CN102105173A - 甘油磷脂用于改善认知功能 - Google Patents
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Abstract
本发明提供了一种制剂,它包含来自非哺乳动物的丝氨酸甘油磷脂与以特定含量和特定结合方式的LA、亚麻酸(α-亚麻酸,γ-亚麻酸)、DHA(二十二碳六烯酸)和二十碳五烯酸(EPA)的结合物的混合物,例如采用不同的来源的类脂,以及该制剂的用途。
Description
相关申请的相互参照
本申请要求美国专利Serial No.12/215,080的优先权,它是于2006年4月28日提交的U.S.Serial No.11/414,150的部分继续申请,U.S.Serial No.11/414,150是于2004年11月19日提交的、现已作废的的U.S.Serial No.10/994,175的部分继续申请,U.S.Serial No.10/994,175是于2004年10月21日提交的PCT国际专利申请申请号为PCT/IL2004/000957的继续申请,该PCT申请要求于2003年10月22日提交的以色列专利申请,其申请号为158552的优先权,该申请的全部内容被参照结合于此。
发明领域
本发明涉及丝氨酸甘油磷脂制剂以及它们在改善认知功能上的效用。
背景技术
甘油磷脂,也称为磷脂,在自然界中无所不在,是细胞类脂双层的关键成分,参与细胞代谢与发出信号。磷脂的甘油骨架上的羟基被亲水的磷酸酯头端和非极性的脂肪酸所构成的憎水尾端所取代。根据头端基团的性质,甘油磷脂可以被再细分为不同的类别,例如像磷脂酰胆碱(phosphatidylcholine,也称为PC或卵磷脂),磷脂酰乙醇胺(phosphatidylethanolamine,PE),磷脂酰丝氨酸(phosphatidylserine,PS)。除了作为细胞膜的主要成分与细胞内和细胞间蛋白质的结合部位,某些甘油磷脂类,如磷脂肌醇(phosphatidylinositols)和磷脂酸是膜衍生的第二信使的前体,或者本身就是膜衍生的的第二信使。动物研究表明PS增强神经元的膜功能,因而减缓,尤其是老年人的认知衰退[McDanielM.A.et al.Nutrition 19:957-75(2003)和Jorissen BL et al.Nutr Neurosci.4(2):121-34(2001)].
许多健康受益都归功于消耗某些脂肪酸。例如,ω-3和ω-6型的多不饱和脂肪酸(polyunsaturated fatty acids,PUFA)对于心血管疾病,免疫功能紊乱和炎症,肾功能障碍,***反应,糖尿病,和癌症具有一些有益健康的好处。大量的临床研究调查了大脑中如二十二碳六烯酸(DHA)那样的ω-3脂肪酸的重要性,发现低水平的DHA与抑郁症,记忆力丧失,痴呆,以及视力问题有关。研究表明,老年人的大脑功能随着血液DHA水平的提高得以改善。另外,DHA在增强大脑功能,婴儿强化配方食品,糖尿病和癌症领域都很重要。
人体不能充分地合成的DHA。因此,必须从食物中来获取它。人类从饮食中获取DHA,最初是通过胎盘,然后通过乳汁,后来又通过食物来源,例如鱼类,红肉,动物器官肉和蛋类。
亚油酸(linoleic acid,LA,C18:2,ω-6)和α-亚麻酸(α-linolenic acid,ALA,C18:3,ω-3)被归类为基本脂肪酸(essential fatty acids,EFA)。人体不能直接合成它们,因此,必须通过提供”现成的”它们的食物来源来获取。最佳的成长和良好的健康状况需要LA和ALA。LA和ALA都是ω-3和ω-6PUFA的前体。需要LA来合成花生四烯酸(arachidonicacid,AA,C20:4,ω-6),它是合成二十烷类的关键中间体,而ALA一部分被用作能量来源,一部分作为代谢产物和长链PUFA的前体。在人体内部,LA和ALA可以被伸长和去饱和以分别生成其他更加不饱和的脂肪酸,主要是AA和DHA(C22:6,ω-3)。
大豆,蛋黄,牛脑和鱼类是获取和产生磷脂,尤其是PS的主要天然来源。在天然磷脂的sn-1和sn-2位置上的脂肪酰残基的类型是变化的,它们的比例通常取决于它们的来源。例如,大豆富含LA脂肪酸(约54%),而源自鱼的卵磷脂则富含DHA脂肪酸残基。自动物大脑组织提取的PS与人脑PS类似,它所含有的脂肪酸的特征是,与植物如大豆磷脂中发现的ω-3,的水平相比,有较高水平的ω-3部分。也已表明,大豆PS对改善认知功能的生物功能度不同于人脑PS[WO2005/037848]。
发明内容
本发明提供了可供选择的,强化的和成本较低的方法来改善受试者的认知功能,通过给予受试者一种类脂制剂,该类脂制剂是通过将ω-3和ω-6脂肪酸,例如LA、亚麻酸(α-亚麻酸,γ-亚麻酸)、DHA和二十酸五烯酰(EPA)以特定量和特定结合方式结合到类脂上(例如利用不同来源的类脂)而制得的。
本发明提供了一种包含来自非哺乳动物的丝氨酸甘油磷脂结合物混合物的制剂,该制剂的特征在于,该混合物包含(a)与PS结合的亚油酸(C18:2)和(b)与PS结合的DHA,其中(a)的w/w%/(b)的w/w%范围在约0.09至约3.6。
另一方面,本发明提供了改善患有认知疾病或功能紊乱受试者的状况的方法,它包括在需要时给予受试者本发明的制剂。
本发明还提供了利用本发明的制剂来制造营养的、药物的或保健滋补品组合物或功能食品的用途。
本发明还提供了本发明的制剂,用于营养的、药物的或保健滋补品组合物或功能食品。
本发明还提供了包含本发明制剂的营养的、药物的或保健滋补品组合物或功能食品。
另一方面,本发明还提供了本发明的制剂用于改善认知疾病或功能紊乱受试者的状况。
附图说明
图1:显示的图表描述了对照给予安慰剂组,给予成人本发明的类脂制剂A时,空间短期记忆,记忆回想和记忆识别。
具体实施方式
本发明的第一方面提供了一种包含来自非哺乳动物的丝氨酸甘油磷脂结合物混合物的制剂,该制剂的特征在于,该混合物包含(a)与PS结合的亚油酸(C18:2)和(b)与PS结合的DHA,其中(a)的w/w%/(b)的w/w%范围在约0.09至约3.6。
在此所用的术语”类脂”应该被理解为包括脂肪和类似脂肪的化合物,其实质上不溶于水,包括但不限于甘油三酯,甾醇,脂肪酸等。
在此所用的互换术语”甘油磷脂”和”磷脂”应该被理解为包括以通式表示的类脂:
式中的取代基R1(sn-1位置上的取代基)和R2(sn-2位置上的取代基)互相独立,选自H或者选自饱和的、单不饱和的和多不饱和的脂肪酸酰基。当X为丝氨酸时,即-CH2CH(COOH)NH2时,该磷脂称为丝氨酸甘油磷脂。
