CN1182873C - 精氨酸硅酸盐肌醇络合物及其应用 - Google Patents
精氨酸硅酸盐肌醇络合物及其应用 Download PDFInfo
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- CN1182873C CN1182873C CNB988023695A CN98802369A CN1182873C CN 1182873 C CN1182873 C CN 1182873C CN B988023695 A CNB988023695 A CN B988023695A CN 98802369 A CN98802369 A CN 98802369A CN 1182873 C CN1182873 C CN 1182873C
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- silicate
- arginine
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- inositol
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Abstract
本发明涉及含有精氨酸硅酸盐的络合物及其预防和治疗动脉粥样硬化的用途,作为食品添加剂的用途以及促进骨骼和关节结构完整性的用途。精氨酸硅酸盐络合物的合成是通过将精氨酸、硅酸钾和肌醇混合。该络合物可每天经口服给药3次,其作为预防或治疗药的用量是约250mg-约2,500mg。
Description
发明领域
本发明涉及精氨酸硅酸盐络合物及其在预防和治疗动脉粥样硬化中作为食品添加剂并提高骨骼和软骨的结构完整性中的应用。
发明背景
动脉粥样硬化是一种复杂的慢性疾病,它涉及了类脂、胶原、弹性纤维和蛋白聚糖在动脉血管壁内的徐缓蓄积。控制动脉粥样硬化的常见方法包括:低脂肪饮食、运动、多种使胆固醇降低的药物。虽然这些方法可以有效延迟动脉粥样硬化的发展,但它们并不完全令人满意。
人们相信,由血管内皮制造的硫酸肝素蛋白聚糖类物质(HSPGs)可以延缓平滑肌细胞的迁移、增殖和表型转变,正是平滑肌细胞的这些行为在动脉粥样硬化过程中发挥着核心的作用,所以HSPG能够通过结合并激活抗凝血酶III来维持一个抗凝血的腔表面(Clowes等人,自然,265:625-626,1977;Guyton等人,循环研究(Circ.Res.),46:625-634,1980;Edelman等人,美国科学院进展,87:3773-3777,1990)。
已经证实,多种硅类化合物经口服或非肠道给药可以抑制兔子体内由胆甾醇诱发的内膜增生(动脉粥样硬化)(Loeper等人,动脉粥样硬化,33:397-408,1979;Loeper等人,硅生物化学及有关问题,Plenum Press,New York,1978,281-296;Garson等人,药物科学杂志,60:1113-1127,1971)。注射或摄食营养性的硅类化合物(即单甲基三甲硅烷醇、硅酸赖氨酸、硅酸钠)可以预防动脉粥样硬化中的特征性的腔体增厚和动脉弹性纤维断裂。此外,若干流行病学调查报导说,增加摄取饮食中的硅可以相应降低人群中冠心病的危险性(Schwarz等人,Lancet,i:454-457,1977;Schwarz等人,Lancet,i:538-539,1977;Bassler,英国医学杂志,1:919,1978;Parr,Lancet,i:1087,1980)。
在生长的幼鼠和鸡中的调查表明,饮食硅的严重缺乏可导致骨骼和关节结构的异常,这显然应归因于胶原和粘多糖类的生成低下(Carlisle,营养杂志,106:478-484,1976;Carlisle,营养杂志,110:1046-1055,1980).硅可促进胶原和粘多糖类化合物的体外合成(Carlisle等人,饮食进展(Fde.Proc.),37:404,1978;Carlisle等人,饮食进展,39:787,1980)。人们还不了解硅通过何种生物化学方法产生上述作用。已经表明,硅能够提高骨的矿物质密度。当用有机硅类化合物(单甲基三甲硅烷醇)以50mg的剂量对绝经后妇女每周给药两次时,给药14个月内她们的股骨密度平均显著地增高4.7%(Eisinger等人,镁的研究,6:247-249,1993)。在卵巢切除的大鼠中,口服硅酸可减缓骨骼的更新,并且提高骨形成速率(Hott等人,Calcif.Tissue Int.53:174-179,1993)。
