CN116284498A - 一种羟丁基壳聚糖及其应用 - Google Patents
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Abstract
本发明一种羟丁基壳聚糖及其应用开发了羟丁基壳聚糖的新用途,将羟丁基壳聚糖作为乳化剂稳定水包油乳液,在低pH下表现出优异的稳定性,并可以通过改变羟基丁基在羟丁基壳聚糖中的比例来控制羟丁基壳聚糖稳定的乳液在低pH下的乳化稳定性。
Description
技术领域
本发明属于生物化学领域,具体涉及羟丁基壳聚糖在食品药物递送中的应用开发。
背景技术
水包油乳液作为食品和递送***的重要组成部分,在食品工业中得到了广泛的应用。然而,水包油乳液在各种环境中的稳定性差是其广泛应用的主要障碍。乳液在低pH条件下的稳定性很重要,因为乳液在食品中的应用和生物活性化合物的递送都与pH有关。更重要的是,乳液在低pH值条件下(如胃酸环境)的稳定性差会导致包埋的药物在胃中释放或者在肠内释放不足。因此,提高乳液在低pH条件下的稳定性是必要的。
蛋白质可以通过降低界面张力,产生空间排斥或静电相互作用来稳定O/W乳化剂,从而抑制乳化剂的聚集或聚结。然而,蛋白质稳定的乳液对低pH值和蛋白酶敏感。多糖稳定的乳液在不同pH值下更稳定,并且不受蛋白酶的影响。但是多糖缺乏表面活性,多糖通常被用作稳定剂而不是乳化剂。
壳聚糖作为一种阳离子多糖,可以作为稳定剂通过增加粘度或与表面活性剂结合来稳定水包油乳液。研究表明,壳聚糖可以在pH值> 6.0时作为Pickering颗粒来稳定水包油乳液。然而,壳聚糖的pH控制乳化特性导致壳聚糖稳定乳液随着pH降低而变得不稳定。对壳聚糖进行化学改性,如使用肉桂醛、柠檬醛、香茅醛和香草醛,通过在醛和壳聚糖之间形成亚胺可以形成具有表面活性的改性产物降低界面张力。然而,这种亚胺键在低pH下被水解,导致界面张力增加,在低pH值下储存的乳液的液滴尺寸随着时间的推移显著增加。这些结果表明,改性壳聚糖乳液体系在低pH条件仍然不稳定。
羟丁基壳聚糖(HBC)是一种热敏聚合物,由1,2-环氧丁烷的羟丁基取代壳聚糖链的羟基和氨基合成。到目前为止,羟丁基壳聚糖的应用主要基于其温度响应特性而用作智能窗户、伤口愈合材料和药物递送如US9173852B2,CN114432498A等,其是否能够耐受肠胃环境的低pH以及含有多种酶的消化道环境,将其作为脂溶性物质的递送载体,现有技术中仍然未有相关记载和报道。
发明内容
本发明开发了羟丁基壳聚糖的新用途,将羟丁基壳聚糖作为乳化剂稳定水包油乳液,在低pH下表现出优异的稳定性,并可以通过改变羟基丁基在羟丁基壳聚糖中的比例来控制羟丁基壳聚糖在低pH下的乳化稳定性。
具体的,本发明提供如下具体载体产品及其应用:
第一方面,本申请提供一种含羟丁基的壳聚糖聚合物,所述的聚合物采用如下方法制备:
1)将壳聚糖溶解在乙酸中,最终浓度为2~4% (w/w);
2)将步骤1)所获得的壳聚糖溶液与等量的KOH/尿素溶液混合,在-80℃下保存4小时;冷冻样品在室温下解冻,得到1~2%(w/w)透明壳聚糖溶液;
3)壳聚糖溶液中加入不同体积的1,2-环氧丁烷,室温下连续搅拌24~72h,然后加入HCl终止反应;将产物透析,冷冻干燥即得到HBC。