在此使用的且在上述通式中指明的sn-1和sn-2位置分别指的是甘油骨架上的碳原子,其中R1和R2被相应的酰基取代。
本发明中,术语“取代的”及其语言上的等效词,以及术语“结合的”及其语言上的等效词是互换地使用的,它们应该被理解为包括脂肪酸酰基以共价键的方式结合在本发明的丝氨酸甘油磷脂的甘油磷脂骨架上。如上所指出的那样,脂肪酸可以结合在sn-1和/或sn-2位置上。
在此使用的术语“脂肪酸”应该被理解为包括带有长的无支链的脂肪尾端(链)的羧酸,它可以是饱和的或者不饱和的,有一个不饱和键(单不饱和脂肪酸)或者两个或更多个不饱和键(多不饱和脂肪酸)。当提到“脂肪酸酰基”时,应该被理解为包括-C(=O)-R基团,其中R为长的无支链的脂肪尾端基,它可以是饱和的或者不饱和的,有一个不饱和键(单不饱和脂肪酸)或者两个或更多个不饱和键(多不饱和脂肪酸)。
饱和脂肪酸的非限制的例子包括丁酸(Butyric acid,C4:0),己酸(Caproic acid,C6:0),辛酸(Caprylic acid,C8:0),癸酸(Capric acid,C10:0),月桂酸(Laurie acid,C12:0),肉豆蔻酸(Myristic acid,C14:0),棕榈酸(Palmitic acid,C16:0),硬脂酸(Stearic acid,C18:0),花生酸(Arachidic acid,C20:0),山嵛酸(Behenic acid,C22:0)。
不饱和脂肪酸的非限制的例子包括肉豆蔻油酸(Myristoleic acid,C14:1,ω-5),棕榈炔酸(Pahnitoleic acid,C16:1,ω-7),油酸(Oleic acidC18:1,ω-9),亚油酸(Linoleic acid,C18:2,ω-6),亚麻酸(Linolenic acid,C18:3)[α-亚麻酸(C18:3,ω-3),γ-亚麻酸(C18:3,ω-6)],二十碳烯酸(Eicosenoic acid,C20:1,ω-9),二十碳四烯酸(Arachidonic acid,C20:4,ω-6),二十碳五烯酸(Eicosapentaenoic acid,C20:5,ω-3),芥酸(Erucic acid,C22:1,ω-9),二十二碳五烯酸(Docosapentanoic acid,C22:5,ω-3)和二十二碳六烯酸(Docosahexaenoic acid,C22:6,ω-3),二十四碳烯酸(Nervonic acid,C24:1,ω-9)。
当提到“与PS…结合的[脂肪酸]…”时,应该被理解为包括PS,其中脂肪酸酰基结合在磷脂骨架的sn-1和/或sn-2位置上(通过甘油的氧原子)。在一个实施例中,一种脂肪酸结合在sn-1位置上,而sn-2位置或者是未取代的(例如在甘油氧原子上有一个氢原子)或者是被一个选自饱和的、单不饱和的和多不饱和的脂肪酸酰基取代的,它可以与sn-1位置上的取代基相同,也可以不相同。在另一个实施例中,一种脂肪酸结合在sn-2位置上,而sn-1位置或者是未取代的(例如在甘油氧原子上有一个氢原子)或者是被一个选自饱和的,单不饱和的和多不饱和的脂肪酸酰基取代的,它可以与sn-2位置上的取代基相同,也可以不相同。
本发明的制剂典型地包含两种或更多种的本发明的丝氨酸甘油磷脂结合物,具有在此披露的脂肪酸结合方式。
当提到本发明的制剂中结合在PS上的脂肪酸的w/w%时,应该被理解为被结合在PS上的所述脂肪酸的w/w%,它是通过相对于结合在该制剂中的PS上的所有脂肪酸计算出来的结果。
在一个实施例中,丝氨酸甘油磷脂结合物的混合物构成了该制剂的至少10%w/w。在另一个实施例中,丝氨酸甘油磷脂结合物的混合物构成了该制剂的至少20%w/w。在另一个实施例中,丝氨酸甘油磷脂结合物的混合物构成了该制剂的至少40%w/w。在还有一个实施例中,丝氨酸甘油磷脂结合物的混合物构成了该制剂的至少50%w/w。还有一个实施例中,丝氨酸甘油磷脂结合物的混合物构成了该制剂的至少54%w/w。
应该注意到,本发明的制剂还可以包含其他的磷脂,像磷脂酰胆碱(phosphatidylcholine,PC),磷脂酰乙醇胺(phosphatidylethanolamine,PE),磷脂酰肌醇(phosphatidyl-inositol,PI),磷脂酰甘油(phosphatidylglycerol,PG)和磷脂酸(phosphatidic acid,PA),脂肪酸酰基在该磷脂的甘油部分的sn-1和/或sn-2位置上共价地与磷脂结合(键合)在一起。任何上述的极性类脂与脂肪酸的结合型式可以与在此披露的PS与脂肪酸的结合型式相同或不相同。
术语“[PS]脂肪酸结合方式”与“[PS]脂肪酸结合型式”在此是互换地使用的,指的是与PS结合的特定量的特定脂肪酸以及它们在PS甘油骨架上的取代位置。
在一个实施例中,本发明的制剂还包含(c)与PS结合的亚麻酸(C18:3)和(d)与PS结合的DHA,其特征在于(c)的w/w%/(d)的w/w%范围在约0.01至约0.3。
在另一个实施例中,本发明的制剂还进一步包含(e)与PS结合的亚油酸(C18:2)和(f)与PS结合的EPA,其特征在于(e)的w/w%/(f)的w/w%范围在约0.23至约9.4。
在还有一个实施例中,本发明的制剂还进一步包含(g)与PS结合的亚麻酸(C18:3)和(h)与PS结合的EPA,其特征在于(g)的w/w%/(h)的w/w%范围在约0.02至约0.8。
本发明的制剂可以利用酶催化的、化学的、或分子生物学的方法来制备。简单地说,PS可以通过酶催化过程来达到使其富含ω-3或ω-6脂肪酸,例如,通过酶催化的酯交换反应/酯化反应,接着将首端基团转化成丝氨酸(利用PLD酶),使天然磷脂/卵磷脂富含ω-3/ω-6脂肪酸,获得PS-ω-3/ω-6结合物。另外一个酶催化的途径是获得一个天然富含ω-3酸的磷脂来源,像来源于海产的卵磷脂(例如磷虾,鱼类或海藻类)或者蛋类磷脂,将它们的首端基团转化成丝氨酸。要注意到,通过这种方法所获得的PS的脂肪酸含量中的ω-3含量是由所选择的来源(鱼类,磷虾,海藻类,大豆等)所预先决定的。这些方法已经在WO2005/038037中描述过。
本发明的PS制剂也可以利用化学的酯交换反应/酯化反应方法来制备,它利用ω-3或ω-6酰残基来富化sn-1和sn-2位置。这些制备PS-ω-3和PS-ω-6的方法已经在WO2005/038037中描述过。
另外,本发明的PS制剂还可以利用基因改性的生物体GMO(genetically modified organisms)/生物技术的方法来制备,例如,使用带有ω-3或ω-6脂肪酸的可产生磷脂的生物体来获得富含ω-3或ω-6PS的磷脂。采用通过基因工程培养的植物或微生物而避免使用动物来源可能是优选的。
