CN106692122A - 以5‑氨基乙酰丙酸或其衍生物、或它们的盐作为有效成分的成人病的预防、改善剂 - Google Patents
以5‑氨基乙酰丙酸或其衍生物、或它们的盐作为有效成分的成人病的预防、改善剂 Download PDFInfo
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- CN106692122A CN106692122A CN201610940104.XA CN201610940104A CN106692122A CN 106692122 A CN106692122 A CN 106692122A CN 201610940104 A CN201610940104 A CN 201610940104A CN 106692122 A CN106692122 A CN 106692122A
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- iron
- ala
- adult diseases
- ferrous
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- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 claims description 8
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Abstract
本发明提供与现有的利用生物化学反应抑制型的成人病的治疗药不同、作用机理为提高基础代谢、无副作用、不会产生成人病的耐药性的药物组合物,使用该药物组合物的成人病的预防、治疗方法。提供含有5‑氨基乙酰丙酸(ALA)或其衍生物或它们的盐,优选含有ALA或其衍生物或它们的盐和柠檬酸亚铁钠、柠檬酸铁钠、柠檬酸铁铵等铁化合物的代谢综合征、糖尿病、高脂血症、高血压、肝功能障碍、肾衰竭、肥胖、***功能障碍、更年期障碍、肩酸和腰痛等成人病的预防、改善组合物,添加有该组合物的成人病的预防、改善用食品或食品原材料,将上述组合物用于成人病的预防、改善剂的制备中的方法等。
Description
本申请是2009年10月27日申请的PCT国际申请PCT/JP2009/005651于2011年3月29日进入中国国家阶段的、申请号为200980138548.X且发明名称为“以5-氨基乙酰丙酸或其衍生物、或它们的盐作为有效成分的成人病的预防、改善剂”的发明专利申请的分案申请。
技术领域
本发明涉及以5-氨基乙酰丙酸(以下称为“ALA”)或其衍生物、或它们的盐作为有效成分的成人病的改善、预防剂,具体地说,涉及以经口、静脉注射、舌下片、腹腔给药、经肠输液、经皮剂、栓剂等方式给药的糖尿病、高脂血症、高血压等成人病的预防、改善组合物,或预防、改善方法等。
背景技术
成人病为包括糖尿病、高脂血症、高血压、肝功能障碍、肾衰竭、肥胖、***功能障碍、更年期障碍、肩酸(肩こり)、腰痛等的疾病、病状的总称,以前认为由于年龄增大而发病,而近年弄清了作为所谓的生活习惯病,长期的生活习惯与发病紧密相关。认为各种疾病的发病、恶化的机理相互关联,对于高血压、高脂血症、糖尿病与肥胖复合的状态,特别是命名为代谢综合征,引起注意,但是现状是,特别是没有固定的治疗剂、治疗方法、预防剂、预防方法,使医疗现场、患者徒然混乱。
成人病显著降低患者的生活质量,有可能引起并发症,特别是发达国家中患者剧增,已经开发了很多用于预防、改善成人病的药品,但是都为降低糖尿病的血糖值、降低血压、降低胆固醇值等对于各种症状的改善剂,作用机理大多为特定酶等的抑制。
例如对于糖尿病,现在的糖尿病大多为抗胰岛素性的所谓的II型,开发了糖代谢的抑制剂、食品吸收抑制剂。这些抑制剂、吸收抑制剂有一定的治疗效果,但是糖尿病的本来的发病原因为细胞中的糖的吸收能力降低,因此认为抑制对细胞、血液供给糖的方法并非本质性的改善对策,降低了患者的生活质量。
对于高脂血症,实现脂肪的吸收抑制的健康食品、胆固醇的代谢抑制剂(所谓的抑制素)满足了市场需求,但是已知抑制素等若在体内显著降低导致动脉硬化的胆固醇的同时,也抑制与基础代谢相关的泛醌等的供给,报告了虽然流行病学上稍微降低心肌梗塞的危险,但是另一方面就癌症等的发病率上升、死亡率上升的结果,将该结果当作问题。
对于高血压,除了一直以来的钙拮抗剂之外,还销售通过各种抑制剂降低血压的降压剂,形成了大的市场,但是仅为对症疗法,并非除去根本性原因的方法。对于降压剂,关于流行病学上有效性、副作用,对服用的有效性进行了讨论。
对于肝功能障碍,关于病毒性肝功能障碍,已知利用干扰素进行的治疗表现出效果,但是对于并非病毒性的一般性的肝功能降低,无有效的方法,现状是依赖于营养剂、民间疗法。由中药发展的熊的胆等经验性地已知有一定的效果,但是作用机理、甚至连有效成分也不特定。即便蚬贝、姜黄存在效果,而销售大量的健康食品,但是效果未得到证明。此外,一直以来使用以原卟啉钠作为主要成分的肝功能改善剂,但是效果不充分,此外,作为副作用,已知光损伤。
