯进行共聚改性处理，处理后的聚氨酯微球因酸性核单元的存在，在低pH的环境中具有更强的稳定性，同时对碱性环境更加敏感，生物可降解性得到提高。
选择聚乙二醇和聚己内酯二元醇这两种低聚物二元醇作为聚氨酯软段的反应物，二者搭配使用对后期的释药性有所帮助。聚乙二醇和聚己内酯二元醇的摩尔比为1:1～2:1，若聚己内酯的用量大于该范围，反应易形成凝胶状物质。
所述聚乙二醇的分子量为200～800，所述聚己内酯二元醇的分子量为1500～2500，若二者的分子量小于该范围，则不能成为球型，分子量大于该范围，则产物易成为凝胶状物质。
所述二异氰酸酯为异佛尔酮二异氰酸酯，使用该化合物合成的聚氨酯具有降解产物对人体无毒无害，组织不会发生炎症，表面易于连接生物试剂，非生物特异作用小等优点。
所述羧甲基纤维素钠的取代度为0.7～1.2，取代度在此范围内，透明度较好。
所述扩链剂为摩尔比为1:4～1:1二羟甲基丙酸和1,4-丁二醇的混合物。使用二羟甲基丙酸可以引入羧基基团，通过中和剂可以生成羧酸盐，使聚氨酯达到自乳化的效果。增加其含量可以提高聚氨酯分子链的刚性，硬段比例增加，合成的微球粒径减小，乳化效果变好；加入1,4-丁二醇，可以使制备出的聚氨酯乳液外观好，贮存稳定性好，加入摩尔比为1:4～1:1范围内的二羟甲基丙酸和1,4-丁二醇的混合物，可以使制备的微球有适合的吸水率，有利于后期的载药释放。
所述酸性核单元为N-烷基化的苏氨酸。N-烷基化的苏氨酸通过以下方法制备：称取一定量的苏氨酸置于三口烧瓶中，加入多聚甲醛和甲酸，三者摩尔比控制在1:2:5～1:3.5:5之间，在反应器中充入N2，并开启真空泵抽真空，之后升温至100-120℃冷凝回流5h，将得到的黄色液体减压蒸馏除去过量的反应物，之后将减压蒸馏剩余的产物在加热的条件下用无水乙醇溶解，溶解完全后缓慢滴加溶解氢氧化钠的无水乙醇溶液至pH值为6.1-6.3，此时溶液中有白色沉淀产生，静置并过滤掉白色沉淀，取滤液用旋转蒸发仪处理得到目标产物N,N-二甲基苏氨酸。
所述中和剂为三乙醇胺、三乙胺、N-甲基二乙醇胺和乙二胺中的至少一种。
所述催化剂为辛酸亚锡或二月桂酸二辛基锡。
一种具有pH响应性的聚氨酯微球的制备方法，包括以下步骤：
预聚合反应，将二异氰酸酯和乙酸乙酯加入到反应釜中，开启搅拌，然后加入低聚物二元醇、羧甲基纤维素钠和酸性核单元，最后加入催化剂，控制反应体系温度为80℃～100℃，反应2～3h；其中，乙酸乙酯的加入量，不做特别限定，只要反应物质可以正常乳液聚合即可。
扩链反应，将反应体系温度降低至50～70℃，加入扩链剂，反应2～3h；
中和反应，将反应体系温度降低至40～45℃，加入中和剂，反应0.5～1h；
乳化反应，将反应体系温度降低至25～30℃，加入去离子水，搅拌2～3h。其中，去离子水用量为各反应原料总质量的2～4倍。
中和反应后，再加入去离子水进行乳液反应，在强烈的搅拌下，可以形成乳状液，制备的乳液乳化效果越好，目标产物越易形成均匀的球形结构。
还包括后处理步骤：乳化反应完成后，对乳液进行减压蒸馏，体系温度控制在80～90℃，去除乙酸乙酯后进行真空干燥，得到白色粉末状固体产物。
实施例1
原料配比：