骨骼和软骨在幼年和成年动物中是动态组织。在骨骼中,破骨细胞溶解骨羟磷灰石基质并降解(骨)胶原,而破骨细胞同时也通过合成胶原及沉积羟磷灰石来使骨骼重建。与此类似,软骨内的软骨细胞在降解胶原和蛋白聚糖基质的同时进行再合成。人们基本上不了解聚硅氧烷在成年动物中对骨骼和软骨形成的影响。但是,极其有可能的是,硅在骨骼和软骨代谢中的作用对于幼年动物来说是有限的。
硅的营养作用能够支持粘多糖、蛋白聚糖和胶原的充分合成(Schwarz等人,自然,239:333-334,1972;Carlisel,科学,178:619-621,1972;Carlisle,营养杂志,06:478-484;Schwarz,硅生物化学及有关问题,Plenum Press,New York,1978,207-230)。优化的硅类营养品可以促进内皮细胞制造具有保护作用的HSPG类物质。
作为一种必需氨基酸,精氨酸是由血管内皮制造的一氧化氮(NO)的生物合成前体(Moncada,新英格兰医学杂志,329:2002-2012,1993),NO具有舒张血管、抗动脉粥样硬化、抗血栓形成的作用,内皮生成NO的不足在动脉粥样硬化、高血压和糖尿病中发挥着突出的病理学作用(Calver等人,高血压杂志,10:1025-1031,1992;Cooke等人,动脉粥样硬化和栓塞,14:653-655,1994;Rubanyi,刊于:内皮衍生血管活性因子的心血管有效性,Futura Publishing Co.Inc.,NewYork,1991,xi-xix)。在有些而不是所有的临床研究中,精氨酸的非肠道或口服给药能够提高血管的NO合成(Drexler等人,Lancet,338:1546-1550,1991)。在高血压的动物模型中,补充精氨酸可以缓和血压的增高(Chen等人.临床研究杂志.88:1559-1567,1991;Laurant等人,高血压的临床试验学,17:1009-1024,1995)。因此,至少在一些情况下,精氨酸的有效性是对NO的生成进行限速。近期公开的临床研究表明,在血胆甾醇过高的青年中口服精氨酸可以提高内皮依赖型松弛(Creager等,临床研究杂志,90:1248-1253,1992;Clarkson等,临床研究杂志,97:1989-1994,1996),这是血管NO生成得到有效提高的指征。
人们始终需要获得能够预防或延缓动脉粥样硬化的发展并促进骨骼和软骨形成的治疗性/预防性药物。本发明满足了这样的需求。
发明概述
本发明的一个实施方案是一种制备精氨酸-硅酸-肌醇络合物的方法,其步骤包括:
(a)将精氨酸、硅酸盐和肌醇混合成悬浮液;
(b)加热该悬浮液以促使形成凝胶;
(c)使所述凝胶结晶;
(d)将步骤(c)中生成的结晶与醇混合,加速结晶;和
(e)收集步骤(d)中的结晶。
优选的硅酸盐是硅酸钾。加热适合在约95℃进行。该方法还可以包括在收集结晶之前反复进行步骤(d)。此优选实施方案的一个方面是,通过过滤来收集结晶。优选的促结晶醇是乙醇。
本发明还提供了一种通过上述方法形成的精氨酸-硅-肌醇络合物。
本发明的另一个实施方案是一种预防或抑制哺乳动物尤其是人体中的动脉粥样硬化的方法,该方法包括:给该哺乳动物预防或抑制动脉粥样硬化有效量的上述的精氨酸-硅酸-肌醇络合物。优选的给药方式是非肠道或口服给药。优选的有效量是约250mg-约2,500mg;更优选的有效量在约500mg-约1,000mg的范围内。对于平均体重为70kg的男子来说,也就是剂量分别等于约3.6-14mg/kg(250-2,500mg)和约7.1mg/kg-14mg/kg(500mg-1,000mg)。
本发明的再一个实施方案是一种补充饮食中精氨酸的方法,该方法包括给个体施用上述络合物。
本发明还提供一种精氨酸-硅酸-肌醇络合物,其中精氨酸∶硅酸∶肌醇的比例约是3∶3∶1。
本发明的另一个实施方案是上述精氨酸-硅酸-肌醇络合物在补充饮食中精氨酸中的应用。
本发明的一个实施方案是所述精氨酸-硅酸-肌醇络合物在预防或抑制动脉粥样硬化中的应用。
本发明的另一个实施方案是一种预防个体内的骨骼脱矿化或软骨退化的方法,其中包括:给个体施用抑制骨骼脱矿化或软骨退化有效量的所述精氨酸硅酸盐络合物。
本发明的一个实施方案是所述精氨酸硅酸盐络合物在预防个体内的骨骼脱矿化或软骨退化中的应用。优选的给药途径是非肠道或口服给药。
本发明也提供一种治疗需治疗个体中的骨骼或软骨疾病的方法,其中包括:给该个体施用有效量的所述精氨酸硅酸盐络合物。在此优选实施方案的一个方面中,所述骨骼疾病是骨质疏松症、成骨不全或骨折。适合的软骨疾病是骨关节炎、风湿性关节炎、腱撕裂或韧带撕裂。优选经非肠道或口服给药。
