CN115569107A - 一种双网络pH敏感释药的水凝胶及其制备方法和应用 - Google Patents
一种双网络pH敏感释药的水凝胶及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种双网络pH敏感释药的水凝胶及其制备方法,应用于肠道药物的载体,本发明以海藻酸钠聚乙二醇与富含羧基的pH敏感单体经聚合和交联反应,形成互穿网络的水凝胶进行载药,利用该水凝胶在低pH的条件下水凝胶羧基质子化基本不释放药物,而在较高pH时羧基去质子化释放药物的特点,从而达到靶向释药的目的。并且本发明结合海藻酸钠和聚甲基丙烯酸‑co‑聚乙二醇于凝胶内部形成的互穿网络结构,在具有优异的机械性能,防止在药物载体破裂引起的突释,同时控制药物载体水凝胶的溶胀,减缓药物的释放,使其具有靶向性,达到定向治疗的目的,解决了现有载体无法对结肠内炎症部位高效定向释药的问题。
Description
技术领域
本发明涉及生物医学仿生材料制备的技术领域,更具体地,涉及一种双网络pH敏感释药的水凝胶的制备方法及应用。
背景技术
溃疡性结肠炎是一种目前尚不清楚其致病机理的疾病,这种病的病变部位位于乙状结肠和直肠,也会延伸至降结肠,甚至整个结肠。发病周期长,而且会反复发作。如果处理不好则会非常的危险。可能产生癌变或大出血。如今,随着工业化的迅猛发展,人们的生活节奏越来越快。饮食习惯也随之发生了较大的变化。导致现在都溃疡性结肠炎发病率越来越高。而且更趋于年轻化。目前的治疗方法有手术、免疫抑制疗法、使用氨基水杨酸和类固醇的传统药物疗法等。但由于溃疡性结肠炎的发病机制比较复杂,而以上的方法有的价格昂贵,有的普适性较差或是副作用较为严重。因此现在大都是采用片剂或灌肠剂来进行治疗,柳氮磺吡啶是目前为止治疗溃疡性结肠炎的一线药物。但随之而来的问题是传统的药物剂型生物利用率低容易导致耐药性的产生。
目前,结肠靶向给药系统由于其高效定向释药的能力而受到人们的广泛关注。水凝胶作为一种三维亲水网络结构,由于其拥有和人体组织十分相近的结构、良好的生物相容性及靶向性而备受青睐。常被用来当做药物的载体,水凝胶可以通过提高疗效、降低毒性和所需剂量来达到治疗的有益效果。水凝胶上具有大量吸附位点能够为药物提供附着位点,因此水凝胶是一个良好的药物载体,水凝胶的pH响应性使得水凝胶在低pH条件下收缩药物不能释放出来,而在碱性的pH条件下水凝胶发生溶涨使药物缓缓从水凝胶中释放出来,由于人的肠道是一个弱碱性的环境,所以pH敏感水凝胶可达到肠道靶向释放的目的。如CN202110623275.0pH响应型羧甲基壳聚糖/海藻酸钠水凝胶球的制备方法公开的采用羧甲基壳聚糖和海藻酸钠在酸液促进下交联,有效降低蛋白质在模拟胃液中的释放,定位至肠道后释放。然而,溃疡性结肠炎发生在结肠部位,给药不仅要在胃液中基本不释放药物,还要保持在经过同样环境的小肠液后,给药还能对结肠炎部位释放出药物,即在小肠停留的3-8h后依然保留药性。并且,载药水凝胶的力学性能对载药凝胶来说是一个不可或缺的部分,若是水凝胶的力学性能较弱的话,可能会使凝胶在胃或小肠道内受到挤压破裂而造成药物的提前释放,从而影响药物对结肠炎的治疗效果。
发明内容
本发明要解决的技术问题是针对现有载体无法对结肠内炎症部位高效定向释药,以及载体容易在肠道受力挤压突释的不足,提供一种双网络pH敏感释药的水凝胶的制备方法。
本发明的目的通过以下技术方案予以实现:
一种双网络pH敏感释药的水凝胶的制备方法,所述水凝胶通过聚乙二醇、pH敏感单体、海藻酸钠的聚合反应得到,具体制备步骤包括:
S1.凝胶的制备
将聚乙二醇和海藻酸钠溶解至碱溶液中,加入pH敏感单体,在引发剂和交联剂的作用下聚合,得到初级凝胶。
S2.双网络凝胶的制备
将步骤S1中得到的初级凝胶放入盐溶液中反应,得到双网络凝胶。
进一步地,所述碱溶液为氢氧化钠溶液,其溶液的浓度0.1-0.3mol/L。
进一步地,聚乙二醇和海藻酸钠在碱溶液的浓度为0.01g/mL。
进一步地,所述pH敏感单体包括丙烯酸、甲基丙烯酸、羧甲基壳聚糖、改性纤维素的一种或多种。
