CN105878226A - 对白天活动量减少及/或抑郁症状具有改善作用的组合物 - Google Patents
对白天活动量减少及/或抑郁症状具有改善作用的组合物 Download PDFInfo
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- CN105878226A CN105878226A CN201610081360.8A CN201610081360A CN105878226A CN 105878226 A CN105878226 A CN 105878226A CN 201610081360 A CN201610081360 A CN 201610081360A CN 105878226 A CN105878226 A CN 105878226A
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Abstract
本发明是新型组合物,该组合物含有花生四烯酸及/或以花生四烯酸为构成脂肪酸的化合物、对白天活动量减少及/或抑郁症状具有改善作用。
Description
本申请是2006年6月29日提交的同名发明专利申请200610100093.0的分案申请。
技术领域
本发明涉及对白天活动量减少及/或抑郁症状具有改善作用的组合物。
背景技术
在高龄者中,经常有被确认为白天活动量减少、抑郁症状的人,有报告指出这种白天活动量与睡眠关系密切,经常会因睡眠障碍而使活动量减少,白天活动量与夜间睡眠的质和量相关[Psychiatry ClinNeurosci Vol.54,309-310(2000)]。睡眠障碍的发生率随着年龄的增加而显著增加,在高龄者的种种睡眠障碍增加的背景下,以中途觉醒增加、中途觉醒后再入眠障碍、总睡眠时间缩短、睡眠效率降低、慢波睡眠减少为代表的睡眠结构的增龄变化作为共同的原因而存在。一般认为这样的生理变化相互叠加,会产生极其多样的睡眠障碍要因,因此引发高龄者的睡眠障碍症状[最新医学Vol.59,468-475(2004)]。
另一方面认为,不仅是老化、各种精神疾病也会直接或通过睡眠障碍等症状引发白天活动量减少、抑郁症状。例如已知综合失调症患者,不仅有急性恶化期的入眠困难、中途觉醒等失眠症状,而且还有因生活方式的变化、不规律的日常生活等睡眠、觉醒规律的混乱引发的睡眠障碍。此外,感情障碍在精神疾病中也是高发病率合并发生睡眠障碍和抑郁症状。单极型抑郁病是指入眠困难、中途觉醒、早朝觉醒、缺少熟睡感、睡眠时间缩短等失眠症状。此外,双极型抑郁病的病相期也表现出与单极型抑郁病同样的失眠症状。但是,双极型抑郁病的特征与单极型抑郁病相比,多认为其是因反复午睡等引起的过眠。此外也发现有因种神经疾患引起的睡眠障碍、抑郁症状。作为常伴随睡眠障碍的神经疾患,可以为脑变性疾病、认知症、Parkinson症候群、致死性家族性失眠症、睡眠相关性癫痫、睡眠时癫痫样发作波重叠、睡眠相关的头痛等[别册日本临床Vol.39,231-248(2003)]。
最近,作为评价睡眠的质量、活动量的方法,都把目光集中于使用活动记录器Actigraph的方法,Actigraph是把测定活动量用的内部装有传感器的手表型测定机器戴在不常用的手腕上,以1周时间为单位,昼夜测定活动量并以此评价活动量变化的机器。通过使用计算机软件分析该Actigraph测定的结果,可以在下述疾病的诊断、过程观察、及治疗结果的判定上发挥威力,所述疾病为精神疾病、神经疾患、及伴随老化的睡眠障碍、活动量减少等。
此外,作为对这种因睡眠障碍、身心功能降低引起的白天活动量减少及抑郁症状的治疗方法,有精神疗法的探讨、非药物疗法、药物疗法。非药物疗法有高照度光照射,现在积极用于治疗季节性感情障碍、违反日常规律引起的睡眠障碍。在睡眠障碍、抑郁症状的药物疗法中,虽然使用了维生素B12、苯二氮桌类(benzodiazepine)睡眠药等,但很难说都得到了确切的效果,仍有待于药物疗法的确立。此外,在治疗感情障碍、神经疾患时,一般合并使用抗抑郁药、抗精神药和睡眠药。但是,现状是仍没有安全有效的并对睡眠障碍、身心功能降低引起的白天活动量减少、抑郁症状具有治疗效果的化合物。
作为控制睡眠、行动的化合物,知道有大麻醇(cannabinoid),有报告指出大麻醇(cannabinoid)通过脑内的大麻醇受体,能够对记忆、学习[Nature Vol.388,773-778(1997)]、摄食、放松、睡眠等行动[JNeurosci Vol.21,5344-5350(2001)]产生影响。作为人的生体内的内因性的大麻醇,已知有安南得迈(anandamide)、2-花生四烯酰甘油(2-arachidonoyl-glycerol)等含有花生四烯酸的化合物,但即使经口摄取这些大麻醇(cannabinoid),因为水解而不能被直接吸收,到目前为止的报告中,也只是停留在活体外(in vitro)或给与受体拮抗剂的实验上。
