CN117088927B - 一种具有免疫调节作用的寡二糖螯合铁的制备方法及其应用 - Google Patents
一种具有免疫调节作用的寡二糖螯合铁的制备方法及其应用 Download PDFInfo
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Abstract
本发明属于医药领域，涉及一种能够调节肠道黏膜免疫的寡二糖螯合铁的制备方法及其应用。所述方法的步骤包括：称取昆布二糖加入水中，加热后，在热的昆布二糖溶液中加入NaOH溶液，把碱性糖溶液迅速加入到三氯化铁溶液中调节pH至8.5‑9.5，搅拌后烘干，得到产物昆布二糖螯合铁。通过昆布二糖螯合铁饲喂葡聚糖硫酸钠盐诱导结肠炎的小鼠后发现，昆布二糖螯合铁显著增加结肠分泌型免疫球蛋白A水平，促进炎症恢复。相对于传统铁元素补充制剂，本发明生产的寡二糖螯合铁具有吸收快，耗能低，载体不易饱和等优势。
Description
技术领域
本发明属于医药领域，涉及一种能够调节肠道黏膜免疫的寡二糖螯合铁的制备方法及其应用。
背景技术
铁是人体细胞的必需成分，在机体代谢过程中发挥着重要作用。新型三价铁螯合物，如糖-铁螯合物、肽-铁螯合物等与前两代亚铁盐铁补充剂相比，具有较少腹泻、便秘等副作用。
来自天然产物中的糖类生物活性大分子具有调节免疫、抗肿瘤、抗氧化等生物活性，金属离子螯合等化学修饰是增强功能糖类生物活性的有效方法。糖的结构中含有羟基、羧基等容易与其他化合物发生反应的基团，为化学修饰提供了基础，近年来受到越来越多的关注。天然糖类不仅可作为微量元素离子的转运和促进吸收的载体，其与金属离子的相互协同作用甚至可以增强功能糖的生物活性，是一种很有前景的微量元素补充剂有机配体。许多研究证实，糖-铁配合物作为天然糖和三价铁的配合物，具有不良反应较少、铁的吸收率较好的优点，是未来营养补充剂的良好选择。
昆布二糖是存在于天然昆布中的高功能活性糖类，是昆布的主要活性物质，它是制药工业中常用的前体物质、强大的发芽剂和防腐剂，以及潜在的益生元。在自然界中，昆布二糖很少以游离形式存在，而是作为许多天然多糖的亚基存在，如海藻海带多糖、地衣多糖等，因此，相较于这些这些多糖，昆布二糖更有价值。同时，昆布二糖拥有较多的-OH键，为其与铁离子的配位结合提供了基础。近年来，由于昆布二糖的生产工艺被不断改进，其制备成本也在不断被压缩，使规模化生产昆布二糖作成为可能。
在已有的铁离子络合的合成研究中，使用的转运载体多为蛋白质副产物；例如，中国专利申请201811196652.1 （一种氨基酸亚铁螯合物的制备方法）公开了一种以硫酸亚铁为铁源，以碳酸钙为阴离子脱出剂的螯合方法，其可以在pH调节剂与还原剂的配合下生产高纯度单一氨基酸螯合铁（甘氨酸/蛋氨酸等）。中国专利申请201210380796.9（一种乌鸡肽铁螯合物生物补铁剂的制备方法）公开了将乌鸡肽和亚铁盐，在pH3-6的条件下制备乌鸡肽铁螯合物。中国专利申请201710973876.8（一种胶原蛋白肽螯合亚铁水凝胶的制备方法与应用）则公开了一种胶原蛋白肽螯合亚铁的制备方法，并且在此基础上进一步制备了胶原蛋白肽螯合亚铁水凝胶增强其吸收效果。尽管这类螯合物能够制备纯度较高的不同蛋白类螯合物，但其所用方法单一并且未有太多创新空间，因此，需要挖掘更多潜在的铁离子天然配体。
近几年，糖类-微量元素络合物的制备方法被成功构建，例如CN103641875A（一种羧麦芽糖铁的制备方法）公开了在反应罐中加入糖浆溶液搅拌，冷却；加入三氯化铁溶液搅拌，加入氢氧化钠溶液，生成棕红色凝胶；加入氢氧化钠溶液所得沉淀物加入沉淀剂洗涤两次后烘干获得的多糖铁复合物。中国专利申请201910530623.2（党参多糖铁复合物的制备方法及应用）和201711069463.3（一种治疗缺铁性贫血的当归黄芪多糖铁复合物的制备方法）中，制备方法包括在多糖中加入柠檬酸为助络合剂，向多糖溶液中恒速滴定直至饱和态以制备多糖铁络合物。虽然糖类载体和铁络合物实际使用效果极佳，但其络合方法较为复杂，甚至需要加入较多的助络合剂来实现，其应用效果也可能有部分归功于助络合剂（柠檬酸钠）。
