CN101043824A - 用于治疗和/或预防营养失调的铁络合物 - Google Patents
用于治疗和/或预防营养失调的铁络合物 Download PDFInfo
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- CN101043824A CN101043824A CNA200580034119XA CN200580034119A CN101043824A CN 101043824 A CN101043824 A CN 101043824A CN A200580034119X A CNA200580034119X A CN A200580034119XA CN 200580034119 A CN200580034119 A CN 200580034119A CN 101043824 A CN101043824 A CN 101043824A
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- Prior art keywords
- iron
- iron complex
- complex
- hydrogen atom
- treatment
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- A—HUMAN NECESSITIES
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- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Abstract
本发明涉及某些用于治疗和/或预防营养失调的铁络合物,所述络合物包括亚铁或者三价铁和含有五-或六元芳环或杂环的单、二、三或者六齿配体;含有这些铁络合物的组合物。这些铁络合物提高了铁的生物利用率,并且特别是用于治疗和/或预防营养失调、缺铁症紊乱和贫血症。
Description
技术领域
本发明涉及用于治疗和/或预防营养失调的铁络合物,所述络合物包括亚铁或者三价铁离子和含有五-或六元芳环或杂环的单、二、三或者六齿配体;包括这些铁络合物的组合物;这些铁络合物在提高铁的生物利用率方面的用途和它们在治疗和/或预防缺铁症紊乱和贫血症中的用途。
背景技术
由于亚铁(Fe(II))和三价铁(Fe(III))涉及于人体所必须的许多生物进程中,因此它们是人体营养的主要成分。例如,铁存在于酶的氧化还原-活性反应中心。它还表现为血红蛋白和肌红蛋白中的关键协调原子,可以调节体内氧的运输、存储和利用。
缺铁症紊乱是全世界最普遍的营养失调之一。根据世界健康组织[WHO/UNICEF/Joint Committee有关健康策略的世界健康组织报告,30th Session.JCHP30/95/4.5.日内瓦]和其它来源[见,例如,Hurrell、Nutr.Rev.55,210-222(1997)],20-33%的世界人口、50%的发展中国家和10%的发达国家,正遭受主要由于营养不良引起的缺铁症。人的贫血症主要是由于在膳食中缺乏或者缺少三价铁或者二价铁的生物利用率。
因为各种原因而含有大量蔬菜和少量红色肉类的膳食,由于含有高肌醇磷酸和多酚可能使得这种情况更为恶化。缺铁症还会影响儿童行为和发育、工作绩效和免疫力。因此,从公众健康的角度来说,保持足够的铁含量是非常重要的。
输送Fe(II)和Fe(III)离子到肠吸收位点的新方法有助于改善铁在人体内的状态和有助于人口更为健康。使用铁盐例如硫酸亚铁或者络合物的食物营养强化就是其中一种方法。例如,WO 01/67897中描述了一种加强食品,该食品包括加强量的一种由亚铁或者三价铁源(例如硫酸亚铁)、磷酸盐和铵制备得到的无机化合物例如磷酸亚铁铵。