也就是说,到目前为止,根本不明白使人体摄取以花生四烯酸为构成脂肪酸的化合物时,是否会对减少的白天活动量、抑郁症状产生影响
[非专利文献1]Psychiatry Clin Neurosci Vol.54,309-310(2000)
[非专利文献2]最新医学Vol.59,468-475(2004)
[非专利文献3]别册日本临床Vol.39,231-248(2003)
[非专利文献4]Nature Vol.388,773-778(1997)
[非专利文献5]J Neurosci Vol.21,5344-5350(2001)
发明内容
本发明要提供含有花生四烯酸及/或以花生四烯酸为构成脂肪酸的化合物、对白天活动量减少及/或抑郁症状具有改善作用的饮食品及其制造方法。更加详细地说,提供下述饮食品及其制造方法:将从花生四烯酸、花生四烯酸醇酯、及构成脂肪酸的一部分或全部是花生四烯酸的甘油三酯、磷脂质、或糖脂质群中选择的至少1种作为有效成分,对由精神疾病(综合失调症、抑郁病等)、神经疾患(脑变性疾病、认知症、Parkinson症候群、致死性家族性失眠症、睡眠相关性癫痫、睡眠时癫痫样发作波重叠、睡眠相关的头痛等)引起、或由伴随老化的身心功能降低的睡眠障碍引起的白天活动量减少及/或抑郁症状,具有预防或改善作用的饮食品及其制造方法。
本发明者等,将花生四烯酸及/或以花生四烯酸为构成脂肪酸的化合物作为有效成分,把证明其对白天活动量减少及抑郁症状的改善效果作为目的,进行了精心研究,结果惊喜地发现,将Actigraph的测定值作为指标进行评价,在人体上证明了以花生四烯酸为构成脂肪酸的化合物对短期进入老人护理机构的高龄者的白天活动量减少及抑郁症状的改善效果。
因此,根据本发明可以提供将花生四烯酸及/或以花生四烯酸为构成脂肪酸的化合物作为有效成分、改善白天活动量减少及/或抑郁症状的改善剂以及对白天活动量减少及/或抑郁症状具有改善作用的组合物及其制造方法。更加详细地说,提供下述改善剂、组合物及其制造方法:将从花生四烯酸、花生四烯酸醇酯、及构成脂肪酸的一部分或全部是花生四烯酸的甘油三酯、磷脂质、或糖脂质组中选择的至少1种作为有效成分,对由精神疾病(综合失调症、抑郁病等)引起的睡眠障碍、神经疾患(脑变性疾病、认知症、Parkinson症候群、致死性家族性失眠症、睡眠相关性癫痫、睡眠时癫痫样发作波重叠、睡眠相关的头痛等)引起的睡眠障碍、或由伴随老化的身心功能降低引起的睡眠障碍引起的白天活动量减少及/或抑郁症状的改善剂、以及具有预防或改善作用的组合物及其制造方法。
附图说明
[图1]表示使用Actigraph评价的含有花生四烯酸的油脂对高龄者白天活动量的影响。
[图2]表示使用Zung抑郁自我评定尺度评价的含有花生四烯酸的油脂对高龄者抑郁症状的影响。
[图3]表示摄取含有花生四烯酸的油脂时,高龄者的白天活动量和Zung抑郁自我评定尺度评分的相关性。
具体实施方式
本发明涉及将花生四烯酸及/或以花生四烯酸为构成脂肪酸的化合物作为有效成分、改善白天活动量减少及/或抑郁症状的改善剂以及对白天活动量减少及/或抑郁症状具有预防或改善作用的组合物及其制造方法。
作为白天活动量减少及/或抑郁症状的原因,可以为精神疾病(综合失调症、抑郁病等)引起的睡眠障碍,神经疾患(脑变性疾病、认知症、Parkinson症候群、致死性家族性失眠症、睡眠相关性癫痫、睡眠时癫痫样发作波重叠、睡眠相关的头痛等)引起的睡眠障碍或由伴随老化的身心功能降低引起的睡眠障碍等,但并不限于这些症状或疾病,而是包括所有的与白天活动量减少及/或抑郁症状相关的症状或疾病。
本发明的有效成分是花生四烯酸,可以利用所有的以花生四烯酸为构成脂肪酸的化合物。以花生四烯酸为构成脂肪酸的化合物,可以为花生四烯酸盐,如钙盐、钠盐等,此外还可以为花生四烯酸的低级醇酯,如花生四烯酸甲酯、花生四烯酸乙酯等,此外还可以利用构成脂肪酸的一部分或全部为花生四烯酸的甘油三酯、磷脂质、糖脂质等。并且,本发明并不限于上述例举的物质,可以利用所有的以花生四烯酸为构成脂肪酸的化合物。
考虑在食品方面应用时,优选花生四烯酸是甘油三酯、磷脂质的形式,特别优选是甘油三酯的形式。含有花生四烯酸的甘油三酯(与含有构成脂肪酸的一部分或全部为花生四烯酸的甘油三酯的甘油三酯含义相同)的天然供给源几乎不存在,本发明者们可以把以花生四烯酸为构成脂肪酸的甘油三酯应用于工业,提供给针对高龄者的白天活动量减少及抑郁症状的摄取试验使用,本发明的有效成分的效果首次在人体试验中得到证明,证明其对白天活动量减少及抑郁症状具有预防或改善效果,并且证明该效果由花生四烯酸产生。
因此,在本发明中可以使用含有本发明的有效成分的构成脂肪酸的一部分或全部为花生四烯酸的甘油三酯的甘油三酯(含有花生四烯酸的甘油三酯)。作为含有花生四烯酸的甘油三酯,构成甘油三酯的全部脂肪酸中花生四烯酸的比例等于或大于20重量(W/W)%、优选等于或大于30重量%、更优选等于或大于40重量%的油脂(甘油三酯)是适用于食品时的优选方式。因此,在本发明中,只要是培养具有生产含有花生四烯酸的油脂(甘油三酯)的能力的微生物得到的油脂,都可以使用。
