CN102558383B - 一种海藻酸铋及其制备方法和应用 - Google Patents
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Abstract
本发明涉及含铋化合物的制备，具体的说是一种海藻酸铋及其制备方法和应用。所述海藻酸铋，如结构式一所示，n＝200-250；将褐藻胶与铋盐或铋碱在碱性水溶液中反应，生成海藻酸铋，经乙醇沉淀分离，脱水后，干燥粉碎，即得到海藻酸；本发明利用海藻酸作为铋的载体，合成出海藻酸铋盐，其铋含量低于目前临床上普遍应用的铋制剂，降低了长期给药铋元素所存在的潜在的毒性。并且它兼具铋制剂与海藻酸二者的生物活性，具有胃黏膜保护、中和胃酸、降低胃蛋白酶活性、杀灭Hp、促进消化性溃疡创面愈合等多重功能，具有很好的新药开发价值。
Description
技术领域
本发明涉及含铋化合物的制备，具体的说是一种海藻酸铋及其制备方法和应用。
背景技术
慢性胃炎和胃溃疡是常见病、多发病，且复发率高，严重危害人们的身体健康。大量研究充分证明，幽门螺杆菌(Helicobacteria pylori，Hp)感染是消化性溃疡的主要病因。
铋制剂具有收敛、止泻、防腐作用，能够抑制和杀灭细菌、病毒、螺旋体等。铋制剂是唯一一个能够直接杀灭幽门螺杆菌的非抗生素类药物，能够克服幽门螺杆菌对抗生素的原发耐药性和避免继发耐药性。因此在世界范围内铋制剂被广泛用于胃溃疡和根除Hp感染的治疗。
口服铋制剂主要在胃内发挥作用，一般吸收率小于0.5％。在常规剂量下铋制剂是安全的。口服铋制剂吸收率主要取决于铋盐的特性，水溶性高的铋盐吸收率高于非水溶性的铋盐。
目前临床上常用的抗胃溃疡铋制剂主要包括次碳酸铋、次硝酸铋、次水杨酸铋、枸橼酸铋、雷尼替丁枸橼酸铋和次没食子酸铋等，铋的含量均高于46％。由于慢性胃炎、胃溃疡需要长期给药。长期应用铋剂可造成头晕，头疼，双手发麻，易疲劳，易激动，注意力不集中，记忆力减退，便秘等，其毒副作用不容忽视，具有潜在的毒性与不安全性。澳大利亚的临床数据评价表明，长期使用大剂量(大于1.5g/d)铋制剂，必须注意铋中毒的发生。但由于铋在医学上的作用，特别是根除幽门螺杆菌感染的作用，因此铋制剂在临床治疗上有着不可替代的地位。亟待开发活性好、铋含量低、更安全可靠的铋制剂。本发明即是针对现有技术的不足，提供一种海藻酸铋及其制备方法和应用。
发明内容
为实现上述目的，本发明采用技术方案为：
一种海藻酸铋，所述海藻酸铋，如结构式一所示，n＝200-250。
式一。
海藻酸铋的制备方法，将褐藻胶与铋盐或铋碱在碱性水溶液中反应，生成海藻酸铋，经乙醇沉淀分离，脱水后，干燥粉碎，即得到海藻酸铋；所述褐藻胶与铋盐或铋碱(以Bi含量计)的质量比为60∶1-6∶1。
将褐藻胶溶解后加入NaOH，至溶解液pH为8-12。
将上述调节溶解液中缓慢加入铋盐或铋碱搅拌0.5-1小时，室温下放置搅拌均匀的溶液，而后加入搅拌均匀溶液2-4倍(V/V)的95％乙醇，搅拌，胶体沉淀，压滤出沉淀物，再用乙醇洗涤沉淀2-3次，干燥，粉碎，即得到海藻酸铋白色粉末。
所述褐藻胶为海藻酸、海藻酸钠或海藻酸铵；铋盐为硝酸铋、次硝酸铋、氧化铋、次碳酸铋、三氯化铋、碱式氯化铋等硝酸铋；铋碱为氢氧化铋。
海藻酸铋的应用，所述海藻酸铋具有抑制幽门螺杆菌的作用。所述海藻酸铋作为制备胃炎或胃溃疡的药物。
本发明所具有的优点为：
海藻酸铋是以生物大分子海藻酸作为载体合成的一种新型胶态铋制剂，其铋含量明显低于目前临床上普遍应用的枸橼酸铋等铋制剂，降低了长期给药铋元素所存在的潜在毒性。
