CN108472325B - 包含蜂斗菜叶提取物的用于改善记忆力的组合物 - Google Patents
包含蜂斗菜叶提取物的用于改善记忆力的组合物 Download PDFInfo
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- CN108472325B CN108472325B CN201680076348.6A CN201680076348A CN108472325B CN 108472325 B CN108472325 B CN 108472325B CN 201680076348 A CN201680076348 A CN 201680076348A CN 108472325 B CN108472325 B CN 108472325B
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Abstract
本发明涉及具有记忆力改善效果的蜂斗菜叶提取物的制备方法及包含蜂斗菜叶提取物的用于改善记忆力的组合物。由本发明的制备方法获得的蜂斗菜叶提取物对神经细胞的保护及再生具有优秀的效果。
Description
技术领域
本发明涉及具有记忆力改善效果的蜂斗菜叶提取物的制备方法及包含蜂斗菜叶提取物的用于改善记忆力的组合物。
背景技术
有关记忆力改善的研究中，主要从生药等天然物提取或者利用复合提取物，动物实验表明一部分的认知能力得以改善，但是局限于呈现出微不足道的水平的改善效果，且依赖于明确的机制或者作用部位不明的实验结果的情况较多，利用生药的单一提取物或者基于韩医学处方的复合提取物包含实际毒性，大量摄取时，存在对肝造成毒性的问题。并且，用于制备蜂斗菜提取物的现有的研究利用因包括连续使用作为有机溶剂的乙醇、己烷、丁醇的提取过程而在每个过程中执行用于去除溶剂的减压浓缩的方法，但是这种过程需要很长时间且在复杂的过程中发生失误的可能性高，由于在提取过程中使用己烷、丁醇等对人体有害的化学物质，因此不仅需要额外的提取设施，而且有效成分的收率低至1％左右，因此具有经济效益下降的缺点。
相关现有技术(授权专利第10-0535655号)中记载了利用乙醇提取的具有抗氧化活性的蜂斗菜提取物及包含其的用于预防及治疗脑疾病的抗氧化剂，但是需要开发从蜂斗菜叶以最佳方式仅提取具有神经细胞保护效果的成分的制备方法，为此，本发明人开发了如下的方法，即，用水提取蜂斗菜叶后，进行冷冻干燥后，制备乙醇沉淀物的方法获得了具有直接保护海马的神经细胞的效果的成分，而不是进行简单的水提取或者乙醇提取来提取蜂斗菜叶，并通过口服给药可直接作用于代谢后的脑组织，且由于没有毒性，即使长期摄取也没有副作用。
发明内容
技术问题
本发明的目的在于，提供一种制备蜂斗菜叶提取物的方法，包括：(a)步骤，向蜂斗菜叶中添加水来进行提取；(b)步骤，对上述蜂斗菜叶的提取物进行冷冻干燥；(c)步骤，向上述蜂斗菜叶的提取物的冷冻干燥水中添加乙醇后进行沉淀；以及(d)步骤，去除通过上述(c)步骤提到的沉淀物的上清液并对沉淀物进行冷冻干燥。
解决问题的方案
本发明为了实现上述目的，提供一种制备蜂斗菜叶提取物的方法，包括：(a)步骤，向蜂斗菜叶中添加水来进行提取；(b)步骤，对上述蜂斗菜叶的提取物进行冷冻干燥；(c)步骤，向上述蜂斗菜叶的提取物的冷冻干燥水中添加乙醇后进行沉淀；以及(d)步骤，去除通过上述(c)步骤提到的沉淀物的上清液并对沉淀物进行冷冻干燥。
制备蜂斗菜叶提取物的方法的特征在于，在上述(c)步骤中，乙醇为50％至80％乙醇，在常温下进行沉淀20小时至30小时。
在本发明中，制备蜂斗菜叶提取物的方法的特征可在于，上述蜂斗菜叶提取物具有记忆力改善能力，包含选自由3，5-二-O-咖啡酰奎宁酸(3，5-di-O-caffeoylquinicacid)、4，5-二-O-咖啡酰奎宁酸(4，5-di-O-caffeoylquinic acid)、3，4-二-O-咖啡酰奎宁酸(3，4-di-O-caffeoylquinic acid)及6，7-二羟基-4-(3，4-二羟基苯)萘-2-羧酸(6，7-dihydroxy-4-(3，4-dihydroxyphenyl)naphthalene-2-carboxylic acid)组成的组中的成分。
