CN104248632A - 瓜氨酸或其盐和精氨酸或其盐提高血液精氨酸水平的用途 - Google Patents
瓜氨酸或其盐和精氨酸或其盐提高血液精氨酸水平的用途 Download PDFInfo
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- CN104248632A CN104248632A CN201410392379.5A CN201410392379A CN104248632A CN 104248632 A CN104248632 A CN 104248632A CN 201410392379 A CN201410392379 A CN 201410392379A CN 104248632 A CN104248632 A CN 104248632A
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- salt
- arginine
- blood
- citrulline
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Abstract
本发明涉及瓜氨酸或其盐和精氨酸或其盐在生产提高血液精氨酸水平的速效口服制剂中的用途,所述速效口服制剂含有瓜氨酸及其盐和精氨酸及其盐作为活性成分,其中瓜氨酸或其盐和精氨酸或其盐的总量,对于成年人来说,以游离瓜氨酸和精氨酸计,为一次给药200mg~3g,并且在所述口服制剂中,瓜氨酸或其盐和精氨酸或其盐的重量组成比例,以游离瓜氨酸和精氨酸计,为1:2~2:1。本发明的速效提高血液精氨酸水平的口服制剂可在1小时内起效,由此在摄入后可以快速有效地提高血液精氨酸水平,并可以快速提供精氨酸摄入效应。
Description
本发明专利申请是基于2008年10月10日提交的发明名称为“可提高血液精氨酸水平的含有瓜氨酸和精氨酸的速效口服制剂”的中国专利申请200880111265.1号的分案申请。
技术领域
本发明涉及提高血液精氨酸水平的、含有瓜氨酸或其盐和精氨酸或其盐的速效口服制剂,它能够快速有效地提高血液精氨酸水平。
背景技术
精氨酸是一种氨基酸,它是一氧化氮(NO)合酶的直接底物。此外,它是肝脏中尿素循环的中间体,在体内产生的氨的脱毒过程中发挥重要作用。至于其生理作用,已经报道了由口服摄入精氨酸引起的血管舒张(非专利文献1),抑制血压升高(非专利文献2),性功能的改善(非专利文献3)等。
此外,已知精氨酸具有生长激素分泌作用(非专利文献4)。因为生长激素具有促进蛋白质合成、糖代谢、脂类代谢等作用,因此预计精氨酸的摄入提供了肌肉合成作用和伤口愈合作用。此外,还有许多通过动物和人类口服摄入所发挥的效应,例如氨脱毒作用(非专利文献5)、免疫刺激作用(非专利文献6)、胰岛素分泌(非专利文献7)、多胺合成作用(非专利文献8)等。
因此,提高身体的精氨酸水平被认为对于维持健康和改善疾病状况是有益的。事实上,精氨酸以预期具有这些效应的药物制品、功能性食品等的形式摄入。
另一方面,瓜氨酸在体内不用作蛋白合成的起始原料,它是一种以游离形式存在的氨基酸。在体内,瓜氨酸作为精氨酸的前体用于精氨酸生物合成、或作为与NO供应相关的NO循环的组成性因子发挥了重要作用。
已知口服摄入的瓜氨酸大部分在肾脏中转变成精氨酸,精氨酸有效供应到全身(非专利文献9)。已报道,为了提高血液精氨酸水平,摄入瓜氨酸比摄入精氨酸本身更加有效(非专利文献10)。此外,据报道,联合摄入瓜氨酸和精氨酸而不是单独摄入每种,增加了NO的生产并加强了抗动脉粥样硬化作用(非专利文献11)。但是,这些是由长期摄入提供的效应。