进一步地,所述海藻酸钠与聚乙二醇的质量比为3∶1-9,优选地,所述海藻酸钠与聚乙二醇的质量比为1∶3。
进一步地,所述pH敏感单体与聚乙二醇的质量比为100∶1-5。
进一步地,所述引发剂为过硫酸铵或过硫酸钾,其浓度为0.1-1mol%。
进一步地,所述交联剂为二乙烯基苯或N,N-亚甲基双丙烯酰胺,其浓度为0.1-3mol%。
进一步地,步骤S1所述聚合反应的温度为50-80℃,时间为1-3h。
进一步地,步骤S2所述中盐溶液为氯化钙溶液、氯化铝或氯化铁溶液,其浓度为0.1g/mL。
进一步地,步骤S2所述初级凝胶在盐溶液中的反应时间为4-6h。
进一步地,步骤S3中所述的溶液含有质量药物的质量浓度为3-10%,浸入时间为2-6h。
根据上述方法得到的双网络pH敏感释药的水凝胶,应用在制备肠道药物凝胶中。
一种肠道载药凝胶的制备方法,包括将得到的双网络凝胶浸入含有肠道治疗药物的溶液中,洗净,烘干得到载药凝胶。
进一步地,所述肠道治疗药物为治疗溃疡性结肠炎的药物。具体地,所述药物为柳氮磺吡啶。
与现有技术相比,有益效果是:
本发明通过海藻酸钠和聚甲基丙烯酸-co-聚乙二醇于凝胶内部形成两种性能相反的互穿网络结构,且两种网络结构以大量的正负离子对方式加强内部静电作用力,大大提高了凝胶的力学性能,能够很好的防止在药物载体破裂引起的突释问题。并且,本发明通过水凝胶互穿网络的作用力控制药物载体水凝胶的溶胀,降低及减缓凝胶的溶胀,从而延缓药物的释放。
本发明水凝胶含有的含氮基团为药物分子提供大量的吸附位点,且结合甲基丙烯酸的pH敏感性使得该水凝胶具有很好的靶向性,在低pH下水凝胶处于收缩状态基本不释放药物,而在肠道所处的碱性环境下pH凝胶发生溶涨将药物缓缓释放出来,使其具有结肠部的靶向性保持药物长时间的效用,达到定向治疗的目的。本发明所述方法制备简单,pH敏感双网络水凝胶具有良好的生物相容性,释药率接近100%,可用于溃疡性结肠炎的治疗。
附图说明
图1是本实施例1制备的双网络pH敏感凝胶溶胀前后对比图;
图2是本发明所述水凝胶的制备过程和形成机理示意图;
图3是实施例1制备的载物凝胶体外释药图;
图4是实施例1制备的载物凝胶的力学性能测试图;
其中,a为p(MAA-co-PEG)SN水凝胶和SA/Ca2+/p(MAA-co-PEG)DN水凝胶的力学性能比较图;b和c为SA/Ca2+/p(MAA-co-PEG)DN水凝胶的压缩循环图;d为对载药水凝胶和未载药水凝胶进行TGA试验图;
图5为实施例1制备的制备的载物凝胶的红外吸收光谱图;
其中,a为载药水凝胶,b为未载药水凝胶,c为柳氮磺胺吡啶,d为甲基丙烯酸,e为海藻酸钠,f为聚乙二醇;
图6为柳氮磺胺吡啶、载药水凝胶和未载药水凝胶的XPS谱;
其中,a为柳氮磺胺吡啶、载药水凝胶和未载药水凝胶的N1s光谱,b为柳氮磺胺吡啶、载药水凝胶和未载药水凝胶的C1s光谱,c为柳氮磺胺吡啶、载药水凝胶和未载药水凝胶的S 2p光谱,d为柳氮磺胺吡啶、载药水凝胶和未载药水凝胶的O 1s光谱。
具体实施方式
下面结合实施例进一步解释和阐明,但具体实施例并不对本发明有任何形式的限定。若未特别指明,实施例中所用的方法和设备为本领常规方法和设备,所用原料均为常规市售原料。
实施例1
一种双网络pH敏感释药的水凝胶的制备方法,具体制备步骤包括:
S1.凝胶的制备
将0.01g的聚乙二醇和0.03g海藻酸钠加入4g的0.2M的NaOH溶液中溶解,再加入1g精制后的甲基丙烯酸单体到上述溶液中,加入0.25mol%的过硫酸铵作为引发剂,1.5mol%的N,N-亚甲基双丙烯酰胺作为交联剂,在60℃下反应1小时完成自由基聚合,得到初级凝胶。
S2.双网络凝胶的制备
将步骤S1中得到的初级凝胶放入30mL含有3g氯化钙的溶液中反应5个小时,得到双网络凝胶。
S3.载药凝胶的制备
将步骤S2中得到的双网络凝胶浸入含有5%柳氮磺吡啶的溶液中4个小时,用去离子水将凝胶冲洗干净,烘干得到载药凝胶。
实施例2
一种双网络pH敏感释药的水凝胶的制备方法,具体制备步骤包括:
S1.凝胶的制备
将0.01g的聚乙二醇和0.02g海藻酸钠加入4g的0.2M的NaOH溶液中溶解,再加入1g精制后的甲基丙烯酸单体到上述溶液中,加入0.25mol%的过硫酸铵作为引发剂,1.5mol%的N,N-亚甲基双丙烯酰胺作为交联剂,在60℃下反应1小时完成自由基聚合,得到初级凝胶。
S2.双网络凝胶的制备
将步骤S1中得到的初级凝胶放入30mL含有3g氯化钙的溶液中反应5个小时,得到双网络凝胶。
S3.载药凝胶的制备
将步骤S2中得到的双网络凝胶浸入含有5%柳氮磺吡啶的溶液中4个小时,用去离子水将凝胶冲洗干净,烘干得到载药凝胶。
实施例3
一种双网络pH敏感释药的水凝胶的制备方法,具体制备步骤包括:
S1.凝胶的制备
将0.01g的聚乙二醇和0.01g海藻酸钠加入4g的0.2M的NaOH溶液中溶解,再加入1g精制后的甲基丙烯酸单体到上述溶液中,加入0.25mol%的过硫酸铵作为引发剂,1.5mol%的N,N-亚甲基双丙烯酰胺作为交联剂,在60℃下反应1小时完成自由基聚合,得到初级凝胶。
S2.双网络凝胶的制备
将步骤S1中得到的初级凝胶放入30mL含有3g氯化钙的溶液中反应5个小时,得到双网络凝胶。
S3.载药凝胶的制备
将步骤S2中得到的双网络凝胶浸入含有5%柳氮磺吡啶的溶液中4个小时,用去离子水将凝胶冲洗干净,烘干得到载药凝胶。
如图1所示,本发明的双网络凝胶凝胶具有良好的溶胀性能。如图2所示,本发明通过海藻酸钠与聚乙二醇与富含羧基的pH敏感单体经聚合反应得到含初级凝胶,然后对初级凝胶进行交联网络反应,形成互穿网络的水凝胶进行载药,利用该水凝胶在低pH的条件下羧基质子化导致凝胶收缩,从而防止药物从凝胶中扩散出来。而在较高pH时,本发明的双网络凝胶凝胶的羧基去质子化使凝胶膨胀,药物便从凝胶中缓慢扩散出来,从而达到靶向释药的目的。
实验例1
将实施例1-3所制备的水凝胶进行载药检测,具体的检测步骤为将载药水凝胶烘干,称重、磨碎后加入PBS缓冲液中然后测定其吸光度;载药结果如下表1所示:
表1
载药率(%) | |
实施例1 | 2.35 |
实施例2 | 2.04 |
实施例3 | 1.57 |
实验例2
将实施例1制备的载药凝胶分别置于pH为1.2和7.4的PBS缓冲溶液中进行释药测试,每间隔一定的时间取5毫升上清液并补充等量的PBS溶液,用紫外分光光度计在波长为359nm处测定上清液的吸光度。测试结果如下表2和图3所示:
表2
如上表及图3所示,本发明制备的双网络凝胶在pH=7.2的环境下能够达到接近100%的释药率,而在pH=1.2的情况下释药率在30%左右,因此,本发明制备的双网络水凝胶具有pH相应释药。且本发明所述的载物凝胶虽然在前期释放部分药物,但是依然在4-24h能够释放大部分的药效,能够稳定、长效的对结肠炎部位释放出药物。
实验例3
对实施例1制备的双网络水凝胶与对比例1制备的单网络水凝胶进行力学性能和热稳定性检测。检测结果如图4所示:
在图4a中,SA/Ca2+/p(MAA-co-PEG)双网络水凝胶的50%压应力下的应力为2.4MPa,而p(MAA-co-PEG)单网络水凝胶在50%的应力下仅为0.2MPa,表明SA/Ca2+/p(MAA-co-PEG)DN水凝胶的力学性能显著高于p(MAA-co-PEG)SN水凝胶的力学性能,可有效避免胃肠道挤压破裂引起的水凝胶中药物的突然释放。
在图4b和图4c中,使用连续的加载-卸载循环方法测试了实施例里的双网络水凝胶的机械稳定性。在经过十次压缩循环后,双网络水凝胶的峰值应力保持在1.83Mpa,水凝胶的能量耗散为15.95%。由此可知,表明水凝胶具有良好的机械稳定性,是一种稳定的药物载体。
在图4d中,使用TGA测量药物加载水凝胶和无药物水凝胶的热稳定性,载药水凝胶和无药水凝胶的热重曲线几乎重叠,表明水凝胶载药对水凝胶热稳定性的影响可以忽略不计。
实验例4