另外，海藻酸是一种存在于褐藻的细胞壁中的酸性多糖。海藻酸对高血压、便秘等慢性病有一定疗效，并可降低血糖、血脂、减少胆固醇，具有防癌、抗癌等作用。尤其是海藻酸具有良好的成膜性，是一种天然植物性创伤修复材料，可用来保护创面等。在胃内低pH环境中海藻酸铋形成凝胶体，可在胃粘膜上形成一层不易被破坏的高强度保护膜，增强胃粘膜的屏障保护作用，尤其是其对受损伤胃肠粘膜上皮细胞有选择性粘附力，使糜烂面和溃疡与胃酸及胃蛋白酶隔离，对受损粘膜起到保护作用，加速溃疡面的愈合和炎症的消失，同时具有一定的止血作用。海藻酸铋凝胶在胃内的停留时间长，有利于胃内幽门螺杆菌的杀灭和根除。海藻酸铋是一种新型大分子铋制剂，分子量大，胶体稳定，难以被人体吸收，无同类药物容易引起的不良反应和副作用。
本发明的另一个优点是：海藻酸铋虽然能够杀灭幽门螺杆菌，但并非抗生素，所以不会产生耐药性菌株。因此海藻酸铋兼具铋制剂与海藻酸二者的功能，具有保护胃粘膜、中和胃酸、降低胃蛋白酶活性、杀灭Hp、促进消化性溃疡创面愈合等多重功能，具有很好的新药开发价值。
附图说明
图1为本发明实施例提供的海藻酸铋制备工艺流程图。
图2为本发明实施例提供的海藻酸铋红外光谱图。
具体实施方式
实施例1
制备海藻酸铋：先称取食品级海藻酸钠11g，加入容器中，用1500ml蒸馏水采用搅拌机搅拌，直至海藻酸钠完全溶解。然后用NaOH水溶液调pH至8-12，继续搅拌下，缓慢加入Bi(OH)3水溶液(含Bi 0.8g)，继续搅拌0.5-1小时，室温下放置搅拌均匀的溶液。而后加入搅拌均匀的溶液2-4倍(V/V)的95％乙醇，搅拌，胶体沉淀，压滤出沉淀物，再用乙醇洗涤沉淀2-3次，真空冷冻干燥，粉碎，过100目筛，制得海藻酸铋白色粉末(参见图1和图2)，如式一所示n＝200-250。所得海藻酸铋含铋4-6％(按重量计，)。
实施例2
称取海藻酸钠10.5g，倒入容器中，加入1500ml水，机械搅拌至完全溶解，制得海藻酸钠溶液。称取硝酸铋(Bi(NO3)3·5H2O，含Bi 2.0g)，加水搅拌至硝酸铋完全溶解，再用NaOH溶液调pH至8-12；边搅拌边将硝酸铋碱性溶液慢慢加入海藻酸钠溶液中，继续搅拌30-60min，然后加入1-3倍(V/V)的乙醇，使海藻酸铋胶体沉淀，离心使固液分离。向沉淀中加入95％乙醇，使沉淀脱水，脱盐，然后将沉淀物干燥，粉碎，过100目筛，得到白色粉末状海藻酸铋。该海藻酸铋中铋含量为15-17％。
实施例3
称取海藻酸钠10g，加入容器中，加1500ml水，机械搅拌至海藻酸钠完全溶解，得到海藻酸钠溶液。称取硝酸铋(Bi(NO3)3·5H2O，含Bi 3.0g)，加蒸馏水溶解，然后加入NaOH溶液，得到Bi(OH)3沉淀，过滤。将滤饼转移到容器中，加入1-3倍(W/W)多元醇，加水搅拌至完全溶解，得到碱性铋溶液；边搅拌边将铋碱溶液缓慢加入海藻酸钠溶液中，然后继续搅拌0.5-1小时，成胶体盐。再加入1-3倍(V/V)的95％乙醇，搅拌，使海藻酸铋沉淀，离心。再用80％乙醇洗涤沉淀物，脱水，脱盐，然后将所得沉淀干燥，粉碎，过100目筛，得到海藻酸铋白色粉末。该粉末中含铋24-26％。
将上述所得化合物经红外光谱鉴定，同时参见表1。
表1海藻酸铋的主要红外光谱峰归属
| 波数(cm-1) | 对应化学基团 | 基团振动 |
| 3502 | -OH | 羟基伸缩振动 |
| 2935 | C-H | C-H伸缩振动 |
| 1612 | COO- | 羧酸盐阴离子羰基的不对称伸缩振动 |
| 1410 | COO- | 羧酸盐阴离子羰基的对称伸缩振动 |