本发明还提供用于改善记忆力的药学组合物及健康功能食品，包含由上述方法获得的蜂斗菜叶提取物。
上述药学组合物的特征可在于，具有神经细胞的保护及再生效果，施用于口服、皮下、静脉内、肌肉内、鼻腔内或腹腔内，被制备成片剂、胶囊剂、颗粒剂、丸剂、糖浆剂、液剂、油剂、悬浮剂或注射剂的形态。并且，上述健康功能食品的特征可在于，具有神经细胞的保护及再生效果，还包含载体、稀释剂、赋形剂及添加剂中的一种以上，并被制成选自由片剂、丸剂、散剂、颗粒剂、粉末剂、胶囊剂及液剂剂型组成的组中的一种剂型。
在本发明中，上述药学组合物或健康功能食品的特征可在于，包含选自由3，5-二-O-咖啡酰奎宁酸、4，5-二-O-咖啡酰奎宁酸、3，4-二-O-咖啡酰奎宁酸及6，7-二羟基-4-(3，4-二羟基苯)萘-2-羧酸组成的组中的成分。
由于蜂斗菜叶的各种成分与通过现有的水提取或酒精提取的蜂斗菜叶提取物一同被提取，仅有效提取具有保护神经细胞效果的成分是有限的。
在本发明中，若用水提取蜂斗菜叶后未经冷冻干燥的步骤，蜂斗菜叶水提取的不必要成分不溶解于乙醇中。在使用乙醇为50％至80％乙醇的情况下，不必要的成分溶解得很好，尤其使用乙醇为70％时，蜂斗菜叶水提取冷冻干燥品的不必要成分溶解得很好，因此，可通过去除溶解有不必要成分的上清液并仅回收沉淀物来获得有用的蜂斗菜叶提取物。在本发明中，蜂斗菜叶依次经水提取的步骤、冷冻干燥的步骤、乙醇提取的步骤，可通过有效去除蜂斗菜叶的不必要成分并仅回收有用的成分来获得具有保护神经细胞效果的蜂斗菜叶提取物。
本发明的用于改善记忆力的健康功能食品的特征在于，还包含载体、稀释剂、赋形剂及添加剂中的一种以上，可被制成选自由片剂、丸剂、散剂、颗粒剂、粉末剂、胶囊剂及液剂剂型组成的组中的一种剂型。可添加本发明的提取物的食品有各种食品类、粉末、颗粒、片剂、胶囊、糖浆剂、饮料、口香糖、茶、维生素复合剂、保健功能食品类等。作为还可包含在本发明的上述添加剂，可使用选自由天然碳水化合物、调味剂、营养剂、维生素、矿物质(电解质)、风味剂(合成风味剂、天然风味剂等)、着色剂、填充剂(奶酪、巧克力等)、果胶酸及其盐、海藻酸及其盐、有机酸、保护胶体增稠剂、pH调节剂、稳定化剂、防腐剂、抗氧化剂、甘油、酒精、碳酸化剂及果肉组成的组中的一种以上成分。作为如上所述的天然碳酸化合物的例有普通的糖及糖醇，上述普通的糖包括：单糖，例如，葡萄糖、果糖等；二糖，例如，麦芽糖、蔗糖等；以及多糖，例如，糊精、环糊精等，上述糖醇包括木糖醇、山梨醇、赤藓糖醇等。作为上述调味剂可使用天然调味剂(马丁、甜菊提取物(例如，莱鲍迪甙A、甘草甜素等)及合成调味剂(糖精、阿斯巴甜等)。
除如上所述的成分以外，本发明的组合物可包含多种营养剂、维生素、矿物质(电解质)、风味剂，如合成风味剂及天然风味剂、着色剂及填充剂(奶酪、巧克力等)、果胶酸及其盐、海藻酸及其盐、有机酸、保护胶体增稠剂，pH调节剂、稳定化剂、防腐剂、甘油、酒精、使用于碳酸饮料的碳酸化剂等。此外，本发明的组合物可包含用于制备天然果汁及蔬菜汁的果肉。这些成分可单独使用或组合使用。
上述载体、赋形剂、稀释剂及添加剂的具体例并不局限于此，优选地，选自乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、赤藓糖醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、明胶、磷酸钙、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、聚乙烯吡咯烷酮、甲基纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁及矿物油组成的组中的一种以上。