对于肾衰竭,治疗中经常进行透析,人工性进行肾脏的机能,就是最明显的对症治疗法,与肾脏机能改善无关。对于肾脏的机能改善,现状是依赖于在肝脏同样的营养剂、民间疗法的范围内的方法。此外,透析为医疗费高涨的最大原因。
肥胖被认为是全部成人病的元凶而被忌讳,但是没有适当的药品,仍然推荐抑制吸收、消化的减肥健康食品或运动,形成巨大的市场,但是不仅是金钱,精神上的负担也大。即使仅摄取相同的食物,随着年龄增长,也确实地比年青时胖,这是由于,随着年龄增长,吸收、消化并未增长,运动不充分不是主要原因而是由于基础代谢降低。没有通过改善基础代谢来消除肥胖的方法。
对于***功能障碍,开发了万艾可等具有卓效的药品,改善了苦于***功能障碍的很多患者的生活,其作用机理为血管扩张,通过给药产生物理性的***现象,但是并非伴随着本来的感情的***,此外,同时引起心脏病等危险。在该领域中,蝮蛇、犀角、海狗、鳖等民间药得到重用,但是完全无科学性,反而已知很多对健康有害的例子。换而言之,未知着眼于随着年龄增长而***减弱的现象的根本性的方法。
对于更年期障碍,通常为由于闭经后的女性的激素平衡不调引起的倦怠感、忧郁等症状的综合,最近已知对于男性也存在更年期,与女性同样地出现倦怠感、忧郁等症状。严重时,对男女都实施激素补偿疗法,而发现效果,但是,女性的情况下,由于长期给药而乳癌、子宫癌等危险上升,心肌梗塞、脑卒中的危险上升成为问题。男性的情况下,***癌的危险上升等成为问题。
肩酸、腰痛等酸疼,正确地来说不是病名而是症状,随着年龄增长,苦于肩酸、腰痛等症状的人增多,针灸、柔道、按摩、温泉疗法等疗法,罨包剂(湿布剤)等药物形成一大产业。肩酸、腰痛等酸疼的原因存在几个,主要原因之一可以举出血流阻塞,现有的疗法、药物主要着眼于这种血流改善。尽管提出了各种方法,但是由随着年龄增长,苦于这些症状的人众多可知,仍然未发现有效的方法。
以上对成人病的真实情况和现状的治疗药物、治疗方法进行了概述,总而言之,成人病可以再定义为,以随着年龄增长而降低的基础代谢作为共通的原因、间接的原因,由于基础代谢降低而导致的糖、脂肪在血中的残留,由于能量生产体系的衰竭所导致的活性氧的泄漏和因此导致的基因异常的蓄积。因此,成人病的根本性的治疗、预防在于如何保持基础代谢健康,已知西医为对于成人病的各种现象,使用生物化学上的抑制剂来进行治疗的尝试,始终仅为对症疗法,不是根治性的治疗方法。中医、传统医学的基本理念是保持根本性的基础代谢非常重要,但是作为具体性的对策,在呼吸法、体操、传统性的药用植物的利用的范围内,效果也不充分。
上述实际情况中,期待不仅仅是对症疗法,而是以提高基础代谢为目的的真正有效的成人病的治疗剂、治疗方法、预防剂、预防方法得到科学上的证明并开发。
另一方面,ALA作为色素生物合成路径的中间体已知,广泛存在于动物、植物、菌类中,通常通过5-氨基乙酰丙酸合成酶,由琥珀酰CoA和甘氨酸生物合成。其自身不具有光敏作用,但是经过色素生物合成路径衍生原卟啉IX(PpIX)。有报告指出通过涂布ALA,照射光,可以治疗皮肤癌(例如参照非专利文献1)以来,报告了利用ALA的各种部位的病变部等的诊断和治疗方法,例如提出了肿瘤诊断、治疗剂等(例如参照专利文献1~3),该肿瘤诊断、治疗剂是基于下述原因开发的:若将ALA或其衍生物或它们的盐(以下也称为“ALA类”)给予体内,则生物合成具有肿瘤亲和性的PpIX,通过对蓄积在肿瘤细胞中的PpIX照射光,对周围的氧分子进行光激发,结果生成单态氧,该单态氧利用其强的氧化力而具有杀细胞效果。
此外已知在膀胱中,由尿道将含有ALA类的增敏剂溶液填充到膀胱中,经过一定时间后照射光,用膀胱镜观察荧光,由此可以检测膀胱癌(例如参照非专利文献2),此外,提出了生发剂(例如参照专利文献4),皮肤粗糙预防、改善剂(例如参照专利文献5),它们的特征在于,含有选自5-氨基乙酰丙酸、其盐和它们的酯衍生物中1种或2种以上的化合物和铁化合物作为有效成分。
现有技术文献
专利文献
专利文献1:日本专利第2731032号公报
专利文献2:日本特开2006-124372号公报
专利文献3:日本特表2002-512205号公报
专利文献4:日本专利第3810018号公报
专利文献5:日本专利第3991063号公报
非专利文献
非专利文献1:J.C Kennedy,R.H Pottier and DC Pross,Photodynamictherapywith endogeneous protoprophyrin IX:basic principles and present clinicalexperience,J.Photochem.,Photobiol.B:Biol.,6(1990)143-148.
非专利文献2:5-アミノレブリン酸(5-ALA)膀胱内注入による蛍光膀胱鏡を用いた膀胱癌の光力学的診断,井上启史、辛岛尚、镰田雅行、执印太郎、仓林睦、大朏祐治、日本泌尿器科学会杂志、Vol.97、pp.719-729.
