CN110652526A - 甘露糖醛二酸的组合物在治疗糖尿病中的应用 - Google Patents
甘露糖醛二酸的组合物在治疗糖尿病中的应用 Download PDFInfo
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Abstract
本发明涉及一种甘露糖醛二酸寡糖组合在治疗糖尿病方面的应用。
Description
技术领域
本发明涉及通过生物活性筛选的方法得到甘露糖醛二酸的最佳组合物在治疗糖尿病方面的应用。
背景技术
糖尿病是目前严重危害人类健康的多发病和常见病,尤其是随着世界老年人口的日益增多,其发病率逐年升高,因此糖尿病的防治显得越来越重要。临床常用的糖尿病防治药物主要包括胰岛素和口服降糖药物,多存在使用不便及毒副作用大等缺点,尤其是缺乏合适的用于II型糖尿病的有效药物。
甘露糖醛二酸由于其潜在的药用价值已经受到广泛的重视。甘露糖醛二酸通常以海藻酸为原料经过多步骤制得。
在原料海藻酸的多糖分子中,有由甘露糖醛酸(D-mannuronic acid)通过β-1,4-糖苷键连接形成的M段、古罗糖醛酸(L-guluronic acid)通过α-1,4-糖苷键连接形成的G段,以及由这两种糖杂合形成的MG段。甘露糖醛酸和古罗糖醛酸的结构式如下(I)式所示:
M段和G段可以从原料海藻酸中分离。通常的方法可以简单描述为:将海藻酸初步降解后可得到聚甘露糖醛酸和聚古罗糖醛酸的混合多糖,混合多糖再经酸法沉淀后,可以除去其中的聚古罗糖醛酸,进一步精制可以得到纯度在90%以上的均聚甘露糖醛酸(下文中也称“M段中间体”)。例如,可参见中国专利申请No.98806637.8以及CN02823707.2所披露的方法。
制备寡聚甘露糖醛酸的一般方法如下:将上述得到的M段中间体在酸性条件下加热进一步酸解得到所需分子量范围的小片段甘露糖醛酸聚合物。另外,也有通过氧化降解的办法提升降解效率,同时可以将还原末端氧化为开环的糖二酸,详见耿美玉等人的中国专利申请200580009396.5(专利文献1)及美国专利US 8835403B2(专利文献2)。为了方便叙述,专利文献1和2在下文中统称为在先专利,它们以引证的方式全部并入本文。
在先专利披露的甘露糖醛二酸的反应过程可通过如下反应方程式(II)表示,即寡聚甘露糖醛酸多糖还原端的甘露糖醛酸C1-位醛基氧化成羧基。
在上述氧化转化过程中,常用的氧化剂有碱性硫酸铜溶液,即菲林试剂,在先专利即采用了该氧化方法,具体为:在碱性条件下,将反应底物聚甘露糖醛酸即上文的M段中间体加入硫酸铜溶液中,在沸水浴中反应15分钟至2小时。该法是以Cu2+离子为氧化剂氧化醛基,反应中产生砖红色的氧化亚铜沉淀,这个反应常用于鉴定还原性糖。
在先专利公开了甘露寡糖二酸具有抗阿尔茨海默病(Alzheimer'sdisease,AD)和抗糖尿病的作用。阿尔茨海默病与II型糖尿病的发病过程与淀粉样蛋白(β-amyloid及amylin)密切相关。淀粉样蛋白聚集以后产生蛋白寡聚体,进一步聚集形成纤维。这些蛋白聚集物有细胞毒性,在细胞内诱导氧化反应损伤线粒体以及引发糖尿病反应等级联反应,造成大量的神经元和β细胞损伤,最终导致阿尔茨海默病与II型糖尿病的发生。甘露寡糖二酸靶向淀粉样蛋白并拮抗其诱导的级联反应,由此具有预防和治疗阿尔茨海默病与II型糖尿病的作用。
发明内容
本发明涉及一种甘露糖醛二酸寡糖组合物在治疗糖尿病中的用途。本发明还涉及一种治疗糖尿病的方法,包括给予需要治疗的患者治疗有效量的本发明所述的甘露糖醛二酸寡糖组合物。
