CN1842329B - 伴随肝损伤的肝脏疾病的预防剂或改善剂 - Google Patents
伴随肝损伤的肝脏疾病的预防剂或改善剂 Download PDFInfo
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Abstract
提供了以ω-9不饱和脂肪酸为活性成分的用于伴随肝损伤的肝脏疾病的预防剂或改善剂。
Description
技术领域
本发明涉及以ω-9不饱和脂肪酸为活性成分或以ω-9不饱和脂肪酸为组成脂肪酸的化合物为活性成分的针对伴随肝损伤的肝脏疾病的预防剂或改善剂、涉及对伴随肝损伤的肝脏疾病具有预防或改善作用的组合物或饮食品,并涉及其制备方法。更具体地,本发明涉及以选自ω-9不饱和脂肪酸、ω-9不饱和脂肪酸的醇酯、以ω-9不饱和脂肪酸为组成脂肪酸的甘油单酯、甘油二酯、甘油三酯和磷脂中的至少之一为活性成分的针对伴随肝损伤的急性或慢性肝炎、急性肝功能衰竭、肝硬变和/或肝细胞癌的预防剂或改善剂、涉及具有预防或改善作用的组合物或饮食品,并涉及其制备方法。
背景技术
由于病毒或多种毒性物质等造成的肝细胞破坏发展而来的肝损伤为引起急性或慢性肝炎、进一步地为引起肝硬变、肝细胞癌等的原因。尤其是急性肝炎与普通肝炎相比,前者存在自觉症状如恶心、呕吐、倦怠感等剧烈、高烧、白细胞数增多、CRP强阳性、黄疸也急剧变坏,已知有时导致成年前死亡。另外,即使没有成年前死亡,从慢性肝炎到肝硬变、肝细胞癌的病例极多,形成了极多的社会问题。
从肝炎的原因来看,特异性感染肝细胞的病毒(甲型肝炎病毒、乙型肝炎病毒、丙型肝炎病毒、丁型肝炎病毒、戊型肝炎病毒)为主要引起急性肝炎的原因,其中丙型病毒性肝炎占日本慢性肝病原因的大半,实际上占肝细胞癌原因的90%。由于自身免疫机制引起的肝损伤称为自身免疫性肝病,其除了自身免疫性肝炎外,还包括原发性胆汁性肝硬变(PBC)、原发性硬化性胆管炎(PSC)及其相关疾病。
醇类主要经肝脏代谢,慢性摄入醇类对肝脏的多种代谢***产生影响,从而引起高尿酸血症、高脂血症、高乳酸血症等。脂肪酸的代谢障碍引起中性脂肪的蓄积、刺激炎性细胞并引发肝炎,有时大量饮酒导致称为重症醇性肝炎的预后不良的急性肝功能衰竭。肝细胞中脂肪的蓄积起因于饮酒而产生的醇性或肥胖引起的营养过剩,这通常不会导致肝炎,但据报道有时伴随着类似醇性肝炎的炎症,偶尔最终引起肝硬变的例子。
肝硬变为所有慢性肝损伤的最终结果。在肝细胞障碍与再生的长期重复过程中,形成了肝脏的纤维化和再生结节。因此,表现出慢性肝损伤的所有肝脏疾病显示出肝细胞功能不全和门脉压亢进。在日本约40万肝硬变患者的病因几乎都是病毒性的,特别是由丙型肝炎病毒引起的为62%,由乙型肝炎病毒引起的为15%。病毒性肝硬变中肝细胞癌的发生率高,这极大影响肝硬变的预后。其他的病因有醇、药物及毒性物质、自身免疫、胆汁郁滞、循环障碍、代谢异常、寄生虫等。
作为治疗方法,对于可避免的病因(醇性、药剂型)避免病因是最重要的,对于病毒性(HBV、HCV)而言目前的治疗法仅为干扰素,其对HBV的效果几乎不可期待,对HCV的效果仅为30%至50%。最近,新研发出对于慢性乙型肝炎可与拉米夫定(lamivudine)(抗病毒剂)联用,对于慢性丙型肝炎可与利巴韦林(ribavirin)(抗病毒剂)联用。另一方面,对于不能清除病毒的病例,为了减缓肝损坏并抑制向肝硬变的发展,作为癌的二次或一次预防目的,可施与糖皮质激素、甘草皂甙制品、熊去氧胆酸等(药局Vol.54,增刊号,2003)。因此,当前以辅助治疗的肝保护疗法为主体,尚无无副作用的有效肝炎治疗剂和肝炎诱发抑制剂(Medical Digest;卷39(4):1990)。
发明公开