发明内容
本发明的目的在于,提供通过改善随着年龄增长而降低的基础代谢,可以改善或预防成人病的药物组合物,即与现有的利用生物化学反应抑制型的成人病的治疗药不同,以提高基础代谢作为作用机理,即代谢的再生为作用机理,无副作用,不会产生成人病的耐药性的药物组合物,使用该药物组合物的成人病的预防、治疗方法。
ALA为在36亿年前的原始地球中,向大气提供落雷的能量生成的有机化合物之一。包含8个分子ALA的四吡咯化合物具有非常长的共振体系,此外,具有非常高的分子的对称性。因此可以保持能量,例如可以吸收光能。
今天已知很多四吡咯化合物参与生物的能量转换体系的反应,认为ALA为生命的根源物质。很多四吡咯化合物参与生命反应,例如叶绿素为中心具有镁的四吡咯化合物,吸收光能。搬运氧的血红素的反应中心为中心配位铁的四吡咯化合物血红素。该叶绿素、血红素的生物合成的律速阶段为ALA的生物合成,含有ALA和镁的肥料,使光合成活跃,若将ALA和铁添加到小猪的食物中,则小猪的贫血得到改善。发明人已经进行了这些发明,一部分制成了制品。
人与ALA的研究落后,作为遗传病的原卟啉症的患者的尿中ALA多,因此有怀疑、研究神经毒性的经过。此外,重金属中毒患者的尿中ALA多,因此还用于劳动安全卫生管理上的指标。如此,ALA算是疾病的指标,对身体没好处的印象强。
在对人给予ALA的尝试中,通过给予ALA,原卟啉IX蓄积在癌中,与光照射组合的癌症的诊断药物、治疗药物是有名的,分别称为光动力学诊断、光动力学治疗,已经得到实用化。此时,ALA作为杀死癌细胞的毒物已知,未预想到通过提高基础代谢来实现对于成人病的改善效果、预防效果。
在人体中,ALA在线粒体内通过氨基乙酰丙酸合成酶,由甘氨酸和琥珀酰CoA的缩合来生物合成。生物合成的ALA一旦转移到细胞质中,通过细胞室内的氨基乙酰丙酸脱氢酶(胆色素原合成酶),2分子缩合形成吡咯环,形成胆色素原。4分子该胆色素原形成卟啉环,形成四吡咯结构,依次用细胞质内的酶转换,形成粪卟啉原III。粪卟啉原III通过ABC转运蛋白进入到线粒体中,依次氧化至原卟啉IX,通过亚铁螯合酶来配位二价铁,形成血红素、细胞色素。
在制备血红素、细胞色素上,线粒体与体细胞协调的同时进行工作的样子认为与16亿年前所称的通过线粒体共生实现的真核生物的诞生和之后的进化相关,意味深长。总之,异源性给予的ALA与内源性ALA同样地在细胞质中转换为粪卟啉原,并到达线粒体内。在线粒体内由ALA衍生得到的血红素、细胞色素发挥各种重要的作用。一部分再次搬运到细胞质中,与蛋白质聚集发挥各种作用,而在线粒体内发挥作用的血红素、细胞色素的最重要的作用为形成电子传递体系。血红素、细胞色素为构成电子传递体系的复合体的II、III、IV的构成要素,此外,细胞色素C直接将电子从复合体III搬运到复合体IV。通常认为人的寿命由电子传递体系的寿命、特别是复合体IV的酶活性规定。这是表示作为能量获得体系的电子传递体系的重要性的良好例子,而该电子传递体系的反应中心为通过ALA衍生得到的细胞色素和血红素。
以上说明随着年龄增长而线粒体内的ALA生物合成能力降低为衰老的原因,为成人病的根本性的原因,假定为通过给予ALA来改善成人病的基本性的机理。进一步地,对于各症状估计的机理以下进行研究。
成为对象的成人病为代谢综合征时,认为通过给予ALA、优选ALA和铁,电子传递体系的血红素、细胞色素增强,所谓的基础代谢提高为第一作用机理。
成为对象的成人病为糖尿病时,认为通过给予ALA、优选ALA和铁,电子传递体系的血红素、细胞色素增强,所谓的基础代谢提高为第一作用机理。电子传递体系活跃而最初TCA循环顺利进行。推测若进行TCA循环则要求作为基质的乙酰CoA,通过醣酵解体系而消耗糖,从而改善糖尿病。
成为对象的成人病为高脂血症时,认为通过给予ALA、优选ALA和铁,电子传递体系的血红素、细胞色素增强,所谓的基础代谢提高为第一作用机理。电子传递体系活跃而最初TCA循环顺利进行。推测若进行TCA循环则要求作为基质的乙酰CoA,通过β氧化而消耗脂肪酸,从而改善高脂血症。脂肪酸以酰基CoA的方式进入到线粒体中,在线粒体中受到β氧化。此外,存在过量的糖时,在细胞质中产生脂肪酸的合成反应,而通过给予ALA和铁,糖的消耗得到抑制,因此可以期待脂肪酸的合成也降低。
成为对象的成人病为高血压时,认为除了基础代谢提高之外,作为血管扩张因子的NO的生成通过由ALA、优选ALA和铁衍生得到的血红素酶而活跃也是作用机理。
成为对象的成人病为肝功能障碍时,推测除了基础代谢提高之外,作为肝功能的重要功能的毒物分解通过在反应中心具有由ALA、优选ALA和铁衍生得到的血红素的P450进行,通过给予ALA、优选ALA和铁,毒物分解能力提高也是作用机理。
