CN112370417A - 用于基胃滞留剂的双网络水凝胶的预辐射制备方法 - Google Patents
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Abstract
本发明提供了一种用于双网络水凝胶基胃滞留剂的预辐射制备方法,属于生物医药材料技术领域。先制备双网络水凝胶第一网络,然后制备双网络水凝胶的预聚体,将所得的硬而脆的刚性网络结构的水凝胶,浸渍于步骤预聚体溶液中,初步形成物理交联的双网络水凝胶,后置于电子束下进行辐射交联反应,所得的产物即为双网络水凝胶。负载药物的双网络水凝胶基胃滞留剂具有生物安全性高、兼容性好、机械强度高、载药率高与可降解性等特点。
Description
技术领域
本发明属于生物医药材料技术领域,涉及一种用于基胃滞留剂的双网络水凝胶的预辐射制备方法。
背景技术
胃滞留给药系统是一类能滞留于胃液中,延长药物释放时间,改善药物在胃或十二指肠的吸收,降低毒副作用,减少服药次数,提高临床疗效的新型给药系统。目前,传统胃滞留给药系统主要有:漂浮型胃滞留给药系统、生物黏附型胃滞留给药系统、膨胀型胃滞留给药系统、沉降型胃滞留给药系统和磁性胃滞留给药系统等,但这些胃滞留剂由于响应因素单一、机械性能差,导致定位不准、血药浓度波动性高以及患者耐受性差等不足,限制了胃滞留剂的广泛应用。
中国专利CN110731950A介绍了一种胃内滞留长效制剂及其制备方法,该制剂包括胃溶胶囊壳和释药单元,释药单元折叠为几何形状设置在所述胃溶胶囊壳内,所述释药单元包括细长构件和生物可降解连接件,细长构件两端封闭且在管壁上开设有至少一个释药孔,在其内部设置有药物;生物可降解连接件用于连接所述细长构件的两端。但由于其释药单元结构复杂、连接部位较多而且连接部位机械性能差、生物降解性差,药物突释风险较高,而且制备技术要求较高,限制了其作为胃肠道给药的应用。
中国专利CN110996922A介绍了一种漂浮型胃滞留剂,其包括基质核心以及膜,基质核心主要由活性剂、超崩解剂、水溶性聚合物、酸和气体发生剂组成,所述膜是一种不溶水的可渗透的弹性自调节膜,其包含增塑剂和至少一种选自丙烯酸乙酯、丙烯酸甲酯及其组合的共聚物。但漂浮型胃滞留剂受胃内容物影响较大,药物缓释性能差,血药浓度波动性较大,并且气体发生剂可能会引起胃部不适,甚至穿孔,限制了其作为胃肠道给药的可能。
中国专利CN1995079A介绍了一类pH敏感型阳离子聚合物水凝胶亚微米粒及其制备方法,该水凝胶主要由亲水性非离子聚合物、阳离子聚合物、引发剂和交联剂组成。同时水凝胶亚微米粒能再分散在纯水、生理盐水、缓冲液等;pH<7时,水凝胶亚微米粒发生溶胀,而pH>7时,水凝胶亚微米粒的粒径变化很小,由于该发明的水凝胶pH敏感范围大,药物缓释可控性较差,限制了其作为胃肠道给药的精确调控。
中国专利CN1834125A利用模板共聚合法,合成了半互穿网络pH敏感水凝胶,该凝胶主要由pH敏感的离子单体,以及对应的一种与离子单体带相反电荷的聚合物作为模板,在交联剂存在下得到产物。主要通过改变凝胶内相反电荷的离子模板聚合物,进而改变凝胶对pH的响应阀值。随着溶液pH的变化,凝胶内部的离子密度发生变化,当离子密度超过某一值时,凝胶开始溶胀,但由于该发明采用合成单体进行模板聚合,相对于天然高分子水凝胶的生物相容性较差。