因此,非常希望研发出可预防或改善伴随肝损伤的肝脏疾病并与食物很好适应的副作用小的化合物。
本发明者们为了解决上述课题进行了大量研究,结果发现了显示极好的抑制肝损伤作用、预防或改善伴随肝损伤的肝脏疾病、显示极好的食品适应的ω-9不饱和脂肪酸或以ω-9不饱和脂肪酸为组成脂肪酸的化合物,从而完成了本发明。因此,本发明者们提供了以ω-9不饱和脂肪酸为活性成分或以ω-9不饱和脂肪酸为组成脂肪酸的化合物为活性成分的针对伴随肝损伤的肝脏疾病的预防剂或改善剂、提供了对伴随肝损伤的肝脏疾病具有预防或改善作用的组合物或饮食品,并提供了其制备方法。
更具体地,本发明提供了以选自ω-9不饱和脂肪酸、ω-9不饱和脂肪酸的醇酯、以ω-9不饱和脂肪酸为组成脂肪酸的甘油单酯、甘油二酯、甘油三酯和磷脂中的至少之一为活性成分的、针对伴随肝损伤的急性或慢性肝炎、急性肝功能衰竭、肝硬变和/或肝细胞癌的预防剂或改善剂;提供了具有预防或改善作用的组合物或饮食品,并提供了其制备方法。
附图简述:
图1为显示蜜酸(mead acid)对半乳糖胺肝损伤中肝功能标志物的效果图。图中对照代表对照食物组,N-3代表DHA食物组,N-9代表蜜酸食物组。施用GalN/LPS的组为每组15只小鼠,施用生理盐水的组为每组3只小鼠。
图2为显示蜜酸对半乳糖胺肝损伤中生存率的效果图。图中对照代表对照食物组,N-3代表DHA食物组,N-9代表蜜酸食物组。每组各使用10只小鼠。
实施发明的最佳实施方式
本发明涉及以ω-9不饱和脂肪酸为活性成分或以ω-9不饱和脂肪酸为组成脂肪酸的化合物为活性成分的针对伴随肝损伤的肝脏疾病的预防剂或改善剂、涉及对伴随肝损伤的肝脏疾病具有预防或改善作用的组合物或饮食品,并涉及其制备方法。本发明的活性成分ω-9不饱和脂肪酸是指与脂肪酸的甲基端最接近的双键位于自甲基开始数的第9位碳和第10位碳之间,具有2个或以上双键,优选地具有18至22个碳原子数,可包括例如6,9-十八碳二烯酸(18:2 ω9)、8,11-二十碳二烯酸(20:2 ω9)和5,8,11-二十碳三烯酸(20:3 ω9)等,它们可分别单独使用或组合使用。
另外,由于天然存在的ω-9不饱和脂肪酸均为顺式,本发明优选使用顺式的ω-9不饱和脂肪酸。
已知ω-9不饱和脂肪酸中如5,8,11-二十碳三烯酸(20:3 ω9,也称为蜜酸(mead acid))和8,11-二十碳二烯酸(20:2 ω9)可作为缺乏必需脂肪酸的动物组织的组成脂肪酸之一而存在。
这些不饱和脂肪酸在体内可成为白三烯3类的前体,其生理活性是很有前景的,已发明了“用白三烯B4(LTB4)作为医学疾病的预防剂和改善剂”(特开平07-041421)、“介导迟发型超敏反应的医学疾病的预防剂和改善剂”(特开平08-053349)、“引起软骨组织异常的疾病的预防药或治疗药”(WO97-05863),报道了其适用于抗炎、抗过敏、抗关节炎和变形性关节病。然而,根据现有技术,不能预见其对伴随肝损伤的肝脏疾病的预防作用,而本发明首次使用本发明的肝损伤模型动物评估而明确。
本发明的活性成分为ω-9不饱和脂肪酸,并且可使用以ω-9不饱和脂肪酸为组成脂肪酸的所有化合物。对于以ω-9不饱和脂肪酸为组成脂肪酸的化合物,可以游离脂肪酸形式使用,也可包括可药用的ω-9不饱和脂肪酸盐,如钠盐、钾盐、锂盐或其它的碱金属盐、锌盐、钙盐、镁盐等。另外,可例举ω-9不饱和脂肪酸的低级醇酯如ω-9不饱和脂肪酸甲酯、ω-9不饱和脂肪酸乙酯等。此外,可使用以ω-9不饱和脂肪酸为组成脂肪酸的甘油单酯、甘油二酯、甘油三酯、磷脂和糖酯等。另外,本发明不限于上述,可利用以ω-9不饱和脂肪酸为组成脂肪酸的所有化合物。