另一方面,在预期通过提高血液精氨酸水平而导致预防或改进的效应中,在由血液流动降低引起的短暂症状,例如对寒冷敏感、肿胀、肩膀僵硬、勃起功能障碍等、由于运动后氨的累积而导致的肌肉疲劳等中,希望在摄入后短时间内表现出效应。但是,在摄入后快速有效提高血液精氨酸水平的口服制剂尚属未知。
非专利文献1:“Journal of the American College of Cardiology(美国心脏病学杂志)”,2000,vol.35,p.706-713
非专利文献2:“Laboratory Investigation(实验室研究)”,1993,vol.68,p.174-184
非专利文献3:“BJU International(英国国际泌尿学杂志)”,1999,vol.83,p.269-273
非专利文献4:“Journal of Laboratory&Clinical Medicine(检验医学与临床杂志)”,2000,vol.135,p.231-237
非专利文献5:“New England Journal of Medicine(新英格兰医学杂志)”,1957,vol.256,p.941-943
非专利文献6:“Surgery(外科学)”,1990,vol.108,p.331-336,336-337
非专利文献7:“Journal of Clinical Investigation(临床研究期刊)”,1966,vol.45,p.1487-1502
非专利文献8:“Nutrition(营养学)”,1999,vol.15,p.563-569
非专利文献9:“Amino acids(氨基酸)”,2005,vol.29,p.177-205
非专利文献10:“Gut(肠)”,2004,vol.53,p.1781-1786
非专利文献11:“PNAS(美国科学院院刊)”2005,vol.102,p.13681-13686
发明内容
本发明待解决的问题
本发明的目的是提供用于在摄入后快速有效地提高血液精氨酸水平的口服制剂和方法,以及提供快速产生精氨酸摄入效应的口服制剂和方法。
解决问题的手段
本发明人进行了深入的研究以力图解决上面提到的问题,并发现,含有瓜氨酸或其盐和精氨酸或其盐作为活性成分的口服制剂,能够在口服摄入后快速提高血液精氨酸水平,从而完成了本发明。
因此,本发明涉及下列第[1]-[18]项。
[1]提高血液精氨酸水平的速效口服制剂,含有瓜氨酸或其盐和精氨酸或其盐作为活性成分。
[2]试剂盒(kit)或套装(set)形式的、提高血液精氨酸水平的速效口服制剂,包含含有瓜氨酸或其盐作为活性成分的口服制剂和含有精氨酸或其盐作为活性成分的口服制剂。
[3]上述[1]或[2]的口服制剂,用于促进血液流动。
[4]上述[1]或[2]的口服制剂,其用于预防或改善由血液流动降低引起的症状。
[5]上述[4]的口服制剂,其中由血液流动降低引起的症状是选自肩膀僵硬、对寒冷敏感、肿胀和勃起功能障碍的至少一种症状。
[6]上述[1]或[2]的口服制剂,其用于抑制血氨水平提高。
[7]上述[1]或[2]的口服制剂,其用于预防或改善由血氨水平提高所引起的症状。
[8]上述[7]的口服制剂,其中由血氨水平提高所引起的症状是运动后肌肉疲劳或疲劳感。
[9]瓜氨酸或其盐和精氨酸或其盐在生产提高血液精氨酸水平的速效口服制剂中的用途。
[10]瓜氨酸或其盐和精氨酸或其盐在生产用于促进血液流动的速效口服制剂中的用途。
[11]瓜氨酸或其盐和精氨酸或其盐在生产用于预防或改善由血液流动降低引起的症状的速效口服制剂中的用途。
[12]瓜氨酸或其盐和精氨酸或其盐在生产用于抑制血氨水平提高的速效口服制剂中的用途。