作为具有生产含有花生四烯酸的油脂(甘油三酯)的能力的微生物,可以是属于被孢霉属(Mortierella)、耳霉属(Conidiobolus)、腐霉属(Pythium)、疫霉属(Phytophthora)、青霉属(Pencillium)、芽枝霉属(Cladosporium)、毛霉属(Mucor)、镰刀菌属(Fusarium)、曲霉属(Aspergillus)、红酵母属(Rhodotorula)、虫霉属(Entomophthora)、Echinosporangium属、水霉属(Saprolegnia)的微生物。
属于被孢霉属(Mortierella)被孢霉属(Mortierella)亚属的微生物,可以为Mortierella elongata、Mortierella exigua、Mortierellahygrophila、Mortierella alpine等。具体来说,可以是Mortierellaelongate IFO8570、Mortierella exigua IFO8571、Mortierellahygrophila IFO5941、Mortierella alpine IFO8568、ATCC16266、ATCC32221、ATCC42430、CBS219.35、CBS224.37、CBS250.53、CBS343.66、CBS527.72、CBS529.72、CBS608.70、CBS754.68等菌株。
这些菌株,都可不受任何限制从大阪市财团法人发酵研究所(IFO)、美国模式菌种收集中心(American Type Culture Collection,ATCC)及Centrralbureau voor Schimmelcultures(CBS)得到。此外本发明的研究组还可以使用从土壤中分离的菌株Mortierellaelongate SAM0219(微工研菌寄第8703号)(微工研条寄第1239号)。
为了培养本发明使用的菌株,可将其菌株的胞子、菌丝、或提前培养得到的前培养液接种到液体培养基或固体培养基上培养。如果是液体培养基,作为碳源一般使用葡萄糖、果糖、木糖、蔗糖、麦芽糖、可溶性淀粉、糖蜜、甘油、甘露醇等,任何碳源都可以使用,并不限于这些。
作为氮源,可以使用胨、酵母浸膏、麦芽浸膏、肉浸膏、酸水解酪素(Casamino acids)、谷物浸提液(corn steep liquor)、大豆蛋白、脱脂大豆、棉籽渣等天然氮源,此外还可以使用尿素等有机氮源,以及硝酸钠、硝酸铵、硫酸铵等无机氮源。此外可根据需要也可将磷酸盐、硫酸镁、硫酸铁、硫酸铜等无机盐及维生素等作为微量营养源使用。这些培养基的成分只要其浓度对微生物的生长发育不产生危害,没有特别限定。实际上一般来说,碳源为0.1重量%~40重量%,优选1重量%~25重量%。开始的氮源添加量为0.1重量%~10重量%,优选0.1重量%~6重量%,培养途中也可以流加氮源。
通过控制培养基碳源的浓度,可以使含有花生四烯酸等于或大于45重量(W/W)%的油脂(甘油三酯)作为本发明的有效成分。对于培养,培养2~4日为菌体增殖期,培养2~4日后为油脂蓄积期。使起初的碳源浓度为1重量%~8重量%,优选1重量%~4重量%的浓度,仅在菌体增殖期和油脂蓄积期的初期之间,逐次添加碳源,逐次添加的碳源的总和为2重量%~20重量%,优选5重量%~15重量%。并且,在菌体增殖期和油脂蓄积初期之间的碳源的逐次添加量,根据起初的氮源浓度进行添加,使培养7日后、优选培养6日后、更优选培养4日后的培养基中的碳源浓度为0,这样可以得到含有花生四烯酸等于或大于45重量%的油脂(甘油三酯),可以作为本发明的有效成分。
花生四烯酸生产菌的培养温度由使用的微生物决定,可以为5℃~40℃,优选20℃~30℃,或者可在20℃~30℃培养使菌体增殖,然后在5℃~20℃继续培养生产不饱和脂肪酸。这样的温度管理可以使生成脂肪酸中的多不饱和脂肪酸的比例提高。使培养基的pH为4~10,优选pH为5~9,进行通气搅拌培养、振荡培养、或静置培养。通常培养2日~30日间,优选5日~20日间,更优选5日~15日间。
作为提高含有花生四烯酸的油脂(甘油三酯)中的花生四烯酸的比例的方法,除控制培养基碳源浓度外,还可以使含有花生四烯酸的油脂进行选择性水解,这样可以得到花生四烯酸高含量的油脂。该选择性水解使用的脂肪酶没有对甘油三酯的位置特异性,其水解活性与双键数量成比例地降低,所以多不饱和脂肪酸以外的脂肪酸的酯键可被水解。而且,生成的PUFA部分在甘油酯间发生酯交换反应等,因此可生成多不饱和脂肪酸高的甘油三酯(“Enhancement of Archidonic:Selective Hydrolysis of a Single-Cell Oil from Mortierella withCandida cylindracea Lipase”:J.Am.Oil Chem.Soc.,72,1323-1327(1998))。
