CN1313030C - 包含生物素的新颖的营养药物性组合物 - Google Patents
包含生物素的新颖的营养药物性组合物 Download PDFInfo
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- CN1313030C CN1313030C CNB038199823A CN03819982A CN1313030C CN 1313030 C CN1313030 C CN 1313030C CN B038199823 A CNB038199823 A CN B038199823A CN 03819982 A CN03819982 A CN 03819982A CN 1313030 C CN1313030 C CN 1313030C
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- diabetes
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- 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
本发明公开了营养药物性组合物,所述组合物包含生物素和至少一种额外成分,所述生物素的量足以给予服用者每kg体重0.01mg至每kg体重约3mg的每日剂量,所述额外成分选自泛硫乙胺或其代谢物、EGCG、植烷酸、硫辛酸和普利醇。所述组合物可用于治疗1型糖尿病和2型糖尿病,并可用于在具有前糖尿病的个体或葡萄糖耐受不良或肥胖的个体中预防2型糖尿病。
Description
本发明涉及新颖的营养药物性(nutraceutical)组合物,所述组合物包含生物素及至少一种额外成分,所述生物素作为活性成分,用于治疗或预防糖尿病,或其它与葡萄糖耐受不良(impaired glucose tolerance)相关的病况,例如X综合征和肥胖;所述额外成分选自泛硫乙胺(pantethine)或其代谢物、EGCG、植烷酸(phytanic acid)、硫辛酸(lipoic acid)和普利醇(policosanol)。本发明在一个方面涉及包含生物素和至少一种额外成分的组合物,所述生物素的量足以给予服用者每kg体重0.01mg至每kg体重约3mg的每日剂量,所述额外成分选自泛硫乙胺或其代谢物、EGCG、植烷酸、硫辛酸和普利醇;本发明在此方面还涉及此类组合物作为营养补充剂在所述治疗或预防中的用途,例如,作为包含维生素和矿物质的复合维生素制剂的添加剂,所述维生素和矿物质对维持正常代谢功能来说是必需的,但其却不能在体内被合成。在另外一个方面,本发明涉及此类生物素组合物及其用途,其中,所述额外成分选自泛硫乙胺或其代谢物、EGCG、植烷酸、硫辛酸。
本发明的组合物特别适用于治疗1型糖尿病和2型糖尿病,以及在具有前糖尿病的个体或葡萄糖耐受不良(IGT)或肥胖的个体中预防2型糖尿病。
所述包含活性组分组合的组合物,具有针对葡萄糖代谢和胰岛素敏感性的不同作用机制,因此为糖尿病的治疗提供了附加的和/或协同的效果,所述活性组分是生物素和至少一种额外成分,所述额外成分选自泛硫乙胺或其代谢物、EGCG、植烷酸、硫辛酸和普利醇。