环境响应型智能水凝胶在药物控释领域具有重要的应用价值。响应环境信息(如温度、pH、特异分子/离子、葡萄糖浓度、光、电场、磁场、压力等)的微小变化,产生相应的体积变化或者其他物理化学性质的变化。环境响应型智能水凝胶性能存在的普遍问题是对环境刺激响应性比较单一、响应速率较慢。与单一刺激响应水凝胶相比,多重协同响应水凝胶可以同时综合各种单一响应水凝胶的优点,在构建智能响应材料方面体现出了很大的优势。
温敏水凝胶作为胃滞留剂可以对胃部病灶周围的温度等异常变化自动感知,自动释放所需药物。这种脉冲式释药模式可以较大发挥药效,同时又可以减小药物的副作用,并避免零级释放产生的耐药性,脉冲式释药可以模仿人体对激素的释放模式。但是温敏水凝胶容易受胃容物的影响,再加上温敏性材料的响应性速度较慢,在胃部还会不断被胃液侵蚀,导致温敏水凝胶释药异常,波动性较强,容易造成药物的突释。因此,单一温敏水凝胶作为胃滞留剂很难达到精准控释的目的。
pH值敏感水凝胶可以在胃酸的刺激下发生电离形成阴/阳离子,使凝胶内部渗透压增大,导致大分子链段间的氢键解离,产生体积变化,在胃内释放出药物。这一给药方法可有效减少药物运输过程中的损失,提高治疗的效果。但是胃液稀释、胃液分泌不足等影响药物释放,再加上pH值敏感水凝胶在胃部还会不断被胃液侵蚀,导致pH值水凝胶释药异常,波动性较强,容易造成药物的突释。
磁性纳米粒加入到水凝胶中,可以利用交变磁场对药物传递系统进行有效调控,进而控制药物脉冲式释放的效果。但是,随着磁敏感水凝胶在胃部不断被胃液侵蚀,磁性纳米颗粒被排出体外,导致磁敏感水凝胶释药异常,波动性较强,容易造成药物的突释。故而,单一磁敏感水凝胶作为胃滞留剂也很难达到完全精确调控药物释放的目的。
为了弥补上述三种水凝胶使用时的不足,我们研发了pH/温度/磁协同响应型双网络水凝胶,该复合水凝胶同时受pH、温度、磁场三个因素的调控,同时三者之间也具有协同响应效应,可以通过交变磁场使磁性纳米粒产生热量,进而引起温度的改变,一方面可以引起温敏材料内部结构的改变,从而实现药物的可控释放;另一方面温度改变还可以引起pH值的变化,进而使得pH敏感材料通过控制水凝胶的溶胀比,使得水凝胶中药物达到脉冲式释放。利用三种调控机制更加有效保证了药物的可控释放。其次水凝胶中包含两个网络,第一网络为含pH敏感的聚电解质网络,硬而脆的聚电解质网络为水凝胶提供刚性支架;第二网络为低度交联的松散的中性温敏聚合物网络,软而韧的中性聚合物网络填充到第一网络中,赋予水凝胶良好的弹性和延展性。此外磁性纳米颗粒的加入,可以为药物提供更多的附着位点,提高了水凝胶的载药率,同时也提高了水凝胶的机械性能。从而有效克服了单一水凝胶机械强度差、容易崩塌、载药率低的缺点。
传统的水凝胶普遍采用化学交联法,制备的水凝胶不仅易在水体中释放残余的有毒交联剂或氧化还原试剂,会出现不均匀交联,局部发生“烧焦现象”,并且化学交联难以控制交联度;其次,水凝胶不易获得均匀分布的凝胶骨胶体系,而且纳米粒子和药物与凝胶分子间的作用力太弱甚至没有,导致其易从凝胶孔洞中流失,从而影响了水凝胶的功能性,制约了水凝胶作为药物控制释放与药物传输的多功能材料的应用。电离辐射法相对于化学法实现了有效的补充和完善,具体表现为:①反应过程不需要添加任何对人体有毒的物质,交联度高,水凝胶纯度高;②反应条件温和,在室温下即可进行,操作简便,反应周期短且易于调控;③通过控制聚合物组分和辐照条件可以准确调控水凝胶的力学性能;④水凝胶制备、塑形及磁性纳米材料和药物的有效负载可同步完成。因此,辐射合成技术已成为智能水凝胶制备极富前景的研究途径。