成为对象的成人病为肾衰竭(肾功能障碍)时,认为除了基础代谢提高、通过血管扩张实现的血流改善之外,通过给予ALA、优选ALA和铁衍生的血红素、细胞色素升高使作为肾脏的重要作用的离子泵的活动活跃也是作用机理。
成为对象的成人病为肥胖时,认为通过给予ALA、优选ALA和铁,电子传递体系的血红素、细胞色素增强,所谓的基础代谢提高为第一作用机理。认为通过基础代谢提高,随着年龄增长而懒得进行的运动易得到恢复也对肥胖的改善发挥作用。
成为对象的成人病为***功能障碍时,基础代谢提高、血管扩张为主要作用机理,类比推理ALA具有提高随着年龄增长而降低的男性激素的分泌的作用。男性激素的代谢的律速阶段为通过处于线粒体中的细胞色素P450scc进行的羟基化,推测通过给予ALA、优选ALA和铁,该酶的活性提高。
成为对象的成人病为更年期障碍时,基础代谢提高为主要作用机理,类比推理ALA具有提高随着年龄增长而降低的性激素的分泌的重要作用。性激素的代谢的律速阶段,男性激素、女性激素都为通过处于线粒体中的细胞色素P450scc进行的羟基化,推测通过给予ALA、优选ALA和铁,该酶的活性提高。
成为对象的成人病为肩酸(肩こり)、腰痛等酸疼时,推测通过给予ALA、优选ALA和铁,利用基础代谢的提高、血管的扩张作用实现的淤血的改善带来了显著的治疗效果。
如上所述,本发明人由正面致力于很多生物化学学者回避的根本性问题,例如什么是成人病、什么是年龄增长现象、什么是衰老、随着年龄增长而基础代谢降低是因为什么而产生的,建立了以下假说:线粒体活性降低、更具体地说线粒体的电子传递体系的弱化降低了能量的获得效率,进而降低TCA循环的活性,由此降低糖、脂肪的吸收,引起糖尿病、高脂血症、肥胖、代谢综合征等成人病。本发明人进一步进行精心研究,建立了以下假说:电子传递体系的活性降低是由于,相当于电子传递体系的电子的通道的血红素化合物、细胞色素随着年龄增长而线粒体的ALA生产能力降低。为了大胆地确立下述假说,即,已知作为血红素、细胞素的前驱体,其生物合成为血红素、细胞素的律速阶段,同样随着年龄增长而其产量降低的ALA的添加,作为成人病的治疗药、预防药是有效的,利用它们可以确立成人病的治疗方法、预防方法,发明人对ALA的给药方法、组合的矿物质的种类或量进行了各种研究,确认含有ALA类的组合物具有成人病的治疗、预防效果,从而完成本发明。
即,本发明涉及,(1)一种成人病的预防、改善组合物,其特征在于,含有5-氨基乙酰丙酸(ALA)或其衍生物、或它们的盐;(2)上述(1)记载的成人病的预防、改善组合物,其特征在于,进一步含有铁化合物;(3)上述(1)~(2)中任意一项记载的成人病的预防、改善组合物,其特征在于,铁化合物为选自柠檬酸亚铁、柠檬酸亚铁钠、柠檬酸铁钠、柠檬酸铁铵、焦磷酸铁、血红素铁、葡聚糖铁、乳酸铁、葡糖酸亚铁、DTPA铁、二亚乙基三胺五乙酸铁钠、二亚乙基三胺五乙酸铁铵、乙二胺四乙酸铁钠、乙二胺五乙酸铁铵、三亚乙基四胺铁、二羧甲基谷氨酸铁钠、二羧甲基谷氨酸铵铁铵、乳铁蛋白铁、转铁蛋白铁、氯化铁、三氧化二铁、铁叶绿素钠、铁蛋白铁、富马酸亚铁、焦磷酸亚铁、含糖氧化铁、乙酸铁、草酸铁、琥珀酸亚铁、琥珀酸柠檬酸铁钠、硫酸铁和硫化甘氨酸铁中的1种或2种以上。
此外,本发明涉及,(4)上述(1)~(3)中任意一项记载的成人病的预防、改善组合物,其特征在于,成人病为选自代谢综合征、糖尿病、高脂血症、高血压、肝功能障碍、肾衰竭、肥胖、***功能障碍、更年期障碍、肩酸和腰痛中的1种或2种以上;(5)一种成人病的预防、改善用食品或食品原材料,其特征在于,添加上述(1)~(4)中任意一项记载的组合物;(6)一种方法,其中,将上述(1)~(4)中任意一项记载的组合物用于成人病的预防、改善剂的制备中;(7)一种成人病的预防、改善方法,其特征在于,给予上述(1)~(4)中任意一项记载的组合物。
附图说明
图1为表示使用糖尿病模型小鼠的通过ALA给药得到的血糖值的变化的图。
图2为表示使用糖尿病模型小鼠的通过ALA给药得到的糖耐量试验的结果的图。
图3为表示使用糖尿病模型小鼠的通过ALA给药得到的脂质的变化的图。
图4为表示使用糖尿病模型小鼠的通过ALA给药得到的胰岛素分泌量的变化的图。
图5为表示糖尿病患者的通过ALA给药得到的空腹时血糖的变化的图。
图6为表示边缘性糖尿病患者的通过ALA给药得到的糖化血红蛋白的变化的图。
图7为表示边缘性糖尿病患者的通过ALA给药得到的糖化血红蛋白的变化的图。
图8为表示糖尿病患者的根据有无ALA给药得到的糖化血红蛋白的变化的图。
图9为表示健康人安全性试验中的通过ALA给药得到的分组的糖化血红蛋白的变化的图。
