CN109568471B - 具有降血糖作用的笼目海带褐藻聚糖硫酸酯复方制剂 - Google Patents

具有降血糖作用的笼目海带褐藻聚糖硫酸酯复方制剂 Download PDF

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CN109568471B
CN109568471B CN201910072517.4A CN201910072517A CN109568471B CN 109568471 B CN109568471 B CN 109568471B CN 201910072517 A CN201910072517 A CN 201910072517A CN 109568471 B CN109568471 B CN 109568471B
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汪秋宽
彭雍博
任丹丹
何云海
宋悦凡
武龙
刘舒
周慧
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Dalian Ocean University
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Abstract

本发明公开一种具有降血糖作用的笼目海带褐藻聚糖硫酸酯复方制剂,由笼目海带海带岩藻聚糖硫酸酯和中药复合制剂按照质量比为1:1混合而成;所述中药复合制剂依次按照如下步骤制备:称取通过60目的中药,所述中药组分及质量比为黄芪23、生地黄20、葛根10、丹参20、山药10、枸杞子8、桑叶5及西洋参4,加8倍体积去离子水,冷水浸泡60 min;分两次煎熬提取,合并提取液;将提取液冷却至60℃,3500 r/min离心10 min后取上清液;将上清液低温冷冻干燥,收集制品。各组分相互配合,可有效降低血糖,无毒副作用,适用于糖尿病患者。