本发明所要解决的问题是公开一种用于胃滞留剂的磁/pH/温度协同响应型双网络水凝胶预辐射合成方法,以克服现有技术存在的上述缺陷。
发明内容
本发明的目的是针对现有的技术存在的上述问题,提供一种用于基胃滞留剂的双网络水凝胶的预辐射制备方法,本发明所要解决的技术问题是利用磁、pH、温度协同刺激响应的方法合成用于胃滞留剂的双网络水凝胶。
本发明的目的可通过下列技术方案来实现:一种用于基胃滞留剂的双网络水凝胶的预辐射制备方法,其特征在于,包括如下步骤:
A、双网络水凝胶第一网络的制备:将20~40wt%的pH敏感型高分子材料、0.1~2.0wt%的pH调节剂、0.5~2.0wt%的磁性纳米颗粒、0.5~2.0wt%的辐照敏化剂、54~78.9wt%的蒸馏水或去离子水搅拌均匀后,注射至厚度在1.5mm~2.5mm之间的 PE密封袋中,通氮气0.5~2h,并置于电子束下进行预辐射交联反应,选择的电子束能量为1~5MeV,辐射吸收剂量为5~40 kGy,剂量率为5~20kGy/pass,所得的产物作为双网络水凝胶硬而脆的刚性第一网络,为水凝胶提供刚性支架;
B、双网络水凝胶的预聚体的制备:利用超声波将20.0~40.0 wt%的温敏单体、56~79.4wt%的蒸馏水或去离子水放入三口烧瓶中,在50~95℃加热并搅拌0.5~2h,搅拌速率为150r/min,使其均匀形成稳定的溶液体系,再通氮气0.5~2h,静置约2h,以除去气泡,并置于电子束下进行预辐射交联反应,选择的电子束能量为1~5MeV,辐射吸收剂量为5~40kGy,剂量率为5~ 20kGy/pass,所得的产物可以作为构建双网络水凝胶软而韧的柔性第二网络的预聚体;
C、将步骤A所得的硬而脆的刚性网络结构的水凝胶,浸渍于步骤B所得的预聚体溶液中,将混合体系放置于厚度在2.5 mm~5.0mm之间的玻璃皿中,并冷冻解冻三次,初步形成物理交联的双网络水凝胶,后置于电子束下进行辐射交联反应,选择的电子束能量为1~5MeV,辐射吸收剂量为10~100kGy,剂量率为10~50kGy/pass,所得的产物即为双网络水凝胶。
进一步的,所述的pH敏感型高分子材料为丙烯酸其衍生物、壳聚糖及其衍生物、N,N-二烷基氨烷基丙烯酸酯类生物中的一种或多种。
进一步的,所述的温敏单体为聚N-异丙基丙烯酰胺 (PNIPAM)、聚甲基丙烯酸N,N-二甲基氨基乙酯(PDMAEMA)、聚(N,N-二乙基丙烯酰胺)-聚(2-羧基异丙基丙烯酰胺)(PCIPAAm)、聚N-乙基吗啉甲基丙烯酸酯(PMEMA)、聚苯醚 (PPO)、聚氧化乙烯(PEO)等中的一种或多种。
进一步的,所述的辐照敏化剂为胶原蛋白、聚乙烯醇、N-异丙基丙烯酰胺等中的一种或多种。
在辐照过程中,辐照敏化剂首先迅速产生活性自由基,从而引发天然聚多糖产生活性自由基,彼此之间迅速发生交联而制备出复合水凝胶。辐照敏化剂的引入,缩短了辐照交联所需的时间,提高了生产效率,确保了复合水凝胶具有适当的交联度。