这样,含有花生四烯酸的油脂进行选择性水解得到的花生四烯酸高含量的油脂(甘油三酯)可以作为本发明的有效成分。相对于本发明的含有花生四烯酸的油脂(甘油三酯)的全部脂肪酸,花生四烯酸的比例从排除其他脂肪酸的影响的目的来看,优选高的比例,但并不限于高比例。实际在应用于食品时,有时花生四烯酸的绝对量会成为问题,实际可以使用含有等于或大于10重量%的花生四烯酸的油脂(甘油三酯)。
在本发明中,作为构成脂肪酸的一部分或全部为花生四烯酸的甘油三酯,可以使用1,3位结合中链脂肪酸、2位结合花生四烯酸的甘油三酯。并且可以使用含有的1,3位结合中链脂肪酸、2位结合花生四烯酸的甘油三酯等于或大于5mol%、优选等于或大于10mol%、更优选等于或大于20mol%、最优选等于或大于30mol%的油脂(甘油三酯)。上述甘油三酯的1,3位结合的中链脂肪酸,可以利用从具有6~12个碳原子的脂肪酸中选择的脂肪酸。作为具有6~12个碳原子的脂肪酸,如可以为辛酸或癸酸等,特别优选1,3-辛酰基-2-花生四烯酰-甘油(以后称“8A8”)。
这些1,3-位结合中链脂肪酸、2位结合花生四烯酸的甘油三酯,以高龄者为对象时,是最合适的油脂(甘油三酯)。一般摄取油脂(甘油三酯),进入小肠内后被胰脂肪酶水解,该胰脂肪酶对1,3位有特异性,甘油三酯的1,3位被切断,形成2分子的游离脂肪酸,同时生成1分子的2-单酰基甘油(2-MG)。该2-MG的胆汁酸溶解性非常高,吸收性良好,因此一般说2位脂肪酸的吸收性好。此外,2-MG在胆汁酸中溶解后,产生表面活性剂的作用,提高游离脂肪酸的吸收性。
游离脂肪酸和2-MG能够与胆固醇、磷脂质等一起生物合成胆汁酸复合胶束(micelle),然后被小肠上皮细胞吸收,再合成三酰基甘油,最终作为乳糜微粒(Chylomicron)在淋巴内释放。但是,该胰脂肪酶的脂肪酸特性具有对饱和脂肪酸高、难于切断花生四烯酸的特征。并且问题是随着年龄的增加胰脂肪酶的活性降低,因此对于高龄者,1,3位结合中链脂肪酸、2位结合花生四烯酸的甘油三酯是最合适的油脂(甘油三酯)。
作为1,3位结合中链脂肪酸、2位结合花生四烯酸的甘油三酯的具体制造方法之一,在含有花生四烯酸的油脂(甘油三酯)及中链脂肪酸存在的条件下,可以使仅仅对甘油三酯的1,3位酯键作用的脂肪酶发挥作用来制造。
作为原料的油脂(甘油三酯)是以花生四烯酸为构成脂肪酸的甘油三酯,在相对于构成甘油三酯的全部脂肪酸中花生四烯酸的比例高时,为了防止因未反应的油脂(原料甘油三酯和1,3位的脂肪酸中只有1个是中链脂肪酸的甘油三酯)的增加引起的反应收率降低,通常的酶反应温度为20℃~30℃、高为30℃~50℃、优选40℃~50℃。
作为对甘油三酯的1,3位的酯键产生特异作用的脂肪酶,如可以是根霉属(Rhizopus)、(Rhizomucor)、曲霉属(Aspergillus)等微生物产生的酶、猪胰脏脂肪酶等。对于所述脂肪酶,可以使用市售的,如戴尔根霉(Rhizopus delemar)的脂肪酶(田边制药(株)制、talipase)、根毛霉属(Rhizomucor miehei)的脂肪酶(诺和诺德NovoNordisk(株)社制、酶性核酸(Ribozyme)IM)、Apergillus niger的脂肪酶(天野制药(株)脂肪酶A)等,但不限于这些酶,只要是对1,3位有特异性的脂肪酶,都可以使用。
上述脂肪酶的使用形式,从提高反应效率的目的来看,反应温度应等于或大于30℃,优选等于或大于40℃,所以优选使用以附加酶的耐热性为目的的在固定化担体上固定的脂肪酶。固定化担体是多孔性树脂,可以为具有约等于或大于100埃(angstrom)的孔径的离子交换树脂担体,如Dowex MARATHON WBA等。但是,并不限于这些固定化担体,只要是能够附加耐热性的固定化担体,都可以使用。
对于固定化担体1,使其悬浮于0.5-20倍重量的对1,3位有特异性的脂肪酶的水溶液中,在悬浮液中边搅拌边慢慢加入2-5倍量的冷丙酮(如-80℃)形成沉淀。将该沉淀物在减压下干燥,可以调制固定化酶。进而简便的方法是,对于固定化担体1,使0.05~0.4倍量的对1,3位有特异性的脂肪酶溶解于最小量的水中,边搅拌边混合固定化担体,在减压下进行干燥可调制固定化酶。通过该操作约90%的脂肪酶可固定在担体上,但这种情况下其本身根本没有酯交换活性,在加入1-10重量(W/V)%水的基质中、优选在加入1-3重量%的基质中进行前处理,能够提供制造活性化效率最高的固定化酶。
根据酶的种类,在本反应系中加入的水分量极为重要,不含水时难于进行酯交换反应,另外水分量多时会发生水解反应,甘油酯的回收率降低(发生水解可生成甘油二酯、单酸甘油酯)。但是,在该情况下如果使用经过前处理的活性化的固定化酶,在本反应中加入的水分量并不重要,即使在完全不含水的体系中,也能够有效地进行酯交换反应。并且可以通过选择酶的种类而省去前处理。