[13]瓜氨酸或其盐和精氨酸或其盐在生产用于预防或改善由血氨水平提高所引起的症状的速效口服制剂中的用途。
[14]速效提高血液精氨酸水平的方法,包括给需要速效提高血液精氨酸水平的受试对象施用瓜氨酸或其盐和精氨酸或其盐的步骤,施用的量足以速效提高受试对象的血液精氨酸水平。
[15]速效促进血液流动的方法,包括给需要速效促进血液流动的受试对象施用瓜氨酸或其盐和精氨酸或其盐的步骤,施用的量足以促进受试对象的血液流动。
[16]速效预防或改善由血液流动降低引起的症状的方法,包括给需要速效预防或改善症状的受试对象施用瓜氨酸或其盐和精氨酸或其盐的步骤,施用的量足以预防或改善受试对象的症状。
[17]速效抑制血氨水平提高的方法,包括给需要速效抑制血氨水平提高的受试对象施用瓜氨酸或其盐和精氨酸或其盐的步骤,施用的量足以抑制受试对象血氨水平提高。
[18]速效预防或改善由血氨水平提高所引起的症状的方法,包括给需要速效预防或改善症状的受试对象施用瓜氨酸或其盐和精氨酸或其盐的步骤,施用的量足以预防或改善受试对象的症状。
发明效果
因为本发明能够快速有效地提高血液精氨酸水平,所以可以在短时间内得到改善各种由血液流动降低或血氨水平提高所引起的症状。此外,因为本发明的口服制剂高度安全,所以不仅可以通过在症状的可预计发生之前摄入所述制剂,而且可以通过常规性地摄入所述制剂,有效预防症状的发生。
附图说明
图1显示了口服用药后血浆精氨酸水平的时间过程变化(单位:nmol/mL)。
图2显示了口服用药后血浆精氨酸水平的时间过程变化(单位:nmol/mL)。
图3显示了口服用药后血浆NO代谢物(NOx)水平的时间过程变化(单位:nmol/mL)。
图4显示了口服用药后血浆cGMP水平的时间过程变化(单位:nmol/mL)。
图5显示了口服用药35~40分钟后促进了耳动脉血液流动。
具体实施方式
本发明涉及含有瓜氨酸或其盐和精氨酸或其盐作为活性成分的、提高血液精氨酸水平的速效口服制剂(有时称为本发明的口服制剂)。在本发明中,“提高血液精氨酸水平的速效口服制剂”,是通过口服摄入或通过口服给药于人类或人类之外的动物,快速提高血液精氨酸水平的口服制剂。
换句话说,本发明的口服制剂可以快速提高体内血液精氨酸水平。在本发明中,“提高血液精氨酸水平”是指与单独施用精氨酸或其盐或瓜氨酸或其盐的每一种相比,增加精氨酸的血液浓度-时间曲线下的面积(AUC)。这里,“血液浓度-时间曲线下的面积(AUC)”是指在显示了药物等的血液浓度的时间过程进展的图中,由曲线(血药物浓度-时间曲线)和水平轴(时间轴)所包围的面积,是体内的药量等的有用指标。
尽管在本发明中使用的瓜氨酸和精氨酸可以是L-型、D-型和DL-型中的任何形式,但L-型是优选的。
此外,在本发明中使用的瓜氨酸和精氨酸及其盐可以通过下述方法获得,所述方法包括从大量含有它们的动物和植物中分离和纯化它们的方法,包含化学合成的方法,包含发酵生产的方法等。此外,其可商购的产品也可以从例如Sigma-Aldrich等购买。
在本发明中使用的瓜氨酸和精氨酸的盐的例子包括酸加成盐、金属盐、铵盐、有机胺加成盐、氨基酸加成盐等。
上面提到的酸加成盐的例子包括无机酸盐例如盐酸盐、硫酸盐、硝酸盐、磷酸盐等,有机酸盐例如乙酸盐、马来酸盐、富马酸盐、柠檬酸盐、苹果酸盐、乳酸盐、α-酮戊二酸盐、葡萄糖酸盐、辛酸盐等。
上面提到的金属盐的例子包括碱金属盐例如钠盐、钾盐等,碱土金属盐例如镁盐、钙盐等,铝盐,锌盐等。
上面提到的铵盐的例子包括铵、四甲基铵等的盐。
上面提到的有机胺加成盐的例子包括吗啉、哌啶等的盐。
上面提到的氨基酸加成盐的例子包括甘氨酸、苯丙氨酸、赖氨酸、天冬氨酸、谷氨酸等的盐。
