CN106535906B - 用于治疗或预防肾结石症的含有植酸、镁和多酚的组合物 - Google Patents
用于治疗或预防肾结石症的含有植酸、镁和多酚的组合物 Download PDFInfo
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- CN106535906B CN106535906B CN201580033945.6A CN201580033945A CN106535906B CN 106535906 B CN106535906 B CN 106535906B CN 201580033945 A CN201580033945 A CN 201580033945A CN 106535906 B CN106535906 B CN 106535906B
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- magnesium
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- calcium
- polyphenol
- phytate
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- 239000000203 mixture Substances 0.000 title claims abstract description 52
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 239000011777 magnesium Substances 0.000 title claims abstract description 33
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- 235000001055 magnesium Nutrition 0.000 title abstract description 7
- QXDMQSPYEZFLGF-UHFFFAOYSA-L calcium oxalate Chemical compound [Ca+2].[O-]C(=O)C([O-])=O QXDMQSPYEZFLGF-UHFFFAOYSA-L 0.000 claims abstract description 28
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- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 6
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Abstract
本发明涉及含有植酸或植酸盐,以盐、氢氧化物或氧化物形式的镁,以及任选的至少一种多酚的组合物。这些化合物可以分离形式或构成富集植物提取物的部分。本发明还涉及这种组合物以药物、营养品或功能性食物或食物补充剂的形式,用于治疗肾结石症、优选钙或草酸钙结石症的用途。
Description
技术领域
本发明涉及包含植酸或其植酸盐中的任一种、镁盐和任选的多酚的组合物,所述组合物可用于治疗肾结石症,主要是钙肾结石症,由于其组分之间的协同作用以抑制钙盐的结晶、游离草酸盐的减少和由于氧化性应激的乳头状损伤。
因此,本发明属于药理学领域。