EDTA已被用于各种饮食。例如,US 4,299,853中公开了EDTA作为酒精饮料例如啤酒、葡萄酒和苹果汁防腐剂的用途。US 3,956,513中公开了一种用于食品或饮料的食用香精中的固态产品,该固态产品含有EDTA的二钠盐或二钾盐与EDTA的四钠盐或四钾盐的混合物。在US 4,820,520中公开了EDTA盐和防腐剂共同使用从而提高饮食中防腐剂的抗真菌活性。US 4,937,085公开了一种食品保藏组合物,其防止蔬菜例如马铃薯变色,该组合物包括柠檬酸、半胱氨酸、抗坏血酸和痕量EDTA。
EDTA还已用于制造各种铁强化食品和饮料。例如,US 5,667,825和US 5,534,275中公开了以乙二胺四乙酸(EDTA)铁作为铁源的即食谷类制品的食品强化。US 6,461,651中描述了无钠的乙二胺四乙酸铁(II)络合物,其可用于铁加强加工食品的制备。此外,WO 03/013283中公开了添加了作为铁源的乙二胺四乙酸(EDTA)铁的饮料和混合粉末状饮料。
U.S.4,020,158、US 4,830,716和US 5,516,925提供了作为营养增补剂给药于人及其他动物的金属(包括铁)氨基酸螯合物。另外,WO03/016332揭示了一种提高这些铁氨基酸螯合物和铁蛋白质盐的溶解度的方法。商品名为Ferrochel(TM)的含有一种铁氨基酸螯合物的食品营养增补剂已经由Albion Laboratories,Inc.(Clearfield,Utah)上市了。美国专利5,653,987公开了一种适于口服或鼻腔给药的液态药剂制剂,包括一种基于蛋白质的药剂、水和至少两种吸收增强化合物,所述吸收增强化合物可以包括乙二胺四乙酸(EDTA)二钠。
在小猪体内进行了口服有机亚铁盐的研究,以调查草酸铁、间苯二酸铁、邻苯二甲酸铁、对酞酸铁和烟酸盐铁的抗贫血作用并将其与延胡索酸铁的抗贫血作用相比较(F.Kratky,“The peroral application ofnew organic iron compounds as a prophylactic measure against pigletphysiological sideropenic anaemia”,Zivocisna Vyroba,(1972),17(12),pp.901-10)。在试验的过程中,对苯二甲酸铁和烟酸铁显示出与延胡索酸盐铁相似的抗贫血活性。
WO96/41627和WO02/24196中公开了含有三价铁或亚铁状态的铁和一个羟基吡喃酮的铁络合物,可用于增加患者血液中的铁的水平。优选羟基-4-吡喃酮和5-羟基吡喃酮,更优选3-羟基-4-吡喃酮,例如麦芽酚和乙基麦芽酚。WO 03/097627还公开了一种形成这类化合物的方法,其中包括铁的一种羧酸盐和一种羟基吡喃酮在pH值大于7的水溶液中反应。
WO 01/12163公开了一种营养增补剂,包括两种不同的铁化合物,即一种迅速溶解的铁化合物和一种缓慢溶解的铁化合物。所述铁化合物可以选自已知的铁化合物,例如铁(II)盐,铁(III)盐和微粒态铁组合物。
很好地报道了由于在生理学的pH值二价铁与三价铁相比具有更为有利的各个氢氧-络合物平衡,因此二价铁比三价铁具有更高的生物利用率。然而,迄今为止,还未有任何一种物质已经被确定在令人满意地提高铁的生物利用率的同时满足食品、饮料和口服药物制剂的感官性能的要求。
发明概述
一方面,本发明提供了一种包括亚铁的或三价铁和单、双、三或六齿配体的铁络合物,其特征在于所述配体为式I所示化合物
其中
m为0或1;
n为1或2;
X为CR或O;
每个R都独立地表示一个氢原子、氧代基团、任选取代的烷基或-OR3,其中R3表示氢原子或一个任选取代的烷基;