(1)将异佛尔酮二异氰酸酯以及乙酸乙酯(与总反应原料等质量)加入三口烧瓶中，开启搅拌，搅拌速度为400rpm，缓慢加入低聚物二元醇(摩尔比为1:1的聚乙二醇和聚己内酯二元醇，聚乙二醇分子量为200，聚己内酯二元醇分子量为1500)、羧甲基纤维素钠(取代度为0.7)和N,N-二甲基苏氨酸，搅拌10min后，均匀缓慢加入布洛芬细粉末(低聚物二元醇、异佛尔酮二异氰酸酯、羧甲基纤维素钠、N,N-二甲基苏氨酸和扩链剂质量和的30％)，搅拌3min后，加入催化剂辛酸亚锡，开启冷凝管循环水并控制烧瓶内反应体系温度为90℃，搅拌速率提高到400～500rpm，反应2h；
(2)将反应体系温度降低至60℃，加入扩链剂(摩尔比为1:4的二羟甲基丙酸和1,4-丁二醇的混合物)，搅拌速率设定为300rpm，反应3h；
(3)将反应体系温度降低至40℃，滴加中和剂三乙醇胺，搅拌速率设定为200rpm，搅拌0.5h；
(4)将体系温度降低至30℃，加入去离子水(总反应原料质量的2倍)，搅拌速率设定600～800rpm，剧烈搅拌2.5h；
(5)将得到的乳液进行减压蒸馏，体系温度控制在85℃，去除乙酸乙酯后进行真空干燥，干燥温度设定100℃，得到白色粉末状固体。
以上分数均为质量分数。
实施例2
原料配比：
(1)将异佛尔酮二异氰酸酯以及乙酸乙酯(与总反应原料等质量)加入三口烧瓶中，开启搅拌，搅拌速度为500rpm，缓慢加入低聚物二元醇(摩尔比为2:1的聚乙二醇和聚己内酯二元醇，聚乙二醇分子量为800，聚己内酯二元醇分子量为2500)、羧甲基纤维素钠(取代度为1.2)和N,N-二甲基苏氨酸，搅拌10min后，均匀缓慢加入布洛芬细粉末(低聚物二元醇、异佛尔酮二异氰酸酯、羧甲基纤维素钠、N,N-二甲基苏氨酸和扩链剂质量和的30％)，搅拌3min后，加入催化剂二月桂酸二辛基锡，开启冷凝管循环水并控制烧瓶内反应体系温度为80℃，搅拌速率提高到400～500rpm，反应3h；
(2)将反应体系温度降低至50℃，加入扩链剂(摩尔比为1:1的二羟甲基丙酸和1,4-丁二醇的混合物)，搅拌速率设定为300rpm，反应2h；
(3)将反应体系温度降低至45℃，滴加中和剂三乙胺，搅拌速率设定为200rpm，搅拌1h；
(4)将体系温度降低至25℃，加入去离子水(总反应原料质量的3倍)，搅拌速率设定600～800rpm，剧烈搅拌2h；
(5)将得到的乳液进行减压蒸馏，体系温度控制在80℃，去除乙酸乙酯后进行真空干燥，干燥温度设定100℃，得到白色粉末状固体。
以上分数均为质量分数。
实施例3
原料配比：
(1)将异佛尔酮二异氰酸酯以及乙酸乙酯(与总反应原料等质量)加入三口烧瓶中，开启搅拌，搅拌速度为600rpm，缓慢加入低聚物二元醇(摩尔比为1.5:1的聚乙二醇和聚己内酯二元醇，聚乙二醇分子量为500，聚己内酯二元醇分子量为2000)、羧甲基纤维素钠(取代度为1)和N,N-二甲基苏氨酸，搅拌10min后，均匀缓慢加入布洛芬细粉末(低聚物二元醇、异佛尔酮二异氰酸酯、羧甲基纤维素钠、N,N-二甲基苏氨酸和扩链剂质量和的30％)，搅拌3min后，加入催化剂辛酸亚锡，开启冷凝管循环水并控制烧瓶内反应体系温度为100℃，搅拌速率提高到400～500rpm，反应2.5h；
(2)将反应体系温度降低至70℃，加入扩链剂(摩尔比为1:2的二羟甲基丙酸和1,4-丁二醇的混合物)，搅拌速率设定为300rpm，反应2.5h；