本发明的又一个实施方案是所述精氨酸硅酸盐络合物在治疗个体内的骨骼或软骨疾病中的应用。
本发明的一个实施方案是一种对抗骨骼脱矿化且抑制软骨退化的药物制剂,其中包括:治疗有效量的所述精氨酸硅酸盐络合物以及可药用载体或稀释剂。
本发明也提供一种治疗哺乳动物以减轻骨质疏松症、成骨不全、骨折、骨关节炎、风湿性关节炎以及其他骨骼和软骨疾病的病理作用的方法,其中该方法包括:给该哺乳动物施用所述的精氨酸硅酸盐络合物,其中该络合物以对抗骨骼脱矿化和抑制软骨退化的有效量施用于哺乳动物。
优选实施方案详述
本发明提供一种通过将精氨酸、硅酸盐和肌醇混合而成的精氨酸硅酸盐络合物、其合成方法及其作为营养添加剂用于预防和治疗动脉粥样硬化或提高骨骼和软骨结构完整性的应用。尽管所述产品含有精氨酸、硅酸和肌醇,但在本说明书中将其称作“精氨酸硅酸盐”。
精氨酸硅酸盐是通过如实施例1所述的精氨酸(游离碱)、硅酸钾和肌醇的反应来合成的。所得络合物可完全溶解,并且以生物利用形式提供具有良好营养利用性的硅酸盐。硅酸盐一般不溶于水溶液。但是,在合成含有精氨酸硅酸盐的络合物时采用肌醇可使络合物溶解在水溶液中。相反,不采用肌醇合成的精氨酸硅酸盐不溶于水溶液。肌醇这种意料外的增溶作用对于所述络合物作为精氨酸和硅酸的生物可利用来源的应用来说是极其重要的。肌醇通过增强精氨酸和硅酸之间的氢键来促进精氨酸硅酸盐的溶解。虽然也可以使用其他多羟基类化合物,其中包括但不限于甘露糖醇和山梨糖醇,但优选肌醇。硅酸盐的生物利用度在实施例3中得以证实。在一个优选实施方案中,精氨酸和硅酸的混合摩尔比约是1∶1,并且肌醇对精氨酸和硅酸盐的比例约是1∶3。尽管在此硅酸钾用作反应物,本发明也包括使用其他硅酸盐,其中包括硅酸钠和硅酸镁。由肌醇、硅酸盐和精氨酸混合得到的混合物是一种极粘的悬浮液,它在加热时变澄清。在优选的实施方案中,将悬浮液在约80℃和约100℃内,优选在约95℃下加热,直至变得澄清。此时,停止加热和搅拌,凝胶开始形成。在凝胶形成的过程中出现精氨酸硅酸盐络合物的结晶。将所得的结晶块与醇一起分散并混合约30分钟,以便结晶更完全并且回收到更纯的产物。终产物内的重金属含量低于5ppm,该含量显然无法被检测出。铁的水平也很低(10ppm)。这些发现表明,事实上产物不含污染物。虽然精氨酸硅酸盐络合物结晶优选采用乙醇,也可以考虑使用其他醇类化合物。可任选地进行第二步醇结晶。通过过滤收集含有精氨酸、硅酸盐和肌醇的终产物,洗涤并干燥。
精氨酸硅酸盐既可以用作必需氨基酸-精氨酸的来源,也可以作为硅酸盐的来源,它们均具有抗动脉粥样硬化作用。该化合物口服给药可将精氨酸和硅酸盐传递到适当的作用部位。精氨酸硅酸盐是动脉粥样硬化的有效治疗或预防药物,还可以作为食品添加剂服用以维持抗致动脉粥样化的状态。因此,预防性应用和治疗性应用均可给予精氨酸硅酸盐。精氨酸硅酸盐极易溶于水并提供良好的精氨酸和硅酸盐的营养利用度。除了提供硅酸盐外,精氨酸硅酸盐络合物也是必需氨基酸精氨酸的良好食品添加剂。
本发明所述的精氨酸硅酸盐络合物能够促进哺乳动物尤其是人体内的骨骼和软骨的形成。上述精氨酸硅酸盐络合物形式的生物可利用的营养硅也可以提高骨密度并防止骨脱矿化。在一个优选实施方案中,预防性地给予该络合物以预防骨骼的脱矿化和软骨退化。该络合物的一个优选用途是预防和治疗绝经后妇女中由于骨骼脱矿化所致的骨质疏松症。该络合物可以有效地预防或治疗任何骨脱矿化疾病,其中包括骨质疏松症和成骨不全。所述精氨酸硅酸盐络合物也在骨折治疗中用作辅助物。例如,通过在打石膏模的同时结合口服本发明精氨酸硅酸盐络合物以促进骨折加快愈合来治疗患有骨折的个体。这样可以在使用石膏模的情况下缩短个体忍受该固定模的时间。精氨酸硅酸盐络合物也可以用于治疗“未成型”骨折,其中骨骼并未真正地分离。
在另一个优选的实施方案中,精氨酸硅酸盐络合物可有效治疗或预防骨关节炎和风湿性关节炎。
在一个优选实施方案中,将精氨酸硅酸盐络合物单独地或在手术后给予患有软骨或肌腱撕裂的个体以修复损伤面。通过促进软骨的形成,精氨酸硅酸盐络合物缩短了术后的恢复期。