本发明使用的ω-9不饱和脂肪酸或以ω-9不饱和脂肪酸为组成脂肪酸的化合物可为任何来源。即,它们可来自能产生ω-9不饱和脂肪酸或以ω-9不饱和脂肪酸为组成脂肪酸的化合物的微生物,其也可由缺乏必需脂肪酸的动物组织、缺乏必需脂肪酸的动物培养细胞产生,也可通过化学或酶法合成,另外也可从天然物质如自动物软骨提取、分离和纯化而产生。
但是,考虑到应用于食品时,ω-9不饱和脂肪酸优选地为甘油单酯、甘油二酯、甘油三酯或磷脂的形式,特别优选地为甘油三酯的形式。虽然不存在包含ω-9不饱和脂肪酸的甘油三酯(与含有的部分或全部组成脂肪酸为ω-9不饱和脂肪酸的甘油三酯同义)的丰富来源,本发明者们使得以ω-9不饱和脂肪酸为组成脂肪酸的甘油三酯可工业应用。通过提供肝损伤模型动物,首次阐明了本发明活性成分的效果,明确了对伴随肝损伤的肝脏疾病具有预防或改善效果。
可产生包含ω-9不饱和脂肪酸的油脂(甘油三酯)的微生物例如为通过对属于被孢霉属(Mortierella)、耳霉属(Conidiobolus)、腐霉属(Pythium)、疫霉属(Phytophthora)、青霉属(Penicillium)、枝孢属(Cladosporium)、毛霉属(Mucor)、镰孢属(Fusarium)、曲霉属(Aspergillus)、红酵母属(Rhodotorula)、虫霉属(Entomophthora)、刺孢囊霉属(Echinosporangium)、水霉属(Saprolegnia)的并可产生花生四烯酸的微生物进行突变处理而得到的Δ12去饱和活性低下或缺乏的微生物。
可产生花生四烯酸的微生物能从作为培养基成分的碳源生物合成硬脂酸(18:0),硬脂酸在Δ9去饱和酶的作用下转化为油酸(18:1 ω9),油酸在Δ12去饱和酶的作用下转化为亚油酸(18:2 ω6),亚油酸在Δ6去饱和酶的作用下转化为γ-亚麻酸(18:3 ω6),γ-亚麻酸在延伸酶的作用下转化为二高γ-亚麻酸(20:3 ω6),二高γ-亚麻酸在Δ5去饱和酶的作用下转化为花生四烯酸(20:4 ω6)。但是,当阻断Δ12去饱和酶时,由Δ6去饱和酶自油酸生物合成产生6,9-十八碳二烯酸(18:2 ω9),在延伸酶的作用下自6,9-十八碳二烯酸生物合成产生8,11-二十碳二烯酸(20:2 ω9),然后在Δ5去饱和酶的作用下自8,11-二十碳二烯酸生物合成产生5,8,11-二十碳三烯酸(20:3ω9)。
具体地,作为可产生包含ω-9不饱和脂肪酸的油脂(甘油三酯)的微生物,包括但不限于通过对特开平5-91888号所述的可产生花生四烯酸的微生物进行突变处理而得到的、具有Δ5去饱和酶活性和Δ6去饱和酶活性且Δ12去饱和酶活性低下或缺乏的微生物,例如高山被孢霉(Mortierellaalpina)SAM1861(FERM BP-3590)(根据布达佩斯条约进行的国际保藏,于1991年9月30日保藏于独立行政法人产业技术综合研究所专利生物保藏中心(茨城县筑波市东1丁目1号1中央第6));进一步地,对可产生花生四烯酸的微生物进行突变处理而得到的、Δ12去饱和酶活性低下或缺乏且在具有Δ5去饱和活性、Δ6去饱和活性和/或链延伸活性中的至少之一得以提高的微生物,例如高山被孢霉SAM2086(FERM BP-6032)(根据布达佩斯条约进行的国际保藏,于1996年8月5日保藏于独立行政法人产业技术综合研究所专利生物保藏中心(茨城县筑波市东1丁目1号1中央第6))(自1996年8月5日保藏的国内保藏FERM P-15766于1997年7月30日转移为国际保藏)。
为了培养用于本发明的菌株,将所述菌株的胞子、菌丝或预培养得到的预培养液接种至液体培养基或固体培养基并培养。当为液体培养基时,作为碳源可使用通常使用的任一碳源,包括但不限于葡萄糖、果糖、鼠李糖、蔗糖、麦芽糖、可溶性淀粉、糖蜜、甘油和甘露糖醇等。