因此,本发明的丝氨酸甘油磷脂结合物的混合物是利用天然的,合成的或半合成的来源或者它们的任意组合来制备。在本发明的一个实施例中,所述的天然来源物质是源自任何一种植物(例如大豆和海藻类),任何一种非哺乳动物的动物(例如磷虾(krill),鱼类(例如鲱鱼(Herring)和蓝牙鳕鱼(blue Whiting))),或者微生物(例如细菌)的来源或者它们的任意组合。不同来源的PS具有不同的与脂肪酸结合方式。例如,与含有较高水平的DHA与PS结合物的海产卵磷脂相比,大豆卵磷脂含有较高水平的亚油酸与PS结合物。
在本发明的还有一个实施例中,所述类脂制剂的生产涉及酶催化反应。
从牛皮质(bovine cortex)提取的PS(BC-PS)与大脑功能和认知能力积极效果相关联,而从大豆提取的PS(SB-PS)就其对改善认知功能的能力得到不确定的结果。不受理论约束的话,这种疗效上的差异归因于两种PS来源的不同脂肪酸组成。BC-PS有相对较高的DHA含量和低的LA含量,而SB-PS富含LA却没有DHA连接在它的骨架上。因此设想具有低的LA/DHA比例的PS组合物可作为较好的认知强化剂。
本发明令人惊讶地提供了特定的PS制剂,其LA/DHA比例为0.09-3.6,在增强认知功能的能力方面,它们与具有更低LA/DHA比例(更多DHA)的PS制剂同样有效,在某些实例中甚至更加有效。
本发明观察到,采用包含具有与脂肪酸特定结合方式结合的丝氨酸甘油磷脂的混合物的本发明的制剂,它们可以是由不同来源获得的或者通过合成制得的。与由单一来源获得的或者模仿由单一来源获得的类脂制剂的脂肪酸含量的类脂制剂相比,由本发明的制剂得到的认知功能结果是类似或者改进的。例如,包含结合了比纯源自海产的类脂制剂更多LA的PS的类脂制剂,与一方面源自植物(例如大豆)的类脂或者另一方面源自海产(例如鱼类)的类脂相比,具有类似或改进的认知功能效果。这样的从多个来源获得的类脂制剂,或者模仿从多个来源获得的脂肪酸含量的经合成制备的类脂制剂,也比纯源自海产的类脂制剂制备起来便宜。
本发明的制剂形式可以是流体油,粉末,颗粒,蜡,糊,油或水乳浊液,以及任何其他能用于目标用途的形式。
另一方面,本发明还提供了利用本发明的制剂来制造营养的、药物的或保健滋补品组合物或功能食品的用途。
还有一个方面,本发明还提供了本发明的制剂,用于营养的、药物的或保健滋补品组合物或功能食品。
更进一步的一个方面,本发明还提供了包含本发明制剂的营养的、药物的或保健滋补品组合物或功能食品。
在此所用的营养组合物包括但不限于,人乳脂肪替代物,婴儿配制食品,乳制品,奶粉,饮料,冰激凌,饼干,大豆制品,烘焙食品,面粉制的糕点和面包,酱汁,汤,方便食品,冷冻食品,调味品,蜜饯,油脂,人造奶油,涂抹、充填、谷类制品,即食制品,婴儿食品,幼儿食品,酒吧、快餐店、糖果和巧克力制品。
在此使用的术语”婴儿配制食品”包括婴儿配制食品(为新生儿至六个月大的婴儿),补充配制食品(为6-12个月大的幼儿)和成长配制食品(为1-3岁大的小孩)。
在此所说的功能食品可以是任何的功能性食品,包括但不限于乳制品,冰激凌,饼干,大豆制品,烘焙食品,面粉制的糕点,蛋糕和面包,即食制品,酱汁,汤,方便食品,冷冻食品,调味品,蜜饯,油脂,人造奶油,涂抹、充填、谷类制品,即食制品,饮料和奶昔,婴儿食品,酒吧、快餐店、糖果和巧克力制品。
在此所说的保健滋补品组合物可以是任何的保健滋补品,它可以是任何作为一种食物或者食物的部分,有医疗或保健益处的物质,包括预防和处理疾病或功能紊乱。这样的保健滋补品组合物包括但不限于食品添加剂,食品补充剂,补充食物,基因工程食物如蔬菜,草本植物制品,以及加工食物如谷类制品,汤和饮料和兴奋功能的食物,疗效食物。补充食物可以采取软胶囊,片剂,糖浆,和其他已知的补充食物转运***的形式。
在本发明的一个实施例中,药物的或保健滋补品组合物采取剂量转运的形式。
本发明组合物的合适给药途径是口服,口腔的,舌下的给药,通过饲管,局部的,经皮的,或者肠胃外的(包括皮下的,肌肉内的,静脉内的和皮肤内的)给药。在一个实施例中,组合物是通过口服给予的。
准确的组合物给药剂量和方式必须取决于要达到的治疗效果(例如改善患有认知疾病或功能紊乱的受试者的状况),还会随着特定的处方、给药的途径、以及需要给予组合物的个体受试者的年龄和条件的不同而变化。
本发明还提供了与(药物上)可接受的辅料以及其他可选的治疗剂混合在一起的本发明的药物的组合物,辅料必须是“可接受的”,意味着它与组合物的其他成分相容,并且对接受者无害。
在一个实施例中,本发明的药物组合物还进一步包含至少一种药物的活性成分。
药物的和保健滋补组合物可以通过任何药剂行业已知的方法来制备。这些方法包括将组合物的成分与任何辅料结合的步骤。辅料,也称之为辅助成分,包括那些业内惯用的,像载体,填料,粘合剂,稀释剂,干燥剂,崩解剂,润滑剂,着色剂,调味剂,抗氧化剂,和润湿剂。
本发明的药物的和保健滋补组合物还可以进一步包含可食的纤维,芳香剂,味觉成分,以及控制物理性质和感官性质的成分。
适合于口服给药的药物的组合物可以分散的剂量单元来提供,例如丸剂,片剂,小糖丸,糖衣锭,或者胶囊,或者粉末或颗粒剂,或者溶液,混悬液或酏剂。
对于肠胃外的给药,合适的组合物包括水的和非水的无菌针剂。组合物可以装在单位剂量或多次剂量的容器中,例如封口的小瓶和安瓿,也可以储存在冻干条件(冻干的)下,使用前只需要加入像水那样的无菌液体作为载体。对于经皮给药的,则可以考虑例如,凝胶,贴剂或喷雾剂。
组合物可以装在单剂量或多次剂量的容器中,例如封口的小瓶和安瓿,也可以储存在冻干条件(冻干的)下,使用前只需要加入像水那样的无菌液体作为载体。
本发明还提供了商品化的包装盒/或试剂盒来制备本发明的组合物,像依照本发明的可食的脂肪源或者食品,它包含(a)一种脂肪源;(b)可选的,至少有一种可食的,生理上可接受的蛋白质,碳水化合物,维生素,矿物质,氨基酸,核苷酸以及活性的或非活性的添加剂;(c)可选的,至少有一种可食的,生理上可接受的载体或稀释剂以携带(a),(b)中所定义的成分;(d)将(a),(b)和/或(c)中所定义的成分混合起来的手段和容器;以及(e)使用指南,如,但不限于,有关储存、制备脂肪源或食品来给药、所需要的稀释、剂量、给药频度等。
依照本发明的商品化的包装盒或试剂盒还可以包含以现成可用形式的本发明的脂肪源,以及使用指南。剂量通常是根据年龄、体重、性别和受试者状况来决定的,与主治医生和其他医务人士所熟知的良好医疗实践相一致。
另一方面,本发明提供了改善患有认知疾病或功能紊乱受试者状况的方法,它包括在需要时给患者服用本发明的制剂。