R1表示一个任选取代的烷基或-CO-R4,其中R4表示氢原子或-OR3,其中R3如上文所定义;并且
R2表示氢原子或-OR3,其中R3如上文所定义;
条件是,当X为O时,m为0,
该铁络合物用于治疗和/或预防营养失调。
第二方面,本发明提供了一种如上文所定义的医药上使用的铁络合物,特别是用于增加患者血液中铁的水平。
第三方面,本发明提供了一种如上文所定义的用于治疗和/或预防缺铁症紊乱和/或贫血症的铁络合物。
第四方面,本发明提供了如上文所定义的铁络合物在制备用于治疗和/或预防营养失调的药物中的用途。
第五方面,本发明提供了如上文所定义的铁络合物在制备用于增加患者血液中铁的水平的药物中的用途。
第六方面,本发明提供了如上文所定义的铁络合物在制备用于治疗和/或预防缺铁症紊乱和/或贫血症的药物中的用途。
第七方面,本发明提供了一种食品或饮料组合物,包括如上文所定义的铁络合物和食品可接受的或可饮用的载体。
第八方面,本发明提供了一种铁加强食品或铁加强饮料,包括加强量的如上文所定义的铁络合物。
第九方面,本发明提供了食物添加剂,包括如上文所定义的铁络合物。
第十方面,本发明还提供了一种药物组合物,包括如上文所定义的铁络合物和药学上可接受的载体。
发明详述
本发明涉及铁络合物的改进,所述铁络合物适于掺入在食品、饮料、食物添加剂和药物组合物中。所述铁络合物包括亚铁或三价铁和含有五-或六-元芳环或杂环的二齿配位体。具体地,所述配位体是式I所示的化合物
其中
m为0或1;
n为1或2;
X为CR或O;
每个R都独立地表示一个氢原子、氧代基团、任选取代的烷基或-OR3,其中R3表示氢原子或一个任选取代的烷基;
R1表示一个任选取代的烷基或-CO-R4,其中R4表示氢原子或-OR3,其中R3如上文所定义;并且
R2表示氢原子或-OR3,其中R3如上文所定义;
条件是,当X为O时,m为0,
该物质用于治疗和/或预防营养失调。
配体更优选为二齿配位体。
任何一个烷基,除非另作说明,可以为最多含有12个碳原子的直链或支链烷基,优选最多含有6个碳原子,特别优选最多含有4个碳原子。优选烷基为甲基、乙基、丙基和丁基,特别是甲基和乙基,并且更特别优选甲基。当烷基为另一基团中的组成部分时,例如烷氧基中的烷基,优选最多含有6个碳原子的烷基,特别是最多含有4个碳原子的烷基。这部分烷基片断优选甲基和乙基,特别优选甲基。
当指任何一个上述取代基被任选取代时,任选存在的取代基可以为那些通常用于改进食品、饮料和/或药物组合物和/或修饰这类化合物对它们的结构/活性、稳定性、生物利用率或其它性质造成影响的基团中的任何一个或多个。这类取代基的具体例子包括,例如,卤素原子、硝基、羟基、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基、烷基氨基、二烷基氨基、甲酰基、烷氧羰基、羧基和烷酰基。
当上述任何一个任选取代基表示或含有一个烷基取代基时,该烷基可以为直链或支链烷基并且最多可以含有6个碳原子,优选最多含有4个碳原子。优选的任选取代基包括卤素原子、羟基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、氨基、C1-4烷基氨基和二-(C1-4烷基)氨基。特别优选的任选取代基包括卤素原子、羟基、C1-4烷基、C1-4烷氧基和氨基,更特别优选卤素原子和羟基。
优选R1表示C1-4烷基,特别是乙基或者,更特别为甲基,或-CO-R4。更优选R1为-CO-R4。优选R4表示氢原子、羟基或C1-4烷氧基。更优选R4表示氢原子或羟基、甲氧基或乙氧基。