在对本发明的用于改善记忆力的健康功能食品进行制剂化的情况下，通过使用通常使用的填充剂、增量剂、粘合剂、润湿剂、崩解剂、表面活性剂等稀释剂或赋形剂来制备。作为上述的剂型内有效成分为本发明的提取物的含量可根据使用形态及目的、患者状态、症状的类型及轻重等进行适当的调节，以固体成为重量为基准为0.001重量百分比至99.9重量百分比，优选地可以为0.01重量百分比至50重量百分比，但并不局限于此。
另一方面，蜂斗菜(俗称：款冬(Butterbur)或学名：Petasites japonicus)是在欧洲及部分亚洲及北美发现的多年生灌木。2000多年来，从蜂斗菜的根及叶分离的提取物被用作治疗剂。如今报告指出，蜂斗菜提取物主要适用于放松肌肉，用于治疗胃肠内腹痛、平滑肌的痉挛，且具有缓解疼痛的效果并可使用于头痛(Eaton J.，Townsend Lett，2000，202，104-106)。并且，据报告，蜂斗菜对哮喘和过敏性疾病具有治疗效果(Thomet OA，SimonHU，Int Arch Allergy Immunol，2002，129(2)，108-12)。
发明效果
通过本发明的制备方法获得的蜂斗菜叶提取物具有对神经细胞的保护及再生具有的优秀的效果。
附图说明
图1为示出蜂斗菜叶提取物的细胞存活率；
图2为示出按KP-1的浓度给药的细胞毒性结果；
图3为示出按KP-1的浓度给药的具有保护神经细胞的效果；
图4为示出KP-1的第一次分离物F1-F8的细胞存活率；
图5为示出KP-1的第二次分离物f3-f11的细胞存活率；
图6为确认按KP-1的浓度给药的记忆力改善效果；
图7为观察实验鼠的海马组织的组织损伤与否及恢复与否；
图8为确认按KP-1的浓度给药的海马组织的组织再生及保护效果；
图9为确认在简单的水提取、乙醇提取中未出现保护神经细胞的效果。
具体实施方式
以下，通过实施例进一步详细说明本发明。对于本技术领域的普通技术人员而言，这些实施例仅用于具体说明本发明，根据本发明的主旨本发明的范围并不局限于这些实施例是显而易见的。
实施例1
确认蜂斗菜叶提取物(KP-1)的制备及细胞毒性和神经细胞保护效果
向1kg的蜂斗菜叶中添加20倍的水来进行提取后，通过对提取物进行冷冻干燥来获得了250g的冷冻干燥品(相对于蜂斗菜叶为25％)。然后，向蜂斗菜叶水提取冷冻干燥品中添加70％乙醇，在常温下洗脱24小时。经24小时后，去除溶解有不必要的物质的上清液，回收仅剩有蜂斗菜叶提取物的沉淀物，通过进行冷冻干燥来获得了150g的冷冻干燥品(相对于水提取冷冻干燥品为60％)。最终收率相对于使用的蜂斗菜叶为15％，相对于蜂斗菜叶水提取冷冻干燥品为60％。如下述表1所示，通过蜂斗菜叶的提取方法制备样品并确认了细胞毒性和神经细胞保护效果。其结果，在样品4中呈现出最佳的效果，将其命名为KP-1(图1)。
表1
| 试样名 | 提取方法 |
| 样品1 | 授权专利第10-0535655号的制备方法 |
| 样品2 | 蜂斗菜水提取物冷冻干燥品在-25℃的温度下的乙醇沉淀的上清液 |
| 样品3 | 蜂斗菜水提取物冷冻干燥品在常温下的乙醇沉淀的上清液 |
| 样品4 | 蜂斗菜水提取物冷冻干燥品在常温下的乙醇沉淀的沉淀物 |
| 样品5 | 蜂斗菜水提取物冷冻干燥品的树脂柱水分离物质 |
| 样品6 | 蜂斗菜水提取物冷冻干燥品的树脂柱乙醇分离物质 |
将作为主管记忆力的海马的细胞组织的HT22细胞在96孔细胞培养板(1×104细胞/孔)中含有10％的FBS(热非活性)、1％的PS的DMEM培养基中培养24小时后，仅处理试样(细胞毒性)或者处理试样及Aβ毒性(神经保护功效)，在37℃的温度下培养12小时后，加入3-(4，5-二甲基噻唑-2-基)-2，5-二苯基溴化四唑(3-(4，5-Dimethylthiazol-2-yl)-2，5-Diphenyltetrazolium Bromide，MTT)溶液进行反应2小时后，在570nm下测定吸光度并进行评价。确认通过按KP-1的浓度给药的细胞毒的结果，确认到没有毒性(图2)。并且，确认通过按KP-1的浓度给药的神经细胞保护效果的结果，在300μm/ml的KP-1中呈现出80％以上的细胞存活率(图3)。