本发明还提供了本发明制剂的用途,用以制造营养的、药物的或保健滋补品组合物或功能食品以改善患有认知疾病或功能紊乱受试者的状况。
另一方面,本发明提供了本发明的制剂,用以改善患有认知疾病或功能紊乱受试者的状况。
在此所使用的术语“认知疾病或功能紊乱”应该被理解为包括任何的认知疾病或功能紊乱。这样的认知疾病或功能紊乱的不受限制的例子有注意力缺损障碍(Attention Deficit Disorder,ADD),注意力缺损多动障碍(Attention Deficit Hyperactivity Disorder,ADHD),诵读困难,年龄相关性记忆力损伤和学习障碍,遗忘症,轻度认知障碍,认知障碍非痴呆的前期阿尔茨海默病,阿尔茨海默病(Alzheimer′s disease),帕金森病(Parkinson′s disease),早期痴呆综合症,痴呆,老年性认知衰退,认知退化,中度精神障碍,年龄相关的心智衰退,影响脑电波强度和/或脑葡萄糖利用率的状况,紧张,焦虑,抑郁,行为障碍,注意力集中损伤,情绪恶化,一般认知和精神状态良好但神经变性障碍,激素紊乱以及它们的任意组合。在一个特别的实施例中,认知障碍时记忆力障碍。
在此所使用的术语“改善患有认知疾病或功能紊乱受试者的状况”应该被理解为包括:改善与疾病、功能紊乱或病理状况有关的不希望有的症状;在症状出现之前防止它的显现;减缓疾病或功能紊乱的发展;减缓疾病或功能紊乱的恶化;减缓疾病或功能紊乱在发展期(或慢性)阶段引起的不可逆转的损伤;推迟发展中的疾病或功能紊乱的发作;降低疾病或功能紊乱的严重程度;治愈疾病或功能紊乱;防止疾病或功能紊乱一起发生(例如发生在一个容易生病的个体身上)或者任何上述的组合。例如,一个例如由于阿尔茨海默病患有记忆障碍的受试者,其症状包括空间短期记忆,记忆回想和/或记忆识别,集中和持久的注意力,学习,执行功能和/或精神上的灵活性上的衰退,通过使用本发明的制剂后症状得到改善。
在本发明的一个实施例中,认知疾病或功能紊乱选自一组由注意力缺损障碍,注意力缺损多动障碍,诵读困难,年龄相关性记忆力损伤和学习障碍,遗忘症,轻度认知障碍,认知障碍非痴呆的前期阿尔茨海默病,阿尔茨海默病,帕金森病,早期痴呆综合症,痴呆,老年性认知衰退,认知退化,中度精神障碍,年龄相关的精神恶化,影响脑电波强度和/或脑葡萄糖利用率的状况,紧张,焦虑,抑郁,行为障碍,注意力集中损伤,情绪恶化,一般认知和精神状态良好但神经变性障碍,激素紊乱以及它们的任意组合所组成的症状。
要意识到本发明的组合物(不论是药物的、保健滋补的、营养的等)或者产品(例如功能食品)可以和业内已知的其他治疗方法结合起来(即综合疗法)。因此,利用本发明的组合物或产品来治疗认知疾病或功能紊乱时,可以结合治疗认知疾病或功能紊乱的常用药物。
指明用于治疗认知疾病或功能紊乱药物的非限定的例子包括,乙酰胆碱酯酶抑制剂(例如像爱忆欣(Aricept,(donepezil)),艾斯能(Exelon,(rivastigmine)),利忆灵(reminyl,(galantamine)),N-甲基-D-天门冬氨酸(N-methyl-D-aspartate,NMDA)受体阻断剂(例如像AP5(APV,R-2-氨基-5-膦酰基戊酸酯,R-2-amino-5-phosphonopentanoate),AP7(2-氨基-7-膦酰基庚酸,2-amino-7-phosphonoheptanoic acid),CPPene(3-[(R)-2-羧哌嗪-4-基]-丙烯-2-基-1-膦酸,3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-l-phosphonic acid),金刚烷胺(Amantadine):右美沙芬(Dextromethorphan),右啡烷(Dextrophan),伊玻加因(Ibogaine),***(Ketamine),美金刚胺(Memantine),氧化亚氮(Nitrous oxide),苯环利定(Phencyclidine),利鲁唑(Riluzole),替来他明(Tiletamine),阿替加奈(Aptiganel),HU-211,HU-210,Remacimide,1-氨基环丙烷羧酸(1-Aminocyclopropanecarboxylic acid),DCKA(5,7-二氯犬尿喹啉酸,5,7-dichlorokynurenic acid),犬尿喹啉酸(Kynurenic acid),和拉科酰胺(Lacosamide)。
本发明的组合物或产品也可以连同其他化合物,包括但不限于叶酸,维生素类,矿物质类,氨基酸类,核苷酸类,抗氧化剂等一起给药。
应该理解到所披露和描述的本发明并不限于特定的实施例、过程的步骤以及在此所披露的材料,因为这样的过程步骤和材料是可以有些变化的。也应该理解到在此所使用的术语只是为了描述特定的实施例,无意受到限制,因为本发明只是被附加的权利要求书和与其相当的要求所限制。
必须认识到在该说明书和权利要求书中使用的单数形式表达“一个”,“一种”和“该”(“a”,“an”and“the”)包括了复数,除非内容另有明确地指出。
贯穿该说明书和权利要求书,除非内容另有需要,词“包含”(“comprise”)以及其变化体(“comprises”and“comprising”)应该理解为,意指包括所述的整体,或者整体的梯级或分组,或梯级,但并不排除任何其他的整体,或者整体的梯级或分组,或梯级。
以下的实施例是发明者在开展本发明各个方面时所采用的有代表性的技术。应该意识到尽管这些技术在实践本发明时是示范性的优选实施例,根据现在所披露的信息,业内人士会认识到可以进行许多改变而不违背本发明的精神和预定的范围。
实施例
实施例1
制备本发明的类脂制剂的方法
类脂制剂A,A1,A2,C,D,F,G,H,I,J,K,L,M,和N的制备方法如下:
从鱼类(主要是鲱鱼和蓝牙鳕鱼)得到的生物质提取获得的海产卵磷脂溶于有机溶剂中,与含有L-丝氨酸,CaCl2,磷脂酶D(phospholipase D,PLD)和pH为5.6的醋酸盐缓冲的水溶液发生反应。得到的PS制剂被移除水相,蒸去有机溶剂和进一步的净化步骤来提纯。得到的粉末含有44%的PS,以及PS脂肪酸中有31%的DHA。
富含PC的大豆卵磷脂与含有L-丝氨酸,CaCl2,PLD和pH为5.6的醋酸缓冲的水溶液发生反应。得到的PS制剂经水洗去除水可溶物质(盐,丝氨酸等),再进一步净化。得到的粉末含有67.4%的PS。
将从海产卵磷脂来源获得的粉末与从大豆卵磷脂来源获得的粉末以表5所述的比例混合在一起。
还可以用另外的方法,如下述来制备类脂制剂A,A1,A2,C,D,F,G,H,I,J,K,L,M,和N:
在3升的实验室玻璃反应器中将120克的海产卵磷脂与60克富含PC的大豆卵磷脂一起溶于有机溶剂中。将所述有机相与含有L-丝氨酸,CaCl2,磷脂酶D(PLD)和pH为5.6的醋酸盐缓冲的水溶液发生反应。得到的PS制剂被移除水相,蒸去有机溶剂和进一步的净化步骤来提纯。
类脂制剂B按如下方法制备:
从鱼类(主要是鲱鱼和蓝牙鳕鱼)得到的生物质提取获得的海产卵磷脂溶于有机溶剂中,与含有L-丝氨酸,CaCl2,磷脂酶D(phospholipaseD,PLD)和pH为5.6的醋酸盐缓冲的水溶液发生反应。得到的PS制剂被移除水相,蒸去有机溶剂和进一步的净化步骤来提纯。得到的粉末含有44%的PS,PS脂肪酸中有31%的DHA。
类脂制剂E按如下方法制备:
富含PC的大豆卵磷脂在含有L-丝氨酸,CaCl2,PLD和pH为5.6的醋酸缓冲的水溶液中与PS发生反应。得到的PS经水洗去除水可溶物质(盐,丝氨酸等),再进一步净化。得到的粉末含有67%的PS。
表5提供了下边实施例的制剂A,B,C,D,E和F的脂肪酸比例以及来源比例。每个磷脂制剂的脂肪酸含量和磷脂含量在下边的表2和表3中详细说明。
磷脂制剂A,A1和A2为同一制备的不同批次。
磷脂制剂A,A1和A2中与PS结合的亚油酸(C18:2)(LA)(w/w%)和与PS结合的二十二碳六烯酸(DHA)(w/w%)之间的比例约为0.9-1.4;与PS结合的亚麻酸(18:3)(w/w%)和与PS结合的DHA(w/w%)之间的比例约为0.08-0.13;与PS结合的LA(18:2)(w/w%)和与PS结合的EPA(w/w%)之间的比例约为2.3-3.5;与PS结合的亚麻酸(18:3)(w/w%)和与PS结合的EPA(w/w%)之间的比例约为0.2-0.3;其特征在于与PS结合的全部DHA占与PS结合的全部脂肪酸的19-22%w/w左右。
磷脂制剂B(100%海产来源)中与PS结合的亚油酸(C18:2)(LA)(w/w%)和与PS结合的DHA(w/w%)之间的比例最高约为0.02;与PS结合的亚麻酸(18:3)(w/w%)和与PS结合的DHA(w/w%)之间的比例最高约为0.02;与PS结合的LA(18:2)(w/w%)和与PS结合的EPA(w/w%)之间的比例最高约为0.05;与PS结合的亚麻酸(18:3)(w/w%)和与PS结合的EPA(w/w%)之间的比例最高约为0.05;其特征在于与PS结合的全部DHA占与PS结合的全部脂肪酸的31%w/w左右。
磷脂制剂C中与PS结合的亚油酸(C18:2)(LA)(w/w%)和与PS结合的DHA(w/w%)之间的比例约为0.1;与PS结合的亚麻酸(18:3)(w/w%)和与PS结合的DHA(w/w%)之间的比例约为0.01;与PS结合的LA(18:2)(w/w%)和与PS结合的EPA(w/w%)之间的比例约为0.23;与PS结合的亚麻酸(18:3)(w/w%)和与PS结合的EPA(w/w%)之间的比例约为0.02;其特征在于与PS结合的全部DHA占与PS结合的全部脂肪酸的30%w/w左右。
磷脂制剂D中与PS结合的亚油酸(C18:2)(LA)(w/w%)和与PS结合的DHA(w/w%)之间的比例约为3.6;与PS结合的亚麻酸(18:3)(w/w%)和与PS结合的DHA(w/w%)之间的比例约为0.3;与PS结合的LA(18:2)(w/w%)和与PS结合的EPA(w/w%)之间的比例约为9.4;与PS结合的亚麻酸(18:3)(w/w%)和与PS结合的EPA(w/w%)之间的比例约为0.8;其特征在于与PS结合的全部DHA占与PS结合的全部脂肪酸的11%w/w左右。
磷脂制剂E(100%大豆来源)中与PS结合的亚油酸(C18:2)(LA)(w/w%)和与PS结合的DHA(w/w%)之间的比例在100以上;与PS结合的亚麻酸(18:3)(w/w%)和与PS结合的DHA(w/w%)之间的比例在10以上;与PS结合的LA(18:2)(w/w%)和与PS结合的EPA(w/w%)之间的比例在100以上;与PS结合的亚麻酸(18:3)(w/w%)和与PS结合的EPA(w/w%)之间的比例在10以上,实际上不含有DHA。
磷脂制剂F中与PS结合的亚油酸(C18:2)(LA)(w/w%)和与PS结合的DHA(w/w%)之间的比例约为9;与PS结合的亚麻酸(18:3)(w/w%)和与PS结合的DHA(w/w%)之间的比例约为0.7;与PS结合的LA(18:2)(w/w%)和与PS结合的EPA(w/w%)之间的比例约为23;与PS结合的亚麻酸(18:3)(w/w%)和与PS结合的DHA(w/w%)之间的比例约为1.8;其特征在于与PS结合的全部DHA占与PS结合的全部脂肪酸的5.6%w/w左右。
为了避免过度发炎的情形,最好给予受试者补充以与ω-6脂肪酸达到一个平衡的比例的ω-3脂肪酸。ω-3脂肪酸增加出血时间,降低血小板凝集,降低血粘度和纤维蛋白原;增加红细胞的变形性;因此有降低形成血栓的倾向。表8显示出于PS结合的ω-6脂肪酸和ω-3脂肪酸的比例,它表明制剂A,C和D的比例平衡,而比例值<0.01(如制剂B)或>10(如制剂E)可能被认为是不平衡的。
要理解到本发明并不限于制剂A,C和D。例如,其他的制剂(G-N)含有例如50%,55%,60%,65%,70%,80%,85%,和90%的海产材料(即50%,45%,40%,35%,30%,20%,15%,和10%的大豆物质)也进行了观察(表9)。
实施例2
类脂制剂A的疗效
I.类脂制剂A(按上述实施例1制备的)的疗效在一项~3个月的单中心、双盲随机、安慰剂对照的试验中,对有认知行为有障碍的老年人身上进行了研究。
根据该研究的设计,160名受试者被设计成随机筛选到以下两个治疗组中的一个,每个治疗组有80名受试者:
(a)含有200mg类脂A的胶囊,每日三次随每餐一起给药,每次一粒。
(b)安慰剂-含有260-270mg纤维素的胶囊,每日三次随每餐一起给药,每次一粒。
含有类脂制剂A的胶囊与安慰剂胶囊在外观,口味和气味上完全相同。
对15名接受制剂A的受试者和18名接受安慰剂胶囊的受试者利用NexAde计算机化的神经心理学评估软件(NexSigNeurologicalExaminationTechnologiesLtd.,Israel)在基线和接着的~三个治疗月中进行测验。