这样,使用具有耐热性的固定化酶,可以提高酶反应的温度,因此,在对于1,3位特异性脂肪酶反应性低的含有花生四烯酸的油脂(甘油三酯)中,不会降低反应效率,而能够有效地制造1,3位结合中链脂肪酸、2位结合花生四烯酸的甘油三酯(8A8)。
作为制造对白天活动量降低及/或抑郁症状具有改善作用的饮食品的制造方法,可以将花生四烯酸及/或以花生四烯酸为构成脂肪酸的化合物单独使用,或者可以将其与实质上不含花生四烯酸、或即使含有也只是微量的饮食原料一起配合。这里的微量,指的是即使饮食原料中含有花生四烯酸,人体摄取配合其的食品后,也达不到下述本发明的1天应摄取花生四烯酸的量。
特别是构成脂肪酸的一部分或全部是花生四烯酸的甘油三酯的情况下,油脂(甘油三酯)的用途有无限的可能性,可以作为食品、饮料、化妆品、医药品的原料及添加物使用。并且其使用目的、使用量不受任何限制。
例如,作为食品组合物,可以是一般食品、其他功能性食品、营养辅助食品、特定保健用食品、早产儿用调制乳、乳儿用调制乳、乳儿用食品、孕产妇食品或老人用食品等。作为含有油脂的食品例子,可以是含有肉、鱼、或果仁等本来的油脂的天然食品,汤等调理时加入油脂的食品,炸面(饼)圈等使用油脂作热介质的食品,黄油等油脂食品,小甜饼干等加工时加入油脂的加工食品,或hard biscuit等加工完成时将油脂喷雾或涂抹油脂的食品等。并且可以添加到不含油脂的农产食品、发酵食品、畜产食品、水产食品或饮料中。而且可以是功能性食品、医药品的形式,例如可以为经肠营养剂、粉末、颗粒、含片、内服液、悬浮液、乳浊液、糖浆等加工形式。本发明的制品可以附加对白天活动量减少及/或抑郁症状具有改善作用的标示。
本发明的组合物,除本发明的有效成分以外,还可以含有一般饮食品、医药品或医药外用品使用的各种担体、添加物。特别优选含有以防止本发明有效成分氧化为目的的抗氧化剂。作为抗氧化剂,可以为生育酚类、黄酮衍生物、甜菜内酯类、麹酸、没食子酸衍生物、儿茶酸类、蜂斗叶酸、棉子酚、吡嗪衍生物、芝麻酚、愈疮木酚、愈疮木酸、P-香豆素酸、去甲二氢愈疮木酸、甾醇、terpen类、核酸碱基类、类胡萝卜素类、木聚糖类等天然抗氧化剂,以及以抗坏血酸棕榈酸酯、抗坏血酸硬脂酸酯、丁基羟基茴香醚(BHA)、丁基羟基甲苯(BHT)、叔丁基对苯二酚(TBHQ)、4-羟甲基-2,6-二叔丁基酚(HMBP)(4-Hydroxymethyl-2,6-di-tert-butylphenol)为代表的合成抗氧化剂。
在生育酚类中,可以为α-生育酚、β-生育酚、γ-生育酚、δ-生育酚、ε-生育酚、ζ-生育酚、η-生育酚及生育酚酯(醋酸生育酚等),甚至可以把生育三烯酚作为类缘化合物。此外,类胡萝卜素类,可以为β-胡萝卜素、角黄素(canthaxanthin)、虾青素(astaxanthin)等。
本发明的组合物,除本发明的有效成分外,担体可以为各种载体担体、填充剂、稀释剂、增量剂、分散剂、赋形剂、粘结剂溶剂(如水、乙醇、植物油)、溶解辅助剂、缓冲剂、溶解促进剂、胶化剂、悬浮剂、小麦粉、米粉、淀粉、玉米淀粉、多糖、乳蛋白质、骨胶原、米油、卵磷脂等。作为添加剂,如可以为维生素类、甜味料、有机酸、着色剂、香料、防潮剂、纤维、电解质、矿物质、营养素、抗氧化剂、保存剂、芳香剂、湿润剂、天然食物提取物、蔬菜提取物等,但并不限于这些。
花生四烯酸及以花生四烯酸为构成脂肪酸的化合物的主药效成分是花生四烯酸。有报告指出:每日从食物中摄取的花生四烯酸的量,关东地区为0.14g、关西地区为0.19-0.20g[脂质营养学4,73,(1995)]。从高龄者摄取的油脂量少、胰脂肪酶活性低等方面来考虑,高龄者必须摄取相当量、或大于相当量的花生四烯酸。因此,本发明的花生四烯酸及以花生四烯酸为构成脂肪酸的化合物的成人(如体重为60kg)每日摄取量,以花生四烯酸量换算应为0.001g~20g、优选0.01g~10g、更优选0.05g~5g、最优选0.1g~2g。
将本发明的有效成分实际应用于饮食品时,在食品中配合的花生四烯酸的绝对量也很重要。但是,在饮食品中配合的绝对量也因配合的饮食品的摄取量而变化,所以将含有构成脂肪酸的一部分或全部为花生四烯酸的甘油三酯的甘油三酯配合在食品中时,配合的花生四烯酸应等于或大于0.001重量%,优选等于或大于0.01重量%,更优选等于或大于0.1重量%。并且,将1,3位结合中链脂肪酸、2位结合花生四烯酸的甘油三酯配合在饮食品中时,配合的花生四烯酸应等于或大于0.0003重量%,优选等于或大于0.003重量%,更优选等于或大于0.03重量%。
本发明的组合物作为医药品使用时,可以按照制剂技术领域惯用的方法如日本药局方所述方法或以此为标准的方法进行制造。
本发明的组合物作为医药品使用时,组合物中的有效成分的配合量,只要能够达到本发明的目的,没有特别限定,可以按照适当的配合比例使用。