实施例2
确认蜂斗菜叶提取物(KP-1)的有效成分
为了探索KP-1的有效成分，利用树脂DIAION HP-20将KP-1分离成F1-F8后，将呈现出最高细胞存活率的F4命名为KP-1F4(图4)。用SEPHADEX LH2将KP-1F4第二次分离至f1-f11。其结果，f1及f2在预实验中没有活性，在f9和f11中呈现出75％以上的细胞存活率(图5)。通过液相色谱-质谱联用仪(LC-MASS)及核磁共振(NMR)对f9及f11进行有效成分纯化，经确认，f9的成分为下述化学式1至化学式3，f11的成分为下述化学式4。
化学式1：
3，5-二-O-咖啡酰奎宁酸
化学式2：
4，5-二-O-咖啡酰奎宁酸
化学式3：
3，4-二-O-咖啡酰奎宁酸
化学式4：
6，7-二羟基-4-(3，4-二羟基苯)萘-2-羧酸
实施例3
确认蜂斗菜叶提取物的记忆力改善效果
将ICR(雄性(male)，7周龄)驯化及饲养一周来使用。将本实验的饲养环境设定为温度为20～24℃、相对湿度为50～60％、换气次数为15次/小时、明暗照明时间为12小时(07:00～19:00)、粗度为150-200Lux并在此处进行饲养，使ICR自由摄取小鼠用固体饲料和水。根据遵守美国国立卫生研究院(NIH，National Institutes of Health)提出的基准(No.86-23，revised 1985)的庆熙大学动物饲养规定进行饲养。
为了确认在Aβ诱导阿尔茨海默型痴呆模型中的蜂斗菜叶提取物的记忆力改善功效而进行了被动回避实验。通过利用小鼠的从明处要到暗处的习性在暗处利用了施加电击的装置。利用隔板将箱子分成两个区域，一旦动物进入暗处就直接使0.5mA的电流通过地板的不锈钢网格3秒钟以施加电击，测定小鼠进入打开照明的区域后直到关闭入口的时间(潜伏(latency))。24小时后，测定再次置于明亮区时直到进入暗区的时间，最大测定时间为5分钟。由其结果确认，在给药蜂斗菜叶提取物的情况下，具有显著的记忆力改善效果。如图6所示，在给药3μm/ml、10μm/ml、30μm/ml的KP-1的情况下，均具有显著的记忆力改善效果((a)正常对照组：口服给药生理食盐水来代替蜂斗菜试样并没有诱导记忆力减退的组、(b)Aβ诱导记忆力减退的对照组：口服给药生理食盐水来代替蜂斗菜试样并通过Aβ立体定向注射(stereotaxic injection)来诱导记忆力减退的组、(c)阳性对照组：口服给药多奈哌齐(donepezil)并通过Aβ立体定向注射来降低认知功能的组、(d)蜂斗菜给药组：口服给药蜂斗菜试样并通过Aβ立体定向注射来降低认知功能的组)。
实施例4
确认脑组织内海马细胞活性
动物实验结果，蜂斗菜叶提取物具有记忆力改善效果，但是为了确认更加客观的功效，切割动物行为实验鼠的海马组织后，客观地观察组织损伤与否及恢复与否。用PBS清洗海马细胞的CA1部位的组织切片后，与甲酚紫(cresyl violet)试剂进行反应，经组织脱水及透明化过程后用显微镜进行观察(甲酚紫染色)。用0.6％的过氧化氢和PBS清洗组织切片后，在4℃的温度下使10％的正常血清(normal serum)与第一抗体进行反应过夜后，在37℃的温度下与第二抗体再次进行反应1小时，经ABC和DAB显色过程后用显微镜进行观察(免疫组织化学染色)(图7)。对组织染色结果进行定量化的结果，在给药3μm/ml、10μm/ml、30μm/ml的KP-1的情况下，均在海马组织内CA1部位中显著呈现出组织再生及保护效果(图8)。
比较例
在进行简单的水提取、乙醇提取来提取蜂斗菜叶的情况下，对蜂斗菜叶提取物是否具有神经细胞保护效果进行实验的结果，因同时提取到蜂斗菜叶的多种成分，而没有有效渗透至组织，因此没有神经细胞保护效果(图9)。
Claims (10)
1.一种制备蜂斗菜叶提取物的方法，其特征在于，包括：
（a）步骤，向蜂斗菜叶中添加水来进行提取；
（b）步骤，对上述蜂斗菜叶的提取物进行冷冻干燥；
（c）步骤，向上述蜂斗菜叶的提取物的冷冻干燥水中添加70%乙醇后进行沉淀；以及