在本发明中,作为瓜氨酸的盐,苹果酸盐是优选的。此外,作为精氨酸的盐,盐酸盐和天冬氨酸盐是优选的。
作为本发明的口服制剂,瓜氨酸或其盐和精氨酸或其盐可以直接摄入或施用。一般来说,希望将它们以各种不同制剂的形式提供。
上面提到的本发明的制剂包含瓜氨酸或其盐和精氨酸或其盐作为活性成分,并可以另外包含任何活性成分。这样的制剂通过将活性成分与一种或多种可药用载体相混合,并按照制药技术领域中任何公知的方法来生产。
本发明的口服制剂的剂型的例子包括片剂、粉剂、颗粒剂、乳液、糖浆、胶囊等,优选为片剂和颗粒剂。在配制本发明的口服制剂时,可以使用例如添加剂,诸如赋形剂、黏合剂、崩解剂、润滑剂、分散剂、悬浮剂、乳化剂、稀释剂、缓冲剂、抗氧化剂、抑菌剂、矫味剂、香料、着色剂等。
例如,当口服制剂的剂型是片剂、粉剂、颗粒剂等时,为了配制制剂,可以添加糖类例如乳糖、白糖、葡萄糖、蔗糖、甘露糖醇、山梨糖醇等,淀粉例如土豆、小麦、玉米等,无机物例如碳酸钙、硫酸钙、碳酸氢钠、氯化钠等,赋形剂例如植物粉末(甘草,黄龙胆粉等)等,崩解剂例如淀粉、琼脂、明胶粉、结晶纤维素、羧甲基纤维素钠、羧甲基纤维素钙、碳酸钙、碳酸氢钠、藻酸钠等,润滑剂例如硬脂酸镁、滑石粉、氢化植物油、聚乙二醇、硅油等,黏合剂例如聚乙烯醇、羟丙基纤维素、甲基纤维素、乙基纤维素、羧甲基纤维素、明胶、淀粉胶溶液等,表面活性剂例如脂肪酸酯等,增塑剂例如甘油等。
当口服制剂的剂型是液体制剂例如糖浆等时,为了配制制剂可以添加水,糖类例如蔗糖、山梨糖醇、果糖等,二醇例如聚乙二醇、丙二醇等,油类例如芝麻油、橄榄油、大豆油等,防腐剂例如对羟基苯甲酸酯等,香料例如草莓香料、薄荷等。
此外,在本发明的口服制剂中,瓜氨酸或其盐和精氨酸或其盐可以包含在同样的口服制剂中,或每种物质可以分别配制成制剂,并且它们可以采用试剂盒或套装的形式(在后文中有时简称为试剂盒等),组合并用作提高血液精氨酸水平的速效口服制剂。
在上面提到的试剂盒等中包含的相应的口服制剂可以采取任何形式,只要它们是个别存在的。例如,相应的口服制剂可以是不同的剂型,或可以个别包装,或可以封装在同样的容器中。
本发明的口服制剂可以就此使用,或通过加入一般用于食品或饮料的添加剂而作为食品或饮料使用,诸如采取例如粉末食品、薄片状食品、瓶装食品、罐装食品、杀菌食品、胶囊食品、药片状食品、流体饮食、可饮用制剂等形式的健康食品、功能性食品、膳食增补剂、用于特定健康用途的食品等。上面提到的添加剂的例子包括甜味剂、着色剂、防腐剂、增粘稳定剂、抗氧化剂、显色剂、增白剂、杀真菌剂、胶基、苦味剂、酶、光亮剂、酸味剂、调味剂、乳化剂、强化剂、制造用剂、香料、香辛料提取物等。此外,当食品或饮料是健康食品、功能性食品、膳食增补剂、用于特定健康用途的食品等时,可以提到的是其中包装瓜氨酸或其盐和精氨酸或其盐用于单次摄入的形式,或将其中含有悬浮或溶解的瓜氨酸或其盐和精氨酸或其盐的饮料装填在瓶等中用于单次消耗的形式等。
在本发明的口服制剂中,瓜氨酸或其盐和精氨酸或其盐的含量大致取决于制剂的种类、通过给药或摄入制剂所预期的效应等。瓜氨酸或其盐和精氨酸或其盐的总量,以游离瓜氨酸和精氨酸计,一般为0.1~100wt%,优选为0.5~80wt%,特别优选为1~70wt%。此外,在本发明的口服制剂中,瓜氨酸或其盐和精氨酸或其盐的重量的组成比例,以游离瓜氨酸和精氨酸计,为1:20~20:1,优选为1:5~5:1,特别优选为1:2~2:1。
尽管本发明的口服制剂用于摄入或给药的剂量和给药频率依赖于给药形式、给药对象的年龄、体重等而变化,但瓜氨酸或其盐和精氨酸或其盐的总量,对于成年人每天来说,以游离瓜氨酸和精氨酸计,一般为50mg~30g,优选为100mg~10g,特别优选为200mg~3g,一般一天一次到分几次给药。此外,尽管用药时间没有具体限制,但一般为1天~1年,优选为1周~3个月。