本发明的组合物作为医药品使用时,优选以给药单位的形式给药,特别优选经口给药。本发明的组合物的给药量随年龄、体重、症状、给药次数等不同而不同,例如,成人(约60kg)每日摄取本发明的花生四烯酸及/或以花生四烯酸为构成脂肪酸的化合物的量,以花生四烯酸量换算,通常约为0.001g~20g,优选0.01g~10g,更优选0.05g~5g,最优选0.1g~2g,1日可分1-3次给药。
脑磷脂质膜的主要脂肪酸是花生四烯酸及二十二碳六烯酸,考虑到平衡,优选与二十二碳六烯酸组合。此外,因为脑磷脂质膜内二十碳五烯酸的比例很低,所以优选几乎不含二十碳五烯酸的花生四烯酸和二十二碳六烯酸组合。并且,在花生四烯酸和二十二碳六烯酸的组合中,花生四烯酸/二十二碳六烯酸比为0.1~15范围,优选0.25~10的范围。此外,优选配合的二十碳五烯酸的量不超过花生四烯酸的五分之一(重量比)的饮食物。
【实施例】
根据实施例对本发明进行更加具体的说明。但是,本发明不限于实施例。
【实施例1:含有花生四烯酸的甘油三酯的制造方法】
作为花生四烯酸生产菌,使用高山被孢霉(Mortierella alpina)CBS754.68,将含有1.8%葡萄糖、3.1%脱脂大豆粉、0.1%大豆油、0.3%KH2PO4、0.1%Na2SO4、0.05%CaCl2·2H2O及0.05%MgCl2·6H2O的培养基6kL加入到10kL的培养槽内调制,开始调整pH为6.0,取前培养液30L接种,在温度26℃、通气量360m3/h、槽内压200kPa的条件下通气搅拌培养8天。且调整搅拌数使溶存氧气浓度维持为10ppm-15ppm。采用流加法使到第4日为止培养基中的葡萄糖浓度为1%-2.5%的范围内,此后维持0.5%-1%(上述%表示重量(W/V)%)。
培养结束后,通过过滤、干燥,回收含有以花生四烯酸为构成脂肪酸的甘油三酯的菌体,利用己烷从得到的菌体中提取油脂,经过食用油脂的精制工序(脱胶、脱酸、脱臭、脱色),得到150kg含有花生四烯酸的甘油三酯(含有构成脂肪酸的一部分或全部为花生四烯酸的甘油三酯的甘油三酯)。将得到的油脂(甘油三酯)进行甲酯化,将得到的脂肪酸甲酯用气相色谱法分析,花生四烯酸占全部脂肪酸的比例为40.84重量%。
并且,棕榈酸、硬脂酸、油酸、亚油酸、γ-亚麻酸、二均-γ-亚麻酸等分别为11.63重量%、7.45重量%、7.73重量%、9.14重量%、2.23重量%、3.27重量%。并且将上述含有花生四烯酸的油脂(甘油三酯)(SUNTGA40S)进行乙酯化,采用规定的高效液相色谱法,从含有40重量%的花生四烯酸乙酯的脂肪酸乙酯混合物中,分离、精制99重量%的花生四烯酸乙酯。
【实施例2:含有等于或大于5mol%8A8的甘油三酯的制造】
将100g离子交换树脂担体(Dowex MARATHON WBA:DowChemical)悬浮于80ml的戴尔根霉(Rhizopus delemar)脂肪酶水溶液中(talipase 12.5%:田边制药(株)),搅拌240ml的冷丙酮(-80℃),进行减压干燥得到固定化的脂肪酶。
接着,取80g实施例1得到的含有40重量%的花生四烯酸的甘油三酯(SUNTGA40S)、160g辛酸、12g上述固定化脂肪酶、4.8ml水,在30℃的条件下搅拌(130rpm)48小时进行反应。反应结束后,除去反应液,得到活性化固定化酶。
接着,取10g固定化脂肪酶[戴尔根霉(Rhizopus delemar)脂肪酶、担体Dowex MARATHON WBA]填充到带有夹层的玻璃柱(1.8×12.5cm、容量31.8ml)内,实施例1得到的SUNTGA40S和辛酸以1:2的比例混合的反应油脂以一定流速(4ml/h)流入柱内,实施连续反应得到400g反应油脂。此外,柱温为40℃-41℃。通过分子蒸馏从得到的反应油脂中除去未反应的辛酸和游离脂肪酸,经过食用油脂的精制工序(脱胶、脱酸、脱臭、脱色),得到含有8A8的油脂(甘油三酯)。
通过气相色谱法和高效液相色谱法,对得到的含有8A8的油脂中8A8的比例进行分析,发现8A8的比例是31.6mol%(且8P8、8O8、8L8、8G8、8D8的比例分别为0.6mol%、7.9mol%、15.1mol%、5.2mol%、4.8mol%,甘油三酯2位结合的脂肪酸P、O、L、G、D分别表示棕榈酸、油酸、亚油酸、γ-亚麻酸、二均-γ-亚麻酸,8P8是1,3-辛酰基-2-棕榈油酸-甘油、8O8是1,3-辛酰基-2-油酰基-甘油、8L8是1,3-辛酰基-2-亚油酰基-甘油、8G8是1,3-辛酰基-2-γ-亚麻酰基-甘油、8D8是1,3-辛酰基-2-二均-γ-亚麻酰基-甘油)。采用规定方法的高速液相色谱法从得到的含有8A8的油脂(甘油三酯)中分离、精制96mol%的8A8。
【实施例3:试验胶囊的制造】