本发明的化合物可以根据需要以适当的剂量单位经非肠道、口服、静脉内、动脉内、肌肉内或其他任何全身性的方式给药。此处的术语“非肠道”包括皮下、静脉内、动脉内、滴注或灌注技术,但不仅限于此。但优选经口服给药。对于口服给药来说,化合物可以作为片剂、水溶液或口服混悬剂、可分散粉剂或颗粒剂、乳剂、硬或软胶囊、糖浆剂或酏剂来提供。用于口服的组合物可以按照制备药物组合物的已知常规方法来制备,并且此类组合物中可含有一种或多种下列试剂:甜味剂、矫味剂、着色剂、防腐剂、增溶剂、湿润剂、稳定剂、色料、抗氧化剂、包衣剂和稀释剂。甜味剂和矫味剂可以提高制剂的可口性。含有与适用于片剂制造的无毒可药用赋形剂混合的精氨酸硅酸盐络合物的片剂是能够被接受的。所述赋形剂包括:惰性稀释剂,例如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;造粒剂和崩解剂,例如玉米淀粉或藻酸;粘合剂,例如淀粉、明胶或阿拉伯胶;和润滑剂,例如硬脂酸镁、硬脂酸或滑石。片剂可以是未经包衣的,也可以是通过已知技术包衣的片剂,这种包衣片剂可以延缓在胃肠道内的崩解和吸收并由此在一个较长的时间内提供延迟的作用。例如,可以单独采用一种延时材料(例如甘油单硬脂酸酯或甘油二硬脂酸酯),或与蜡合用。
用于口服的制剂也可以作为硬明胶胶囊,其中活性成分与惰性固体稀释剂(例如碳酸钙、磷酸钙或高岭土)混合,也可以作为软明胶胶囊,其中活性成分与水或油性介质(例如花生油、液体石蜡或橄榄油)相混合。
含水混悬剂可以含有与适于制备含水混悬剂的赋形剂相混合的本发明化合物。所述赋形剂包括悬浮剂、分散剂或湿润剂、一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂以及一种或多种甜味剂(例如蔗糖或糖精)。
油性混悬剂可以通过将活性成分悬浮在植物油(例如花生油、橄榄油、芝麻油、椰子油)或矿物油(例如液体石蜡)中来制得。油性混悬剂可以含有:增稠剂,例如蜂蜡、硬石蜡或鲸蜡醇。也可以添加甜味剂(例如上述甜味剂)和矫味剂来得到可口的口服制剂。这些组合物可以通过添加抗氧化剂(例如抗坏血酸)来防腐。本发明可分散的粉剂和颗粒剂适合通过加入水来配制成悬浮水溶液,它可以提供与分散剂或湿润剂、悬浮剂及一种或多种防腐剂相混合的活性成分。也可以含有其它赋形剂,例如甜味剂、矫味剂和着色剂。糖浆剂和酏剂是与甜味剂,例如甘油、山梨糖醇或蔗糖一起配制的。这种剂型还可以含有缓和剂、防腐剂、矫味剂或着色剂。为了有助于本发明组合物的配制,人们可以参考Remington氏药物科学,15版,Mack PubishingCo.,Easton,PA。
适合非肠道给药的精氨酸硅酸盐制剂可以以无菌注射剂的形式给药,例如无菌注射用水或油性悬浮液。这种悬浮液可以按照所属领域技术人员熟知的常规方法制备,并且采用分散剂或湿润剂及悬浮剂。该无菌注射剂还可以是存在于无毒非肠道可接受稀释剂或溶剂中的无菌注射用溶液或悬浮液(例如1,3-丁二醇的溶液)。适用的稀释剂包括,例如,水、林格氏溶液和等渗氯化钠溶液。此外,通常可采用无菌混合油作为溶剂或悬浮介质。为了用于此目的,可采用任何温和的混合油,其中包括合成的甘油单酯和甘油二酯。另外,在制备注射用制剂时也可以采用脂肪酸,例如油酸。
任选地,本发明的药物组合物可以含有精氨酸硅酸盐络合物以及一种或多种具有不同活性的化合物,例如抗生素或其他药理学活性原料。
在与载体材料相混合制造单剂量剂型时,精氨酸硅酸盐的量取决于被治疗的宿主和给药的特定形式。
在一个优选实施方案中,作为动脉粥样硬化或骨和软骨疾病的预防药或治疗药,精氨酸硅酸盐可以以约250mg-约2,500mg的量每天给药3次。在一个更优选的实施方案中,该化合物可以以约500mg-约1,000mg的量每天给药3次。也可以考虑每天给药1或2次而不是3次,这取决于动脉粥样硬化损害的严重程度。
精氨酸硅酸盐按照下列实施例合成。
实施例1
精氨酸硅酸盐的制备
将精氨酸(3.8g,21.8mmol)加入到剧烈搅拌下的肌醇(1.25g,6.9mmol)在硅酸钾[5ml,29.80Be,8.3%K2O(0.52g,5.5mmol),20.8%SiO2(1.3g,21.8mmol)]的溶液中,得到极粘的悬浮液。将该悬浮液加热到95℃。当混合物变澄清并开始形成凝胶时停止加热和搅拌。将混合物在室温下放置过夜以析出结晶。将所得结晶块用乙醇(5ml)分散并混合,放置30分钟。用另一份5ml的乙醇对所得的结晶重复该过程并放置过夜,直至结晶完全。过滤收集精氨酸硅酸盐终产物,用乙醇洗涤并真空下干燥。产物的产量为7.7g,其为水合物(是所有反应物总量的111%)。
在真空下和90℃下将其分析样品保存1小时,由于失去水分减重11.5%.元素分析表明:25.13%C,6.24%H,14.11%N,8.25%Si(17.68%SiO2)。用一种试剂盒(HACH,Co.,Loveland CO,Catalog No.234394)并基于已知的四苯基硼酸盐法检测钾的含量(5.4%)。这些结果与精氨酸硅酸盐产物中元素的理论含量相吻合。
实施例2
精氨酸硅酸盐产物的动力学