本发明中使用的甘露糖醛二酸寡糖组合物具有特定的组成,包含具有式(III)的甘露糖醛二酸或其药学上可接受的盐:
其中n为选自1-9的整数,m选自0,1或2,m’选自0或1,
并且其中,
n=1-5的甘露糖醛二酸的重量总和占所述组合物总重量的60%以上:
n=1-2的甘露糖醛二酸的重量总和占所述组合物总重量的低于60%。
附图说明
图1是产品A中二糖、三糖和四糖的质谱图。
图2是产品A中五糖、六糖和七糖的质谱图。
图3是产品A中八糖、九糖和十糖的质谱图。
图4表示各单一聚合度的甘露寡糖二酸对胰淀素损伤胰岛β细胞的保护作用,横坐标的数值表示各寡糖的聚合度。
图5表示寡糖组合物、六糖对糖尿病小鼠餐后血糖的影响;图中横坐标的编号分别对应的样品为:i:对照组;ii:模型组;iii:产品A;iv:产品B;v:产品C;vi:产品D;vii:六糖。
具体实施方式
下文将对本发明的各个方面进行具体说明,但本发明并不限于这些具体的实施方式。本领域技术人员可以根据下文公开内容的实质对本发明进行一些修改和调整,这些调整也属于本发明的范围。
本发明涉及一种甘露糖醛二酸寡糖组合物在治疗糖尿病中的用途。本发明还涉及一种治疗糖尿病的方法,包括给予需要治疗的患者治疗有效量的本发明所述的甘露糖醛二酸寡糖组合物。本发明中使用的甘露糖醛二酸寡糖组合物具有特定的组成,包含具有式(III)的甘露糖醛二酸或其药学上可接受的盐:
其中n为选自1-9的整数,m选自0,1或2,m’选自0或1,
并且其中,
n=1-5的甘露糖醛二酸的重量总和占所述组合物总重量的60%以上;
n=1-2的甘露糖醛二酸的重量总和占所述组合物总重量的低于60%。
本发明涉及的甘露糖醛二酸寡糖组合物是不同聚合度的甘露糖醛二酸的混合物,其主要成分是聚合度为2至10的甘露糖醛二酸寡糖。已知在甘露糖醛二酸中,活性最高的糖为4-10糖,特别是6糖。但是,发明人现发现,在活性最高的4-10糖基础上添加一定比例活性较低的2-3糖,同等质量的给药剂量下,生物活性不降低甚至还有提高。不囿于任何理论,推测这可能是由于分子量较小的2-3糖虽然不能单独起效,但跟其他寡糖混合后能起到协同增效的作用。但当2-3糖的比例过高时,组合物的整体活性降低。因此,组合物中2-3糖的比例必须控制在一定的范围之内。
在实际制备过程中,氧化降解反应中会产生显著量的2-3糖,通常会因其活性低,为避免影响到产品的药效,而将其从产物中分离后去除。而基于发明人的上述发现,通过控制氧化降解反应的条件而将2-3糖的比例控制在一定的范围之内,则可获得活性更高的组合物,且因不用将2-3糖作为杂质去除,产品得率理论上也显著高于在先申请所公开的产品得率,大大降低生产成本,减少废弃物的排放,在实际生产中更容易实现,更易于实现工业化大生产。
根据一个优选的实施方案,本发明的甘露糖醛二酸寡糖组合物中m+m’=1或2的甘露糖醛二酸的重量总和不低于所述组合物总重量的50%以上,优选60%-90%,更优选70%-90%。特别地,本发明的甘露糖醛二酸寡糖组合中m+m’=1的甘露糖醛二酸的重量总和不低于所述组合物总重量的10%,优选30-40%。在另一个优选实施方案中,本发明的甘露糖醛二酸寡糖组合物中m+m’=2的甘露糖醛二酸的重量总和不低于所述组合物总重量的10%,优选30-50%。
根据一个优选实施方案,本发明的甘露糖醛二酸寡糖组合物中n=1-5的甘露糖醛二酸寡糖的重量总和占所述组合物总重量的80-95%。
根据一个优选实施方案,本发明的甘露糖醛二酸寡糖组合物中n=1-2的甘露糖醛二酸寡糖的重量总和所述组合物总重量的10-50%,优选25-50%。