本文中使用的术语“营养药物性”表示了在营养领域及制药领域应用中的有效性。因此,所述新颖的营养药物性组合物可作为食物和饮料的补充剂,也可作为药物制剂用于肠道或非肠道应用,所述制剂可以是固体制剂,例如胶囊或药片,或是液体制剂,例如溶液或悬浮液。从前文明显可知,术语“营养药物性组合物”也包含含有生物素和至少一种额外成分的食物和饮料,所述额外成分选自泛硫乙胺或其代谢物、EGCG、植烷酸、硫辛酸和普利醇,以及含有前述活性组分的补充剂组合物。
糖尿病是一种常见的慢性疾病,迄今为止没有治疗方法。糖尿病的发病率和流行程度正呈指数增长,在发达国家和发展中国家其是最普遍的代谢紊乱之一。糖尿病是多种致病因素导致的复杂疾病,其特征为碳水化合物、蛋白质及脂肪代谢受损,这与胰岛素分泌不足和/或与胰岛素抗性相关。这会导致空腹及餐后的血清葡萄糖升高,如果未被治疗则会导致并发症。此疾病有两大类,胰岛素依赖型糖尿病(insulin-dependent diabetesmellitus,IDDM,1型)和非胰岛素依赖型糖尿病(non-insulin-dependentdiabetes mellitus,NIDDM,2型)。
1型糖尿病及2型糖尿病与高血糖、高胆固醇血和高脂血相关。1型及2型糖尿病中,对胰岛素的不敏感性和胰岛素的绝对缺乏会导致肝脏、肌肉和脂肪组织对葡萄糖的利用减少,并且导致血液中葡萄糖水平升高。由于微血管和大血管疾病的风险增加,未受控制的高血糖与增加的死亡率和过早死亡率相关,所述疾病包括肾病、神经病、视网膜病、高血压、中风和心脏病。新近证据表明,严格血糖控制是预防1型糖尿病和2型糖尿病的上述并发症的主要因素。因此,通过药物或治疗进行最优血糖控制,是治疗糖尿病的重要手段。
对2型糖尿病的治疗最初涉及膳食及生活方式的改变,当上述措施无法保持足够的血糖控制时,就会用口服的降血糖制剂和/或外源胰岛素对病人进行治疗。目前用于治疗2型糖尿病的口服药物制剂包括加强胰岛素分泌的药物(磺脲制剂)、增进胰岛素在肝脏中作用的药物(缩二胍制剂)、增加胰岛素敏感性的制剂(噻唑烷二酮类)以及作用于抑制葡萄糖吸收的制剂(α-葡糖苷酶抑制剂)。然而,由于胰腺细胞功能的逐渐丧失导致高血糖逐渐恶化,目前可利用的药物通常不能长期保持足够的血糖控制。能够保持目标血糖水平的病人比例在一定时间之后会显著降低,因此必须施用额外/另外的药物制剂。此外,所述药物可能具有不想要的副作用,而且其同高无效率和高复发率联系在一起。最后,降血糖药物的使用可能对控制血液中葡萄糖水平有效,但其却可能无法预防糖尿病的所有并发症。因此,目前用于治疗所有类型的糖尿病的方法不能达到令血糖量正常的目标,也无法预防糖尿病的并发症。
因此,虽然被选用于治疗1型及2型糖尿病的方法基本都基于施予胰岛素和口服降血糖药物,但人们却需要副作用极小的安全有效的营养补充剂,用于糖尿病的治疗和预防。很多病人都对另外的疗法感兴趣,所述疗法能将与高剂量药物相关的副作用降至最小,并能产生额外的临床效益。糖尿病人对被认为是“自然的”治疗特别感兴趣,所述治疗具有温和的抗糖尿病效果,而且没有大的副作用,其可被用作辅助治疗。2型糖尿病是逐渐发展的慢性疾病,其通常不为病人所知,直到产生胰岛素的胰腺细胞出现了明显的损伤。因此,人们对于发展可用于预防糖尿病发展的膳食补充剂的兴趣也在增加,所述预防针对风险人群,尤其是处于糖尿病发展的高风险状态的老年人。此外,2型还是一种并发疾病,其源自多种器官位点上同时存在的缺陷:肌肉和脂肪组织中对胰岛素作用的抗性、胰腺对胰岛素的分泌有缺陷、肝脏中葡萄糖无限制的产生伴随脂肪异常和内皮功能障碍。因此,鉴于2型糖尿病中的多种病理生理损伤,组合疗法对其控制来说是有吸引力的手段。