X可以是CR或O。因此,当X是CR时,五或六元环的全部位置都可以被取代。然而,五-或六-元环也可以仅在一个位置被取代或者某几个位置被取代。当X是O时,该O-原子上不被取代,但是剩余还原子中的一个、一些或全部剩余环原子可以被取代。
虽然m可以为0或1,但是当X是CR时,优选m为1。优选R2表示氢原子或羟基或C1-4烷氧基。更优选R2表示氢原子或羟基或甲氧基,特别是羟基。
优选,每个R都独立地表示氢原子或羟基、C1-4烷基或C1-4烷氧基。更优选每个R都独立地表示氢原子或羟基、甲基或甲氧基。
当X为O时,R还可以表示氧代基团。优选氧代基团位于化合物的2-或3-位,也就是说,为呋喃-2-酮和呋喃-3-酮,特别是呋喃-3-酮。
在优选的化合物亚组中,m是1,n是1,X是CR,每个R各自独立地表示氢原子或羟基或甲氧基,R1是-CO-R4,其中R4表示氢原子或羟基、特别是氢原子,并且R2表示氢原子或羟基。特别优选二-或三-取代的苯基。优选的取代型式包括1,2-、1,2,3-、1,2,4-、1,3,4-和1,2,5-位取代的苯环。特别优选在-CO-R4基团邻位具有羟基的化合物。
特别优选的化合物亚组包括2-羟基苯甲醛、2-羟基-3-甲氧基苯甲醛(o-香草醛)、2,5-二羟基苯甲醛、2-羟基-4-甲氧基苯甲醛和3-羟基-4-甲氧基苯甲酸。
在另一个优选的化合物亚组中,m是0,n是1,X是O,R表示氢原子、氧代基团或甲基或乙基,R1是甲基或-CO-R4其中R4表示氢原子,并且R2表示氢原子。特别优选二-取代的呋喃基团。优选的取代型式为2,5-取代。
特别优选的化合物亚组包括5-甲基-2-呋喃甲醛、2-乙基-4-羟基-5-甲基-3(2H)-呋喃酮、2,5-二甲基-4-羟基-3(2H)-呋喃酮和4-羟基-5-甲基-3(2H)-呋喃酮。
该铁络合物可溶于水是其一项特别的优点。
二价铁或三价铁可以由任何适当的来源提供。二价铁来源可以为任何食品或药物级别的亚铁盐,例如硫酸亚铁、硫酸亚铁铵、氯化亚铁、苹果酸亚铁、乙酸亚铁、葡萄糖酸亚铁、硝酸亚铁、乳酸亚铁、富马酸亚铁、琥珀酸亚铁、氧化亚铁、氢氧化亚铁或它们的混合物。特别优选硫酸亚铁。
三价铁来源可以是任何食品或药物级别的铁盐,例如硫酸铁、氯化铁、硝酸铁、乙酸铁、苹果酸铁、乙酸铁铵、甲酸铁、三氧化二铁、氢氧化铁或它们的混合物。特别优选硫酸铁。
制备如上文所定义的铁络合物的方法包括二价铁或三价铁盐与如上文所定义的式I化合物在溶剂中反应。优选铁盐与式I化合物的摩尔比为1∶1-1∶6,更优选1∶2-1∶3,特别是1∶2。
如上文所定义的铁络合物可以用于提高铁的生物利用率。因此本发明铁络合物便于以组合物的形式给药。因此本发明还提供了一种组合物,包括如上文所定义的铁络合物和载体。
所述组合物可以为食品组合物,而在这种情况下的载体可以为食品可接受的载体。合适的食品可接受的载体包括蛋白质、脂肪、淀粉、糖等等。所述组合物可以为饮料组合物,在这种情况下所述载体可以为适于饮用的载体。适当的适于饮用的载体包括水、牛奶及其他合适的液体。饮料组合物包括立即可饮的饮料和混合粉末状饮料,混和粉末状饮料在加入适当的液体后可以再构成。
本发明还包括含有加强量的如上文所定义的铁络合物的铁加强食品,和含有加强量的如上文所定义的铁络合物和适于饮用的液体的铁加强饮料。这种铁加强饮料包括立即可饮的饮料以及混合粉末状饮料。优选的食品包括谷类和面粉以及由谷类和/或面粉制作的产品例如粥和营养性糕点。还优选乳制品,例如牛奶制品。病人和老年人食用的食品还可以用根据本发明进行铁加强。
这些食品或饮料组合物中铁的含量可以为1-200ppm,优选5-100ppm,更优选10-75ppm。理想地,铁的量应当为每天不多于3次给药达到40mg每天的每日建议摄取量(RDA)。
本发明进一步包括一种食物添加剂,包括如上文所述的铁络合物。这种食物添加剂可以单独给药或加入到食品或饮料中给药。