图10为表示健康人安全性试验中的通过ALA给药得到的分组的血糖值的变化的图。
具体实施方式
作为本发明的成人病的预防、改善组合物(预防、改善剂),若为含有由ALA或其衍生物或它们的盐构成的ALA类作为有效成分或主要成分的组合物则不特别限定,上述ALA还称为δ-氨基乙酰丙酸,为用式HOOC-(CH2)2-(CO)-CH2-NH2所示的氨基酸的一种。这些ALA类可以通过化学合成、利用微生物进行的生产、利用酶进行的生产等中的任意一种公知的方法来制备。
ALA类中,作为ALA的衍生物,可以举出例如ALA的具有酯基和酰基的衍生物,可以优选举出甲酯基和甲酰基、甲酯基和乙酰基、甲酯基和正丙酰基、甲酯基和正丁酰基、乙酯基和甲酰基、乙酯基和乙酰基、乙酯基和正丙酰基、乙酯基和正丁酰基的组合。
ALA类中,作为ALA或衍生物的盐,可以举出例如盐酸盐、氢溴酸盐、氢碘酸盐、磷酸盐、硝酸盐、硫酸盐、乙酸盐、丙酸盐、甲苯磺酸盐、琥珀酸盐、草酸盐、乳酸盐、酒石酸盐、乙醇酸盐、甲磺酸盐、丁酸盐、戊酸盐、柠檬酸盐、富马酸盐、马来酸盐、苹果酸盐等酸加成盐,以及钠盐、钾盐、钙盐等金属盐,铵盐,烷基铵盐等。而且,这些盐在使用时以溶液方式使用,优选为其作用与ALA的情况效果相同的盐。这些盐类还可以形成水合物或溶剂合物,此外可以单独使用任意一种或适当组合2种以上来使用。
本发明中,成人病指的是长期的生活习惯与发病紧密相关的生活习惯病,可以优选举出代谢综合征、糖尿病、高脂血症、高血压、肝功能障碍、肾衰竭、肥胖、***功能障碍、更年期障碍、肩酸和腰痛等。
本发明的成人病预防、改善组合物,优选进一步含有铁化合物作为有效成分。作为本发明中的铁化合物,若为在分子内具有铁的化合物则不特别限定,可以举出例如柠檬酸亚铁、柠檬酸亚铁钠、柠檬酸铁钠、柠檬酸铁铵、焦磷酸铁、血红素铁、葡聚糖铁、乳酸铁、葡糖酸亚铁、DTPA铁、二亚乙基三胺五乙酸铁钠、二亚乙基三胺五乙酸铁铵、乙二胺四乙酸铁钠、乙二胺五乙酸铁铵、三亚乙基四胺铁、二羧甲基谷氨酸铁钠、二羧甲基谷氨酸铵铁铵、乳铁蛋白铁、转铁蛋白铁、氯化铁、三氧化二铁、铁叶绿素钠、铁蛋白铁、富马酸亚铁、焦磷酸亚铁、含糖氧化铁、乙酸铁、草酸铁、琥珀酸亚铁、琥珀酸柠檬酸铁钠、硫酸铁和硫化甘氨酸铁,其中优选为柠檬酸亚铁、柠檬酸铁钠。这些铁化合物可以分别单独使用或混合2种以上来使用。本发明的成人病预防、改善组合物中含有的铁化合物通常相对于ALA的给药量,以摩尔比计为0~100倍即可,优选为0.1~8倍。
本发明的成人病的预防、改善组合物作为成人病的预防、改善剂是有用的,可以以经口给药剂型或静脉注射剂型方式使用。作为经口给药剂型的预防、改善剂的剂型,可以举出粉末、颗粒、片剂、胶囊剂、糖浆剂、悬浮液等,作为静脉注射剂型的预防、改善剂的剂型,可以举出注射剂、点滴剂等。将本发明的成人病的预防、改善组合物制备为注射剂等水溶液时,为了防止ALA类的分解,优选注意使水溶液不形成碱性来进行制备。形成碱性时,可以通过除去氧来防止有效成分的分解。
本发明的预防、改善组合物中,根据需要可以加入其它的药效成分、营养剂、载体等其它的任意成分。作为任意成分,例如可以添加结晶性纤维素、明胶、乳糖、淀粉、硬脂酸镁、滑石、植物性和动物性脂肪、油脂、树胶、聚烷撑二醇等可药用的通常的载体、粘合剂、稳定剂、溶剂、分散介质、增量剂、赋型剂、稀释剂、pH缓冲剂、崩解剂、增溶剂、溶解辅助剂、等渗剂等各种制剂用配合成分。
本发明的成人病的预防、改善剂中含有的ALA类中,最优选为ALA、ALA甲酯、ALA乙酯、ALA丙酯、ALA丁酯、ALA戊酯,这些ALA酯类等的盐酸盐、磷酸盐、硫酸盐等。
作为本发明的成人病的预防、改善剂的优选给药法,可以举出包括舌下给药的经口给药以及包括点滴的静脉注射,通过罨包剂(発布剤)、栓剂等进行的经皮给药,这些预防、改善剂中含有的ALA类的量按照ALA盐酸盐换算,成人每人每天0.1mg~1000mg即可,优选为0.3mg~300mg,进一步优选为1mg~100mg。此外,对本发明的成人病的预防、改善剂的优选给药时期不特别限定,可以为早晨或傍晚,而给药量多时可以分多次给药。
本发明的成人病的预防、改善组合物还可以与其它的成人病的预防剂或改善剂或治疗剂组合使用。本发明的给药预防、改善组合物由于现有的该领域的药物为特定反应的抑制剂,与提高基础代谢的本药物的作用机理不同,因此可以期待相加的、根据需要协同的效果。