根据一个优选实施方案,本发明的甘露糖醛二酸寡糖组合物中n=1-3的甘露糖醛二酸寡糖的重量总和所述组合物总重量的20-70%。
根据一个优选实施方案,本发明的甘露糖醛二酸寡糖组合物中n=1-3的甘露糖醛二酸的重量总和与n=4-7的甘露糖醛二酸寡糖重量总和的比例在1.0-3.5之间,优选在1.0-3.0之间。
根据一个优选实施方案,本发明的甘露糖醛二酸寡糖组合物中各聚合度甘露糖醛二酸寡糖在所述组合物中的重量百分含量为:二糖5-25%,三糖15-30%,四糖15-28%,五糖5-25%,六糖2-20%,七糖2-20%,八糖2-20%,九糖2-20%,十糖2-20%。特别地,组合物中寡糖的重量百分含量为:二糖5-25%,三糖15-30%,四糖15-28%,五糖10-20%,六糖5-15%,七糖3-10%,八糖2-5%,九糖1-5%,十糖1-5%。更优地,组合物中寡糖的重量百分含量为:二糖10-20%,三糖18-30%,四糖15-28%,五糖15-20%,六糖5-10%,七糖3-5%,八糖2-5%,九糖1-3%,十糖1-3%。
本发明的甘露糖醛二酸寡糖组合中,其中所述药学上可接受的盐是钠盐或钾盐。
本专利申请的发明人发现,当各单独的寡糖按照一定的比例进行复配,可以得到高活性的寡糖组合物,其活性比活性最好的六糖还要高;尤其是含有一定比例二糖和三糖的组合物,其活性高于不含二糖和三糖的组合物。高活性寡糖组合物中的各寡糖比例需要按照如下的比例关系进行组合:
组合物中n=1-5的甘露糖醛二酸的重量总和占所述组合物总重量的60%以上,优选80-95%。n=1-2的甘露糖醛二酸的重量总和占所述组合总重量的低于60%,优选10-50%,更优选25-50%。n=1-3的甘露糖醛二酸寡糖的重量总和所述组合总重量的20-70%。其中n=1-3的甘露糖醛二酸寡糖的重量总和与n=4-7的甘露糖醛二酸寡糖重量总和的比例在1.0-3.5之间,优选在1.0-3.0之间。
本发明所述用于治疗糖尿病的药物包含甘露糖醛二酸寡糖组合物,其包含具有式(III)的甘露糖醛二酸或其药学上可接受的盐,以及一种或多种药学上可接受载体。本发明所述药物可以是片剂、硬胶囊、软胶囊、肠溶胶囊、微囊剂、颗粒剂、糖浆剂、注射剂、颗粒剂、乳剂、悬浮液、溶液和用于口服或非口服给药的缓释制剂的形式。
本发明所述药学上可接受载体是指本领域技术人员熟知的药学上可接受的载体,本发明的药学上可接受载体包括但不限于:填充剂、润湿剂、黏合剂、崩解剂、润滑剂、粘合剂、助流剂、掩味剂、表面活性剂、防腐剂等。填充剂包括但不限于乳糖、微晶纤维素、淀粉、糖粉、糊精、甘露醇、硫酸钙等。润湿剂与黏合剂包括但不限于羧甲基纤维素钠、羟丙基纤维素、羟丙基甲基纤维素、明胶、蔗糖、聚乙烯吡咯烷酮等。崩解剂包括但不限于羧甲基淀粉钠、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、低取代羟丙基纤维素等。润滑剂包括但不限于硬脂酸镁、微粉硅胶、滑石粉、氢化植物油、聚乙二醇、月桂醇硫酸镁等。粘合剂包括但不限于***胶、藻酸、羧甲基纤维素钙、羧甲基纤维素钠、葡萄糖结合剂、糊精、右旋糖、乙基纤维素、明胶、液体葡萄糖、瓜尔胶、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、硅酸铝镁、麦芽糖糊精、甲基纤维素、聚甲基丙烯酸酯、聚乙烯吡咯烷酮、预明胶化淀粉、藻酸钠、山梨醇、淀粉、糖浆和黄蓍胶。助流剂包括但不限于胶体二氧化硅、粉状纤维素、三硅酸镁、二氧化硅和滑石粉。掩味剂包括但不限于阿斯巴坦、甜菊苷、果糖、葡萄糖、糖浆、蜂蜜、木糖醇、甘露醇、乳糖、山梨醇、麦芽糖醇、甘草甜素。表面活性剂包括但不限于吐温-80、泊洛沙姆。防腐剂包括但不限于尼泊金酯、苯甲酸钠、山梨酸钾等。