同时，传统的糖铁复合物制备中，往往过分强调铁的作用，反而弱化了载体糖的作用，例如蔗糖铁是一种常见的补铁剂，中国专利申请201510454272.3（一种稳定的糖-铁复合物及其制备方法）公开了蔗糖和铁复合物的制备方法，制备的糖铁复合物可以降低在治疗缺铁性贫血等疾病中病人的不良反应，提高铁利用率。大多糖铁复合物中糖源往往是某些低值易取得的糖类，很少高功能活性的糖被用作被配位体进行铁元素的络合修饰。
本发明研究认为，糖铁复合物对改善缺铁性贫血的效果显着。糖铁络合物以糖类为载体，既保留了糖和金属离子的活性，又增强了它们的活性。糖铁复合物作为一种新型补铁剂，具有副作用小、配位稳定、溶解性好、尤其是高浓度、无毒等优点。此外，糖-铁配合物还可以有效避免游离亚铁离子引起的消化道不良反应，当其释放铁时，糖配体具有多种生物活性。这些有益成分可以被吸收利用，起到一定的调节免疫、抗病毒等生物活性的作用。用生物多糖和铁合成补铁的研究已有报道，但目前还没有报道用昆布二糖合成铁络合物。
发明内容
本发明的目的在于提供一种不同于传统微量元素络合物的制备方法，具体来说是提供昆布二糖螯合铁的制备方法，其中昆布二糖螯合铁分子式为C12H22O11Fe，结构式如式I：
式I
具体地，本发明提供一种寡二糖螯合铁的制备方法，其步骤是：称取昆布二糖加入水中，加热后，在热的昆布二糖溶液中加入NaOH溶液或氨水，把碱性糖溶液迅速加入到三氯化铁溶液中调节pH至8.5-9.5，搅拌后烘干，得到产物昆布二糖螯合铁。
优选地，昆布二糖溶于水中的昆布二糖溶液的浓度为0.5-1.5g/mL；三氯化铁溶液的浓度为0.005-0.015g/mL。
优选地，加热的温度为70-90℃，加热时间为5-15min。
优选地，NaOH溶液浓度为3-8 mol/L，按体积计，NaOH溶液的用量为昆布二糖溶液的1/6至1/4。
优选地，所述搅拌是将混合溶液在45-55℃条件下搅拌15-45min；所述烘干是50-60℃下进行。
更优选地，昆布二糖溶液的浓度为1 g/mL；NaOH溶液浓度为5 mol/L，按体积计，NaOH溶液的用量为昆布二糖溶液的1/5；所述加热的温度为80℃，加热时间为10min；三氯化铁溶液的浓度为0.009g/mL；所述搅拌是将混合溶液在50℃条件下搅拌30min；所述烘干是55℃下进行。
本发明提供由所述的制备方法获得的寡二糖螯合铁。
进一步提供所述的寡二糖螯合铁在制备具有抗炎症药品中的应用。
具体地，所述炎症是肠炎，所述寡二糖螯合铁作为添加剂添加于所述药品中。
在本发明中，通过与昆布二糖和铁盐络合合成了昆布二糖螯合铁配合物。其属于一锅合成法，适用于大生产，优势比较明显。之前的多糖络合物合成多为NaOH滴定法控制pH，此方法在实际生产中操作性差，易生成不溶物沉淀，并且对于金属离子含量的控制精准度差。本发明的方法中，通过在常温的金属离子溶液中，加入过热的碱性糖溶液，使其在快速的分子运动中发生强配位结合，制备昆布二糖螯合铁络合物。
.因此，本发明的有益效果是：本发明相对于传统铁元素补充制剂，所生产的二糖的吸收快，耗能低，载体不易饱和，铁离子运载体昆布二糖代谢于人体中糖通道。吸收速快，吸收率高。通过对人体补充昆布二糖螯合铁，可以作为药品的添加剂，使用方便。其中，铁离子与昆布二糖协同作用提高了昆布二糖的生物活性，增强应用价值。
附图说明
图1为游离昆布二糖扫描电镜结果。
图2为昆布二糖螯合铁络合物扫描电镜结果。
图3为昆布二糖螯合铁络合物结构判定图。
图4为昆布二糖和昆布二糖螯合铁对肠炎小鼠结肠SlgA的影响。
实施方式
下面结合实施例对本发明作进一步说明。但不构成对本发明的限制。
实施例一、昆布二糖螯合铁的制备，其形貌学分析和结构判定
1、昆布二糖螯合铁的制备
具体方法步骤如下：1g昆布二糖加入至10ml水中，80℃下加热10min，然后在热的昆布二糖溶液中加入2ml（5M）的NaOH溶液，把碱性糖溶液迅速加入到三氯化铁（0.009g/ml，0.72g FeCl3+80ml水）溶液中调节pH至9.0，50℃搅拌半小时，55℃烘干。