作为氮源,可使用蛋白胨、酵母提取物、麦芽提取物、肉膏、酪蛋白氨基酸、玉米浆、大豆蛋白、脱脂大豆、棉籽碾碎物等天然氮源、尿素等有机氮源、以及硝酸钠、硝酸铵、硫酸铵等无机氮源。此外,根据需要,可将磷酸盐、硫酸镁、硫酸铁、硫酸铜等无机盐和维生素等作为微量营养源使用。对这些培养基成分只要不为损害微生物生长的浓度,并无特定的限制。实践中,碳源的总添加量通常为0.1至40重量%,优选地为1至25重量%,氮源的总添加量通常为0.1至20重量%,优选地为1至10重量%,可在培养开始时或在培养过程中为了达到总碳源量和总氮源量而添加碳源及氮源。
ω-9不饱和脂肪酸产生菌的培养温度虽然取决于所使用的微生物,但可在5至40℃,优选地在20至30℃,或在20至30℃培养使菌体增殖然后在5至20℃继续培养,从而产生不饱和脂肪酸。通过这样的温度管理,所产生的脂肪酸中高度不饱和脂肪酸的比例可上升。培养基的pH为4至10,优选地为5至9,通过通气搅拌培养、振荡培养或静置培养进行。培养通常进行2至30天,优选地为5至20天,更优选地进行5至15天。
进一步地,作为提高含有ω-9不饱和脂肪酸的油脂(甘油三酯)中ω-9不饱和脂肪酸比例的方法,可对含有ω-9不饱和脂肪酸的油脂进行选择性加水分解而得到高含有ω-9不饱和脂肪酸的油脂。所述选择性加水分解所使用的脂肪酶对甘油三酯不具有位置特异性,由于加水分解活性与双键数成反比,不为高度不饱和脂肪酸的脂肪酸酯键被加水分解。这样,所产生的PUFA部分甘油酯间的酯交换反应等产生高度不饱和脂肪酸提高的甘油三酯(Enzymatic Fractionation and Enrichment of n-9 PUFA,J.Am.OilChem.Soc.,80,37-42(2003))。
因此,可将对含有ω-9不饱和脂肪酸的油脂(甘油三酯)进行选择性加水分解而得到的高含有ω-9不饱和脂肪酸的油脂(甘油三酯)作为本发明的活性成分。相对于含有本发明ω-9不饱和脂肪酸的油脂(甘油三酯)的总脂肪酸,ω-9不饱和脂肪酸的比率优选地高,以排除其他脂肪酸的影响,其中所述ω-9不饱和脂肪酸具体而言为至少一种或一种以上选自6,9-十八碳二烯酸(18:2 ω9)、8,11-二十碳二烯酸(20:2 ω9)及5,8,11-二十碳三烯酸(20:3 ω9)的ω-9不饱和脂肪酸。
然而,本发明不限于高比率,在实际中,当应用于食品时有时会碰上ω-9不饱和脂肪酸的绝对量,基本上可使用含有ω-9不饱和脂肪酸20%重量或以上,优选地30%重量或以上,更优选地40%重量或以上的油脂(甘油三酯)。进一步地,基本上可使用含有5,8,11-二十碳三烯酸(20:3 ω9)10%重量或以上,优选地20%重量或以上,更优选地30%重量或以上的油脂(甘油三酯)。
自可产生ω-9不饱和脂肪酸的微生物的培养菌体开始,通过菌体破坏,根据需要使干燥,用有机溶剂例如正己烷等进行提取处理或通过用超临界碳酸气提取处理可获得含有ω-9不饱和脂肪酸的油脂。另外,对上述油脂进行加水分解和酯化操作可获得含有ω-9不饱和脂肪酸的游离脂肪酸混合物或脂肪酸酯混合物。接下来,对上述游离脂肪酸混合物或脂肪酸酯混合物通过常规的尿素分级法、液液分配色谱、柱层析等,可获得纯度80%或以上的游离脂肪酸6,9-十八碳二烯酸、8,11-二十碳二烯酸及5,8,11-二十碳三烯酸以及脂肪酸酯。
另外,本发明的活性成分ω-9不饱和脂肪酸不必限于高纯度的纯化品,也可使用以ω-9不饱和脂肪酸为组成脂肪酸的化合物,具体而言为含有ω-9不饱和脂肪酸的甘油单酯、甘油二酯、甘油三酯、磷脂和糖脂。此外,可将以ω-9不饱和脂肪酸为组成脂肪酸的化合物单独使用或与含有ω-9不饱和脂肪酸的游离脂肪酸混合物或脂肪酸酯混合物组合使用。