在100重量份明胶和35重量份食品添加甘油中,加水在50℃~60℃溶解,调制黏度为2000cp的明胶被膜。接着在实施例1得到的含有花生四烯酸的油脂(甘油三酯)中混合0.05重量%的维生素E油,调制内容物1。使用该内容物1,根据常法进行胶囊成型和干燥,制造每粒含有200mg内容物的软胶囊。作为人体试验用的模拟胶囊,同时制造内容物为橄榄油的软胶囊。
【实施例4:对于短期进入老人护理机构的高龄者的白天活动量减少及抑郁症状产生影响的含有花生四烯酸的食用油脂胶囊的摄取试验】
白天及夜间的活动量的测定,在不好使的手腕上带上内部装有传感器用于测定活动量的手表型测定器Actigraph,连续1周时间昼夜测定活动量。用计算机软件分析该Actigraph的测定结果,评价白天活动量、夜间睡眠质量等。此外,本发明的人体试验是在遵守helsinki宣言精神、十分关照的情况下实施的。
进行是否同意参加试验的说明会,对70名同意的短期进入老人护理机构的高龄者,分为A和B两个组(A:N=4、B:N=3),为了使A组每日能够摄取240mg花生四烯酸,使其每日摄取3粒实施例3调制的含有花生四烯酸的食用油脂胶囊(花生四烯酸为80mg/粒),服用1个月,使B组服用3粒模拟胶囊。在摄取胶囊前后,在不好使的手腕上带上Actigraph,连续1周昼夜测定活动量。其后,A组、B组的被验者停止摄取胶囊2周时间,作为洗胃期间。洗胃之后使A组服用模拟胶囊、B组服用含有花生四烯酸的食用油脂胶囊,服用1个月,同样在摄取胶囊前后在不好使的手腕上带上Actigraph,连续1周昼夜测定活动量(双盲试验、交叉试验)。
同时在摄取各胶囊前后,为了判定抑郁症状的程度,实施Zung抑郁自我评定尺度的检查。使用该Zung抑郁自我评定尺度的评分(等于或大于40分:轻度抑郁症状,等于或大于50:中度抑郁症状),评价抑郁程度的变化。
摄取胶囊前后的白天平均活动量的变化如图1所示,由Zung抑郁自我评定尺度测定的评分的变化如图2所示。摄取模拟胶囊时,白天平均活动量和由Zung抑郁自我评定尺度测定的评分都没有显著的变化,摄取含有花生四烯酸的食用油脂胶囊后,白天平均活动量明显增加19.1counts/day,由Zung抑郁自我评定尺度测定的评分明显改善3.2点。
接着,用根据最小二乘法的一次近似曲线求出白天平均活动量和由Zung抑郁自我评定尺度测定的评分之间的相关性(图3),发现白天平均活动量和由Zung抑郁自我评定尺度测定的评分之间存在显著相关性(相关系数R=-0.561),原来Zung抑郁自我评定尺度的测定的平均分为37.6分,虽没有达到轻度抑郁症状的程度,但证明抑郁程度减轻可使白天活动量增加。这样首次证明,服用含有花生四烯酸的食用油脂,能够改善白天活动量减少及抑郁症状,并且首次证明其效果是由花生四烯酸产生的。
【实施例5:调制配合含有花生四烯酸的油脂(甘油三酯)的胶囊的例子】
在100重量份明胶和35重量份食品添加物用甘油中,加水在50℃~60℃溶解,调制黏度为2000cp的明胶被膜。接着在实施例2得到的含有32mol%8A8的油脂(甘油三酯)中,混合0.05重量%维生素E油,调制内容物2。取50重量%的实施例1得到的含有花生四烯酸的油脂(甘油三酯)和50重量的%鱼油(金枪鱼油:二十碳五烯酸及二十二碳六烯酸占全部脂肪酸的比例分别为5.1%和26.5%)混合,再混合0.05重量%的维生素E油,调制内容物3。
取80重量%的含有花生四烯酸的油脂(甘油三酯)和20重量%的鱼油(金枪鱼油:二十碳五烯酸及二十二碳六烯酸占全部脂肪酸的比例分别为5.1%和26.5%)混合,再混合0.05重量%的维生素E油,调制内容物4。在实施例1得到的99%花生四烯酸乙酯内,混合0.05重量%的维生素E油,调制内容物5。使用这些内容物2到5,根据常法进行胶囊成形和干燥,制造每粒含有180mg内容物的软胶囊。
【实施例6:在脂肪输液剂中使用】
取400g实施例2得到的含有96mol%8A8的油脂(甘油三酯)、48g精制卵黄卵磷脂、20g油酸、100g甘油及40ml 0.1N苛性苏打加在一起,用均浆器分散,加入注射用蒸馏水调整为4立升。接着用高压喷雾式乳化机乳化,调制成脂质乳液。分别取该脂质乳液200ml注入塑料制袋子,然后在121℃高压蒸汽灭菌处理20分钟,成为脂肪输液剂。
【实施例7:在果汁中使用】
将2gβ-环糊精添加到20ml的20%乙醇水溶液中,这里用搅拌器边搅拌边加入100mg实施例1得到的含有花生四烯酸的甘油三酯(配合0.05%维生素E),50℃保持2小时。冷却到室温(约1小时)后,进一步继续搅拌,在4℃保持10小时。将生成的沉淀离心分离然后回收,用正己烷洗净,然后进行冻结干燥,得到1.8g含有花生四烯酸的甘油三酯的环糊精包接化合物。取1g该粉末均匀混合在10L果汁中,调制含有花生四烯酸的甘油三酯的果汁。
Claims (22)
1.组合物,其含有花生四烯酸及/或以花生四烯酸为构成脂肪酸的化合物、对白天活动量减少及/或抑郁症状具有改善作用。