Description

具有降血糖作用的笼目海带褐藻聚糖硫酸酯复方制剂
技术领域
本发明涉及一种降血糖药物,尤其是一种具有降血糖作用的笼目海带褐藻聚糖硫酸酯复方制剂。
背景技术
褐藻聚糖硫酸酯(fucoidan)是一种水溶性结合有硫酸基团的活性杂多糖,主要成分为岩藻糖和硫酸基。褐藻聚糖硫酸酯具有广泛的生理和生物活性,研究表明,不同的提取方法、不同的藻类中提取的褐藻聚糖硫酸酯,其组成成分和结构等存在较大差异。褐藻聚糖硫酸酯的生物活性不但取决于其组成成分、结构、硫酸基团的含量及其位置,还取决于可能与多糖链接的多酚含量。笼目海带(Kjellmaniella crassifolia Miyabe)为褐藻优势种质资源,它在系统分类上属于海带目(Laminariales),海带科(Laminariaceae),Kjellmaniella属,是近几年研究团队培育栽培的优质褐藻。笼目海带一方面富含褐藻聚糖硫酸酯,另一方面因低温的生长环境使其富含以U-fucoidan为主的优质褐藻聚糖硫酸酯,具有抗肿瘤、降血脂、保肝护肝等多种生物活性。
黄芪、生地黄、葛根、丹参、山药、枸杞子、桑叶及西洋参均为常用的中药,分别有提高免疫力、调节脾胃等功效,但迄今为止并没有与笼目海带褐藻聚糖硫酸酯进行合理复配制备降血糖药物的相关报道。
发明内容
本发明是为了解决现有技术所存在的上述技术问题,提供一种具有降血糖作用的褐藻聚糖硫酸酯复方制剂。
本发明的技术解决方案是:一种具有降血糖作用的笼目海带褐藻聚糖硫酸酯复方制剂,其特征在于由笼目海带海带岩藻聚糖硫酸酯和中药复合制剂按照质量比为1:1混合而成;
所述笼目海带褐藻聚糖硫酸酯依次按照如下步骤制备:以清洗后的笼目海带为原料,向原料中加入复合酶,在 pH4.0~pH5.5和温度40~60℃条件下酶解40~70分钟,所述复合酶添加量为原料质量的0.51~0.90%,然后在96~100℃水浴加热3~4小时,降至室温,离心得上清液A,所述复合酶由纤维素酶、果胶酶和蛋白酶按质量比为5:5~8:0.1~0.5混合而成;在上清液A中加入乙醇至乙醇质量浓度为20%产生沉淀,离心得上清液B;在上清液B中加入乙醇至乙醇质量浓度为60%产生沉淀,离心得沉淀;将沉淀溶于水中,加入乙醇至乙醇质量浓度为30%产生沉淀,离心去沉淀得上清液C;在上清液C中继续添加乙醇至乙醇质量浓度为70%产生沉淀,离心得沉淀;冷冻干燥沉淀得白色粉末;
所述中药复合制剂依次按照如下步骤制备:称取通过60目的中药,所述中药组分及质量比为黄芪23、生地黄20、葛根10、丹参20、山药10、枸杞子8、桑叶5及西洋参4,加8倍体积去离子水,冷水浸泡60 min;分两次煎熬提取,合并提取液;将提取液冷却至60 ℃,3500r/min离心10 min后取上清液;将上清液低温冷冻干燥,收集制品。
本发明笼目海带褐藻聚糖硫酸酯与黄芪、生地黄、葛根、丹参、山药、枸杞子、桑叶及西洋参等中药有效成分进行合理复配,各组分相互配合,可有效降低血糖,无毒副作用,适用于糖尿病患者。
附图说明
图1是各实验组糖尿病大鼠肾脏组织HE染色形态学观察(400×)图。
具体实施方式
实施例1:
本发明的具有降血糖作用的笼目海带褐藻聚糖硫酸酯复方制剂(KCA),由笼目海带海带岩藻聚糖硫酸酯和中药复合制剂按照质量比为1:1混合而成;
所述笼目海带褐藻聚糖硫酸酯(KF)依次按照如下步骤制备:以清洗后的笼目海带为原料,向原料中加入复合酶,在 pH5.5和温度60℃条件下酶解40分钟,所述复合酶添加量为原料质量的0.90%,然后在100℃水浴加热3小时,降至室温,离心得上清液A,所述复合酶是取5.0g纤维素酶,5.0g果胶酶和0.1g蛋白酶混合配制而成,纤维素酶、果胶酶和蛋白酶的酶活分别为80,000u/g、80,000 u/g和1,000,000 u/g;在上清液A中加入乙醇至乙醇质量浓度为20%产生沉淀,离心得上清液B;在上清液B中加入乙醇至乙醇质量浓度为60%产生沉淀,离心得沉淀;将沉淀溶于水中,加入乙醇至乙醇质量浓度为30%产生沉淀,离心去沉淀得上清液C;在上清液C中继续添加乙醇至乙醇质量浓度为70%产生沉淀,离心得沉淀;冷冻干燥沉淀得白色粉末;
所述中药复合制剂(ACM)依次按照如下步骤制备:称取通过60目的中药,所述中药组分及质量比为黄芪23g、生地黄20g、葛根10g、丹参20g、山药10g、枸杞子8g、桑叶5g及西洋参4g,加8倍体积去离子水,冷水浸泡60 min;分两次煎熬提取,首次熬制45 min,末次熬制35 min,合并提取液;将提取液冷却至60 ℃,3500 r/min离心10 min后获得上清液;将上清液低温冷冻干燥,收集制品。
实施例2:
与实施例1所不同的是笼目海带褐藻聚糖硫酸酯(KF)依次按照如下步骤制备:以清洗后的笼目海带为原料,向原料中加入复合酶,在 pH4.0和温度40℃条件下酶解70分钟,所述复合酶添加量为原料质量的0.51%,然后在96℃水浴加热4小时,降至室温,离心得上清液A,所述复合酶是取5.0g纤维素酶,8.0g果胶酶和0.5g蛋白酶混合配制而成,纤维素酶、果胶酶和蛋白酶的酶活分别为80,000u/g、80,000 u/g和1,000,000 u/g;在上清液A中加入乙醇至乙醇质量浓度为20%产生沉淀,离心得上清液B;在上清液B中加入乙醇至乙醇质量浓度为60%产生沉淀,离心得沉淀;将沉淀溶于水中,加入乙醇至乙醇质量浓度为30%产生沉淀,离心去沉淀得上清液C;在上清液C中继续添加乙醇至乙醇质量浓度为70%产生沉淀,离心得沉淀;冷冻干燥沉淀得白色粉末。