本发明组合物还可以为药物组合物形式,在这种情况下载体可以为药学上可接受的载体。
药学上可接受的载体可以为任何材料,铁络合物和这种材料一起配制可以促进给药。载体可以为固体或液体,包括普通气态材料但是该气态材料已经压缩形成液态,并且可以使用常用于配制药物混合物的任何载体。优选本发明组合物含有0.5-95%重量的活性成分。
本发明的铁络合物可以配制成例如片剂、胶囊、栓剂或溶液。这些制剂可以通过已知的方法使用常规的固体载体例如乳糖、淀粉或滑石粉或者液体载体例如水、油脂或液体石蜡制造。可以使用的其它的载体包括来源于动物或者植物蛋白的材料,例如白明胶、糊精和大豆、小麦和车前草种子蛋白;树胶例如***树胶、瓜耳胶、琼脂和黄原胶(xanthan);多糖;藻朊酸盐;羧甲基纤维素;卡拉胶;右旋糖酐;果胶;合成聚合物例如聚乙烯吡咯烷酮;多肽/蛋白质或者多糖复合物例如白明胶-***胶复合物;糖例如甘露醇、葡萄糖、半乳糖和海藻糖;环状糖例如环糊精;无机盐例如磷酸钠、氯化钠和硅酸铝;和具有2-12个碳原子的氨基酸例如甘氨酸、L-丙氨酸、L-天冬氨酸、L-谷氨酸、L-羟脯氨酸、L-异亮氨酸、L-亮氨酸和L-苯丙氨酸。
组合物的组分还可以包括辅料例如片剂崩解剂、增溶剂、防腐剂、抗氧化剂、表面活性剂、粘度增强剂、着色剂、调味剂、pH调节剂、增甜剂或者味道掩蔽剂。合适的着色剂包括红色、黑色和黄色氧化铁和FD & C染料例如从Ellis & Everard得到的FD & C蓝No.2和FD & C红No.40。合适的调味剂包括薄荷、覆盆子、甘草、橙、柠檬、葡萄柚、焦糖、香草、樱桃和葡萄食用香精和它们的组合。合适的pH调节剂包括钠碳酸氢盐、柠檬酸、酒石酸、磷酸、盐酸和马来酸。合适的增甜剂包括阿斯巴特、乙酰舒泛K和非洲竹芋甜素。合适的味道掩蔽剂包括钠碳酸氢盐、离子交换树脂、环糊精包藏复合物、吸附剂或者微囊密封的或者微囊密封的活性物质。
如上所述,已经发现如上文所定义的铁络合物能够提高铁的生物利用率并且增加患者血液中铁的水平。因此,本发明还提供一种用于医药的如上文所定义的铁络合物,特别是用于治疗和/和预防营养失调,优选缺铁症紊乱和,特别是,贫血症。本发明还包括如上文所定义的铁络合物在制备用于治疗和/和预防营养失调药物中的用途,特别是缺铁症紊乱和,尤其是,贫血症。本发明进一步提供了如上文所定义的铁络合物在制备用于增加患者血液中铁的水平的药物中的用途。
另一方面,本发明提供了一种治疗或预防营养失调、特别是缺铁症紊乱和尤其是贫血症的方法,包括给予患者治疗有效量的或者预防有效量的如上文所定义的铁络合物。
通过下列实施例对本发明作进一步说明。
实施例
材料和方法
化学制剂来自Sigma-Aldrich。水为去离子过滤水(MiIIi-Q)。
使用天然化合物测定铁络合作用
一体积的0.1mM FeSO4溶液与一体积含有0.3mM潜在铁络合剂的溶液混和。接着,加入一体积0.2mM三联吡啶溶液。三联吡啶-铁络合物生成在555nm波长具有最大吸收的红色溶液。为了模拟肠道的pH范围,在pH7、pH 4.5和pH 2条件下进行该试验。
络合物的制备
在氮保护恒定搅拌下,在FeSO4(0.899mol)的去离子(MiIIi-Q)和脱气水(680ml)溶液中加入溶于足够量绝对乙醇中的三倍摩尔量过量的(2.7mol)各个络合剂。通过从轻微的绿色到黛绿/绿-红色的迅速的变色,能够观察到自发的络合物形成。
生面团(dough)的制备
面粉(100g,Pelikan,Meneba,NL)与该先前制备的溶液(68mL)逐渐地混和直到获得均质的生面团。将得到的粗面团均分成小块(10g±0.5g),用于铁透析(dialysability)试验。
铁透析(dialysability)试验