背景技术
已知植酸(植酸盐)的离子种类具有抑制生物学流体中的钙盐沉积的发展,因此减少钙肾脏结石及其他病理性钙化两者的危险的能力。还已知在哺乳动物的组织和流体中发现的植酸盐主要来自饮食。近来,已显示一水草酸钙乳头状肾脏结石由于源于肾乳头组织的损伤而发生(F Grases,A Costa-Bauza,RM Prieto,A Conte,A Servera,BMC Urol,2013,13:14,doi:10.1186/1471-2490-13-14)。这些损伤导致在乳头内组织中以羟磷灰石形式的组织钙化过程,当在大小中增加并且穿过覆盖乳头的上皮且与尿(所述尿在草酸钙中永久性过饱和)接触时,所述组织钙化过程导致乳头状结石的发展的开始。结晶抑制剂连同免疫系统可逆转这个过程,因为当结晶过程停止时,巨噬细胞可破坏最初形成的羟磷灰石(F Grases,RM Prieto,P Sanchis,C Saus,T De Francisco,J Nephrol,2008,21(5),768-75)。显而易见地,损伤数目越少,起始乳头状结石的发展过程的概率越小。近期研究已显示具有抗氧化剂性质的某些化合物例如多酚显著减少乳头内钙化的发展(F.Grases,RMPrieto,I Gomila,P Sanchis,A Costa-Bauza,Urol Res,2009,37(1),35-40),这是它们为何可在预防肾结石症中具有重要作用的原因。
草酸钙结石代表大约70%的肾脏结石,尿草酸盐的水平是其发展的重要危险因素。监测尿中的游离草酸盐是针对草酸钙结石发展的治疗中的非常重要的方面。因此,通过与草酸盐离子形成可溶性复合物,镁显著减少草酸钙过饱和,这导致生成草酸钙结晶的困难增加。
发明内容
本发明的目的是呈现用于治疗肾结石症、优选钙肾结石症的新制剂,与现有技术章节中描述的方面相关,并且与关于植酸和/或其药学可接受的植酸盐与多酚和镁盐的组合的近期发现相关。这个组合对于肾脏结石,优选钙肾脏结石,并且更优选地草酸钙肾脏结石的治疗可为非常有益的,因为植酸盐对钙盐结晶的抑制能力增加多酚对源于氧化性应激的乳头状损伤的有益作用。这两种效应与镁减少尿中的游离草酸盐浓度的能力组合,通过与其形成可溶性复合物且因此减少就草酸钙而言的过饱和。另外,镁协同增强植酸盐抑制草酸钙结晶的能力。本发明提供了借助于植酸盐、多酚和/或镁盐、氢氧化物或氧化物的组合使用,用于治疗和预防肾钙化的方法。
因此,本发明的第一方面涉及包含植酸或其盐中的任一种(其可为分离形式或富集植物提取物的形式)以及以盐、氢氧化物或氧化物形式的镁的组合物。
术语‘钙化’或‘结石’包括暗示/诱导尿中的固体沉淀物形成的所有此类过程或状况。因此,诱导钙化或肾脏结石的状况包括但不限于高水平的尿草酸盐,钙的尿排泄中的高水平,或成核现象和晶体生长抑制剂的存在或活性减少。
术语‘尿草酸盐’指尿中的草酸盐排泄。8-30mg/天视为正常水平,而如果它们超过45m/g天,则视为高草酸尿的情况。尿中的草酸盐水平可在具有原发性高草酸尿的患者中达到90至270mg/天的水平。
‘高钙尿’指超过300mg/天或4mg/kg/天的升高的尿钙排泄。
“成核现象和晶体固体生长抑制剂的存在或活性减少”指可调节所述过程的所有这些化合物,所述化合物包括但不限于糖蛋白例如肾钙蛋白或骨桥蛋白以及某些无机和有机聚磷酸盐。这些化合物与晶体相互作用且抑制其生长。
在本发明中,‘植酸’或‘肌醇-六磷酸’理解为下式的分子:
并且‘植酸盐’是具有至少少一个氢的植酸形式,使得相应的磷酸基与阳离子(K、Mg、Ca、Mn、Zn和Fe)相互作用。本发明有利的植酸盐主要是钠盐、钾盐、钙盐、镁盐、锌盐和钙-镁盐。
在一个优选实施例中,本发明的组合物包含至少一种多酚。
在本发明中,多酚意指特征在于超过一个酚基团/分子的存在的在植物中发现的一组化学品。这些产物具有显著的抗氧化剂性质并且还适合于人消耗。对于本发明的组合物特别有利的多酚是从红葡萄或白葡萄的种子中提取的那些,尽管它们可来自其他植物物种例如浆果、茶、啤酒、橄榄油、巧克力/可可、坚果、石榴等。本发明的优选多酚的具体例子是表儿茶素、儿茶素、没食子儿茶素、表没食子儿茶素、槲皮素、白藜芦醇、丹宁酸或没食子酸。
因此,已显示在使用具有包含1%植酸盐伴随从白葡萄籽中提取的多酚补充剂的组合物的实验动物的‘体内’模型中,实现50%肾钙化的减少,例如实例2中解释的。
其他研究已显示人工尿中的镁的存在协同增强植酸盐抑制草酸钙结晶的能力,例如实例1中显示的。
镁与植酸盐形成比钙盐更可溶的盐,因此它增加植酸盐在肠中的吸收,导致在尿中排泄的植酸盐的增加,并且因此导致其针对草酸钙肾脏结石形成的抑制能力中的增加。
这些模型显示以另外含有多酚和/或镁盐或氧化物形式的包含植酸盐的制剂可用于制造药剂或饮食补充剂用于治疗或预防肾结石症,优选钙肾结石症,并且更优选草酸钙肾结石症。
为了本发明的目的,植酸和/或其药学可接受的盐可以游离形式如纯物质,含有其的植物物种提取物,例如白米或糙米的提取物使用,或通过含有其的植物物种携带,例如小麦、燕麦、大豆、杏仁、槐豆等谷物或水果的芽或外部部分。
多酚还可以游离形式作为纯物质或含有其的植物物种的提取物或药学可接受的使用。
镁可以其药学可接受的盐的形式供应,所述药学可接受的盐例如氧化镁、氢氧化镁、柠檬酸镁、硬脂酸镁、碳酸镁、氯化镁和硫酸镁。
在一个优选实施例中,本发明的组合物包含按重量计40至50%的植酸或其盐。
在一个优选实施例中,本发明的组合物包含按重量计25至40%的以盐、氢氧化物或氧化物形式的镁。
在一个优选实施例中,本发明的组合物包含按重量计10-30%的多酚。
本发明的另一个方面涉及本发明的组合物用于制造药剂的用途。
本发明的另一个方面涉及描述的组合物用于制造用于治疗肾结石症的药剂的用途。优选地,肾结石症是钙肾结石症。
本发明的另一个方面涉及本发明的组合物用于制备药剂的用途,所述药剂预期减少患有与草酸钙结晶相关的疾病的患者的危险且改善患有与草酸钙结晶相关的疾病的患者的健康状况。
使用植酸盐、多酚和镁的组合的非常重要的优点在于草酸钙结晶的抑制剂的作用与多酚的作用组合,通过避免或减少乳头状组织的损伤,所述多酚还减少草酸钙的异质成核剂数目,并且伴随与草酸盐形成可溶性复合物的镁的作用,因此减少草酸钙的尿过饱和。
植酸盐、多酚和镁的组合可以固体形式(包括颗粒、粉末或栓剂)或液体形式(例如溶液、悬浮液或乳状液)施用。依次地,它们可像这样施用或在经历操作例如灭菌、添加防腐剂、添加稳定剂或添加乳化剂之后施用。
植酸盐、多酚和镁的共施用可与一种或多种化合物组合,所述一种或多种化合物有利于其通过所选择的施用途径的吸收。因此,它们可与乳糖、蔗糖、滑石、硬脂酸镁、纤维素、钙盐、明胶、脂肪酸以及其他药学上可接受的物质一起施用。
含有植酸盐、多酚和镁的药物组合物包括每种有效成分的量,所述量允许有效减少尿草酸盐水平。关于这个目的的有效量取决于因素例如施用途径、个体健康或草酸盐尿水平,尽管这些因素不限制帮助限定推荐量的其他因素的包括。在任何情况下,应理解每个个体将服用的每种有效成分的量将由专科医生取决于个体情况来决定。在一个优选实施例中,组合物以500mg/天至1,000mg/天的合适剂量用于施用。