作为本发明的成人病的预防、改善用食品或食品原材料,若为添加有上述本发明的成人病的预防、改善组合物的食品或食品原材料则不特别限定,通过向饮食品中添加含有ALA类的本发明的组合物,可以形成成人病的预防、改善用的食品或食品原材料。此外,作为本发明的使用方法,若为在成人病的预防、改善剂的制备中使用上述本发明的成人病的预防、改善组合物的方法则不特别限定,在预防、改善剂的制备中使用含有ALA类的本发明的组合物的方法中,可以举出向ALA类中配合上述任意成分来制备经口给药剂型或静脉注射剂型的预防、改善剂的方法。进一步地,作为本发明的成人病的预防、改善方法,若为给予上述本发明的成人病的预防、改善组合物的方法则不特别限定,作为给药方法,如上所述可以举出经口给药、静脉注射、经皮给药。
作为上述本发明的成人病的预防、改善用食品或食品原材料的实施方式,可以举出其特征在于添加有ALA类,附有大意为用于预防、改善成人病的表达的食品或食品原材料,将添加有ALA类的食品或食品原材料用作成人病的预防、改善用的食品或食品原材料的方法,将ALA类用作成人病的预防、改善用的食品或食品原材料的配合剂的方法,其特征在于将ALA类添加到食品或食品原材料中的成人病的预防、改善用的食品或食品原材料的制造方法等。
作为本发明的成人病的预防、改善用的食品或食品原材料,可以举出例如酸奶、酸奶饮料、果汁、牛奶、豆浆、酒类、咖啡、红茶、煎茶、乌龙茶、运动饮料等各种饮料,布丁、小甜饼、面包、蛋糕、果冻、脆饼干等焙烤点心,羊羹等日本点心,冰冻甜点、口香糖等面包、点心类,乌冬面、荞麦面等面类,鱼糕、火腿、鱼肉香肠等鱼肉加工产品,大酱、酱油、调味汁、蛋黄酱、甜调味品等调料,干酪、黄油等乳制品,豆腐、魔芋(こんにゃく)、其它咸烹海味、饺子、炸肉饼、沙拉等各种家常菜,营养食品等。而且,成人病的预防、改善用指的是在食品或食品原材料的包装容器、说明书等中大意表示对成人病的预防、改善有效的情况等ALA类的使用用途为对成人病的预防、改善。
以下通过实施例对本发明进行补充,但是本发明不受该实施例所限定。
实施例1
使61岁男性早晚各摄取1个含有氨基乙酰丙酸磷酸盐(5-氨基乙酰丙酸磷酸盐)5mg和柠檬酸亚铁钠2.87mg的胶囊,摄取后2周发现下述生物化学值的改善。
TG 314→132
GOT 19→19
GPT 17→15
γ-GTP 60→48
HbA1c 6.2→5.9
脂质代谢、肝功能、糖代谢都得到改善。特别是表现出脂质代谢被改善至正常值的显著治疗效果。由本例可知,ALA给药对于各种成人病是有效的。
实施例2
使60岁男性每天摄取1个含有氨基乙酰丙酸磷酸盐5mg和柠檬酸亚铁钠2.87mg的胶囊,摄取1个月后发现下述生物化学值的改善。
TC 264→260
LDL 192→173
HDL 65→58
由本例可知,ALA给药对于脂质代谢和肝功能改善是有效的。
实施例3
使73岁男性每天摄取1个含有氨基乙酰丙酸磷酸盐5mg和柠檬酸亚铁钠2.87mg的胶囊,摄取后高血压改善,1个月后中止一直以来持续给予的降压药,但是血压保持在正常值。由本例可知,ALA给药对于高血压是有效的。
实施例4
使70岁的边缘性糖尿病男性患者每天摄取1个含有氨基乙酰丙酸磷酸盐5mg和柠檬酸亚铁钠2.87mg的胶囊,摄取1个月后、2个月后、3个月后发现下述生物化学值的改善。
开始前 1个月后 2个月后 3个月后
HbA1c 7.4 7.2 6.9 6.8
由本例可知,氨基乙酰丙酸的给药对于糖尿病的改善和预防是有效的。
实施例5
使68岁男性每天摄取1个含有氨基乙酰丙酸磷酸盐5mg和柠檬酸亚铁钠2.87mg的胶囊,摄取1周后发现长期的肩酸得到改善。由本例可知,氨基乙酰丙酸的给药对于肩酸等酸痛是有效的。
实施例6
使42岁男性每天摄取1个含有氨基乙酰丙酸磷酸盐5mg和柠檬酸亚铁钠23mg的胶囊,从摄取第二天开始发现40岁后苦恼的偏头痛得到改善,摄取1周时偏头痛完全治愈。由本例可知,氨基乙酰丙酸的给药对于男性更年期障碍是有效的。
实施例7
使47岁男性每天摄取2个含有氨基乙酰丙酸磷酸盐5mg和柠檬酸亚铁钠2.87mg的胶囊,摄取后第二天早晨产生消失很久的***。在摄取第二天具有隔1年之后的***,此后平均2周继续1次***。由本例可知,氨基乙酰丙酸的给药对于***功能障碍有效,对于防止伴随着衰老的精力衰退也是有效的。
实施例8
使45岁男性每天摄取2个含有氨基乙酰丙酸磷酸盐5mg和柠檬酸亚铁钠23mg的胶囊,从第二天感到体力和精力充实,在摄取第三天具有隔半年之后的***,此后平均1周继续2次***。由本例可知,氨基乙酰丙酸的给药对于***功能障碍有效,对于防止伴随着衰老的精力衰退也是有效的。
实施例9
使47岁男性每天摄取1个含有氨基乙酰丙酸磷酸盐50mg和柠檬酸亚铁钠57.4mg的胶囊,从摄取后第二天感到体力和精力充实。用女性体温计测定体温后发现,摄取前后升高0.1~0.2℃。摄取3个月时体重从79kg减少5kg至74kg,白发、皱纹等也得到改善。由此可知,氨基乙酰丙酸的给药对于代谢综合征等成人病是有效的。