本发明的口服制剂不仅可用于人类,而且可用于人类之外的动物(在后文中简称为非人类动物)。非人类动物的例子包括哺乳动物、鸟类、爬行类、两栖类、鱼类等,优选为非人类哺乳动物。
尽管给药于非人类动物的剂量依赖于动物的年龄和物种、症状的种类或严重性等而变化,但瓜氨酸或其盐和精氨酸或其盐的总量,以游离瓜氨酸和精氨酸计,一般为每天每公斤体重1~600mg,优选为2~200mg,更优选为4~60mg,一般每天一次给药到分几次给药。此外,尽管用药时间没有具体限制,但一般为1天~1年,优选为1周~3个月。
本发明的口服制剂可用于促进血液流动。此外,本发明的口服制剂可用于预防或改善由血液流动降低引起的症状。由血液流动降低引起的症状的例子包括肩膀僵硬、对寒冷敏感、肿胀、勃起功能障碍等。
此外,本发明的口服制剂可用于抑制血氨水平的升高。此外,本发明的口服制剂可用于预防或改善由血氨水平升高所引起的症状。由血氨水平升高所引起的症状的例子包括运动后肌肉疲劳和疲劳感等。因为本发明的口服制剂是速效的,因此通过在运动之前或之后摄入,可以有效预防肌肉疲劳、疲劳感等,或从中快速恢复。
此外,在本发明中,瓜氨酸或其盐和精氨酸或其盐被用于生产提高血液精氨酸水平的速效口服制剂。提高血液精氨酸水平的速效口服制剂,可以被生产成用于促进血液流动的口服制剂,或用于预防或改善由血液流动降低引起的症状的口服制剂,或用于抑制血氨水平升高的口服制剂,或用于预防或改善由血氨水平升高所引起的症状的口服制剂。
此外,本发明包涵了速效提高血液精氨酸水平的方法。本发明的方法包括给需要速效提高血液精氨酸水平的受试对象施用瓜氨酸或其盐和精氨酸或其盐的步骤,施用的量足以速效提高受试对象的血液精氨酸水平。作为速效促进血液流动的方法或者速效预防或改善由血液流动降低引起的症状的方法,方法包括给需要促进血液流动或者预防或改善症状的受试对象施用瓜氨酸或其盐和精氨酸或其盐的步骤,施用的量足以速效促进受试对象的血液流动或者速效预防或改善受试对象的症状。此外,方法还包括速效抑制血氨水平提高的方法或速效预防或改善由血氨水平提高所引起的症状的方法,它们包含了给需要抑制血氨水平提高或者预防或改善症状的受试对象施用瓜氨酸或其盐和精氨酸或其盐的步骤,施用的量足以速效抑制受试对象血氨水平提高或者速效预防或改善受试对象的症状。
用于上面提到的速效提高血液精氨酸水平的口服制剂的生产等的瓜氨酸或其盐和精氨酸或其盐的具体实施方案、使用量等,以及上面提到的速效提高血液精氨酸水平等的方法等,如上文所描述。此外,在上文中,“受试对象”包括人类和非人类动物。
实施例
下面,通过参考实施例,对本发明进行更详细的解释。
首先,显示了实验例,其中研究了含有L-瓜氨酸和L-精氨酸的速效提高血液精氨酸水平的口服制剂的效果。
[实验例1]
将导管留置于15只9周龄雄性SD大鼠(日本エスエルシー株式会社)的每只的颈静脉中。大鼠预先饲养3天,并分成3组。在未禁食条件下,给第1组和第2组大鼠分别口服L-瓜氨酸和L-精氨酸,通过探测器控制这两组中的每只大鼠的口服量为2.85mmol/kg(分别为499.3mg/kg和496.5mg/kg)。此外,给第3组大鼠口服L-瓜氨酸和L-精氨酸,通过探测器控制每只大鼠的口服量为1.43mmol/kg(分别为250.5mg/kg和249.1mg/kg)。