用10%HNO3清洗全部的玻璃仪器和搅拌棒(24h),并且用MiIIi-Q水漂清五次。使用Braun Blender Type 4142,在水平1搅拌1s、水平2搅拌1s、水平3搅拌10s,使1g生面团均匀分散在40mlMiIIi-Q水中。将得到的悬浮液倾倒入VanKel Vial中,并且用MiIIi-Q水(20ml)冲洗搅拌器烧杯两次,将洗液合并到悬浮液中。搅拌棒的搅拌的速度调节为200rpm,37℃(VanKel VK700,Varian)。使用6N HCl调节悬浮液pH至2.0,加入胃蛋白酶HCl溶液(5mL)。保温15分钟后,使用0.5N NaOH调节pH至2.0,加入MiIIi-Q水使悬浮液达到90mL。继续搅拌105分钟。均匀等分为大约每份20g的三份样品,(i)其中一份在-20℃下储藏,(ii)另一份加入到5ml胰腺胆汁溶液中,并用0.5N NaOH调节pH至7.5,和(iii)第三份样品移入锥形瓶(20mL)中。样品(ii)保温30分钟,然后用0.5N NaOH调节pH至7.5(如果必要的话),NaOH的量用来决定调节模拟胃溶液到pH 7.5所需的NaCO3的量。在一个洁净的渗析膜(20cm,Spectra/Por7,分子量小于等于(cut-off)8kD)中充满确定量的0.1M NaCO3溶液,并加入MiIIi-Q水调节总体积为25mL。将该渗析袋置于含有等分部分(iii)的锥形瓶中,在监视其pH值的同时,在37℃以100下/分钟的速度震动30分钟。刚一完成,就在烧瓶中加入5ml胰腺/胆汁-提取物,并且连续振荡2小时。上述操作结束后,回收渗析袋内的物质,用于铁含量的定量分析。
铁总含量的测定
通过感应耦合等离子体原子发射光谱法测定酵母和小麦粉的铁总含量。简要地,微波炉中高温高压(110bar)下,在密闭容器中用5ml65%硝酸和0.5ml 30%过氧化氢消化样品。消化后,用软化水调节溶液体积到50ml,并且喷到等离子体发射光谱仪(Perkin Elmer 3300 DV感应电偶等离子体光学发射光谱仪)的感应耦合等离子体中。在特定波长测定单个元素的发射,并使用标准溶液定量浓度。
透析液中铁离子的测量
使用Roche/Hitachi分析器和以FerroZine铁溶剂(即3-(2-吡啶基)-5,6-二苯基-1,2,4-三嗪-p,p′-二磺酸,单钠盐水合水合物)为基础分析人血清中的铁的试剂测定可透析的铁离子(Fe2+和Fe3+的总和)。根据试剂供应者的指导(Roche Diagnostics Nederland BV),使用离体铁利用率试验的渗析液代替血清进行分析。
实施例
铁络合
表1:分子的铁结合特征
在pH 7.0、4.5和2.0,评定分子的溶解度和铁络合作用。数值为555nm波长与乙二胺四乙酸钠铁的相对吸光率。值越高,铁与指定化合物的结合越强,以及络合剂越好。数据为单次测量的结果。
化合物 | 溶解性/络合作用 | ||
pH 7 | pH 4.5 | pH 2 | |
2-羟基苯甲醛2-羟基-3-甲氧基苯甲醛(o-香草醛)5-甲氧基-2-糠醛2,5-二羟基苯甲醛2-羟基-4-甲氧基苯甲醛3-羟基-4-甲氧基苯甲酸2-乙基-4-羟基-5-甲基-3(2H)-呋喃酮2,5-二甲基-4-羟基-3(2H)-呋喃酮4-羟基-5-甲基-3(2H)-呋喃酮 | 0.942.191.241.701.890.880.870.810.89 | 0.370.390.610.380.460.610.590.650.46 | 0.530.600.630.890.620.791.061.041.01 |
食物的铁透析