以每kg体重大约0.01mg至每kg体重大约3mg的每日剂量使用生物素,尤其是与分别发挥不同作用机理的泛硫乙胺或其代谢物、EGCG和/或植烷酸组合使用,有助于使糖尿病患者获得并保持目标血糖水平。
上文列出的活性组分的组合是优选的,因为它们具有不同作用,以利用额外/协同及多器官效应。由于不同的活性组分具有独特的作用机制,故而所述组合不仅能改善血糖控制,而且在某些情况下能使药物剂量更少,不利效应也被降至最低。因为它们具有独特的机制和作用位点,上述膳食补充剂的特定组合还能利用额外/协同效应,以获得较之单种制剂效果更好的降葡萄糖效果。因此,虽然被选用于治疗1型及2型糖尿病的方法基本都基于施予胰岛素和施予口服降血糖药物,但合适的营养疗法对于成功治疗糖尿病来说也有着很高的重要性。
下面描述了本发明的营养药物性组合物中每种活性组分的功能:
生物素:生物素补充剂增强了对肝中葡萄糖的清除,这导致循环系统中葡萄糖浓度降低,诱导了肝PEPCK活性的降低。PEPCK是限速的胞质酶,其催化肝中葡萄糖异生的第一个关键步骤。肝PEPCK活性降低导致肝葡萄糖输出减少。根据本发明已发现,口服(2-16mg/天)或注射(0.1mg/天)生物素,会提高糖尿病KK小鼠(NIDDM模型)、链脲霉素糖尿病大鼠(IDDM)和具有前糖尿病的Otsuka Long-Evans Tokushima脂肪型(Otsuka Long-Evans Tokushima fatty,OLETF)大鼠(NIDDM)的口服葡萄糖耐受。对人类的初步研究表明,补充生物素后,1型及2型糖尿病患者的空腹血液葡萄糖水平降低。
因此,高剂量的生物素会使1型及2型糖尿病患者的高血糖有所改善。生物素降低肝葡萄糖输出,有利于受葡萄糖激发的胰岛素分泌。因此,生物素与能增强外周胰岛素敏感性的产品的组合,对糖尿病的治疗颇有价值。此类产品特别是植烷酸和硫辛酸。
EGCG:表没食子儿茶素没食子酸酯(epigallocatechin gallate,EGCG)是发现于绿茶中的主要儿茶素。在大鼠中,绿茶儿茶素会抑制在进食富含淀粉或蔗糖的食物后血浆中葡萄糖和胰岛素水平的增加,所述抑制是剂量依赖性的。根据本发明的生物素和EGCG的组合对以下病人特别有用:葡萄糖耐受不良的病人、由于年老发展出餐后葡萄糖增加的年长病人以及未得到确诊的糖尿病人。
泛硫乙胺:在对人类的研究中,口服泛硫乙胺会导致总胆固醇、甘油三酯、低密度脂蛋白(low density lipoprotein,LDL)胆固醇的逐渐减少,以及高密度脂蛋白(high density lipoprotein,HDL)胆固醇的增加。因此,其会导致更优的Chlo/HDL比率,这就降低了心血管疾病的风险。糖尿病伴随增加3至4倍的冠心病风险。2型糖尿病对血浆中脂肪的情况有不利影响,其使得导致动脉粥样化的脂肪水平增加,例如低密度脂蛋白(LDL)和极低密度脂蛋白(very low density lipoprotein,VLDL),而且其会降低高密度脂蛋白(HDL)的水平,HDL是抗动脉粥样化的脂肪。动脉粥样硬化的症状并不仅仅在具有糖尿病的个体中常见,其还会导致显著而长期的并发症。因此,含有泛硫乙胺的口服补充剂有助于糖尿病患者的脂肪水平正常化,降低冠心病和血栓的风险。除泛硫乙胺之外,泛硫乙胺的代谢物,例如半胱胺,也可用于本发明。