在一个具体的实施例中,所述的步骤1)中乙酸的浓度为1%(w/w);在另外一个具体的实施例中,所述步骤2)中的KOH/尿素溶液为24%(w/w)KOH/16%(w/w)尿素溶液;在另外一个具体的实施例中,所述步骤3)中1,2-环氧丁烷的添加量与壳聚糖的重量比为5~20:1;优选的为5:1,10:1或20:1,最优选的为20:1。在另外一个具体的实施例中,所述的羟丁基的壳聚糖聚合物为取代度从0.66~2.19;优选的为2.19。
本发明的第二个方面是提供一种羟丁基壳聚糖聚合物的制备方法,所述的方法为:
1)将壳聚糖溶解在乙酸中,最终浓度为2~4% (w/w);
2)将步骤1)所获得的壳聚糖溶液与等量的KOH/尿素溶液混合,在-80℃下保存4小时;冷冻样品在室温下解冻,得到1~2%(w/w)透明壳聚糖溶液;
3)壳聚糖溶液中加入不同体积的1,2-环氧丁烷,室温下连续搅拌24~72h,然后加入HCl终止反应;将产物透析,冷冻干燥即得到HBC。
在一个具体的实施例中,所述的步骤1)中乙酸的浓度为1%(w/w);在另外一个具体的实施例中,所述步骤2)中的KOH/尿素溶液为24%(w/w)KOH/16%(w/w)尿素溶液;在另外一个具体的实施例中,所述步骤3)中1,2-环氧丁烷的添加量与壳聚糖的重量比为5~20:1;优选的为5:1,10:1或20:1,最优选的为20:1。
本发明的第三个方面提供一种耐酸性的含有羟丁基壳聚糖聚合物的水包油乳液,其特征在于,所述的水包油乳液由以下方法制备:
1)将本发明第一个方面制备的所述的HBC溶解于超纯水中,用HCl调节pH值,得到HBC溶液;
2)将步骤1)获得的HBC溶液与饱和中链脂肪酸甘油三脂以3~5:1的体积混合,超声振荡处理,获得水包油乳液。
在一个具体的实施例中,所述的制备方法中的步骤1)中HBC-5,HBC-10或HBC-20的溶解后的浓度为1~3mg/mL;pH值调节为6.0~6.5。
在另外一个具体的实施例中,其中所述制备方法中的步骤2)中的HBC溶液与饱和中链脂肪酸甘油三酯的体积比为3:1,超声振荡的条件为35%振幅,超声2-3min,超声共工作5~10s,休息5~10s。
本发明第四个方面提供一种耐酸性的含有羟丁基壳聚糖聚合物的水包油乳液的制备方法,所述的方法为:
1)将本发明第一个方面制备的所述的HBC溶解于超纯水中,用HCl调节pH值,得到HBC溶液;
2)将步骤1)获得的HBC溶液与饱和中链脂肪酸甘油三脂以3~5:1的体积混合,超声振荡处理,获得水包油乳液。
在一个具体的实施例中,所述的制备方法中的步骤1)中HBC-5,HBC-10或HBC-20的溶解后的浓度为1~3mg/mL;pH值调节为6.0~6.5。
在另外一个具体的实施例中,其中所述制备方法中的步骤2)中的HBC溶液与饱和中链脂肪酸甘油三酯的体积比为3:1,超声振荡的条件为35%振幅,超声2-3min,超声共工作5~10s,休息5~10s。
本发明的第五个方面是提供第一方面的羟丁基壳聚糖聚合物或第三方面所述的耐酸性的含有羟丁基壳聚糖聚合物的水包油乳液在制备药物或营养物质包封和/或肠内输送载体中的应用;在另外一个具体的实施例中,所述的药物或营养物质为脂溶性的。
本发明的有益效果为:通过调节壳聚糖与1,2-环氧丁烷的比例,获得不同取代度的HBC,发现其在低pH的环境下较常规的水包油递送乳液更加稳定,是脂溶性药物或营养物质的递送载体。
附图说明
图1羟丁基壳聚糖HBC合成以及取代度检测。