在服药前,以及服药后30分钟、1、2和4小时,从颈静脉收集血液。将血液收集在其中含有事先分配的1%肝素的1.5mL管中,并离心(12000rpm,10min,4℃)以得到血浆。然后,加入与血浆同样量的3%磺基水杨酸并混合,将混合物在冰上静置1小时并离心(12000rpm,10min,4℃),以给脱蛋白的血浆作为分析用样品。用于分析的样品中的L-精氨酸使用自动化氨基酸分析仪(JOEL JLC-500/V)定量。
血浆中L-精氨酸(Arg)的定量结果显示在图1中。
在图1中,在第3组(L-瓜氨酸和L-精氨酸给药组)中,在给药后30分钟和1小时时,观察到了与第1组(L-瓜氨酸给药组)和第2组(L-精氨酸给药组)相比,最大药物浓度(Cmax)的显著提高和最大药物浓度时间(Tmax)缩短。
此外,计算了血液浓度-时间曲线下的面积(AUC,由血液药物浓度和时间所围住的面积),它是比较药物的生物利用度等的有用指标。结果显示在表1中。
表1
正如从表1中清楚看到的,在第3组(L-瓜氨酸和L-精氨酸给药组)中,在给药后30分钟内和1小时内,观察到了与第1组(L-瓜氨酸给药组)和第2组(L-精氨酸给药组)相比,血液浓度-时间曲线下面积的显著增加。
[实验例2]
购买14周龄的雄性新西兰兔(KITAYAMA LABES Co.,Ltd.),预先饲养28天,并分成3组(n=3或4)。在禁食16小时后,给第1组和第2组兔分别口服L-瓜氨酸和L-精氨酸,通过探测器控制这两组中每只兔的口服量为2.85mmol/kg(分别为499.3mg/kg和496.5mg/kg)。此外,给第3组兔口服L-瓜氨酸和L-精氨酸,通过探测器控制每只兔的口服量为1.43mmol/kg(分别为250.5mg/kg和249.1mg/kg)。
在服药前,以及服药后30分钟、1、2和4小时,从耳静脉收集血液,并进行血浆中L-精氨酸、NO代谢物和cGMP的定量。将血液收集在其中含有事先分配的1%肝素的1.5mL管(用于L-精氨酸的定量)和添加有乙二胺四乙酸二钠(EDTA-2Na)的管中(用于NO代谢物和cGMP的定量),并离心(12000rpm,10min,4℃)以得到血浆。然后,在肝素血浆中加入与血浆同样量的3%磺基水杨酸并混合,将混合物在冰上静置1小时并离心(12000rpm,10min,4℃),以给脱蛋白的血浆作为分析用样品。
用于分析的样品中的L-精氨酸使用自动化氨基酸分析仪(JOELJLC-500/V)定量,NO代谢物(NOx:NO2+NO3)使用氮氧化物分析仪(Eicom ENO10)定量,cGMP通过高效液相色谱(HPLC)(AmershamPharmacia RPN226)定量。
此外,在服药后35分钟到40分钟时,使用激光多普勒血液流动分析仪(Laser Doppler Perfusion Imager PIMII)测量耳动脉附近的血液流动。血液流动在距离耳动脉根部和动脉稍部3cm的两个点处测量,并取平均值。确定每个组与取为1的服药前血液流动相比的相对值,并表示成与服药前相比的增加量(Δ血液流动)。
血浆中L-精氨酸(Arg)、NO代谢物(NOx)和cGMP的定量结果显示在图2-图4中,血液流动的测量结果显示在图5中。
正如从图2-图4清楚看到的,在第3组(L-瓜氨酸和L-精氨酸给药组)中,在给药后30分钟和1小时观察到了与第1组(L-瓜氨酸给药组)和第2组(L-精氨酸给药组)相比,血浆中L-精氨酸、NO代谢物和cGMP的最大药物浓度(Cmax)全部增加。此外,在血浆中的L-精氨酸和cGMP中,观察到了最大药物浓度时间(Tmax)的缩短。
在图2中,第3组在0.5小时后的血浆L-精氨酸水平与第1组显示出P<0.05的显著差异。在图3中,第3组在1小时后的血浆NO代谢物水平与第1组和第2组显示出P<0.05的显著差异。在图4中,第3组在2小时后的血浆cGMP水平与第2组显示出P<0.05的显著差异。