计算机化的神经心理学评估软件由七个独立的任务组成,它包括:符号定位,图案识别,图案回忆,数字-符号替换,数字广度向前,数字广度向后和延迟的图案回忆。根据单项任务测验得到的结果,计算出八个认知组合得分,包括集中注意力(区别地对特定视觉的,听觉的或触觉的刺激响应的能力),持续的注意力(在连续和反复的活动过程中保持一致行为响应的能力),记忆识别(识别先前储存下来的信息的能力),记忆回想(涉及深入到记忆中并且在刺激/响应的基础上提取出信息),视觉空间学习,空间短期记忆(一种记忆***,它将空间信息储存数秒钟以便用于进行中的认知任务),执行功能和脑力的灵活性。考虑到所有这些认知组合得分计算出最后的得分。该软件提供了虽然是相当的但是不同形式的测验,可以反复进行测验。所有的程序单元都是由计算机控制的,无需有以往关于计算机或打字的经验(Aharonson V,Korczyn AD:Human computer interaction in the administration and analysis of neuropsychological tests.Elsevier science publishers B.V.2004;73:43-53)。
结果
图1显示在接着的~3个治疗月期间内类脂制剂A改善了的记忆参数。
图1证实了三项测验过的参数:记忆回想,记忆识别和空间短期记忆。记忆回想和识别是一个”过程”,用以从记忆中将信息找回来。记忆回想涉及深入到记忆中并在刺激/响应的基础上提取出信息,记忆识别表明识别先前储存下来的信息的能力。空间短期记忆是一种记忆***,它将空间信息储存数秒钟以便用于进行中的认知任务。图1中所呈现出的结果显示出类脂制剂A与安慰剂相比,改善了学习的认知行为和记忆能力。
因此,类脂制剂A改善了轻度认知障碍和年龄相关性记忆障碍。
II.类脂制剂A(按上述实施例1制备)的疗效在一项三个月的单中心试验中,在52位认知行为有障碍的老年人(年龄≥60岁)身上进行了进一步的调研。
受试者每日三次每次接受一粒含有200mg的类脂制剂A(含有100mg PS)的胶囊。
受试者的记忆功能通过下述的测验步骤在基线时和接着的3个治疗月中进行测验。
1.NexAdeTM计算机化的认知评估软件(如上所述),
2.雷氏听觉词语学习测验(AVLT,Rey-Auditory Verbal Learning Test)(ReyA:L’ Examen Cliniqueen Psychologic Paris:Presss Universitaire France 1964)。
该测验由一张有15个普通名词的表组成,它们在连续的五个试验中(试验1至试验5)被唸给受试者听;每唸一次后就紧跟着一项自由回忆任务。在试验6,提出一张有15个新的普通名词的干扰表,接着是自由回忆这些新名词。在试验7,没有额外唸另外的名词,受试者被再次要求来回忆第一张表。20分钟后,还是没有额外唸另外的名词,受试者被再次要求来回忆第一张表(试验8)。从测验中得到五个不同的得分;即刻记忆回想(试验1得分),总的即刻回想(试验1和试验6得分之总和),最佳学习(试验5),总的词语学习(试验1至试验5得分之总和)和延迟记忆回想(试验8)。
结果
表1表明类脂制剂A显著地改善了计算机化认知评估工具的最后得分。该得分是一个调整过的计算值,它将不同组合分数加在一起。表1证实个别的测验(数字向前回想和向后回想)和特定的组合得分(集中注意力,记忆回想和记忆识别)被显著地改善了。断定类脂制剂A显著地改善了许多认知参数,像注意力,记忆和学习。
表1:类脂制剂A对于计算机化认知评估工具参数的效果
测验参数 | 与基线相比的变化的平均值±SE | p* |
数字向前回忆 | 5.44±2.54 | 0.076 |
数字向后回忆 | 2.98±2.38 | 0.001 |
集中注意力 | 3.81±1.65 | 0.003 |
记忆识别 | 8.29±2.06 | 0.032 |
记忆回想 | 5.17±1.46 | 0.025 |
最后成绩 | 5.12±1.77 | 0.002 |
*根据相依样本的双侧“学生”T-检验
(Based on two-side students’T-test for dependent samples)
表2表明类脂制剂A改善了Rey-AVLT步骤的不同参数,因而进一步证实该制剂增强认知功能的性质。尤其是,类脂组合物A显著地改善了即刻和延迟的记忆回想,最佳学习以及总的即刻回想。
表2:类脂制剂A对于Rey-AVLT参数的效果
测验参数 | 与基线相比的变化的平均值±SE | p* |
即刻记忆回想 | 1.87±0.26 | <0.001 |
最佳学习 | 0.65±0.28 | <0.001 |
延迟记忆回想 | 1.10±0.32 | <0.001 |
总的词语学习 | 6.17±0.94 | <0.001 |
全部即刻回想 | 2.19±0.43 | <0.001 |
*根据相依样本的双侧“学生”T-检验
最后,类脂制剂A改善了轻度认知障碍和年龄相关性记忆障碍。
实施例3
类脂制剂B,C,D,E,和F的疗效
所有描述过的试验测验同样的人群(认知行为有障碍的老年受试者)并且利用同样的认知评估工具。
类脂制剂B的疗效
类脂制剂B(按上述实施例1制备)的疗效在一项~3个月的单中心、公开标记的试验中,在16位认知行为有障碍的老年人(年龄≥60岁)身上进行了调研。
受试者每日三次随每餐每次接受一粒含有227mg的制剂B(含有100mg PS)的胶囊。
受试者的记忆功能通过基本上如上述实施例2所述的计算机化认知评估工具在基线时和接着的3个治疗月中进行测验。
结果
表3表明类脂制剂B改善了计算机化认知评估工具的最后得分。尽管这种改善未达到统计意义上的显著性,但它的改善度与接受类脂制剂A后的改善度相当(见表1)。在个别测验(数字向前回忆和向后回忆)和特定的组合得分(空间短期记忆、集中注意力、记忆回想和记忆识别)中发现类脂制剂B有所改善。再次地,它的效果程度与接受类脂制剂A后的程度相当(见表1),但是这种改善并未总是达到统计意义上的显著性。因而断定类脂制剂B与类脂制剂A相似,改善了一些认知功能的参数,然而由于这种改善并未总是达到统计意义上的显著性,所以看来在改善认知技能和治疗轻度认知障碍及年龄相关性的记忆力衰退方面,类脂制剂A优于类脂制剂B。这些结果令人惊讶,因为与类脂制剂A相比,类脂制剂B的LA/DHA比例较低(更多的DHA)。
表3:类脂制剂B对于计算机化认知评估工具参数的效果
测验参数 | 与基线相比的平均变化±SE | p* |
数字向前回忆 | 4.63±5.70 | 0.870 |
数字向后回忆 | 0.88±4.94 | 0.987 |
集中注意力 | 3.25±3.21 | 0.070 |
记忆识别 | 2.75±2.20 | 0.033 |
记忆回想 | 5.94±2.79 | 0.032 |
最后成绩 | 5.05±2.67 | 0.133 |