实施例3:
与实施例1所不同的是笼目海带褐藻聚糖硫酸酯(KF)依次按照如下步骤制备:以清洗后的笼目海带为原料,向原料中加入复合酶,在 pH5.0和温度50℃条件下酶解50分钟,所述复合酶添加量为原料质量的0.80%,然后在98℃水浴加热3.5小时,降至室温,离心得上清液A,所述复合酶是取5.0g纤维素酶,6.5g果胶酶和0.3g蛋白酶混合配制而成,纤维素酶、果胶酶和蛋白酶的酶活分别为80,000u/g、80,000 u/g和1,000,000 u/g;在上清液A中加入乙醇至乙醇质量浓度为20%产生沉淀,离心得上清液B;在上清液B中加入乙醇至乙醇质量浓度为60%产生沉淀,离心得沉淀;将沉淀溶于水中,加入乙醇至乙醇质量浓度为30%产生沉淀,离心去沉淀得上清液C;在上清液C中继续添加乙醇至乙醇质量浓度为70%产生沉淀,离心得沉淀;冷冻干燥沉淀得白色粉末。
对实施例1、实施例2、实施例3所得笼目海带褐藻聚糖硫酸酯、中药制剂进行分析,笼目海带褐藻聚糖硫酸酯的纯度为80.0%以上,总糖质量为50.0~65.0%,硫酸根质量21.0~35.0%%,中药制剂的总糖含量为90.0%以上,黄酮含量为6.0%以上,蛋白质含量为4%以上。
实验:
1. 动物实验说明
Ⅱ型糖尿病大鼠模型建立。SPF级Wistar雄性大鼠96只,实验分组如表1所示,给予基础饲料适应性喂养一周后,预留Wistar大鼠12只,作为空白对照组,15周实验期间给予基础饲料,其余各组大鼠依次给予高糖高脂饲料(1-13周)和高脂饲料(13-15周)。实验第五周,空白对照组大鼠腹腔注射无菌生理盐水(10 mL·kg-1 BW.ip);其余Wistar大鼠腹腔注射30 mg·kg-1 BW.ip STZ(实验前预冷后枸橼酸盐缓冲液配制);腹腔注射4 h后,各实验大鼠饮水更换为5 %葡萄糖(24 h),避免注射STZ后低血糖导致小鼠死亡。首次腹腔注射7 d后,再次腹腔注射。空白对照组Wistar大鼠,腹腔注射无菌生理盐水(10 mL·kg-1 BW.ip);剩余Wistar大鼠,腹腔再次注射30 mg·kg-1 BW.ip STZ;腹腔注射4 h后,各实验大鼠饮水更换为5 %葡萄糖(24 h)。糖尿病大鼠稳定性观察7 d后,动物禁食10 h,尾尖针刺取血,测定空腹血糖值,注射STZ组小鼠血糖值>11 mmol/L为高血糖建模成功动物。建模成功后,实验动物组按血糖值随机分组,实验周期共计15周。实验期间,均给予正常饮水。
表1 实验动物分组及给药
Figure DEST_PATH_IMAGE001
表1中KCA为本发明实施例3制备的笼目海带褐藻聚糖硫酸酯复方制剂。
2. 本发明实施例3笼目海带褐藻聚糖硫酸酯复方制剂对Ⅱ型糖尿病降空腹血糖值的降低作用
造模成功后各组糖尿病大鼠空腹血糖值如表2所示。
表2笼目海带褐藻聚糖硫酸酯复方制剂对糖尿病大鼠空腹血糖值影响
Figure DEST_PATH_IMAGE002
结果表明造模成功后各组糖尿病大鼠空腹血糖值显著高于空白对照组(Control),各药物干预组空腹血糖值与模型组(Negative)组间无显著性差异;模型组(Negative)组糖尿病大鼠空腹血糖值在造模成功后无明显差异,这表明糖尿病大鼠造模成功且在灌胃期间保存稳定。灌胃2周后,KCB各组的大鼠组空腹血糖值相较模型组(Negative)无显著差异;灌胃至第八周,大鼠空腹血糖值测定结果显示Positive组、KCB-L组、KCB-M组、KCB-H组糖尿病大鼠空腹血糖值显著或极显著下降。阳性对照组(Positive)大鼠空腹血糖值较模型组(Negative)下降26.65 %,KCB-L组、KCB-M组、KCB-H组大鼠空腹血糖值下降38.65 %、25.18 %、37.84 %,由此可见,本发明的笼目海带褐藻聚糖硫酸酯复方制剂对Ⅱ型糖尿病治疗效果优于中药制剂和褐藻聚糖硫酸酯。
3.各实验组糖尿病大鼠肾脏组织HE染色形态学观察(400×)
肾脏组织光镜观察结果如图1所示,图中a:Control组;b:Negative组;c:Positive组;d:KF组;e:CHM组;f:KCB-L组;g:KCB-M组;h:KCB-H组。结果表明:空白对照组(Control)Wistar大鼠肾小球和肾小管结构完整、紧密,为表现出病理学变化。而模型组(Negative)糖尿病大鼠肾小球面积增大,系膜增宽、系膜细胞增生,细胞外基质增多;肾小管上皮细胞出现空泡样变,管腔扩张,肾间质被炎症细胞浸润;同时肾小球内及肾小管周围可见大量胶原质纤维沉积,且肾小球包曼氏囊扩张明显,系膜基质增宽,肾小球毛细血管基底膜增厚。比较模型组(Negative)组,阳性对照组(Positive)糖尿病大鼠肾小球系膜细胞增生水平及肾间质炎症细胞浸润降低,肾脏纤维化水平和系膜基质厚度也得到改善,肾小球毛细血管基底膜轻度增厚,其它干预组糖尿病大鼠肾脏病变均有不同程度的减轻,特别是KCB剂量组(低、中、高剂量组)糖尿病肾病抑制效果最佳。