在精氨酸硅酸盐产物的水溶液中进行的动力学试验表明,非解离精氨酸硅酸盐络合物的形成是所用浓度的函数。精氨酸硅酸盐的解离形式相对于非解离形式的比例是用HACH试剂盒(Catalog No.24296-00)进行测定的,其中在452nm下的吸收度是在酸性条件下硅钼酸盐所形成的浓度的函数,并且表示为二氧化硅(SiO2)的百分含量。在适当的时间将精氨酸硅酸盐产物的水溶液(10g/l)稀释至0.5g/l,按照HACH法测定二氧化硅的含量。在0时刻时二氧化硅的水平为17.5%;在1小时时为11.8%;在2小时时为10.8%;在24小时时是9.2%。在0.5g/l精氨酸硅酸盐的水溶液中,二氧化硅的水平为17.5%,并且在24小时后仍保持不变,这证明了产物的溶解度。
实施例3
精氨酸硅酸盐的生物利用度
制备精氨酸硅酸盐的溶液(8g/l),在取24小时的基础尿样后,一名志愿者每天服用3杯该溶液并连续3天。在第3天,再次取该志愿者24小时内的尿样。硅分析表明,尿排泄出的硅较基础值高10倍。在第3天的尿样中,硅含量约是每天由精氨酸硅酸盐溶液摄取的硅的25%。这证实可溶性精氨酸硅酸盐中的硅的良好生物利用度。
虽然本发明是以具体实施方案来进行详细描述的,但显然,所属领域的专业人员可以理解这些实施方案是举例而不是限定,本发明真实的保护范围由权利要求书决定。
Claims (16)
1.一种制备精氨酸-硅酸盐-肌醇络合物的方法,该方法包括的步骤是:
(a)将精氨酸、硅酸盐和肌醇混合成悬浮液;
(b)加热该悬浮液以促使形成凝胶;
(c)使所述凝胶结晶;
(d)将步骤(c)中生成的结晶与醇混合,加速结晶;和
(e)收集步骤(d)中的结晶。
2.权利要求1所述的方法,其中所述硅酸盐是硅酸钾。
3.权利要求1所述的方法,其中所述加热在约95℃下进行。
4.权利要求1所述的方法,该方法还包括在收集结晶前重复步骤(d)。
5.权利要求1所述的方法,其中通过过滤收集结晶。
6.权利要求1所述的方法,其中步骤(d)中的醇是乙醇。
7.权利要求1所述方法制得的精氨酸-硅酸盐-肌醇络合物。
8.精氨酸-硅酸盐-肌醇络合物在制造用于预防或抑制动脉粥样硬化的药物中的用途。
9.精氨酸-硅酸盐-肌醇络合物在制造用于补充饮食精氨酸的药物中的用途。
10.一种精氨酸-硅酸盐-肌醇络合物,其中精氨酸∶硅酸盐∶肌醇的摩尔比是3∶3∶1。
11.精氨酸-硅酸盐-肌醇络合物在制造用于补充饮食硅酸盐的药物中的用途。
12.精氨酸-硅酸盐-肌醇络合物在制造用于预防骨骼脱矿化或软骨退化的药物中的用途。
13.精氨酸-硅酸盐-肌醇络合物在制造用于治疗骨或软骨疾病的药物中的用途。
14.权利要求13所述的用途,其中所述骨疾病选自骨质疏松症、成骨不全和骨折。
15.权利要求13所述的用途,其中所述软骨疾病选自骨关节炎、炎症性关节炎、腱撕裂或韧带撕裂。
16.权利要求7的络合物在制造用于治疗哺乳动物以减轻骨质疏松症、成骨不全、骨折、骨关节炎以及其他骨和软骨疾病的病理作用的药物中的用途。
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Families Citing this family (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5707970A (en) | 1997-02-12 | 1998-01-13 | Nutrition 21 | Arginine silicate complex and use thereof |
US20020068365A1 (en) * | 1998-07-28 | 2002-06-06 | Eric H. Kuhrts | Controlled release nitric oxide producing agents |
WO2002008175A2 (en) * | 2000-07-24 | 2002-01-31 | Nutrition 21, Inc. | Arginine saccharate and use thereof |
US6552074B2 (en) * | 2000-11-16 | 2003-04-22 | Fukumi Morishige | Arginine/ascorbic acid mixed powder as an oral supplement |
TWI283427B (en) * | 2001-07-12 | 2007-07-01 | Semiconductor Energy Lab | Display device using electron source elements and method of driving same |