本文使用的术语“治疗”一般是指获得需要的药理和/或生理效应。该效应根据完全或部分地预防疾病或其症状,可以是预防性的;和/或根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用,可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗,包括:(a)预防易感染疾病或症状但还没诊断出患病的患者所发生的疾病或症状;(b)抑制疾病的症状,即阻止其发展;或(c)缓解疾病的症状,即,导致疾病或症状退化。
甘露糖醛二酸寡糖组合
本发明所述用于治疗糖尿病的甘露糖醛二酸寡糖组合物,其包含具有式(III)的甘露糖醛二酸或其药学上可接受的盐:
其中n为选自1-9的整数,m选自0,1或2,m’选自0或1,
并且其中,
n=1-5的甘露糖醛二酸的重量总和占所述组合总重量的60%以上;
n=1-2的甘露糖醛二酸的重量总和占所述组合总重量的低于60%。
在一个示例性的实施方案中,本发明所述用于治疗糖尿病的甘露糖醛二酸寡糖组合物的制备方法包括如下几个步骤:
(1)甘露糖醛二酸产品的制备:
M段中间体的制备。如前文所述,本发明中采用的原料M段中间体可以通过现有技术中已知的方法制备。例如中国专利申请No.98806637.8以及CN02823707.2所披露的方法。通常的方法可以简单描述为:将海藻酸初步降解后可得到聚甘露糖醛酸和聚古罗糖醛酸的混合多糖,混合多糖再经酸法沉淀后,可以除去其中的聚古罗糖醛酸,进一步精制可以得到纯度在90%以上的均聚甘露糖醛酸,即M段中间体。
臭氧氧化降解。在室温或者加热条件下使M段中间体溶解于适量的水中,搅拌,持续通入臭氧,反应开始进行。反应pH值可以通过滴加稀盐酸或者稀NaOH溶液调节至3-13之间,优选4-10,更优选6-8。温度优选为0-70℃,更优选10-45℃。反应完成以后,停止通入臭氧,调节pH至中性。
膜分离纯化。将上述所得的反应产物配成约10%浓度的溶液,通过分子截留膜分离,去除单糖以下的降解产物,收集未透过液。所采用的分子截留膜MWCO规格为1000Da-3000Da,优选2000Da。收集液经旋转蒸发仪浓缩、真空干燥即得寡聚甘露糖醛二酸混合物。经分析发现这些产品均是以二糖-十糖的寡糖且其含量是在一定比例范围的组合物。实施例1-3是该方法步骤的实例。
(2)单一聚合度寡糖的制备
将步骤(1)所得的寡糖混合物溶解,配成约10%左右的浓度,经P6凝胶色谱柱分离,紫外检测,收集各流出组分,合并相同聚合度的组分。收集到2-10糖的9个组分,分别经G10凝胶柱层析脱盐,旋转蒸发仪浓缩,真空干燥即得。一个具体的纯化制备过程可见实施例4。这些柱层析、脱盐和干燥等操作是本领域技术人员所已知的。
将这9个单一聚合度的寡糖分别用抗糖尿病动物模型评价药理活性,发现六糖的活性最好。
(3)寡糖组合物的活性比较
对所制备的本发明的寡糖组合物与经纯化的六糖进行实验以比较药理活性,结果表明本发明的寡糖组合物比单一聚合度寡糖中活性最好的六糖还要好,而包含高含量的二、三糖的组合物的活性略低于六糖。由此看出,单个寡糖经复配后能发挥协同增效的作用,当组合物中二-六糖的比例高于60%以上,且二、三糖的比例低于60%时,组合物的活性最高;但二、三糖的比例超过60%时,组合物的活性也会降低。
动物模型及药效活性评价步骤
1、甘露寡糖二酸对胰淀素损伤胰岛β细胞的保护作用