*根据相依样本的双侧“学生”T检验
类脂制剂C的疗效
类脂制剂C的疗效在一项~3个月的单中心、公开标记的试验中,在8位认知行为有障碍的老年人身上进行了调研。
受试者每日三次随每餐每次接受一粒含有222mg的制剂C(含有100mg PS)的胶囊。
受试者的记忆功能通过基本上如上述实施例2所述的计算机化认知评估工具和Rey-AVLT进行测验。
结果
在接着的~3个月的治疗期内,类脂制剂C改善了记忆回想,记忆识别,注意力,专注,学习和空间短期记忆。所有测验参数的改善类似于经过~3个月的类脂制剂A(实施例2)治疗所得到的改善,类似于或好于经过~3个月的类脂制剂B治疗所得到的改善。
类脂制剂D的疗效
类脂制剂D(按上述实施例1制备)的疗效在一项~3个月的单中心、公开标记的试验中,在8位认知行为有障碍的老年人身上进行了调研。
受试者每日三次随每餐每次接受一粒含有176mg的制剂D(含有100mg PS)的胶囊。
受试者的记忆功能通过基本上如上述实施例2所述的计算机化认知评估工具和Rey-AVLT进行测验。
结果
在接着的~3个月的治疗期内,类脂制剂D改善了记忆回想,记忆识别,注意力,专注,学习和空间短期记忆。所有测验参数的改善类似于类脂制剂A(实施例2)和C在接着的~3个月的治疗所得到的改善,类似于或好于类脂制剂B经过~3个月的治疗所得到的改善。
类脂制剂E的疗效
类脂制剂E(按上述实施例1制备)的疗效在一项~3个月的单中心、公开标记的试验中在24位认知行为有障碍的老年人(年龄≥60岁)身上进行了调研。
受试者每日三次随每餐每次接受一粒含有150mg的制剂E(含有100mg PS)的胶囊。
受试者的记忆功能通过基本上如上述实施例2所述的计算机化认知评估工具和Rey-AVLT在基线时和接着的3个治疗月中进行测验。
结果
表4表明类脂制剂E,如同类脂制剂A,改善了Rey-AVLT测验步骤的参数。不过,与类脂制剂A相比,效果程度要小得多。将类脂制剂A与E相比时,暴露出统计学显著性上的差异,在即刻回想(p=0.05)和总的即刻回想(p=0.03)以及总的学习得分趋势(p=0.13)方面,这两种疗法以制剂A占优。该差异反映了在治疗认知衰退上类脂制剂A优于类脂制剂E。
表4:类脂制剂E对于Rey-AVLT参数的效果
测验参数 | 与基线相比的变化平均值±SE | p* |
即刻记忆回想 | 0.96±0.36 | 0.032 |
*根据相依样本的双侧“学生”T检验
另外,受试者的记忆功能通过基本上如上述实施例2所述的计算机化认知评估工具在基线时和接着的3个治疗月中进行测验。
结果
类脂制剂E在接着的~3个月的治疗中倾向于仅以较低的程度改善记忆回想,记忆识别,注意力,专注,学习和空间短期记忆。所有测验参数的改善都低于类脂制剂A(实施例2),B,C和D在接着的~3个月的治疗中所表现出的改善。
类脂制剂F的疗效
类脂制剂D(按上述实施例1制备)的疗效在一项~3个月的单中心、公开标记的试验中在8位认知行为有障碍的老年人身上进行了调研。
受试者每日三次随每餐每次接受一粒含有162mg的制剂D(含有100mg PS)的胶囊。
受试者的记忆功能通过基本上如上述实施例2所述的计算机化认知评估工具和Rey-AVLT进行测验。
结果
类脂制剂F在接着的~3个月的治疗中倾向于仅以较低的程度改善记忆回想,记忆识别,注意力,专注,学习和空间短期记忆。所有测验参数的改善都低于类脂制剂A(实施例2),B,C和D在接着的~3个月的治疗中所表现出的改善。
表5:制剂A-F的脂肪酸含量与来源
*与PS结合的某一脂肪酸占与PS结合的所有脂肪酸重量的重量百分比
表6:制剂A-F的磷脂含量(w/w%)
PS | PC | PI | PE | PA | |
制剂A | 50 | 0-1 | 0-3 | 3 | 8 |
制剂A1 | 54 | 0-1 | 0-3 | 3.5 | 9 |
制剂A2 | 54 | 0-1 | 0-3 | 3.5 | 9 |
制剂B | 44 | 0-1 | 0-3 | 4 | 7.5 |
制剂C | 45 | 0-1 | 0-3 | 4 | 8 |
制剂D | 57 | 0-1 | 0-3 | 2.5 | 9 |
制剂E | 67 | 0-1 | 0-3 | 1 | 11 |
制剂F | 62 | 0-1 | 0-3 | 2 | 10 |
表7:与PS结合的脂肪酸(占与PS结合的全部脂肪酸的重量百分数)
C14 | C16 | C16:1 | C18 | C18:1 | C18:2 | C18:3 | C20:1 | C20:5 | C22:6 | |
制剂A | 1.5 | 24.7 | 1.7 | 3.1 | 16.5 | 20.5 | 1.7 | 1.5 | 8.0 | 20.6 |
制剂A1 | 1.6 | 20.6 | 0.9 | 2.7 | 15.1 | 20.7 | 2.0 | 1.6 | 8.8 | 22.0 |
制剂A2 | 1.4 | 19.9 | 0.9 | 3.0 | 15.7 | 26.2 | 2.4 | 1.3 | 7.6 | 19.0 |
制剂B | 2.2 | 29.8 | 2.6 | 2.2 | 18.0 | ≤0.5 | ≤0.5 | 2.2 | 12.0 | 31.0 |
制剂C | 2.1 | 29.1 | 2.5 | 2.3 | 17.8 | 2.7 | 0.2 | 2.1 | 11.5 | 29.6 |
制剂D | 0.8 | 19.9 | 0.9 | 4.0 | 15.1 | 39.6 | 3.2 | 0.8 | 4.2 | 10.9 |
制剂E | ≤0.5 | 14.5 | ≤0.5 | 5.0 | 13.5 | 61.0 | 5.0 | ≤0.5 | ≤0.5 | <0.5 |
制剂F | 0.4 | 17.3 | 0.5 | 4.5 | 14.3 | 50 | 4.1 | 0.4 | 2.2 | 5.6 |
表8:PS上ω-6脂肪酸与ω-3脂肪酸的比例
ω-6/ω-3的比例 | |
制剂A | 0.7 |
制剂A1 | 0.63 |
制剂A2 | 0.9 |
制剂B | ≤0.01 |
制剂C | 0.06 |
制剂D | 2.2 |
制剂E | ≥10 |
制剂F | 4.2 |
表9:制剂G-N的脂肪酸含量*与来源
*与PS结合的某一脂肪酸占与PS结合的所有脂肪酸重量的重量百分比
Claims (18)
1.一种包含来自非哺乳动物的丝氨酸甘油磷脂结合物混合物的制剂,该制剂的特征在于,该混合物包含(a)与PS结合的亚油酸(C18:2)和(b)与PS结合的DHA,其特征在于(a)的w/w%/(b)的w/w%范围在约0.09至约3.6。