本发明涉及以ω-9不饱和脂肪酸为活性成分或以ω-9不饱和脂肪酸为组成脂肪酸的化合物为活性成分的针对伴随肝损伤的肝脏疾病的预防剂或改善剂、涉及对伴随肝损伤的肝脏疾病具有预防或改善作用的组合物或饮食品,并涉及其制备方法。作为本发明对象的伴随肝损伤的肝脏疾病,可列举如病毒性肝炎、药物性肝炎、醇性肝炎或脂肪型肝炎等引起的急性肝炎或慢性肝炎等。进一步地,作为考虑了这些肝炎发展而发病的疾病,可列举急性肝功能衰竭、肝硬变、肝细胞癌等。
对伴随肝损伤的肝脏疾病具有预防或改善作用的饮食品的制备方法中,可将ω-9不饱和脂肪酸和/或以ω-9不饱和脂肪酸为组成脂肪酸的化合物单独使用,或与基本上不含有ω-9不饱和脂肪酸的饮食品原料或与既使含有也仅含有少量ω-9不饱和脂肪酸的饮食品原料组合使用。
特别地,在组成脂肪酸的部分或全部为ω-9不饱和脂肪酸的甘油三酯的情况下,油脂(甘油三酯)可用于无数种用途,可作为食品、饮料、化妆品、医药品的原料和添加物。因此,对其使用目的、使用量无任何限制。
例如,作为食品组合物,除了一般食品外,可例举功能性食品、营养品、补助食品、早产儿配方奶、婴幼儿配方奶、婴幼儿食品、孕产妇食品或老人用食品等。此外,根据医生的处方在营养师的管理下,在医院调配饭食时可向任一食品中加入本发明的ω-9不饱和脂肪酸和/或以ω-9不饱和脂肪酸为组成脂肪酸的化合物,以当场制备好的食品形式施与患者。
作为含油脂的食品例如有肉、鱼和坚果等本身含有油脂的天然食品、汤等在烹调时加入了油脂的食品、油炸圈饼(donut)等作为热介质而使用油脂的食品、奶油等油脂食品、小甜饼干等加工时加入油脂的加工食品、或硬饼干等加工结束时喷或涂上油脂的食品。进一步地,可将油脂添加至不含油脂的农产品、发酵食品、畜产品、水产品或饮料中。进一步地,它们可为功能性产品或药品的形式,例如可为经肠营养剂、粉末剂、颗粒剂、片剂、内服液、悬液、乳液、糖浆等加工形式。
另外,本发明的组合物除了含有本发明的活性成分外,还可含有通常在饮食品、药品或准药品中使用的多种载体或添加物。特别优选地含有防止本发明的活性成分氧化的抗氧化剂。抗氧化剂包括例如生育酚、黄酮衍生物、叶甜素、曲酸、没食子酸衍生物、儿茶酸、款冬酸、棉酚、吡嗪衍生物、芝麻酚、愈创木酚、愈创木酸、对香豆酸、去甲二氢愈创木酸、固醇类、萜类、核酸碱基类、类胡萝卜素类和木素类等天然抗氧化剂、以及以抗坏血酸-棕榈酸酯、抗坏血酸-硬脂酸酯、丁基羟基苯甲醚(BHA)、丁基羟基甲苯(BHT)、单-叔丁基羟基醌(TBHQ)和4-羟甲基-2,6-二叔丁基酚(HMBP)为代表的合成抗氧化剂。
在生育酚中,作为相关化合物,可提及α-生育酚、β-生育酚、γ-生育酚、δ-生育酚、ε-生育酚、ξ-生育酚、η-生育酚和生育酚酯(生育酚乙酸酯等)以及生育三烯酚。在类胡萝卜素中可提及例如β-胡萝卜素、角黄素、虾青素等。
本发明的组合物除了包含本发明的活性成分外,还可包含作为载体的多种载体、补充剂、稀释剂、填充剂、分散剂、赋形剂、结合剂溶剂(如水、乙醇、植物油)、助溶剂、缓冲剂、溶解促进剂、胶凝剂、混悬剂、小麦粉、米粉、淀粉、玉米淀粉、多糖、乳蛋白、胶原、米油、卵磷脂等。作为添加剂,包括但不限于例如维生素类、甜味剂、有机酸、着色剂、香料、防湿剂、纤维、电解质、矿物质、营养素、抗氧化剂、防腐剂、芳香剂、湿润剂、天然食物提取物、蔬菜提取物等。
当本发明的活性成分实际应用于饮食品时,食品中混合的ω-9不饱和脂肪酸的绝对量也变得重要。但是,在食品中混合的绝对量也随所混合的饮食品的摄取量而变化,因此当将含有组成脂肪酸的一部分或全部为ω-9不饱和脂肪酸的甘油三酯的甘油三酯与食品混合时,以ω-9不饱和脂肪酸的量为0.001重量%或以上、优选地0.01重量%或以上、更优选地0.1重量%或以上进行混合。进一步地,对5,8,11-二十碳三烯酸,可使用0.0003重量%或以上、优选地0.003重量%或以上、更优选地0.03重量%或以上,并且根据常规的制备法进行加工制备。