进一步的,所述的pH调节剂为磷酸氢二钠、磷酸一氢钠、碳酸氢钠、己二酸、乙酸、Tris-HCl、亚氨基二乙酸、三乙醇胺中的一种或多种。
pH调节剂的引入,不仅保证了纳米复合水凝胶的pH响应性,同时也可以调节高分子和纳米材料形成的混合乳液体系的等电点和稳定的分散性,确保高分子自身不缠结,有利于后期辐射交联的顺利进行。
进一步的,所述的磁性纳米颗粒为Fe3O4、BiFeO4、CoFeO、 FeCrMo、FeAlC、CuNiFe、FeCrCo、PtCo、MnAlC、MnBi中的一种或多种。
磁性纳米颗粒的引入,确保了纳米复合水凝胶在药物控释和给药系统中的磁性响应性,同时保证了磁/pH/温度协同刺激响应性,提高纳米复合水凝胶的响应灵敏度。
本发明的有益效果
1、有效克服了传统水凝胶环境刺激响应性单一、响应速率较慢的缺点。既实现了纳米复合水凝胶综合性能的优化,也实现了磁、pH、温度三元协同刺激响应的灵敏性和多重可调性,血药浓度波动性小,减少了药物突释带来的风险。
2、该纳米复合水凝胶具有生物安全性高、兼容性好、机械强度高、载药率高与可降解性强等特点,既能充分发挥药效,保证血药浓度维持恒定,也能最大程度地减小药物对身体的毒副作用,可广泛应用于药物控释与传输等医药领域的可控治疗。
3、辐照技术无毒、反应条件温和,反应过程不添加交联剂、引发剂以及任何对人体有毒的物质,可有效避免二次污染。
具体实施方式
以下是本发明的具体实施例,对本发明的技术方案作进一步的描述,但本发明并不限于这些实施例。
实施例1:将定量丙烯酸(20wt%)、磷酸氢二钠(0.1wt%)、 Fe3O4(0.5wt%)、胶原蛋白(0.5wt%)、蒸馏水或去离子水(78.9 wt%)搅拌均匀后,注射至厚度在1.5mm~2.5mm之间的PE密封袋中,通氮气0.5h,并置于电子束下进行预辐射交联反应,选择的电子束能量为1MeV,辐射吸收剂量为5kGy,剂量率为20 kGy/pass,所得的产物作为丙烯酸基水凝胶第一层网络。利用超声波将温敏单体N-异丙基丙烯酰胺(NIPAAM)(20.0wt%)、蒸馏水或去离子水(80wt%),放入三口烧瓶中,加热50℃,搅拌速率150r/min,时间为0.5h,使其均匀形成稳定的溶液体系,静置约2h,以除去气泡,并置于电子束下进行预辐射交联反应,选择的电子束能量为1MeV,辐射吸收剂量为5kGy,剂量率为 20kGy/pass,所得的产物即为聚N-异丙基丙烯酰胺(PNIPAM) 预聚体。将丙烯酸基水凝胶浸渍于PNIPAM预聚体中,混合均匀后放置于厚度在2.5mm~5.0mm之间的玻璃皿中,并冷冻解冻三次,初步形成物理交联的双网络水凝胶,后置于电子束下进行辐射交联反应,选择的电子束能量为1MeV,辐射吸收剂量为10kGy,剂量率为10kGy/pass,所得的产物烘干后即为三元Fe3O4/ 丙烯酸/PNIPAM协同响应型双网络水凝胶。
以大分子BSA为药物模型,测试Fe3O4/丙烯酸/PNIPAM双网络水凝胶对BSA的可控释放性能。将该水凝胶样品置于37℃、 pH=1.0的模拟胃液中,其药物负载率高达92%,14天近线性释放速率达到80%,累计释放速率达到了82%。
实施例2:
将定量壳聚糖(30wt%)、磷酸一氢钠(1.5wt%)、 BiFeO4(1.5wt%)、聚乙烯醇(1.5wt%)、蒸馏水或去离子水(65.5 wt%)搅拌均匀后,注射至厚度在1.5mm~2.5mm之间的PE密封袋中,通氮气1h,并置于电子束下进行预辐射交联反应,选择的电子束能量为1MeV,辐射吸收剂量为30kGy,剂量率为10 kGy/pass,所得的产物为壳聚糖基水凝胶第一层网络。利用超声波将温敏单体甲基丙烯酸N,N-二甲基氨基乙酯(DMAEMA)(30.0 wt%)、蒸馏水或去离子水(70wt%),放入三口瓶中,加热80℃,搅拌速率150r/min,时间为1h,使其均匀形成稳定的溶液体系,静置约2h,以除去气泡,并置于电子束下进行预辐射交联反应,选择的电子束能量为3MeV,辐射吸收剂量为30kGy,剂量率为 10kGy/pass,所得的产物即为聚甲基丙烯酸N,N-二甲基氨基乙酯预聚体(PDMAEMA)。将壳聚糖基水凝胶浸置于PDMAEMA预聚体中,混合均匀后放置于厚度在2.5mm~5.0mm之间的玻璃皿中,并冷冻解冻三次,初步形成物理交联的双网络水凝胶,后置于电子束下进行辐射交联反应,选择的电子束能量为3MeV,辐射吸收剂量为70kGy,剂量率为35kGy/pass,所得的产物烘干后即为壳聚糖/PDMAEMA/BiFeO4三元协同响应型双网络水凝胶。
以大分子BSA为药物模型,测试壳聚糖/PDMAEMA/BiFeO4双网络水凝胶对BSA的可控释放性能,将该水凝胶样品置于 37℃、pH=1.0的模拟胃液中,其药物负载率达到了88%,14天近线性释放速率为83%,累计释放速率达到了84%。
实施例3:将定量N,N-二烷基氨烷基丙烯酸酯(40.0wt%)、碳酸氢钠(2.0wt%)、FeCrMo(2.0wt%)、N-异丙基丙烯酰胺(2.0 wt%)、蒸馏水或去离子水(54.0wt%)搅拌均匀后,注射至厚度在 1.5mm~2.5mm之间的PE密封袋中,通氮气2h,并置于电子束下进行预辐射交联反应,选择的电子束能量为5MeV,辐射吸收剂量为40kGy,剂量率为20kGy/pass,所得的产物N,N-二烷基氨烷基丙烯酸酯基水凝胶第一层网络。利用超声波将苯醚(PO)(40.0wt%)温敏单体、蒸馏水或去离子水(60wt%),放入三口瓶中,加热95℃,搅拌速率150r/min,时间为2h,使其均匀形成稳定的溶液体系,静置约2h,以除去气泡,并置于电子束下进行预辐射交联反应,选择的电子束能量为5MeV,辐射吸收剂量为 40kGy,剂量率为20kGy/pass,所得的产物即为聚苯醚才预聚体 (PPO)。将N,N-二烷基氨烷基丙烯酸酯基水凝胶浸置于PPO预聚体中,混合均匀后放置于厚度在2.5mm~5.0mm之间的玻璃皿中,并冷冻解冻三次,初步形成物理交联的双网络水凝胶,后置于电子束下进行辐射交联反应,选择的电子束能量为5MeV,辐射吸收剂量为100kGy,剂量率为50kGy/pass,所得的产物烘干后即为N,N-二烷基氨烷基丙烯酸酯/PPO/FeCrMo三元协同响应型双网络水凝胶。
以大分子BSA为药物模型,测试N,N-二烷基氨烷基丙烯酸酯/PPO/FeCrMo三元协同响应型双网络水凝胶对BSA的可控释放性能,将该水凝胶样品置于37℃、pH=1.0的模拟胃液中,其药物负载率达到90%,14天近线性释放速率达到87%,累计释放速率达到了85%。