实施例10
使苦于冷感的46岁女性每天摄取1个含有氨基乙酰丙酸磷酸盐5mg和柠檬酸亚铁钠2.87mg的胶囊,摄取二天后感到四肢温暖,冷感得到改善,便秘也消失。由本例可知,氨基乙酰丙酸的给药对于冷感、便秘也是有效的。
实施例11
使苦于更年期障碍的55岁女性每天摄取2个含有氨基乙酰丙酸磷酸盐5mg和柠檬酸亚铁钠23mg的胶囊,从摄取一周左右感到体力改善、皮肤再生,身体的潮热、焦躁感等更年期障碍的症状消失。由此可知,氨基乙酰丙酸的给药对于更年期障碍是有效的。
实施例12
使苦于肩酸的47岁男性在腰痛、肩酸的部位每天涂布以重量计分别为1%的氨基乙酰丙酸磷酸盐和DTPA铁((二亚乙基·三胺·五·乙酸)-Fe)1次,1周肩酸消失。
实施例13
以在试验开始前同意参加的22岁~63岁的男女30例为对象,实施摄取含有ALA磷酸盐以及ALA磷酸盐与柠檬酸亚铁的胶囊的双盲试验。1组连续4周每天摄取1个含有ALA磷酸盐5mg的胶囊,2组连续4周每天摄取1个含有ALA磷酸盐15mg的胶囊,3组连续4周每天摄取1个含有ALA磷酸盐5mg和柠檬酸亚铁2.87mg的胶囊。摄取开始2周后、4周后和试验结束后2周后实施血液生物化学检查。在血液生物化学检查中表现出显著变动的项目如下所述。
1)ALP
·2组2周后降低18.0±23.2U/L(195.2±74.7vs 177.2±55.2U/L)。
2)总蛋白
·2组4周后降低0.29±0.22g/dL(7.28±0.48vs 6.99±0.47g/dL)。
3)白蛋白
·3组2周后降低0.12±0.11g/dL(4.43±0.26vs 4.31±0.26g/dL)。
4)肌酐
·2组4周后降低0.040±0.037mg/dL(0.701±0.134vs 0.661±0.109mg/dL)。
5)总胆固醇
·3组2周后降低13.2±15.0mg/dL(204.1±21.0vs 190.9±30.3mg/dL)。
6)HDL-胆固醇
·1组4周后降低3.7±4.9mg/dL(64.6±17.3vs 60.9±15.8mg/dL)。
·3组2周后降低2.6±2.8mg/dL(67.8±12.4vs 65.2±11.7mg/dL)。
·结束2周后降低2.8±3.7mg/dL(67.8±12.4vs 65.0±11.4mg/dL)。
7)LDL-胆固醇
·3组2周后降低10.7±7.8mg/dL(122.5±20.6vs 111.8±25.9mg/dL)。
8)Na
·3组结束2周后升高0.7±0.7mEq/L(140.4±1.6vs 141.1±1.5mEq/L)。
ALP的降低为肝功能得到改善的好的变化,总蛋白、白蛋白、肌酐的降低意味着蛋白质代谢提高。进一步地,总胆固醇、HDL-胆固醇、LDL-胆固醇的降低为向着脂质代谢得到改善的方向的好的变动。钠的升高推测与从细胞排出钠有关,预想肾功能改善。
以上的试验以健康人为对象进行,但是表现出与成人病相关的代谢向着好的方向发展,表现出本发明的成人病的预防、改善效果。
实施例14
按照常规方法饲养自发性型II型糖尿病模型小鼠KK-Ay小鼠,肥胖后每1kg体重给予5-氨基乙酰丙酸磷酸盐(ALA)10mg和柠檬酸亚铁钠(柠檬酸铁)92g以及ALA 30mg和柠檬酸铁276mg时的血糖值如图1所示,糖耐量试验的结果如图2所示,期间的中性脂肪的推移如图3所示,胰岛素的分泌量的经过如图4所示。实验以各组10只来进行。
由图可知,通过ALA与铁的给药,血糖值降低,糖基化能力提高,脂质代谢也提高,胰岛素的分泌也恢复,对糖尿病、高脂血浆是有效的。认为一般性的糖尿病改善剂使脂质代谢变差,而ALA和铁使线粒体的电子传递体系活跃,连锁的TCA循环的运转得到改善,因此发现所谓的基础代谢的改善,糖、脂质的消耗都得到改善。
实施例15
对53岁男性的II型糖尿病患者在胰岛素治疗中早晨给予10单位、中午给予5单位、晚上给予10单位的胰岛素。使该患者每天摄取ALA磷酸盐25mg和摩尔比计为ALA的0.5倍的柠檬酸铁时的空腹时血糖的变化如图5所示。
空腹时血糖因前一天的饮食生活等变化大,虽然上下变动,但是平均如辅助线所示,1个月降低15mg/dl左右,对糖尿病的改善是有效的。
实施例16
使实施例4的男性继续以相同条件继续摄取,摄取开始5个月后HbA1c降低至5.9,8个月后降低至5.2,完全脱离了糖尿病。结果如图6所示。
实施例17