图2 不同pH值下不同取代度的HBC在不同pH下(2,4.5,7)的稳定性检测:图2A-图2C,壳聚糖组;图2D-图2F,HBC-5组;图2G-图2I,HBC-10组;图2J-图2L,HBC-10组。
图3 不同pH值下不同取代度的HBC的粒径检测。
图4 体外模拟消化处理下HBC-20与商业乳化剂酪蛋白酸钠制备的乳液的粒径检测。
图5 HBC-20与商业乳化剂酪蛋白酸钠制备的乳剂的脂解速率和脂解程度检测。
具体实施方式
以下通过参考示范性实施例,本发明的目的和功能以及用于实现这些目的和功能的方法将得以阐明。然而,本发明并不受限于以下所公开的示范性实施例;可以通过不同形式来对其加以实现。说明书的实质仅仅是帮助相关领域技术人员综合理解本发明的具体细节。
实施例1 羟丁基壳聚糖HBC的制备
1)将壳聚糖溶解在1%(w/w)的乙酸中,最终浓度为2% (w/w)。将壳聚糖溶液与等量的24%(w/w)KOH/16%(w/w)尿素溶液混合,在-80℃下保存4小时。冷冻样品在室温下解冻,得到1%(w/w)透明壳聚糖溶液。
2)向100g壳聚糖溶液(含1g壳聚糖)中加入不同体积(5,10,20 mL)的1,2-环氧丁烷,室温下连续搅拌48 h,然后加入4mol/L HCl终止反应。将产物透析2天,冷冻干燥即得到HBC;壳聚糖分别与5,10,20 mL 1,2-环氧丁烷反应得到的HBC样品分别被记为HBC-5,HBC-10和HBC-20。
3)采用核磁氢谱检测HBC结构。将HBC溶于氘代水,在25℃下测定HBC的核磁氢谱谱图,结果如图1所示,相比于壳聚糖,HBC在0.8-1.5 ppm范围内出现了两个强度比为3:2的峰,分别为羟基丁基中的甲基和亚甲基。表明在壳聚糖链上引入了羟基丁基,成功合成了HBC。基于1H NMR结果,利用羟丁基甲基质子与壳聚糖H1质子的积分面积比值计算HBC的取代度,结果如图1所示。随着1,2-环氧丁烷体积从5 mL/g壳聚糖增加到20 mL/g壳聚糖,HBC的取代度从0.66增加到2.19。HBC-5、HBC-10和HBC-20的取代度的差异表明成功制备了不同羟基丁基密度的HBC。
实施例2水包油乳液的制备
1)将HBC-5,HBC-10和HBC-20(2 mg/mL)溶解于超纯水中,用HCl调整其pH至6.2。将得到的HBC溶液与饱和中链脂肪酸甘油三酯(MCT)以3:1的体积比混合。以35%振幅超声处理2min(工作时间5s;休息时间,5秒),得到水包油乳液。
实施例3 稳定性表征
1)合成HBC后即时检测稳定性:将实施例2制备获得的乳液调至不同pH(2、4.5、7),采用Turbiscan稳定性分析仪测定水包油乳液稳定性。将制备好的乳液倒入测量瓶中,近红外光源(λair = 880 nm)从测量瓶底到瓶顶垂直扫描,检测被样品反射的背散射光。背散射光值与乳液液滴粒径和浓度有关,乳液液滴粒径变大,浓度下降,背散射光值下降;反之亦然。因此,通过比较测量样品的背散射光值随时间的变化,观察到乳液在测定过程中是否发生乳液液滴上浮、絮凝或者聚并的现象。测定程序如下:25 ℃扫描24 h,扫描频率为
10 min/次。结果如图2(图2A-图2L)所示,结果显示在低pH下,具有最高羟丁基取代(取代度为2.19)的HBC-20具有优异的稳定性。