硫辛酸:硫辛酸(1,2-二硫戊环-3-戊酸,1,2-dithiolane-3-pentaenoicacid)在从葡萄糖产生能量的线粒体特异性途径中起重要作用,并可能对葡萄糖氧化的速率产生潜在影响。硫辛酸会激发培养的肌肉和脂肪细胞中的葡萄糖转运。此外,向葡萄糖不耐受动物及非胰岛素依赖型糖尿病动物施用硫辛酸,还会增强骨骼肌的基础葡萄糖吸收和胰岛素激发的葡萄糖吸收。另外,硫辛酸增进了2型患者体内的葡萄糖清除,硫辛酸可被添加到本发明的营养药物性组合物中,以预防和/或治疗糖尿病相关并发症,并作为具有增加胰岛素敏感性活性的制剂。
植烷酸:浓度在大约10μM至大约100μM范围内的植烷酸(3,7,11,15-四甲基十六烷酸)能增加大鼠原代肝细胞(primaryhepatocyte)对葡萄糖的吸收。与特异性的PPAR-γ激动药例如环格列酮(ciglitazone)相比,植烷酸对前脂肪细胞到成熟脂肪细胞的分化仅施加较小的作用。因此,摄入的植烷酸可协助增加胰岛素敏感性,并可通过对PPARs和RXR的激活,作为针对2型糖尿病和X综合征的预防性措施。
普利醇:普利醇是从植物蜡(plant waxes),主要是甘蔗中分离和纯化出来的一级脂肪醇的混合物。所述混合物的脂肪醇是CH3-(CH2)n-CH2OH醇,其链长在18至40个碳原子间变化。所述混合物中典型的脂肪醇是二十八烷醇、二十六烷醇、二十七烷醇、三十烷醇和三十二烷醇。在动物模型、健康的志愿者以及具有II型高胆固醇血症的患者中都已显示出,普利醇能导致胆固醇降低。因此,其对于与2型糖尿病相关的血脂异常来说是有用的。
本发明中的营养药物性组合物中还可以加入复合维生素及矿物质补充剂,以获得足够数量的必需营养物,所述营养物在某些膳食中是缺乏的。复合维生素及矿物质补充剂还可用于疾病预防和防止营养缺乏及缺陷,所述营养缺乏及缺陷是由于生活方式以及通常不充分的饮食模式造成的,所述不充分的饮食模式有时可见于糖尿病。此外,氧化胁迫也已被暗示与胰岛素抗性的发展有牵连。活性氧类(reactive oxygen species)可能通过扰乱胰岛素受体信号级联过程来破坏由胰岛素激发的葡萄糖吸收。用抗氧化剂,例如α-生育酚(维生素E)、抗坏血酸(维生素C),来控制氧化胁迫对于治疗糖尿病来说可能是有价值的。因此,复合维生素补充剂可添加到上述活性物质中,以保持良好的平衡营养。
本发明的营养药物性组合物含有生物素,其数量足以以每天每kg体重约0.01mg至每kg体重约3mg的剂量施予服用者,优选为每天每kg体重约0.1mg至约0.5mg。因此,在所述营养药物性组合物是食物或饮料的情况下,其中含有的生物素的量适合在每份约0.03mg至每份约50mg的范围内。如果所述营养药物性组合物是药物制剂,那么此类制剂的每个固体剂量单位,例如每一药片或胶囊中,可以含有约0.35mg至约200mg,或者在液体制剂中含有相当的剂量,或者由大约0.35mg的每日剂量至大约200mg的每日剂量。
在本发明的优选方面,本发明的营养药物性组合物进一步地含有泛硫乙胺。所述组合物中泛硫乙胺的量可以是能向被施予组合物的服用者提供每kg体重约1mg至每kg体重约50mg的每日剂量。食物或饮料适于含有每份约20mg至每份约800mg的泛硫乙胺。如果所述营养药物性组合物是药物制剂,那么此类制剂的每个剂量单位,例如每一胶囊或药片可以含有约20mg至约1000mg的泛硫乙胺,或者对液体制剂而言,从约70mg的每日剂量至约3500mg的每日剂量。