以对伴随肝损伤的疾病的预防改善或健康维持为目的,作为标准,将含有本发明的脂肪酸的饮食品以每天经口摄入本发明的脂肪酸0.001g至10g,优选地0.001g至5g,更优选地0.001g至2g。
本发明的组合物作为药品使用时,可按照制剂技术领域惯用的方法如日本药典中所记载的方法或根据所述方法的方法制造。
本发明的组合物作为药品使用时,对组合物中的活性成分的混合量没有特别的限制,只要能达到本发明的目的即可,可使用合适的混合比例。
本发明的组合物作为药品使用时,可以为任何剂型,只要经口施与或非经口施与可行即可,例如可列举注射剂、输注液、散剂、颗粒剂、锭剂、胶囊剂、肠溶剂、片剂、内用液剂、悬浮剂、乳剂、糖浆剂、外用液剂、湿布剂、滴鼻剂、滴耳剂、滴眼剂、吸入剂、软膏剂、洗剂、坐剂等,它们可根据相应的症状分别使用,特别地,优选经口施与。这些制剂可按照常规方法根据目的在主要成分中使用已知的辅助剂进行制剂,其中所述已知的辅助剂为稳定剂、防氧化剂、赋形剂、结合剂、崩解剂、润滑剂、矫味剂等在药物的制剂技术领域通常可使用的辅助剂。
本发明的组合物的施与量根据年龄、体重、症状、施与次数等而不同,例如成人(约60kg)一天施用本发明的ω-9不饱和脂肪酸和/或以ω-9不饱和脂肪酸为组成脂肪酸的化合物以ω-9不饱和脂肪酸换算通常约0.001g至20g,优选地0.01g至10g,更优选地0.05g至5g,最优选地0.1g至2g,一日1次-3次施与。进一步地,以5,8,11-二十碳三烯酸换算通常约0.0001g至10g,优选地0.001g至5g,更优选地0.01g至2g,最优选地0.05g至2g,一日1次-3次施与。
知道了本发明的活性成分脂肪酸为在生物体内缺乏必需脂肪酸的状态下被生物合成的生物体组分。通过对7周龄的ICR雄性小鼠以2g/kg/天连续施与(经口施与)2周,没有观察到任何异常的症状,可见在安全性方面也是良好的。
实施例:
下面通过实施例对本发明进一步具体地说明。但是,本发明不限于这些实施例。
参考例1 以ω-9不饱和脂肪酸为组成脂肪酸的甘油三酯的制备方法
将含有4%葡萄糖和1%酵母提取物的培养基(pH6.0)5L置于10L发酵罐中,于120℃灭菌30分钟。接种高山被孢霉(Mortierella alpina)的突变株SAM1861或SAM2086的100ml预培养液,通气量1vvm,搅拌数为300转/分钟,进行8天的通气搅拌培养。培养温度为:培养开始时为28℃,自培养第2天下降至20℃。培养的第1至4天,每天添加1%的葡萄糖。
培养结束后,通过过滤、干燥回收具有以ω-9不饱和脂肪酸为组成脂肪酸的菌体,自得到的菌体通过己烷提取获得油脂,经过食用油脂的纯化步骤(脱胶、脱酸、脱味、脱色)得到含有ω-9不饱和脂肪酸的甘油三酯(ω-9不饱和脂肪酸在甘油三酯的任一位置处结合)。
将得到的油脂(甘油三酯)甲酯化,对得到的脂肪酸甲酯气相色谱分析时,培养SAM1861株可得到6,9-十八碳二烯酸(18:2 ω9)、8,11-二十碳二烯酸(20:2 ω9)和5,8,11-二十碳三烯酸(20:3 ω9)占总脂肪酸比例分别为12.94%、3.29%、16.38%;培养SAM2086株可得到6,9-十八碳二烯酸(18:2 ω9)、8,11-二十碳二烯酸(20:2 ω9)和5,8,11-二十碳三烯酸(20:3 ω9)占总脂肪酸比例分别为12.41%、3.58%、20.87%。