将实施例1制备的载物凝胶进行红外吸收光谱检测,结果如图5所示,磺胺吡啶的傅里叶变换红外光谱(FTIR)分析表明,1020cm-1处的峰为-S=O峰。水凝胶峰与单体峰在3470、3440、1710、1620、1610cm-1处明显不同,表明水凝胶中形成了新的键,可能是由分子内氢键的形成和基团之间的静电吸附引起的。FTIR结果显示,凝胶中的药物峰出现在1020cm-1处,表明药物的原始峰没有受到影响,凝胶中出现有效药物峰,水凝胶并不会影响药物的治疗效果。
实验例5
将柳氮磺胺吡啶、实施例制备的载药水凝胶和未载药水凝胶进行N1s,C 1s,S 2p和O1s的XPS检测,如图6所示图谱,在药物释放水凝胶的C1s频谱图中,285.90eV处的峰值被认为是连接到N原子的C原子。在S 2p频谱图中,柳氮磺胺吡啶在167.13eV处的峰值被视为S-N,在168.34eV处的峰值被视为C-SOX。比较载药水凝胶的高分辨率N1s与载药水凝胶的高分辨率N1s可以看出,在401.89eV时增加了0.18eV,在399.83eV时降低了0.18eV,而柳氮磺胺吡啶药物载水凝胶S 2p的高分辨率光谱的结合能在167.13eV和168.34eV下降低了0.88eV和0.87eV,这分别表明水凝胶中的-NH是活性位点并与药物相互作用。也就是说,水凝胶中的含氮基团在药物负荷中起主要作用。从O1s高分辨率能谱的对比变化可以看出,含氧基团在药物负荷中不起主要作用。因此,载药水凝胶对柳氮磺胺吡啶的负载归因于水凝胶中的含氮基团。
显然,本发明的上述实施例仅仅是为清楚地说明本发明所作的举例,而并非是对本发明的实施方式的限定。对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。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,均应包含在本发明权利要求的保护范围之内。
Claims (10)
1.一种双网络pH敏感释药的水凝胶的制备方法,其特征在于,所述水凝胶通过聚乙二醇、pH敏感单体、海藻酸钠的聚合反应得到,具体制备步骤包括:
S1.凝胶的制备
将聚乙二醇和海藻酸钠溶解至碱溶液中,加入pH敏感单体,在引发剂和交联剂的作用下聚合,得到初级凝胶;
S2.双网络凝胶的制备
将步骤S1中得到的初级凝胶放入盐溶液中反应,得到双网络凝胶。
2.根据权利要求1所述双网络pH敏感释药的水凝胶的制备方法,其特征在于,所述pH敏感单体包括丙烯酸、甲基丙烯酸、羧甲基壳聚糖、改性纤维素的一种或多种。
3.根据权利要求1所述双网络pH敏感释药的水凝胶的制备方法,其特征在于,所述海藻酸钠与聚乙二醇的质量比为3∶1-9;所述pH敏感单体与聚乙二醇的质量比为100∶1-5。
4.根据权利要求1所述双网络pH敏感释药的水凝胶的制备方法,其特征在于,所述引发剂为过硫酸铵或过硫酸钾,其引发剂浓度的0.1-1mol%;所述交联剂为二乙烯基苯或N,N-亚甲基双丙烯酰胺,其交联剂浓度的0.1-3mol%。
5.根据权利要求1所述双网络pH敏感释药的水凝胶的制备方法,其特征在于,步骤S1所述聚合反应的温度为50-80℃,时间为1-3h;步骤S2所述中盐溶液为氯化钙溶液、氯化铁或氯化铝溶液的一种或多种,反应时间为4-6h。
6.权利要求1-5任一所述方法得到的双网络pH敏感释药的水凝胶。
7.权利要求6所述双网络pH敏感释药的水凝胶在制备肠道药物凝胶中的应用。
8.一种肠道载药凝胶的制备方法,其特征在于,将双网络凝胶浸入含有肠道治疗药物的溶液中,洗净,烘干得到载药凝胶。
9.根据权利要求8所述肠道载药凝胶的制备方法,其特征在于,所述肠道治疗药物为治疗溃疡性结肠炎的药物。
10.根据权利要求9所述肠道载药凝胶的制备方法,其特征在于,所述药物为柳氮磺吡啶。
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CN116041779B (zh) * | 2023-01-15 | 2024-05-07 | 陕西科技大学 | 一种载有核酸裂解液的pH响应型大孔水凝胶及其制备方法和应用 |
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