如果本发明的组合物中存在EGCG,那么EGCG的量可以是能向被施予组合物的服用者提供每kg体重约0.3mg至每kg体重约30mg的每日剂量。食物或饮料适于含有每份约5mg至每份约500mg的EGCG。如果所述营养药物性组合物是药物制剂,那么此类制剂的每个剂量单位,例如每一胶囊或药片可以含有约10mg至约500mg的EGCG,或者对液体制剂而言,从约20mg的每日剂量至约2000mg的每日剂量。
如果本发明的营养药物性组合物中存在植烷酸,那么植烷酸的量可以是能向被施予组合物的服用者提供每kg体重约1mg至每kg体重约100mg的每日剂量。食物或饮料适于含有每份约20mg至每份约2000mg的植烷酸。如果所述营养药物性组合物是药物制剂,那么此类制剂的每个剂量单位,例如每一胶囊或药片可以含有约30mg至约500mg的植烷酸,或者对液体制剂而言,从约70mg的每日剂量至约7000mg的每日剂量。以其生物等同衍生物形式存在的植烷酸也是可以使用的,例如酯,例如其甲酯或乙酯。
如果本发明的营养药物性组合物中存在硫辛酸,那么硫辛酸的量可以是能向被施予组合物的服用者提供每kg体重约0.3mg至每kg体重约30mg的每日剂量。食物或饮料适于含有每份约5mg至每份约500mg的硫辛酸。如果所述营养药物性组合物是药物制剂,那么此类制剂的每个剂量单位,例如每一胶囊或药片可以含有约5mg至约800mg的硫辛酸,或者对液体制剂而言,从约5mg的每日剂量至约2000mg的每日剂量。
如果本发明的营养药物性组合物中存在普利醇,那么普利醇的量可以是能向被施予组合物的服用者提供每kg体重约0.002mg至每kg体重约1.5mg的每日剂量的量。食物或饮料适于含有每份约0.1mg至每份约20mg的普利醇。如果所述营养药物性组合物是药物制剂,那么此类制剂的每个剂量单位,例如每一胶囊或药片可以含有约0.1mg至约30mg的普利醇,或者对液体制剂而言,从约0.1mg的每日剂量至约100mg的每日剂量。
本发明的营养药物性组合物优选包含生物素和泛硫乙胺的组合。还优选的是:
包含生物素和植烷酸的组合物;
包含生物素和EGCG的组合物;
包含生物素和硫辛酸的组合物;
包含生物素、植烷酸和EGCG的组合物;
包含生物素、植烷酸和泛硫乙胺的组合物;
包含生物素、泛硫乙胺和EGCG的组合物;以及
包含生物素、植烷酸、泛硫乙胺和EGCG的组合物。
剂量范围(对70kg的人而言)
生物素:0.7mg/天至210mg/天
EGCG:20mg/天-2100mg/天
泛硫乙胺:70mg/天-3500mg/天
植烷酸:70mg/天-7000mg/天
硫辛酸:20mg/天-2100mg/天
普利醇:0.15mg/天-100mg/天
下述实施例将进一步地阐述本发明。
A.可以用下列组分按照传统配制工序来制备药物组合物:
实施例1 软明胶胶囊
使用下列组分按照传统工序来制备软明胶胶囊:
活性组分:生物素30mg、泛硫乙胺100mg
其它组分:甘油、水、明胶、植物油
实施例2 硬明胶胶囊
使用下列组分按照传统工序来制备硬明胶胶囊:
活性组分:生物素30mg、泛硫乙胺100mg
其它组分:填料:数量足够的乳糖或纤维素或纤维素衍生物
润滑剂:如果需要的话,硬脂酸镁(0.5%)
实施例3 药片
使用下列组分按照传统工序来制备药片:
活性组分:生物素20mg、泛硫乙胺50mg
其它组分:微晶纤维素、二氧化硅(SiO2)、硬脂酸镁、交联羧甲基纤维素钠。
B.可以使用下列组分按照传统工序来制备食物产品:
实施例4 有30%果汁的软饮
活性组分:该食物产品中加入了生物素,以及可选地,有一种或多种额外成分,所述额外成分选自泛硫乙胺、EGCG、植烷酸、硫辛酸和普利醇。