WO2003053288A1 (en) * | 2001-12-20 | 2003-07-03 | Trivascular, Inc. | Advanced endovascular graft |
US7147661B2 (en) * | 2001-12-20 | 2006-12-12 | Boston Scientific Santa Rosa Corp. | Radially expandable stent |
EP1534302A4 (en) * | 2002-08-22 | 2009-01-07 | Nutrition 21 Inc | ARGININILICATE / INOSITOL COMPLEX AND ITS USE |
US6803456B1 (en) * | 2003-08-13 | 2004-10-12 | Rutherford Chemicals Llc | Process for the production of arginine-silicate complex |
US7803178B2 (en) * | 2004-01-30 | 2010-09-28 | Trivascular, Inc. | Inflatable porous implants and methods for drug delivery |
US20050228484A1 (en) * | 2004-03-11 | 2005-10-13 | Trivascular, Inc. | Modular endovascular graft |
WO2006129353A1 (ja) * | 2005-06-01 | 2006-12-07 | Coral Biotech Kabushiki Kaisha | 新規な血圧上昇抑制剤 |
ITMI20060677A1 (it) * | 2006-04-06 | 2007-10-07 | Damor Farmaceutici | Profarmaci dell'arginina ad elevata attivita'terapeutica |
EP2070541A4 (en) * | 2006-09-21 | 2011-04-13 | Toshiki Oguro | MEANS FOR PROMOTING REGENERATION OF HARD FABRIC |
EP2134351B1 (en) | 2007-03-13 | 2016-04-27 | Nutrition 21, Inc. | Methods and compositions for the sustained release of chromium |
WO2009002867A2 (en) | 2007-06-26 | 2008-12-31 | Nutrition 21, Inc. | Multiple unit dosage form having a therapeutic agents in combination with a nutritional supplement |
GB0805279D0 (en) * | 2008-03-20 | 2008-04-30 | Univ Nottingham Trent | Food supplement |
WO2012035364A1 (en) | 2010-09-15 | 2012-03-22 | Creogen D.O.O. | Stabilized solution of ortho-silicic acid, its preparation and use |
WO2012119007A1 (en) | 2011-03-01 | 2012-09-07 | N21 Acquisition Holding, Llc | Compositions of insulin and chromium for the treatment and prevention of diabetes, hypoglycemia and related disorders |
US11191735B2 (en) | 2015-03-13 | 2021-12-07 | Nutrition 21, Llc | Arginine silicate for periodontal disease |
GB2557471A (en) * | 2015-06-30 | 2018-06-20 | Jds Therapeutics Llc | Arginine silicate inositol for improving cognitive function |