进一步地,将上述含有ω-9不饱和脂肪酸的油脂(甘油三酯)乙酯化,因为为含有20%5,8,11-二十碳三烯酸乙酯的脂肪酸乙酯混合物,通过常规的高效液相色谱,可以分离纯化98%纯度的5,8,11-二十碳三烯酸乙酯。
实施例1通过肝损伤模型动物评价含有ω-9不饱和脂肪酸的油脂1
将8%棕榈油(对照食物)添加至市售饲料、将参考例1制备的6,9-十八碳二烯酸(18:2 ω9)、8,11-二十碳二烯酸(20:2 ω9)和5,8,11-二十碳三烯酸(20:3 ω9)占总脂肪酸比例分别为12.94%、3.29%、16.38%的比例形成组成脂肪酸的油脂SUNTGM17 8%(蜜酸食物)添加至市售饲料、以及将含有22%DHA的鱼油5%和三油精甘油酯3%的混合物(DHA食物)添加至市售饲料,施与4周龄雄性ddY品系小鼠3周后,使用生理盐水溶解D-半乳糖胺和脂多糖分别至800mg/kg和25μg/kg,将它们混合(GalN/LPS)并腹膜内施用。施用GalN/LPS 6周后取血,分离血清,测定血清中GPT、GOT活性,确认了虽然施用GalN/LPS使得诱发了肝损伤,GPT、GOT活性上升,但蜜酸食物组与对照食物组和DHA食物组相比GPT、GOT活性显著性降低,蜜酸明显地可抑制肝损伤,该抑制效果较DHA强(图1)。
实施例2通过肝损伤模型动物评价含有ω-9不饱和脂肪酸的油脂2
将8%棕榈油(对照食物)添加至市售饲料、与实施例1同样的SUNTGM17 8%(蜜酸食物)添加至市售饲料、以及将含有22%DHA的鱼油5%和三油精甘油酯3%的混合物(DHA食物)添加至市售饲料,施与4周龄雄性ddY品系小鼠3周后,使用生理盐水溶解D-半乳糖胺和脂多糖分别至800mg/kg和75μg/kg,将它们混合(GalN/LPS)并腹膜内施用。施用GalN/LPS后,每隔1小时调查生存数,直至24小时后。计算生存率时,蜜酸食物组的生存率明显高于对照组和DHA食物组(图2)。
实施例3通过肝损伤模型动物评价5,8,11-二十碳三烯酸乙酯
自参考例1制备的油脂SUNTGM17纯化的5,8,11-二十碳三烯酸乙酯(蜜酸)10mg/kg经口施用1周后,使用生理盐水溶解D-半乳糖胺和脂多糖分别至800mg/kg和25μg/kg,将它们混合(GalN/LPS)并腹膜内施用。施用GalN/LPS 6周后取血,分离血清,测定血清中GPT、GOT活性,在对照食物组中GOT活性为1024±94 IU/L,与之相比蜜酸施与组为413±37 IU/L,认为其可显著性抑制肝损伤。
实施例4制备胶囊
向明胶100重量份和食品添加剂甘油35重量份中加水,50至60℃溶解,制备粘度2000cp的明胶包衣。接下来,向自参考例1制备的以ω-9不饱和脂肪酸为组成脂肪酸的油脂(甘油三酯)混合0.05重量%的维生素E油,制备内容物1。然后向参考例1获得的98%5,8,11-二十碳三烯酸乙酯混合维生素E油0.05重量%,制备内容物2。使用这些内容物1和2,通过常规方法进行胶囊化和干燥,制备1粒中含有200mg内容物的软胶囊。
实施例5用于脂肪输注液中
加入参考例1获得的以ω-9不饱和脂肪酸为组成脂肪酸的油脂(甘油三酯)400g、纯化的卵黄卵磷脂48g、油酸20g、甘油100g和0.1N氢氧化钠40ml,使用匀浆器分散后,加入注射用蒸馏水至4L。将其使用高压喷雾式乳化器进行乳化,制备脂质乳液。将每200ml该脂质乳液分注入塑料袋中后,于121℃ 20分钟进行高压蒸汽灭菌处理,成为脂肪输注液。
实施例6用于汁液中
将2g β-环糊精添加至20%的乙醇水溶液20ml中,边用搅拌器搅拌边向其中加入参考例1获得的以ω-9不饱和脂肪酸为组成脂肪酸的油脂(甘油三酯)(混合有0.05重量%的维生素E)100mg,50℃孵育2小时。室温冷却(约1小时)后,接下来于搅拌的同时在4℃孵育10小时。通过离心回收所产生的沉淀,用正己烷洗净后,进行冷冻干燥,获得含有以ω-9不饱和脂肪酸为组成脂肪酸的油脂(甘油三酯)的环糊精包接物1.8g。将该粉末1g均匀混合至10L汁液中,制备了含有以ω-9不饱和脂肪酸为组成脂肪酸的油脂(甘油三酯)的汁液。