术语‘肾结石症’、‘尿石症’或‘肾结石’指通过肾或尿道(输尿管、膀胱)内的钙或结石的存在引起的病症。肾脏结石由尿中的正常物质(钙盐、尿酸、胱氨酸等)组成,所述物质出于不同原因已浓缩且沉淀,形成更大或更小尺寸的碎片。
术语‘尿酸晶体’或‘尿酸结石’包括所有此类过程或状况,其暗示/诱导这种物质涉及其中的尿中的固体沉淀物形成。
在一个优选实施例中,组合物是药物组合物或营养品或功能性食物。
在本发明中,‘营养品’或‘功能性食物’理解为对健康具有有益作用的食物。以相同方式,术语营养品可应用于来源于常见食物的提取物或化学化合物。归于营养品性质的食物的例子是橄榄油、红葡萄酒、青花菜、大豆等。营养品通常用于营养混合物和医药工业中。以与一些食物可分类为营养品的相同方式,一些营养补充剂也像这样分类,例如脂肪酸例如来源于鱼油的ω-3以及一些蔬菜或抗氧化剂和维生素。
可用于所述组合物中的药学可接受的佐剂和媒介物是本领域技术人员已知且常用于制备治疗组合物的佐剂和媒介物。
说明书和权利要求自始至终,单词‘包含’及其变体不预期排除其他技术特征、添加剂、组分或步骤。对于本领域技术人员,本发明的其他目的、优点和特征根据说明书将变得部分显而易见且根据本发明的实践变得部分显而易见。下述实例和附图提供用于举例说明,并且不预期限制本发明。
附图说明
图1.它显示在合成尿中、在不同镁和植酸盐浓度下、关于200mg/L钙和50mg/L草酸盐溶液的结晶诱导时间(以分钟表示)的图示。
具体实施方式
实例1.在镁和植酸盐的存在下的草酸钙结晶的测量。
来自200mg/L钙和50mg/L草酸盐溶液,在合成尿中,关于草酸钙结晶的诱导时间已在不同植酸盐和/或镁浓度的存在下进行计算。表1显示了所述诱导时间,如由图1中明确可见的,所述诱导时间随着镁和植酸盐的浓度增加而增加。因此,当不存在镁或植酸盐时,草酸钙花费1分钟结晶。当加入100mg/L镁时,这个时间增加直到10分钟,并且依次地,如果除10mg/L镁外,还添加1mg/L植酸盐,则这个时间增加直到44分钟。
表1:在合成尿中、在不同镁和植酸盐浓度下、关于200mg/L钙和50mg/L草酸盐溶液的结晶诱导时间(以分钟表示)。
实例2.本发明的组合物对经历致结石饮食的Wistar大鼠的作用。
一组Wistar大鼠用从白葡萄籽中提取的多酚(以200mg/L的浓度加入饮用水中)和植酸盐(喂给动物的固体饮食的1%,以植酸钙镁的形式,所述植酸钙镁为钙镁盐)进行预处理。随后,乳头状肾结石症通过施用乙二醇进行诱导,并且继续预防处理。通过与相应对照组的比较,多酚+植酸盐混合物的抗结石活性通过动物的肾(在实验结束时提取)的钙含量和肾组织的相应组织学研究进行评估。观察到所应用的预防处理使肾钙化减少50%。
实例3.本发明的组合物对具有肾结石症问题的患者的作用。
在本实例中,示出了本发明的三种药物组合物。
组合物1.
化合物 | 量 |
植酸钙-镁 | 300mg |
柠檬酸镁 | 250mg |
表儿茶素 | 100mg |
组合物2.
化合物 | 量 |
植酸钙-镁 | 300mg |
柠檬酸镁 | 250mg |
儿茶素 | 150mg |
组合物3.
化合物 | 量 |
等价于植酸盐的量的糙米提取物 | 250mg |
氧化镁 | 150mg |
等价于多酚的量的黑葡萄籽提取物 | 150mg |
组合物4.