US10703608B2 (en) | 2015-07-13 | 2020-07-07 | Otis Elevator Company | Deterrent device inhibition key |
US20170135969A1 (en) | 2015-11-12 | 2017-05-18 | Jds Therapeutics, Llc | Topical arginine-silicate-inositol for wound healing |
CN109069532A (zh) | 2016-02-11 | 2018-12-21 | 营养21有限责任公司 | 含铬组合物用于改善健康和健身 |
JP2019526638A (ja) | 2016-09-01 | 2019-09-19 | ジェイディーエス・セラピューティクス、エルエルシー | ビオチン酸マグネシウム組成物および使用方法 |
CN113329680A (zh) | 2018-11-02 | 2021-08-31 | 营养21有限责任公司 | 用于改善视频游戏者认知功能的含有肌醇稳定的精氨酸硅酸盐复合物和肌醇的组合物 |
EP4076413A1 (en) | 2019-12-16 | 2022-10-26 | Nutrition 21, LLC | Methods of production of arginine-silicate complexes |
WO2023086567A1 (en) * | 2021-11-12 | 2023-05-19 | Nutrition21, LLC | Compositions and methods for treating or preventing myopathy in poultry |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3337403A (en) * | 1963-09-05 | 1967-08-22 | Hoffmann La Roche | Stable and palatable pharmaceutical compositions |
US4297349A (en) * | 1980-04-15 | 1981-10-27 | Sandoz, Inc. | Silicon-bearing carboxylic acids and amides |
US4385052A (en) * | 1981-07-20 | 1983-05-24 | International Plant Research Institute, Inc. | Use of trialkylsilyl-6-aminonicotinamides for the treatment of psoriasis |
FR2610522B1 (fr) * | 1987-02-06 | 1989-08-18 | Gueyne Jean | Produit therapeutique a base de derives organiques du silicium |
US5250569A (en) * | 1991-04-22 | 1993-10-05 | Godfrey Science & Design, Inc. | Amino acid flavorings of aluminum astringent for oral use |
US5622980A (en) * | 1993-08-17 | 1997-04-22 | Applied Analytical Industries, Inc. | Oral compositions of H2-antagonists |
FR2745498A1 (fr) * | 1996-02-29 | 1997-09-05 | Giroux Jean Marc | Composition pur augmenter conjointement la tolerance biologique et l'efficacite amincissante des produits hyperproteines hypocaloriques destines au traitement de l'obesite |
US5707970A (en) * | 1997-02-12 | 1998-01-13 | Nutrition 21 | Arginine silicate complex and use thereof |