Claims (5)
1.具有2个或以上双键的ω-9不饱和脂肪酸或以具有2个或以上双键的ω-9不饱和脂肪酸为组成脂肪酸的化合物的用途,其用于制备伴随肝损伤的肝脏疾病的预防剂或改善剂,其中所述伴随肝损伤的肝脏疾病是病毒性肝炎、醇性肝炎或脂肪型肝炎引起的急性肝炎或慢性肝炎,所述以具有2个或以上双键的ω-9不饱和脂肪酸为组成脂肪酸的化合物是具有2个或以上双键的ω-9不饱和脂肪酸的醇酯、以具有2个或以上双键的ω-9不饱和脂肪酸为组成脂肪酸的甘油单酯、甘油二酯和/或甘油三酯、或者磷脂,所述以具有2个或以上双键的ω-9不饱和脂肪酸为组成脂肪酸的甘油三酯含有的具有2个或以上双键的ω-9不饱和脂肪酸相对于组成所述甘油三酯的总脂肪酸为20%以上,所述具有2个或以上双键的ω-9不饱和脂肪酸为至少一种选自6,9-十八碳二烯酸(18:2ω9)、8,11-二十碳二烯酸(20:2ω9)及5,8,11-二十碳三烯酸(20:3ω9)的ω-9不饱和脂肪酸。
2.根据权利要求1所述的用途,其中所述以具有2个或以上双键的ω-9不饱和脂肪酸为组成脂肪酸的甘油三酯是通过对属于被孢霉属(Mortierella)、耳霉属(Conidiobolus)、腐霉属(Pythium)、疫霉属(Phytophthora)、青霉属(Penicillium)、枝孢属(Cladosporium)、毛霉属(Mucor)、镰孢属(Fusarium)、曲霉属(Aspergillus)、红酵母属(Rhodotorula)、虫霉属(Entomophthora)、刺孢囊霉属(Echinosporangium)、水霉属(Saprolegnia)的并可产生花生四烯酸的微生物进行突变处理而得到的Δ12去饱和活性低下或缺乏的微生物在培养基中培养,并自培养物提取而得到的。
3.具有2个或以上双键的ω-9不饱和脂肪酸或以具有2个或以上双键的ω-9不饱和脂肪酸为组成脂肪酸的化合物的用途,其用于制备对伴随肝损伤的肝脏疾病具有预防或改善作用的组合物或饮食品,其中所述伴随肝损伤的肝脏疾病是病毒性肝炎、醇性肝炎或脂肪型肝炎引起的急性肝炎或慢性肝炎,所述以具有2个或以上双键的ω-9不饱和脂肪酸为组成脂肪酸的化合物是具有2个或以上双键的ω-9不饱和脂肪酸的醇酯、以具有2个或以上双键的ω-9不饱和脂肪酸为组成脂肪酸的甘油单酯、甘油二酯和/或甘油三酯、或者磷脂,所述以具有2个或以上双键的ω-9不饱和脂肪酸为组成脂肪酸的甘油三酯含有的具有2个或以上双键的ω-9不饱和脂肪酸相对于组成所述甘油三酯的总脂肪酸为20%以上,所述具有2个或以上双键的ω-9不饱和脂肪酸为至少一种选自6,9-十八碳二烯酸(18:2ω9)、8,11-二十碳二烯酸(20:2ω9)及5,8,11-二十碳三烯酸(20:3ω9)的ω-9不饱和脂肪酸。
4.根据权利要求3所述的用途,其中所述以具有2个或以上双键的ω-9不饱和脂肪酸为组成脂肪酸的甘油三酯是通过对属于被孢霉属、耳霉属、腐霉属、疫霉属、青霉属、枝孢属、毛霉属、镰孢属、曲霉属、红酵母属、虫霉属、刺孢囊霉属、水霉属的并可产生花生四烯酸的微生物进行突变处理而得到的Δ12去饱和活性低下或缺乏的微生物在培养基中培养,并自培养物提取而得到的。
5.根据权利要求3或4所述的用途,其中所述饮食品为功能性食品、营养补助食品、特定保健用食品或老人用食品。
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