2.如权利要求第1项所述的制剂,该制剂的特征在于,该丝氨酸甘油磷脂构成了该制剂的至少10%w/w。
3.如权利要求第2项所述的制剂,该制剂的特征在于,该丝氨酸甘油磷脂构成了该制剂的至少20%w/w。
4.如权利要求第3项所述的制剂,该制剂的特征在于,该丝氨酸甘油磷脂构成了该制剂的至少40%w/w。
5.如权利要求第4项所述的制剂,该制剂的特征在于,该丝氨酸甘油磷脂构成了该制剂的至少50%w/w。
6.如权利要求第5项所述的制剂,该制剂的特征在于,该丝氨酸甘油磷脂构成了该制剂的至少54%w/w。
7.如权利要求第1至第6项的任意一项所述的制剂,该制剂还进一步包含(c)与PS结合的亚麻酸(C18:3)和(d)与PS结合的DHA,其特征在于(c)的w/w%/(d)的w/w%范围在约0.01至约0.3。
8.如权利要求第7项所述的制剂,该制剂还进一步包含(e)与PS结合的亚油酸(C18:2)和(f)与PS结合的EPA,其特征在于(e)的w/w%/(f)的w/w%范围在约0.23至约9.4。
9.如权利要求第8项所述的制剂,该制剂还进一步包含(g)与PS结合的亚麻酸(C18:3)和(h)与PS结合的EPA,其特征在于(g)的w/w%/(h)的w/w%范围在约0.02至约0.8。
10.一种改善患有认知疾病或功能紊乱的受试者状况的方法,该方法包括在需要时给予受试者如权利要求第1-9项中任意一项所述的制剂。
11.如权利要求第10项所述的方法,其特征在于,所述认知疾病或功能紊乱选自以下小组,该小组包含:注意力缺损障碍,注意力缺损多动障碍,诵读困难,年龄相关的记忆力损伤和学习障碍,遗忘症,轻度认知障碍,认知障碍非痴呆的前期阿尔茨海默病,阿尔茨海默病,帕金森病,早期痴呆综合症,痴呆,年龄相关的认知衰退,认知退化,中度精神障碍,年龄相关的心智衰退,影响脑电波强度和/或脑葡萄糖利用率的状况,紧张,焦虑,抑郁,行为失调,注意力集中损伤,情绪恶化,一般认知和精神状态良好但神经变性失调,激素紊乱以及它们的任意组合。
12.如权利要求第1-9项所述的制剂的用途,用以制造营养的、药物的或保健滋补品组合物或功能食品。
13.如权利要求第12项所述制剂的用途,其特征在于,所述营养的、药物的或保健滋补品组合物或功能食品用于改善患有认知疾病或功能紊乱受试者的状况。
14.如权利要求第13项所述的用途,其特征在于,所述认知疾病或功能紊乱选自以下小组,该小组包含:注意力缺损障碍,注意力缺损多动障碍,诵读困难,年龄相关的记忆力损伤和学习障碍,遗忘症,轻度认知障碍,认知障碍非痴呆的前期阿尔茨海默病,阿尔茨海默病,帕金森病,早期痴呆综合症,痴呆,年龄相关的认知衰退,认知退化,中度精神障碍,年龄相关的心智衰退,影响脑电波强度和/或脑葡萄糖利用率的状况,紧张,焦虑,抑郁,行为失调,注意力集中损伤,情绪恶化,一般认知和精神状态良好但神经变性失调,激素紊乱以及它们的任意组合。
15.如权利要求第1-9项任意一项所述的制剂,其用于营养的、药物的或保健滋补品组合物或功能食品。
16.如权利要求第1-9项任意一项所述的制剂,其用于改善患有认知疾病或功能紊乱受试者的状况。
17.如权利要求第16项所述的制剂,其特征在于,所述认知疾病或功能紊乱选自以下小组,该小组包含:注意力缺损障碍,注意力缺损多动障碍,诵读困难,年龄相关的记忆力损伤和学习障碍,遗忘症,轻度认知障碍,认知障碍非痴呆的前期阿尔茨海默病,阿尔茨海默病,帕金森病,早期痴呆综合症,痴呆,年龄相关的认知衰退,认知退化,中度精神障碍,年龄相关的心智衰退,影响脑电波强度和/或脑葡萄糖利用率的状况,紧张,焦虑,抑郁,行为障碍,注意力集中损伤,情绪恶化,一般认知和精神状态良好但神经变性失调,激素紊乱以及它们的任意组合。
18.营养的、药物的或保健滋补品组合物或功能食品,其包含如权利要求第1-9项任意一项所述的制剂。
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- 2009-06-24 CN CN201510056932.2A patent/CN104721203A/zh active Pending
- 2009-06-24 EP EP09769797.3A patent/EP2307058B1/en not_active Revoked
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2013
- 2013-10-25 US US14/063,401 patent/US9168310B2/en active Active
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2015
- 2015-06-02 JP JP2015112433A patent/JP2015212266A/ja active Pending
- 2015-09-30 US US14/871,260 patent/US9585966B2/en active Active
- 2015-10-12 HK HK15109939.8A patent/HK1209315A1/zh unknown
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2017
- 2017-01-10 US US15/402,812 patent/US9782487B2/en not_active Expired - Fee Related
- 2017-09-07 US US15/698,240 patent/US9962455B2/en not_active Expired - Fee Related
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103356664A (zh) * | 2012-04-05 | 2013-10-23 | 日本水产株式会社 | 脑萎缩预防剂 |
CN104379757A (zh) * | 2012-06-13 | 2015-02-25 | 株式会社钟化 | 含磷脂组合物的制造方法及含磷脂组合物 |
CN104379757B (zh) * | 2012-06-13 | 2017-03-15 | 株式会社钟化 | 含磷脂组合物的制造方法及含磷脂组合物 |
CN107206026A (zh) * | 2014-11-04 | 2017-09-26 | 地球波兰股份公司 | 用于治疗bdnf依赖性失调的富含脯氨酸的多肽复合物 |
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