| 1087 | O-C-O | C-O伸缩振动 |
| 1025 | C-O | C-O伸缩振动 |
| 942 | CO | 糖醛酸羰基伸缩 |
| 893 | C1-H | 甘露糖醛酸残基C1-H变形 |
应用例
将上述实施例所得海藻酸铋做体外抗幽门螺杆菌试验，采用肉汤浓度稀释法。用上述海藻酸铋(含铋15.04％)溶液的浓度为5mg/ml。菌液浓度为1.0×107cfu/ml。取13支无菌试管，分别加入不同体积的肉汤培养液和海藻酸铋溶液，配成总体积为1.0ml的培养液，再加入菌液0.1ml(第12、13支试管不加菌液)，混匀，置37℃微氧环境下中培养，48小时后观察各试管有无细菌生长并形成液体混浊。取每管液体培养物，接种于改良Skirrow培养基(参见表3)，37℃下继续培养48小时，以无菌落出现浓度为最低杀菌浓度(MBC)。
海藻酸铋体外抗菌实验结果参见表2。结果表明海藻酸铋(含铋15.04％)最低杀菌浓度(MBC)为0.5mg/ml。在此浓度下，样品中铋的含量为0.075mg/ml。
海藻酸铋有很强的抗幽门螺杆菌活性，具有广阔的新胃药开发前景。
表2海藻酸铋体外抗幽门螺杆菌活性
注：“-”固体培养无菌落；“+”固体培养出现菌落
表3改良Skirrow氏琼脂培养基成分：
| 蛋白胨 | 10.0g |
| 胰蛋白胨 | 5.0g |
| 酵母浸膏 | 5.0g |
| 氯化钠 | 5.0g |
| 琼脂粉 | 15.0g |
| 甲氧苄氨嘧啶(Trimethoprin，TMP) | 5.0mg |
| 万古霉素(Vancomycin) | 10.0mg |
| 多粘菌素B(Polymyxin B) | 250.0IU |
| 头孢菌素 | 15mg |
| 乳酸 | 1-2滴 |
| 冻溶马血 | 70.0ml |
| 水 | 1000.0ml |
Claims (7)
1.一种海藻酸铋，其特征在于：所述海藻酸铋，如结构式一所示，n＝200-250；
式一。
2.一种权利要求1所述的海藻酸铋的制备方法，其特征在于：将褐藻胶与铋盐或铋碱在碱性水溶液中反应，生成海藻酸铋，经乙醇沉淀分离，脱水后，干燥粉碎，即得到海藻酸铋；以Bi含量计所述褐藻胶与铋盐或铋碱的质量比为60:1-6:1。
3.按权利要求2所述的海藻酸铋的制备方法，其特征在于：将褐藻胶溶解后加入NaOH，至溶解液pH为8-12。
4.按权利要求2或3所述的海藻酸铋的制备方法，其特征在于：将上述调节溶解液中缓慢加入铋盐或铋碱搅拌0.5-1小时，室温下放置搅拌均匀的溶液，而后加入搅拌均匀溶液2-4倍V/V的95％乙醇，搅拌，胶体沉淀，压滤出沉淀物，再用乙醇洗涤沉淀2-3次，干燥，粉碎，即得到海藻酸铋白色粉末。
5.按权利要求2所述的海藻酸铋的制备方法，其特征在于：所述褐藻胶为海藻酸、海藻酸钠或海藻酸铵；铋盐为硝酸铋、次硝酸铋、氧化铋、次碳酸铋、三氯化铋、碱式氯化铋；铋碱为氢氧化铋。
6.权利要求1所述的海藻酸铋在制备抑制幽门螺杆菌药物中的作用。
7.权利要求1所述的海藻酸铋在制备胃炎或胃溃疡的药物中的应用。
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| CN1513882A (zh) * | 2003-05-14 | 2004-07-21 | 中国海洋大学 | 羧甲基壳聚糖铋的制备及其在治疗胃炎胃溃疡中的应用 |
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