本文中所描述的具体实施例仅仅是对本发明精神作举例说明。本发明所属技术领域的技术人员可以对所描述的具体实施例做各种各样的修改或补充或采用类似的方式替代,但并不会偏离本发明的精神或者超越所附权利要求书所定义的范围。
Claims (6)
1.用于基胃滞留剂的双网络水凝胶的预辐射制备方法,其特征在于,包括如下步骤:
A、双网络水凝胶第一网络的制备:将20~40wt%的pH敏感型高分子材料、0.1~2.0wt%的pH调节剂、0.5~2.0wt%的磁性纳米颗粒、0.5~2.0wt%的辐照敏化剂、54~78.9wt%的蒸馏水或去离子水搅拌均匀后,注射至厚度在1.5mm~2.5mm之间的PE密封袋中,通氮气0.5~2h,并置于电子束下进行预辐射交联反应,选择的电子束能量为1~5MeV,辐射吸收剂量为5~40kGy,剂量率为5~20kGy/pass,所得的产物作为双网络水凝胶硬而脆的刚性第一网络,为水凝胶提供刚性支架;
B、双网络水凝胶的预聚体的制备:利用超声波将20.0~40.0wt%的温敏单体、56~79.4wt%的蒸馏水或去离子水放入三口烧瓶中,在50~95℃加热并搅拌0.5~2h,搅拌速率为150r/min,使其均匀形成稳定的溶液体系,再通氮气0.5~2h,静置约2h,以除去气泡,并置于电子束下进行预辐射交联反应,选择的电子束能量为1~5MeV,辐射吸收剂量为5~40kGy,剂量率为5~20kGy/pass,所得的产物可以作为构建双网络水凝胶软而韧的柔性第二网络的预聚体;
C、将步骤A所得的硬而脆的刚性网络结构的水凝胶,浸渍于步骤B所得的预聚体溶液中,将混合体系放置于厚度在2.5mm~5.0mm之间的玻璃皿中,并冷冻解冻三次,初步形成物理交联的双网络水凝胶,后置于电子束下进行辐射交联反应,选择的电子束能量为1~5MeV,辐射吸收剂量为10~100kGy,剂量率为10~50kGy/pass,所得的产物即为双网络水凝胶。
2.根据权利要求1所述的用于基胃滞留剂的双网络水凝胶的预辐射制备方法,其特征在于,所述的pH敏感型高分子材料为丙烯酸其衍生物、壳聚糖及其衍生物、N,N-二烷基氨烷基丙烯酸酯类生物中的一种或多种。
3.根据权利要求2所述的用于基胃滞留剂的双网络水凝胶的预辐射制备方法,其特征在于,所述的温敏单体为聚N-异丙基丙烯酰胺(PNIPAM)、聚甲基丙烯酸N,N-二甲基氨基乙酯(PDMAEMA)、聚(N,N-二乙基丙烯酰胺)-聚(2-羧基异丙基丙烯酰胺)(PCIPAAm)、聚N-乙基吗啉甲基丙烯酸酯(PMEMA)、聚苯醚(PPO)、聚氧化乙烯(PEO)等中的一种或多种。
4.根据权利要求3所述的用于基胃滞留剂的双网络水凝胶的预辐射制备方法,其特征在于,所述的辐照敏化剂为胶原蛋白、聚乙烯醇、N-异丙基丙烯酰胺等中的一种或多种。
5.根据权利要求4所述的用于基胃滞留剂的双网络水凝胶的预辐射制备方法,其特征在于,所述的pH调节剂为磷酸氢二钠、磷酸一氢钠、碳酸氢钠、己二酸、乙酸、Tris-HCl、亚氨基二乙酸、三乙醇胺中的一种或多种。
6.根据权利要求5所述的用于基胃滞留剂的双网络水凝胶的预辐射制备方法,其特征在于,所述的磁性纳米颗粒为Fe3O4、BiFeO4、CoFeO、FeCrMo、FeAlC、CuNiFe、FeCrCo、PtCo、MnAlC、MnBi中的一种或多种。
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