正如从图5中清楚看到的,与第1组(L-瓜氨酸给药组)和第2组(L-精氨酸给药组)相比,第3组(L-瓜氨酸和L-精氨酸给药组)的耳动脉血液流动显示出增加。但是,因为数量小(n=2),没有观察到统计学显著的差异。
此外,计算了血浆中L-精氨酸、NO代谢物和cGMP的血液浓度-时间曲线下面积,结果显示在表2~表4中。
表2
表3
表4
正如从表2~表4清楚看到的,与第1组和第2组相比,第3组在服药后30分钟内和1小时内显示出L-精氨酸、NO代谢物和cGMP的全部血液浓度-时间曲线下面积增加。
下面显示本发明的实施例。
[实施例1:含有L-瓜氨酸和L-精氨酸的片剂的生产]
通过锥形混合器对L-瓜氨酸(68.1kg)、L-精氨酸(68.1kg)、微晶体纤维素(36.0kg)、蔗糖脂肪酸酯(6.6kg)、磷酸钙(1.2kg)和β-环糊精(20.0kg)进行混合。将获得的混合物在旋转压缩成型机中压制成型,以制造片剂。
[实施例2:含有L-瓜氨酸和L-精氨酸的肠溶片的生产]
将实施例1中生产的片剂的表面用虫胶溶液涂层,制造肠溶片。
[实施例3:含有L-瓜氨酸和L-精氨酸的肠溶胶囊的生产]
通过锥形混合器对L-瓜氨酸(68.1kg)、L-精氨酸(68.1kg)、微晶体纤维素(36.0kg)、蔗糖脂肪酸酯(6.6kg)、磷酸钙(1.2kg)和β-环糊精(20.0kg)进行混合。将获得的混合物(20kg)与二氧化硅(0.2kg)混合并搅拌。将获得的混合物进料到胶囊灌装机中,填充到硬质胶囊中以制造硬胶囊。将获得的硬胶囊的表面用玉米蛋白溶液涂层,制造肠溶胶囊。
[实施例4:含有L-瓜氨酸和L-精氨酸的饮料的生产]
将L-瓜氨酸(0.64kg)、L-精氨酸(0.64kg)、赤藓糖醇(3kg)、柠檬酸(0.05kg)、人工甜味剂(3g)和香料(0.06kg)通过搅拌溶解在水中(50L,70℃),用柠檬酸将溶液调整到pH3.3。通过板式杀菌对混合物进行灭菌,并装填到瓶中。然后通过巴氏灭菌器对瓶子进行灭菌,以制造饮料。
[实施例5:含有L-瓜氨酸和L-精氨酸的饮料的生产]
将L-瓜氨酸(1.00kg)、L-精氨酸(0.28kg)、赤藓糖醇(3kg)、柠檬酸(0.05kg)、人工甜味剂(3g)和香料(0.06kg)通过搅拌溶解在水中(50L,70℃),用柠檬酸将溶液调整到pH3.3。通过板式杀菌对混合物进行灭菌,并装填到瓶中。然后通过巴氏灭菌器对瓶子进行灭菌,以制造饮料。
[工业实用性]
根据本发明,可以提供能够快速有效提高血液精氨酸水平的速效提高血液精氨酸水平的口服制剂。通过摄入本发明的口服制剂,由血液流动降低和血氨水平升高所引起的各种不同症状,可以在短时间内得到改善或有效预防。
尽管在上面已经详细描述了本发明的某些实施方案,但是,对于本技术领域的普通专业人员来说,有可能对所显示的具体实施方案进行各种不同修改和变化而基本上不背离本发明的讲述和优点。这样的修改和改变包涵在随附的权利要求书中提出的本发明的精神和范围之内。
本申请基于在日本提交的专利申请No.2007-264090,其内容在此全部引为参考。
Claims (3)
1.瓜氨酸或其盐和精氨酸或其盐在生产提高血液精氨酸水平的速效口服制剂中的用途。
2.如权利要求1所述的用途,其中瓜氨酸或其盐和精氨酸或其盐的总量,对于成年人来说,以游离瓜氨酸和精氨酸计,为一次给药200mg~3g,并且在所述口服制剂中,瓜氨酸或其盐和精氨酸或其盐的重量组成比例,以游离瓜氨酸和精氨酸计,为1:2~2:1。
3.如权利要求1所述的用途,其中所述口服制剂在1小时内起效。
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