2、昆布二糖螯合铁的形貌学分析
高倍电子显微镜观察前述制备的昆布二糖螯合铁络合物微观形貌。如图1所显示的，游离昆布二糖铁为不规则短棍状，如图2所显示的，昆布二糖螯合铁具有较明显的层状内部结构，且在分子周边发现不规则吸附物，有可能为纳米铁。
3、昆布二糖螯合铁的结构判定
将干燥的昆布二糖螯合铁与溴化钾（KBr）粉末快速研磨均匀，置于压片机上压制成透明的薄片，以不加昆布二糖螯合铁样品的KBr薄片作为空白对照，采用傅立叶变换红外光谱（FT-IR）在400 cm-1-4000 cm-1范围内对样品进行扫描，分辨率为4 cm-1，每个样品被扫描16次，对昆布二糖螯合铁红外吸收光谱进行测定。通过红外图谱（图3），其中昆布二糖螯合铁在3410 cm-1处的峰变宽，表明铁与昆布二糖之间可能有缔合作用，516 cm-1处有明显新峰生成，预示着配位键的生成，表明铁离子通过Fe-O键与昆布二糖共价交联。
实施例二、含有昆布二糖螯合铁的日粮对炎症小鼠的喂养实验
选取健康，体况良好，体重为6周龄的BALB/c雌鼠，共40只，小鼠随机分为4组，每组10只。
分组如下：1）空白组；2）DSS（炎症诱导）组；3）DSS+昆布二糖组；4）DSS+昆布二糖螯合铁组。
第1-11天，空白组：自由饮用纯水+基础日粮；其余三组自由饮用3% DSS水+基础日粮。
第12-18天，每天定时上午八点灌胃，空白组：灌胃生理盐水，饮用纯水+基础日粮；DSS组：灌胃生理盐水，饮用纯水+基础日粮；DSS+昆布二糖组：灌胃50 mg/kg昆布二糖，饮用纯水+基础日粮；DSS+昆布二糖螯合铁组：灌胃50 mg/kg昆布二糖螯合铁，饮用纯水+基础日粮。试验结束后收集小鼠结肠组织，进行SlgA检测，结果见图4。
由于SIgA是机体免疫关键因子，SIgA表达量越高，机体的免疫反应越强。结果表明，对照组小鼠结肠中SIgA平均含量为21.60μg/mL，炎症小鼠结肠中的SIgA平均含量为17.87μg/mL，显著低于对照组（P<0.01），昆布二糖组小鼠结肠中的SIgA平均含量为20.80μg/mL，昆布二糖螯合铁组小鼠结肠中的SIgA平均含量为23.92μg/mL，与DSS炎症组小鼠相比，昆布二糖饲喂后显著提高了炎症小鼠结肠的SIgA的表达量（P<0.01），昆布二糖螯合铁饲喂后极显著提高了炎症小鼠结肠的SIgA的表达量（P<.001），并且昆布二糖螯合铁组小鼠结肠的SIgA的表达量要高于昆布二糖组（是单独昆布二糖免疫效果的1.15倍）。
Claims (6)
1.一种具有免疫调节作用的昆布二糖螯合铁的制备方法，其特征在于，称取昆布二糖加入水中，70-90℃加热5-15min后，在热的昆布二糖溶液中加入NaOH溶液，把碱性糖溶液迅速加入到三氯化铁溶液中调节pH至8.5-9.5，将混合溶液在45-55℃条件下搅拌15-45min后于50-60℃下进行烘干，得到产物昆布二糖螯合铁；
其中，昆布二糖溶于水中的昆布二糖溶液的浓度为0.5-1.5g/mL；三氯化铁溶液的浓度为0.005-0.015g/mL；
NaOH溶液浓度为3-8 mol/L，按体积计，NaOH溶液的用量为昆布二糖溶液的1/6至1/4。
2.如权利要求1所述的制备方法，其特征在于，昆布二糖溶液的浓度为1 g/mL；NaOH溶液浓度为5 mol/L，按体积计，NaOH溶液的用量为昆布二糖溶液的1/5；所述加热的温度为80℃，加热时间为10min；三氯化铁溶液的浓度为0.009g/mL；所述搅拌是将混合溶液在50℃条件下搅拌30min；所述烘干是55℃下进行。
3.如权利要求1或2所述的制备方法获得的昆布二糖螯合铁。
4.如权利要求3所述的昆布二糖螯合铁在制备具有抗炎症药品中的应用。
5.如权利要求4所述的应用，其特征在于，所述炎症是肠炎。
6.如权利要求5所述的应用，其特征在于，其中所述昆布二糖螯合铁作为添加剂添加于所述药品中。
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