化合物 | 量 |
等价于植酸盐的量的槐豆芽提取物和干小麦提取物 | 150mg |
氧化镁 | 100mg |
等价于多酚的量的白葡萄籽提取物 | 90mg |
200mg植酸钙-镁(植酸钙镁)连同200mg柠檬酸镁和100mg槲皮素一起经口施用于患者,每天两次,在早餐时和在晚餐后。在处理后,观察到患者的尿针对草酸钙结晶的抑制能力就在摄入植酸盐之前自身患者的尿而言增加40%。尿的抗氧化能力(使用铂电极进行电位评估)增加15%。这些变化可由复发的显著减少到结石形成过程的总消除暗示,因为它们消除和/或标准化结石形成过程中的关键因素,例如尿的抑制能力、草酸尿和针对氧化性应激的保护。
Claims (24)
1.用于治疗患者的肾结石症的包含植酸或其盐中的任一种以及盐、氢氧化物或氧化物形式的镁的组合物,其中所述肾结石症是草酸钙肾结石症,并且其中所述草酸钙肾结石症与草酸钙结晶相关;并且其中所述镁处于选自下列的形式:氧化镁、氢氧化镁、柠檬酸镁、硬脂酸镁、碳酸镁、氯化镁和硫酸镁;并且其中所述组合物协同地抑制草酸钙结晶。
2.根据权利要求1所述的组合物,所述组合物包含至少一种多酚。
3.根据权利要求2所述的组合物,其中所述多酚选自表儿茶素、儿茶素、没食子儿茶素、表没食子儿茶素、槲皮素、白藜芦醇、没食子酸和丹宁酸。
4.根据权利要求2所述的组合物,其中所述多酚是来自葡萄籽的富集植物提取物的形式。
5.根据权利要求1-4中任一项所述的组合物,其中所述植酸盐选自钠、钾、钙、镁、锌或钙-镁。
6.根据权利要求1-4中任一项所述的组合物,其中所述植酸盐是来自水稻、槐豆、小麦、燕麦、大豆或杏仁的富集植物提取物的形式。
7.根据权利要求1-4中任一项所述的组合物,所述组合物包含按重量计40-50%的植酸或其盐。
8.根据权利要求1-4中任一项所述的组合物,所述组合物包含按重量计25-40%的盐、氢氧化物或氧化物形式的镁。
9.根据权利要求2-4中任一项所述的组合物,所述组合物包含按重量计10-30%的多酚。
10.根据权利要求1-4中任一项所述的组合物,所述组合物还包含乳糖、蔗糖、滑石、硬脂酸镁、纤维素、钙盐、明胶或脂肪酸。
11.根据权利要求1-4中任一项所述的组合物,所述组合物以药物组合物、功能性食物、营养产品或食物补充剂的形式呈现。
12.根据权利要求1-4中任一项所述的组合物,其中所述组合物以500mg/天至1,000mg/天的合适剂量用于施用。
13.植酸或其盐中的任一种以及盐、氢氧化物或氧化物形式的镁在制备用于治疗患者的肾结石症的组合物中的用途,其中所述肾结石症是草酸钙肾结石症,并且其中所述草酸钙肾结石症与草酸钙结晶相关;并且其中所述镁处于选自下列的形式:氧化镁、氢氧化镁、柠檬酸镁、硬脂酸镁、碳酸镁、氯化镁和硫酸镁;并且其中所述组合物协同地抑制草酸钙结晶。
14.根据权利要求13所述的用途,其中所述组合物还包含至少一种多酚。
15.根据权利要求14所述的用途,其中所述多酚选自表儿茶素、儿茶素、没食子儿茶素、表没食子儿茶素、槲皮素、白藜芦醇、没食子酸和丹宁酸。
16.根据权利要求14所述的用途,其中所述多酚是来自葡萄籽的富集植物提取物的形式。
17.根据权利要求13-16中任一项所述的用途,其中所述植酸盐选自钠、钾、钙、镁、锌或钙-镁。
18.根据权利要求13-16中任一项所述的用途,其中所述植酸盐是来自水稻、槐豆、小麦、燕麦、大豆或杏仁的富集植物提取物的形式。
19.根据权利要求13-16中任一项所述的用途,其中所述组合物包含按重量计40-50%的植酸或其盐。
20.根据权利要求13-16中任一项所述的用途,其中所述组合物包含按重量计25-40%的盐、氢氧化物或氧化物形式的镁。
21.根据权利要求14-16中任一项所述的用途,其中所述组合物包含按重量计10-30%的多酚。
22.根据权利要求13-16中任一项所述的用途,其中所述组合物还包含乳糖、蔗糖、滑石、硬脂酸镁、纤维素、钙盐、明胶或脂肪酸。
23.根据权利要求13-16中任一项所述的用途,其中所述组合物以药物组合物、功能性食物、营养产品或食物补充剂的形式呈现。
24.根据权利要求13-16中任一项所述的用途,其中所述组合物以500mg/天至1,000mg/天的合适剂量用于施用。
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