人胰岛β细胞NIT株用含10%FBS的DMEM培养基培养,以1×104个/孔接种于96孔板,细胞融合后,加入100μg/ml单一聚合度甘露寡糖二酸作用24小时,正常对照组和模型组加入等量的生理盐水;模型组和单一聚合度寡糖组加入终浓度为30μM老化的胰淀素(amylin,又称胰岛淀粉样蛋白多肽,简称IAPP),正常对照组加入等量生理盐水,继续培养48小时后,以MTT法测定细胞的存活。
2、抗糖尿病的药效评价动物模型
取雄性NIH小鼠,随机为正常对照组、模型组、给药组,每组10只。试验当天,除正常组外,其余动物均腹腔注射链脲霉素150mg/kg。连续给予相应药物10天,第11天摘眼球取血,测血糖浓度。
本发明的优点在以下非限制性的实施例中进一步进行说明。但实施例中采用的具体材料及其用量,以及其他实验条件并不应理解为对本发明的限制。除非特别指明,本发明中份数、比例、百分比等均以质量计。
实施例
实施例1:
步骤1):甘露糖醛二酸寡糖混合物的制备
如在先专利所披露的方法制备M段中间体,具体操作简述如下:将5Kg海藻酸钠配成约10%的溶液,加稀盐酸调pH至3.0左右,升温至80℃,搅拌,反应10hr,停止加热,冷却至室温后,加NaOH调pH值至9.0,再加稀盐酸回调pH至2.85,离心机5000rpm离心10min,收集上清,加HCl调pH至1.0,离心,收集沉淀,旋转蒸发仪浓缩,真空干燥得M段中间体1500g。称取500g M-段中间体,加蒸馏水溶解后,配成5L体积的溶液,NaOH调pH至6.5,水浴加热,控制反应温度到75℃。调节氧气钢瓶出口的气流量和臭氧发生器的功率,使得臭氧质量浓度流量达到8g/hr,通入反应液中。反应4hr后停止通入臭氧,加适量水调整溶液浓度至10%左右,以截留分子量为2000Da的超滤膜过滤,收集未透过液,旋转蒸发仪浓缩,真空干燥,得350g甘露糖醛二酸产品A。
步骤2):甘露糖醛二酸产品A中各聚合度寡糖的比例和结构分析
精密称取100mg上述干燥的甘露糖醛二酸产品A,加水溶解配制成10mg/mL的浓度,过0.22um滤膜,做为供试样品溶液。采用Superdex peptide(GE公司)分子排阻色谱联用多角度激光散射(MALS,怀雅特公司)测定组合物中不同聚合度寡糖的比例。实验方法如下:
色谱柱:Superdex peptide 10/300G1
流动相:0.1mol/L NaCl
进样量:10uL
流速:0.3mL/min
测试结果:二糖-十糖分别以dp2-dp10表示,分别为dp2为19%,dp3为25%,dp4为22%,dp5为13%,dp6为9%,dp7为6%,dp8为3%,dp9为2%,dp10为1%。
步骤3):LC-MS分析甘露糖醛二酸产品A中各聚合度寡糖的结构
实验条件:
色谱柱:Superdex peptide 10/300G1
流动相:20%甲醇+80%80mmol/L NH4Ac
流速:0.1mL/min
柱温:25℃±0.8℃。
质谱条件:Agilent 6540 QTOF;离子源:ESI碰撞电压120V;负离子模式。采集信号(m/z)宽度为100-1000。
各聚合度寡糖的质谱图见附图1-3所示。对质谱图中各信号峰进行归属,验证了产品A中所有寡糖的分子结构,即通式(III)所示的结构。信号归属及该信号所对应的结构见下表1。
由上述质谱结构解析发现,产品A中糖链还原末端的甘露糖醛酸氧化为糖二酸结构(结构见通式III),该糖二酸可以是含6个碳(m+m’=3)的甘露糖二酸结构,含量约为10%~30%,也可以是甘露糖二酸的脱羧产物,即5个碳(m+m’=2)的糖二酸(30~50%)和4个碳(m+m’=1)的糖二酸(30%~40%)。