（d）步骤，去除通过上述（c）步骤提到的沉淀物的上清液并对沉淀物进行冷冻干燥，
在上述步骤（c）中，冷冻干燥水的不纯物溶解在乙醇中，所得到的沉淀物中包含选自由3，5-二-O-咖啡酰奎宁酸、4，5-二-O-咖啡酰奎宁酸、3，4-二-O-咖啡酰奎宁酸及6，7-二羟基-4-（3，4-二羟基苯）萘-2-羧酸组成的组中的成分。
2.根据权利要求1所述的制备蜂斗菜叶提取物的方法，其特征在于，在上述（c）步骤中，在常温下进行沉淀20小时至30小时。
3.根据权利要求1所述的制备蜂斗菜叶提取物的方法，其特征在于，上述蜂斗菜叶的提取物具有记忆力改善能力。
4.一种用于改善记忆力的药学组合物，其特征在于，包含通过权利要求1所述的制备蜂斗菜叶提取物的方法来获得的蜂斗菜叶提取物。
5.根据权利要求4所述的用于改善记忆力的药学组合物，其特征在于，上述药学组合物具有神经细胞的保护及再生效果。
6.根据权利要求4所述的用于改善记忆力的药学组合物，其特征在于，上述药学组合物施用于口服、皮下、静脉内、肌肉内、鼻腔内或腹腔内。
7.根据权利要求4所述的用于改善记忆力的药学组合物，其特征在于，上述药学组合物被制备成片剂、胶囊剂、颗粒剂、丸剂、液剂、油剂、悬浮剂或注射剂的形态。
8.一种用于改善记忆力的健康功能食品，其特征在于，包含通过权利要求1所述的制备蜂斗菜叶提取物的方法来获得的蜂斗菜叶提取物。
9.根据权利要求8所述的用于改善记忆力的健康功能食品，其特征在于，上述健康功能食品具有神经细胞的保护及再生效果。
10.根据权利要求8所述的用于改善记忆力的健康功能食品，其特征在于，上述健康功能食品还包含载体、稀释剂、赋形剂及添加剂中的一种以上，并被制成选自由片剂、丸剂、散剂、颗粒剂、粉末剂、胶囊剂及液剂剂型组成的组中的一种剂型。
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| CN102020623B (zh) * | 2010-12-15 | 2012-06-20 | 中国人民解放军第二军医大学 | 蜂斗菜提取物及其制备方法和用途 |
| KR20150085204A (ko) * | 2014-01-14 | 2015-07-23 | 주식회사 네이처바이오 | 천연물을 활용한 퇴행성 뇌질환 개선 소재 |
| CN105622776A (zh) * | 2016-03-10 | 2016-06-01 | 广西大学 | 款冬花多糖的提取与纯化方法 |
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2016
- 2016-06-08 KR KR1020160070868A patent/KR101689656B1/ko active IP Right Grant
- 2016-10-26 JP JP2018534843A patent/JP6735347B2/ja active Active
- 2016-10-26 WO PCT/KR2016/012051 patent/WO2017213306A1/ko active Application Filing
- 2016-10-26 CN CN201680076348.6A patent/CN108472325B/zh active Active
Also Published As
| Publication number | Publication date |
|---|---|
| WO2017213306A1 (ko) | 2017-12-14 |
| JP2019501181A (ja) | 2019-01-17 |
| KR101689656B1 (ko) | 2016-12-26 |
| JP6735347B2 (ja) | 2020-08-05 |
| CN108472325A (zh) | 2018-08-31 |
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