(3)将反应体系温度降低至40℃，滴加中和剂N-甲基二乙醇胺，搅拌速率设定为200rpm，搅拌0.5h；
(4)将体系温度降低至30℃，加入去离子水(总反应原料质量的4倍)，搅拌速率设定600～800rpm，剧烈搅拌3h；
(5)将得到的乳液进行减压蒸馏，体系温度控制在90℃，去除乙酸乙酯后进行真空干燥，干燥温度设定100℃，得到白色粉末状固体。
以上分数均为质量分数。
将实施例1～3所制得的微球进行pH响应性测定，具体测定方法如下：
配置pH＝3.5，pH＝7，pH＝7.8的缓冲溶液，取相同质量的实施例1～3的产物，分别加入到上述缓冲液中，密封后放入37℃烘箱，定时取样，离心分离后测定上清液在263nm处的吸光度，根据吸光度的不同，换算得到聚氨酯微球中布洛芬的残余量。实验数据如表1所示：
表1不同时间聚氨酯微球中布洛芬的残余量
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种具有pH响应性的聚氨酯微球，其特征在于，由以下质量分数的原料制成，20～30％的低聚物二元醇、45～55％的二异氰酸酯、3～5％的羧甲基纤维素钠、3～5％的酸性核单元、5～15％的扩链剂、10～15％的中和剂以及0.01～0.05％的催化剂，其中，低聚物二元醇为摩尔比为1:1～2:1的聚乙二醇和聚己内酯二元醇的混合物。
2.根据权利要求1所述的具有pH响应性的聚氨酯微球，其特征在于，所述，所述聚乙二醇的分子量为200～800，所述聚己内酯二元醇的分子量为1500～2500。
3.根据权利要求1所述的具有pH响应性的聚氨酯微球，其特征在于，所述二异氰酸酯为异佛尔酮二异氰酸酯。
4.根据权利要求1所述的具有pH响应性的聚氨酯微球，其特征在于，所述羧甲基纤维素钠的取代度为0.7～1.2。
5.根据权利要求1所述的具有pH响应性的聚氨酯微球，其特征在于，所述扩链剂为摩尔比为1:4～1:1二羟甲基丙酸和1,4-丁二醇的混合物。
6.根据权利要求1所述的具有pH响应性的聚氨酯微球，其特征在于，所述酸性核单元为N-烷基化的苏氨酸。
7.根据权利要求1所述的具有pH响应性的聚氨酯微球，其特征在于，所述中和剂为三乙醇胺、三乙胺、N-甲基二乙醇胺和乙二胺中的至少一种。
8.根据权利要求1所述的具有pH响应性的聚氨酯微球，其特征在于，所述催化剂为辛酸亚锡或二月桂酸二辛基锡。
9.权利要求1～8中任一项所述的具有pH响应性的聚氨酯微球的制备方法，其特征在于，包括以下步骤：
预聚合反应，将二异氰酸酯和乙酸乙酯加入到反应釜中，开启搅拌，然后加入低聚物二元醇、羧甲基纤维素钠和酸性核单元，最后加入催化剂，控制反应体系温度为80～100℃，反应2～3h；
扩链反应，将反应体系温度降低至50～70℃，加入扩链剂，反应2～3h；
中和反应，将反应体系温度降低至40～45℃，加入中和剂，反应0.5～1h；
乳化反应，将反应体系温度降低至25～30℃，加入去离子水，搅拌2～3h。
10.根据权利要求9所述的具有pH响应性的聚氨酯微球的制备方法，其特征在于，还包括后处理步骤：乳化反应完成后，对乳液进行减压蒸馏，体系温度控制在80～90℃，去除乙酸乙酯后进行真空干燥，得到粉末状固体产物。
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