实施例2:
称取100g实施例1中的M-段中间体,加蒸馏水溶解后,配成0.8L体积的溶液,NaOH调pH至4.0,室温25℃反应。调节氧气钢瓶出口的气流量和臭氧发生器的功率,使得臭氧质量浓度流量达到1g/hr,通入反应液中。反应10hr后停止通入臭氧,加适量水调整溶液浓度至15%左右,以截留分子量为1000Da的超滤膜过滤,收集未透过液,旋转蒸发仪浓缩,真空干燥,得80g甘露糖醛二酸产品B。
采用Superdex peptide(GE公司)分子排阻色谱联用多角度激光散射(MALS,怀雅特公司)测定B中各聚合度寡糖组分的比例。测定方法同实施例1中相关部分。测试结果:二糖-十糖分别以dp2-dp10表示,分别为dp2为20%,dp3为25%,dp4为19%,dp5为12%,dp6为9%,dp7为5%,dp8为5%,dp9为3%,dp10为2%。
实施例3:
称取100g实施例1中的M-段中间体,加蒸馏水溶解后,配成1.5L体积的溶液,NaOH调pH至9.0,水浴45℃反应。调节氧气钢瓶出口的气流量和臭氧发生器的功率,使得臭氧质量浓度流量达到3g/hr,通入反应液中。反应2hr后停止通入臭氧,加适量水调整溶液浓度至5%左右,以截留分子量为3000Da的超滤膜过滤,收集未透过液,旋转蒸发仪浓缩,真空干燥,得60g甘露糖醛二酸产品C。
采用Superdex peptide(GE公司)分子排阻色谱联用多角度激光散射(MALS,怀雅特公司)测定C中各聚合度寡糖组分的比例。测定方法同实施例1中相关部分。测试结果:二糖-十糖分别以dp2-dp10表示,分别为dp2为8%,dp3为20%,dp4为28%,dp5为19%,dp6为13%,dp7为6%,dp8为3%,dp9为2%,dp10为1%。
实施例4:
步骤1)单一聚合度的甘露糖醛二酸寡糖的制备,方法如下:
1、样品准备:由实施例1中制备得到的甘露糖醛二酸产品A中取出300g,加水溶解,配置成1000mL的浓溶液,放置在4℃冰箱备用。每次使用时取出50mL加水稀释1倍后,用0.22um超滤膜抽滤。
2、色谱分离条件:色谱仪为AKTA pure 150(购置于GE公司),配UV检测器和自动收集器。分离色谱柱:1.2kg BioGel P6(购于伯乐公司)用去离子水混合,真空脱气以后,手动填装到玻璃柱(10cm内径)中,纯水冲洗10倍柱体积以后,色谱柱床稳定,高度为1.0m。然后改用0.02M的NaCl溶液为流动相,平衡10倍柱体积以后,开始上样。
3、上样和分离:泵的流速设置为1mL/min,将100mL的样品溶液通过色谱仪自带的泵抽到色谱柱顶端后,切换到流动相,以5mL/min的流速洗脱,待死水体积部分流出以后,开始自动收集,每管收集50mL。
4、重复上样,20次重复制备以后,合并相同组分,旋转蒸发仪浓缩,冷冻干燥,得到二糖至十糖共9个单一聚合度的寡糖。
步骤2)药理活性评价
单一聚合度的甘露寡糖二酸寡糖的药理活性评价步骤如下:
取二糖-十糖各10g,实验过程按照“甘露寡糖二酸对胰淀素损伤胰岛β细胞的保护作用”的方法进行。
结果发现IAPP模型组与正常对照组相比,细胞活力明显降低。而各个单一聚合度寡糖组均有增加细胞活力的趋势,其中聚合度4-10的单一聚合度甘露糖醛二酸寡糖均可明显增加细胞活力,5-8四种聚合度寡糖作用尤佳。六糖的活性最佳,见附图4。
实施例5
组合物与六糖之间的药理活性评价,考察组合物中不同聚合度寡糖之间的协同增效作用及寡糖比例范围。
样品准备:
组合物产品D:实施例4中制备得到的单一聚合度的甘露糖醛二酸寡糖,按照聚合度的大小从二糖到十糖准确称量,各糖取出的重量如下:二糖3.0g,三糖3.0g,四糖1.5g,五糖1.5g,六糖0.4g,七糖0.2g,八糖0.2g,九糖0.1g,十糖0.1g,混匀得10g组合物产品D。
实施例1、2、3中分别制备得到的产品A、B、C、本实施例中的产品D的寡糖比例如下表2所示。
表2甘露糖醛二酸寡糖组合物产品及对比试验样品中的寡糖百分比
以上A、B、C、D四个样品各取10g,按照“抗糖尿病的药效评价动物模型”所描述的方法,比较这些组合物与六糖(6T)的药理活性。
实验中,模型组与正常对照组相比较,前者餐后血糖明显升高,说明该评价模型造模成功。与模型组相比,各个给药组餐后血糖明显降低,其中产品A、B、C的药效活性均好于之前预期的活性最高的单一聚合度的六糖,但产品D的活性弱于六糖。不囿于任何理论,推测组合物中各寡糖之间的比例对于产品的活性有显著影响,添加一定比例的二糖、三糖有协同增效作用,但当二糖、三糖的比例过高时则会降低组合物的活性,见附图5。
Claims (14)
2.根据权利要求1所述的用途,其中所述的甘露糖醛二酸寡糖组合物中,n=1-2的甘露糖醛二酸的重量总和占所述组合物总重量的10-50%,优选25-50%。
3.根据权利要求1所述的用途,其中所述的甘露糖醛二酸寡糖组合物中,n=1-3的甘露糖醛二酸的重量总和与n=4-7的甘露糖醛二酸重量总和的比例在1.0-3.5之间。
4.根据权利要求1所述的用途,其中所述的甘露糖醛二酸寡糖组合物中,m+m’=1或2的甘露糖醛二酸的重量总和不低于所述组合物总重量的50%以上,优选60%-90%,更优选70%-90%。
5.根据权利要求5所述的用途,其中m+m’=1的甘露糖醛二酸的重量总和不低于所述组合物总重量的10%,优选30-40%。
6.根据权利要求5所述的用途,其中m+m’=2的甘露糖醛二酸的重量总和不低于所述组合物总重量的10%,优选30-50%。
7.根据权利要求1所述的用途,其中n=1-5的甘露糖醛二酸的重量总和占所述组合物总重量的80-95%。
8.根据权利要求1所述的用途,其中n=1-3的甘露糖醛二酸的重量总和占所述组合物总重量的20-70%。
9.根据权利要求4所述的用途,其中n=1-3的甘露糖醛二酸的重量总和与n=4-7的甘露糖醛二酸重量总和的比例在1.0-3.0之间。
10.根据权利要求1-9任一项所述的用途,其中各聚合度甘露糖醛二酸在所述组合物中的重量百分含量为:二糖5-25%,三糖15-30%,四糖15-28%,五糖5-25%,六糖2-20%,七糖2-20%,八糖2-20%,九糖2-20%,十糖2-20%。
11.据权利要求11所述的用途,其中各聚合度甘露糖醛二酸在所述组合物中的重量百分含量为:二糖5-25%,三糖15-30%,四糖15-28%,五糖10-20%,六糖5-15%,七糖3-10%,八糖2-5%,九糖1-5%,十糖1-5%。
12.根据权利要求12所述的用途,其中各聚合度甘露糖醛二酸在所述组合物中的重量百分含量为:二糖10-20%,三糖18-30%,四糖15-28%,五糖15-20%,六糖5-10%,七糖3-5%,八糖2-5%,九糖1-3%,十糖1-3%。
13.根据权利要求1-13所述的用途,其中所述药学上可接受的盐是钠盐或钾盐。
14.一种治疗患有糖尿病的患者的方法,其包括给予需要的患者有效量的根据权利要求1-14任一项所述的甘露糖醛二酸寡糖组合物。
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