在pH值7时,所有HBC稳定的乳液的背散射光强度(BS%)在样品底部下降,在样品顶部上升,表明发生了脂肪上浮。无论是在样品底部还是顶部,BS%的变化率随着取代度的增加而降低。表明在pH值7时,HBC稳定的乳液的稳定性随着羟基丁基密度的增加而增加。在相同的pH值下,壳聚糖稳定的乳液也会发生脂肪上浮(CS组),但是壳聚糖稳定的乳液的BS%远低于HBC稳定的乳液,这可能是由于壳聚糖自身没有乳化性能,通过形成Pickering颗粒稳定乳液,因此粒径更大,因为BS%随着油滴尺寸的增加而降低。在pH 4.5时,壳聚糖和HBC-5稳定的乳液的BS%在试管顶部下降,这表明这些乳液发生了破乳。HBC-20稳定的乳液在pH降低到2.0时仍然保持稳定,而此时无论是HBC-10或者HBC-5还是壳聚糖稳定的乳液均发生破乳。这些结果表明, HBC羟基丁基的密度对水包油乳状液的稳定起着关键作用,高取代度的HBC在极低pH下仍然能保持其稳定性。
2)贮藏后检测稳定性
结果如图3所示,在低pH下贮藏30天,HBC-20稳定的乳液粒径不发生显著性变化(图3),在低pH下具有极好的贮藏稳定性。而其他组别的乳液在低pH下贮藏30天后粒径发生显著性变化,在低pH环境稳定性差。
实施例4 体外消化测定
1)用相同浓度的酪蛋白酸钠采用相同方法制备的水包油乳液,与HBC-20稳定的乳液采用pH-stat方法进行体外消化实验。取2 mL乳液分散于23 mL磷酸盐缓冲液(5 mmol/L,pH 7)中,37℃孵育。然后与等量的模拟胃液(2mg /mL NaCl, 3.2 mg/mL胃蛋白酶,7mlHCl/1L水)混合。调整pH值至2后,在37℃下孵育2 h,模拟胃消化。用1 mol L-1 NaOH或HCl将25 mL胃液样品调整到pH 7.0。然后在样品中加入1.5 mL模拟肠盐溶液(37.47 mg/mLCaCl2·2H2O,219.15 mg/mL NaCl)和3.5 mL胆盐(54 mg/mL)。将pH调至7.0后,在上述混合物中加入2.15 mL新鲜制备的脂肪酶溶液(24 mg/mL)。然后在37℃下连续搅拌2 h,模拟肠道消化。测定消化前初始乳液和经过胃肠道消化后乳液的粒径,比较HBC-20和酪蛋白酸钠稳定的乳液在胃肠道消化过程中的稳定性。结果如图4所示,结果表明,商业乳化剂酪蛋白酸钠稳定的乳液粒径在经过胃消化后显著增加,不耐胃酸和胃蛋白酶降解。HBC-20稳定的乳液在经过胃消化后的粒径没有发生显著变化。与酪蛋白酸钠相比,HBC-20稳定的乳液具有良好的耐胃酸和胃蛋白酶降解的能力,在肠道内的脂解速率和程度也显著高于酪蛋白酸钠稳定的乳液,是脂溶性药物和营养物质的理想包封和肠内输送载体。
2)检测水包油乳液的脂解速率和脂解程度
在1)中小肠消化阶段,使用0.1 mol L-1 NaOH将混合物滴定至pH 7.0。然后记录NaOH的体积,以表征乳剂中游离脂肪酸的释放。如图5所示,HBC-20稳定乳剂的脂解速率和脂解程度明显高于酪蛋白酸钠稳定的乳液。这是因为在胃液消化后HBC-20稳定乳剂的液滴尺寸较小,导致油滴表面积增加,这增加了脂肪酶对MCT油的接触,促进了脂肪的水解。结果表明,在胃消化过程中保持乳液的稳定性可以导致更有效的脂肪分解和亲脂分子的充分释放。HBC-20稳定的乳液对胃蛋白酶和胃酸具有抗性,在肠道内的脂解速率和程度较高,是脂溶性药物和营养物质的理想包封和肠内输送载体。因为乳液的脂解速率和程度与脂溶性营养素如β-胡萝卜素的生物可及性呈正相关。