2.如权利要求1所述的组合物,其中,以花生四烯酸为构成脂肪酸的化合物是花生四烯酸醇酯,或者是构成脂肪酸的一部分或全部是花生四烯酸的甘油三酯、磷脂质或糖脂质。
3.如权利要求2所述的组合物,其中,构成脂肪酸的一部分或全部为花生四烯酸的甘油三酯是1,3位结合中链脂肪酸、2位结合花生四烯酸的甘油三酯。
4.如权利要求3所述的组合物,其中,中链脂肪酸是从具有6~12个碳原子的脂肪酸中选择的脂肪酸。
5.组合物,其含有甘油三酯、对白天活动量减少及/或抑郁症状具有改善作用,所述甘油三酯含有构成脂肪酸的一部分或全部为花生四烯酸的甘油三酯。
6.如权利要求5所述的组合物,其特征在于,甘油三酯的花生四烯酸的比例相对于构成甘油三酯的全部脂肪酸等于或大于10重量%,所述甘油三酯含有构成脂肪酸的一部分或全部为花生四烯酸的甘油三酯。
7.如权利要求5或6所述的组合物,其中,甘油三酯是从属于被孢霉属(Mortierella)、耳霉属(Conidiobolus)、腐霉属(Pythium)、疫霉属(Phytophthora)、青霉属(Pencillium)、芽枝霉属(Cladosporium)、毛霉属(Mucor)、镰刀菌属(Fusarium)、曲霉属(Aspergillus)、红酵母属(Rhodotorula)、虫霉属(Entomophthora)、Echinosporangium属、水霉属(Saprolegnia)的微生物中提取的组合物,所述甘油三酯含有构成脂肪酸的一部分或全部为花生四烯酸的甘油三酯。
8.如权利要求5~7中任一项所述的组合物,其中,含有构成脂肪酸的一部分或全部为花生四烯酸的甘油三酯的甘油三酯是几乎不含二十碳五烯酸的甘油三酯。
9.组合物,其含有甘油三酯、对白天活动量减少及/或抑郁症状具有改善作用,所述甘油三酯含有等于或大于5mol%的1,3位结合中链脂肪酸、2位结合花生四烯酸的甘油三酯。
10.如权利要求9所述的组合物,其中,中链脂肪酸是从具有6~12个碳原子的脂肪酸中选择的脂肪酸。
11.如权利要求1~10中任一项所述的组合物,其中,白天活动量减少或抑郁症状的原因是综合失调症、抑郁病的精神疾患。
12.如权利要求1~10中任一项所述的组合物,其中,白天活动量减少或抑郁症状的原因是脑变性疾患、认知症、Parkinson症候群的神经疾患。
13.如权利要求1~10中任一项所述的组合物,其中,白天活动量减少或抑郁症状的原因是因老化引起的身心功能的降低。
14.如权利要求1~13中任一项所述的组合物,其中,组合物是食品组合物或医药品组合物。
15.如权利要求14所述的组合物,其特征在于,食品组合物是一般食品、饮食物、功能性食品、营养辅助食品、特定保健用食品、早产儿用调制乳、乳儿用调制乳、乳儿用食品、孕产妇食品或老人用食品。
16.如权利要求1~15中任一项所述的组合物,其中还含有二十二碳六烯酸及/或以二十二碳六烯酸为构成脂肪酸的化合物。
17.如权利要求16所述的组合物,其中,以二十二碳六烯酸为构成脂肪酸的化合物是二十二碳六烯酸醇酯,或者是构成脂肪酸的一部分或全部是二十二碳六烯酸的甘油三酯、磷脂质、或糖脂质。
18.如权利要求16或17所述的组合物,其特征在于,在组合所述花生四烯酸和二十二碳六烯酸时,花生四烯酸/二十二碳六烯酸的重量比在0.1~15的范围。
19.如权利要求1~18中任一项所述的组合物,其特征在于,相对于组合物中的花生四烯酸,组合物中的二十碳五烯酸的量不超过五分之一。
20.食品组合物的制造方法,其特征在于,是对于白天活动量减少及/或抑郁症状具有改善作用的饮食品的制造方法,花生四烯酸及/或以花生四烯酸为构成脂肪酸的化合物可以单独使用,或者可以与实际上不含花生四烯酸、或即使含有也只是少量的饮食品原料进行配合。
21.预防或治疗方法,其包括将花生四烯酸及/或以花生四烯酸为构成脂肪酸的化合物向需要使用该药的对象进行给药的过程,对白天活动量减少及/或抑郁症状具有改善作用。
22.饮食物,其附有含有花生四烯酸及/或以花生四烯酸为构成脂肪酸的化合物、对白天活动量减少及/或抑郁症状具有改善作用内容的标示。
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CN105106191B (zh) | 2021-09-07 |
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AU2006266755A1 (en) | 2007-01-11 |
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US9168241B2 (en) | 2015-10-27 |
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CA2613345C (en) | 2016-01-05 |
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