表2:计算得出铁含量和离体可透析铁的百分比,并且得出的铁含量和离体可透析铁的百分比用于计算由添加了50mg/kg不同的化合物铁的整粒小麦粉得到的生面团的相对铁利用率,正如显示的那样。结果为4-5次实验的平均数±SD。
铁化合物 | 相对利用率* |
硫酸铁2-羟基苯甲醛铁2-羟基-3-甲氧基苯甲醛(o-香草醛)铁5-甲基-2-糠醛铁2,5-二羟基苯甲醛铁2-羟基-4-甲氧基苯甲醛铁3-羟基-4-甲氧基苯甲酸铁2-乙基-4-羟基-5-甲基-3(2H)-呋喃酮铁2,5-二甲基-4-羟基-3(2H)-呋喃酮铁4-羟基-5-甲基-3(2H)-呋喃酮铁 | 1.01.5**2.4**1.31.8**1.11.05.0**1.31.3 |
*相对于由添加了硫酸亚铁的整粒小麦粉制得的生面团的铁利用率进行归一化的。
**显著不同于硫酸亚铁(ANOVA、p<0.05)。
Claims (26)
2.根据权利要求1的铁络合物,其中配体为二齿配体。
3.根据权利要求1或2的铁络合物,其中R1表示C1-4烷基或-CO-R4。
4.根据上述任一权利要求的铁络合物,其中R1表示-CO-R4。
5.根据上述任一权利要求的铁络合物,其中R4表示氢原子、羟基或C1-4烷氧基。
6.根据上述任一权利要求的铁络合物,其中R2表示氢原子、羟基或C1-4烷氧基。
7.根据上述任一权利要求的铁络合物,其中R各自独立地表示氢原子或羟基、C1-4烷基或C1-4烷氧基。
8.根据上述任一权利要求的铁络合物,其中X为CR。
9.根据上述任一权利要求的铁络合物,其中m为1。
10.根据权利要求1-7中任一项的铁络合物,其中X为O。
11.根据上述任一权利要求的铁络合物,其中n为1。
12.根据上述任一权利要求的铁络合物,其可溶于水。
13.如权利要求1-12中任一项所定义的的铁络合物,用于医药。
14.如权利要求1-12中任一项所定义的铁络合物,用于增加患者血液中铁的水平。
15.如权利要求1-12中任一项所定义的铁络合物,用于治疗和/或预防缺铁症紊乱。
16.权利要求1-12中任一项所定义的铁络合物,用于治疗和/或预防贫血症。
17.权利要求1-12中任一项所定义的铁络合物在制备用于治疗和/或预防营养失调的药物中的应用。
18.权利要求1-12中任一项所定义的铁络合物在制备用于增加病人血液中铁的水平的药物中的应用。
19.权利要求1-12中任一项所定义的铁络合物在制备用于治疗和/或预防缺铁性疾病的药物中的应用。
20.权利要求1-12中任一项所定义的铁络合物在制备用于治疗和/或预防贫血症的药物中的应用。
21.食品组合物,包含权利要求1-12中任一项所定义的铁络合物和食品可接受载体。
22.铁加强食品,包含加强量的权利要求1-12中任一项所定义的铁络合物。
23.饮料组合物,包含权利要求1-12中任一项所定义的铁络合物和可饮用载体。
24.铁加强饮料,包含加强量的权利要求1-12中任一项所定义的铁络合物和可饮用液体。
25.食品添加剂,包含权利要求1-12中任一项所定义的铁络合物。
26.药物组合物,包含权利要求1-12中任一项所定义的铁络合物和可药用载体。
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IL181829A0 (en) | 2007-07-04 |
EP2015647A2 (en) | 2009-01-21 |
AR051741A1 (es) | 2007-02-07 |
WO2006037449A2 (en) | 2006-04-13 |
US20060078594A1 (en) | 2006-04-13 |
RU2007117147A (ru) | 2008-11-20 |
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