-
1997
- 1997-02-12 US US08/799,784 patent/US5707970A/en not_active Expired - Lifetime
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1998
- 1998-02-11 CN CNB988023695A patent/CN1182873C/zh not_active Expired - Fee Related
- 1998-02-11 EP EP98905010A patent/EP1007096B1/en not_active Expired - Lifetime
- 1998-02-11 CA CA002279233A patent/CA2279233A1/en not_active Abandoned
- 1998-02-11 KR KR1019997007243A patent/KR20000070977A/ko not_active Application Discontinuation
- 1998-02-11 AT AT98905010T patent/ATE251914T1/de not_active IP Right Cessation
- 1998-02-11 DK DK98905010T patent/DK1007096T3/da active
- 1998-02-11 BR BR9807675-2A patent/BR9807675A/pt not_active Application Discontinuation
- 1998-02-11 DE DE69819016T patent/DE69819016T2/de not_active Expired - Fee Related
- 1998-02-11 WO PCT/US1998/002443 patent/WO1998034647A1/en active IP Right Grant
- 1998-02-11 PT PT98905010T patent/PT1007096E/pt unknown
- 1998-02-11 HU HU0001998A patent/HUP0001998A3/hu unknown
- 1998-02-11 ES ES98905010T patent/ES2209112T3/es not_active Expired - Lifetime
- 1998-02-11 JP JP53496698A patent/JP2001512443A/ja not_active Ceased
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DE69819016D1 (de) | 2003-11-20 |
CN1246801A (zh) | 2000-03-08 |
WO1998034647A1 (en) | 1998-08-13 |
DK1007096T3 (da) | 2003-12-01 |
ATE251914T1 (de) | 2003-11-15 |
BR9807675A (pt) | 2000-02-15 |
AU6273798A (en) | 1998-08-26 |
US6344444B1 (en) | 2002-02-05 |
HUP0001998A2 (hu) | 2000-10-28 |
HUP0001998A3 (en) | 2002-01-28 |
PT1007096E (pt) | 2004-03-31 |
JP2001512443A (ja) | 2001-08-21 |
DE69819016T2 (de) | 2004-04-29 |
CA2279233A1 (en) | 1998-08-13 |
KR20000070977A (ko) | 2000-11-25 |
EP1007096A1 (en) | 2000-06-14 |
AU722975B2 (en) | 2000-08-17 |
US5707970A (en) | 1998-01-13 |
ES2209112T3 (es) | 2004-06-16 |
EP1007096B1 (en) | 2003-10-15 |
US6156735A (en) | 2000-12-05 |
IL130925A0 (en) | 2001-01-28 |
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