苦于II型糖尿病的72岁女性在医生的指导下,虽然生活对饮食生活、运动进行了注意,但是HbA1c缓慢升高。2008年11月7日开始每天摄取ALA磷酸盐50mg和摩尔比计为ALA的0.5倍的柠檬酸铁后,发现HbA1c急速改善,半年得到改善。期间的经过如图7所示。此外,摄取开始时的11月7日的空腹时血糖为195mg/dl,在第二年5月9日改善为107mg/dl。
实施例18
使II型糖尿病的69岁女性开始每天摄取ALA磷酸盐15mg和摩尔比计为ALA的0.5倍的柠檬酸铁,中断摄取一次,恢复再次摄取。图8表示期间的HbA1c的变化。粗箭头表示的为摄取时间。通过摄取而HbA1c得到改善。此外,若中止则HbA1c升高,由此明确了ALA具有效果。
实施例19
作为安全性试验,使健康人开始摄取ALA磷酸盐25mg和摩尔比计为ALA的0.5倍的柠檬酸铁,摄取4周,包括摄取前、摄取中止2周,每2周检查血液,未发现平均值有显著变化。进一步地,将健康人分为摄取前的HbA1c高于4.8的组和4.8以下的组,结果如图9所示。由图9可知,HbA1c超过4.8的组中发现若干的降低趋势,而4.8以下的组相反发现升高的趋势,为对正常人没有影响的安全性高的效果。同样地,分为开始时的空腹血糖为90以上的组和低于90的组时的血糖值变化如图10所示。由图10可知,属于正常范围内高的组中可见缓慢降低,而低的组中几乎未看到变化,为不会对正常人引起低血糖的安全效果。
实施例20
边缘性糖尿病男性6名的ALA摄取量、时间、HbA1c的变化如表1所示。可知6名所有成员的HbA1c都得到改善,本发明的盖然性高。
[表1]
通过5-ALA对糖尿病患者的初步研究结果
工业实用性
根据本发明,通过改善随着年龄增长而降低的基础代谢,可以改善或预防成人病。本发明与现有的利用生物化学反应抑制型的成人病的治疗药不同,作用机理为提高基础代谢,即作用机理为代谢的恢复,无副作用,不会产生成人病的耐药性。此外,由于与现有药物和作用机理不同,通过与现有药物联用,可以期待进一步提高效果。
Claims (3)
1.5-氨基乙酰丙酸(ALA)或ALA酯类、或它们的盐在制备用于改善HbA1c值的组合物或者用于改善HbA1c值的食品或食品原材料中的用途。
2.如权利要求1所述的用途,其特征在于,用于改善HbA1c值的组合物或者用于改善HbA1c值的食品或食品原材料进一步含有铁化合物。
3.如权利要求1或2所述的用途,其特征在于,铁化合物为选自柠檬酸亚铁、柠檬酸亚铁钠、柠檬酸铁钠、柠檬酸铁铵、焦磷酸铁、血红素铁、葡聚糖铁、乳酸铁、葡糖酸亚铁、DTPA铁、二亚乙基三胺五乙酸铁钠、二亚乙基三胺五乙酸铁铵、乙二胺四乙酸铁钠、乙二胺五乙酸铁铵、三亚乙基四胺铁、二羧甲基谷氨酸铁钠、二羧甲基谷氨酸铵铁铵、乳铁蛋白铁、转铁蛋白铁、氯化铁、三氧化二铁、铁叶绿素钠、铁蛋白铁、富马酸亚铁、焦磷酸亚铁、含糖氧化铁、乙酸铁、草酸铁、琥珀酸亚铁、琥珀酸柠檬酸铁钠、硫酸铁和硫化甘氨酸铁中的1种或2种以上。
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EP2340821A1 (en) | 2011-07-06 |
US20150290159A1 (en) | 2015-10-15 |
KR20110058902A (ko) | 2011-06-01 |
JPWO2010050179A1 (ja) | 2012-03-29 |
JP5665544B2 (ja) | 2015-02-04 |
EP2340821A4 (en) | 2012-10-03 |
CN102164596A (zh) | 2011-08-24 |
CA2935654A1 (en) | 2010-05-06 |
CA2736866C (en) | 2016-09-06 |
WO2010050179A1 (ja) | 2010-05-06 |
CA2736866A1 (en) | 2010-05-06 |
US20110196033A1 (en) | 2011-08-11 |
CA2935654C (en) | 2019-01-08 |
EP2340821B1 (en) | 2017-01-25 |
EP3192506A3 (en) | 2017-10-25 |
KR101322259B1 (ko) | 2013-10-28 |
EP3192506A2 (en) | 2017-07-19 |
CN103800310A (zh) | 2014-05-21 |
US9730904B2 (en) | 2017-08-15 |
US9095165B2 (en) | 2015-08-04 |
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