Claims (1)

1. 一种具有降血糖作用的笼目海带褐藻聚糖硫酸酯复方制剂,其特征在于由笼目海带海带岩藻聚糖硫酸酯和中药复合制剂按照质量比为1:1混合而成,灌胃剂量为100 mg·kg-1·day-1
所述笼目海带海带岩藻聚糖硫酸酯依次按照如下步骤制备:以清洗后的笼目海带为原料,向原料中加入复合酶,在 pH4.0~pH5.5和温度40~60℃条件下酶解40~70分钟,所述复合酶添加量为原料质量的0.51~0.90%,然后在96~100℃水浴加热3~4小时,降至室温,离心得上清液A,所述复合酶由纤维素酶、果胶酶和蛋白酶按质量比为5:5~8:0.1~0.5混合而成;在上清液A中加入乙醇至乙醇质量浓度为20%产生沉淀,离心得上清液B;在上清液B中加入乙醇至乙醇质量浓度为60%产生沉淀,离心得沉淀;将沉淀溶于水中,加入乙醇至乙醇质量浓度为30%产生沉淀,离心去沉淀得上清液C;在上清液C中继续添加乙醇至乙醇质量浓度为70%产生沉淀,离心得沉淀;冷冻干燥沉淀得白色粉末;
所述中药复合制剂依次按照如下步骤制备:称取通过60目的中药,所述中药组分及质量比为黄芪23、生地黄20、葛根10、丹参20、山药10、枸杞子8、桑叶5及西洋参4,加8倍体积去离子水,冷水浸泡60 min;分两次煎熬提取,合并提取液;将提取液冷却至60 ℃,3500 r/min离心10 min后取上清液;将上清液低温冷冻干燥,收集制品。
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