增加脂解程度有利于游离脂肪酸的释放,同时游离脂肪酸是胶束过程中提高脂溶性营养素生物可及性的表面活性成分(Chitosanhydrochloride/carboxymethyl starch complex nanogels stabilizedPickeringemulsions for oral delivery of β-carotene: Protection effect and invitrodigestion study)。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于此。在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,包括各个技术特征以任何其它的合适方式进行组合,这些简单变型和组合同样应当视为本发明所公开的内容,均属于本发明的保护范围。
Claims (10)
1.一种羟丁基壳聚糖聚合物,所述的聚合物采用如下方法制备:
1)将壳聚糖溶解在乙酸中,最终浓度为2~4% (w/w);
2)将步骤1)所获得的壳聚糖溶液与等量的KOH/尿素溶液混合,在-80℃下保存4小时;冷冻样品在室温下解冻,得到1~2%(w/w)透明壳聚糖溶液;
3)壳聚糖溶液中加入不同体积的1,2-环氧丁烷,室温下连续搅拌24~72h,然后加入HCl终止反应;将产物透析,冷冻干燥即得到HBC;
所述的羟丁基的壳聚糖聚合物为取代度从0.66~2.19。
2.根据权利要求1所述的羟丁基壳聚糖聚合物,所述的步骤1)中乙酸的浓度为1%(w/w)。
3.根据权利要求1所述的羟丁基壳聚糖聚合物,所述步骤2)中的KOH/尿素溶液为24%(w/w)KOH/16%(w/w)尿素溶液。
4.根据权利要求1所述的羟丁基壳聚糖聚合物,所述步骤3)中1,2-环氧丁烷的添加量与壳聚糖的重量比为5~20:1。
5.根据权利要求1所述的羟丁基壳聚糖聚合物,其中步骤3)中1,2-环氧丁烷的添加量与壳聚糖的重量比为为5:1,10:1或20:1,获得HBC-5,HBC-10以及HBC-20。
6.一种耐酸性的含有羟丁基壳聚糖聚合物的水包油乳液,其特征在于,所述的水包油乳液由以下方法制备:
1)将权利要求1-5任一项中所述的HBC溶解于超纯水中,用HCl调节pH值,得到HBC溶液;
2)将步骤1)获得的HBC溶液与饱和中链脂肪酸甘油三脂以3~5:1的体积混合,超声振荡处理,获得水包油乳液。
7.根据权利要求6所述的耐酸性的含有羟丁基壳聚糖聚合物的水包油乳液,其特征在于,所述的制备方法中的步骤1)中HBC-5,HBC-10或HBC-20的溶解后的浓度为1~3mg/mL;pH值调节为6.0~6.5。
8.根据权利要求6或7所述的耐酸性的含有羟丁基壳聚糖聚合物的水包油乳液,其中所述制备方法中的步骤2)中的HBC溶液与饱和中链脂肪酸甘油三酯的体积比为3:1,超声振荡的条件为35%振幅,超声2-3min,超声共工作5~10s,休息5~10s。
9.权利要求1-5任一项所述的羟丁基壳聚糖聚合物或权利要求6-8任一项所述的耐酸性的含有羟丁基壳聚糖聚合物的水包油乳液在制备药物或营养物质包封和/或肠内输送载体中的应用。
10.根据权利要求9所述的应用,所述的药物或营养物质为脂溶性的。
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