生物素:每份0.03mg-50mg
泛硫乙胺:每份20mg-800mg
EGCG:每份5mg-500mg
植烷酸:每份20mg-200mg
硫辛酸:每份5mg-500mg
普利醇:每份0.1mg-20mg
典型份量:240ml
I.用下述组分制备软饮复合物:
果汁浓缩物和水溶性香料
[g]
橙汁浓缩物
60.3°白利糖度(Brix),5.15%酸度 657.99
柠檬浓缩物
43.5°白利糖度,32.7%酸度 95.96
水溶性橙味香料 13.43
水溶性杏味香料 6.71
水 26.46
1.2颜料
β-胡萝卜素10%CWS 0.89
水 67.65
1.3酸和抗氧化剂
抗坏血酸 4.11
无水柠檬酸 0.69
水 43.18
1.4稳定剂
果胶 0.20
安息香酸钠 2.74
水 65.60
1.5油溶性香料
油溶性橙味香料 0.34
蒸馏得到的甜橙油 0.34
1.6活性组分
以上文提到的浓度存在的活性组分(这指上文提到的活性组分:生物素以及一种或多种下述物质:EGCG、泛硫乙胺、硫辛酸和/或植烷酸)。
果汁浓缩物和水溶性香料在没有空气掺入的条件下混合起来。颜料被溶于去离子水中。抗坏血酸和柠檬酸溶于水中。安息香酸钠溶于水中。搅拌下加入果胶,煮沸令其溶解。冷却所述溶液。油溶性香料和甜橙油预先混合起来。1.6中提到的活性组分被干燥地混合起来,然后优选搅拌添加到果汁浓缩物混合物(1.1)中。
为制备所述的软饮复合物,3.1.1至3.1.6的所有部分都被混合到一起,然后用Turrax再用高压均质机(p1=200bar,p2=50bar)对其进行均质。
II.用下述组分来制备瓶装糖浆:
[g]
软饮复合物 74.50
水 50.00
糖浆,60°白利糖度 150.00
所述瓶装糖浆的组分被混合到一起。用水将所述瓶装糖浆稀释到1L,成为现成可用的饮料。
变化:
可以对所述饮料进行巴氏消毒来代替使用安息香酸钠。所述饮料还可经过碳酸化。
实施例5 五谷面包
活性组分:该食物产品中加入了生物素以及一种或多种额外成分,所述额外成分选自泛硫乙胺、EGCG、植烷酸、硫辛酸和普利醇。
生物素:每份0.03mg-50mg
泛硫乙胺:每份20mg-800mg
EGCG:每份5mg-500mg
植烷酸:每份20mg-2000mg
硫辛酸:每份5mg-500mg
普利醇:每份0.1mg-20mg
典型份量:50g
[%]
五谷粉(5 cereal flour) 56.8
水 39.8
酵母 2.3
盐 1.1
所述酵母被溶于一部分水中。将所有组分混合到一起制成面团。在揉捏过程结束时加盐。发酵之后,对面团进行再次处理,并将其分开,然后制成块状。烘焙之前,用水冲刷所述的块表面,并撒上面粉。
工艺参数:
揉捏:
螺旋揉捏系统: 第一档4分钟,第二档5分钟
面团发酵: 60分钟
面团温度: 22℃-24℃
发酵时间 30分钟
烘焙:
烤箱: 荷兰式烤箱
烘焙温度: 250℃/220℃
烘焙时间: 50-60分钟
实施例6 Milano类型的曲奇饼
活性组分:该食物产品中加入了生物素以及一种或多种额外成分,所述额外成分选自泛硫乙胺、EGCG、植烷酸、硫辛酸和普利醇。
生物素:每份0.03mg-50mg
泛硫乙胺:每份20mg-800mg
EGCG:每份5mg-500mg
植烷酸:每份20mg-2000mg
硫辛酸:每份5mg-500mg
普利醇:每份0.1mg-20mg
典型份量:30g
[g]
小麦面粉,550型 41.0
糖 20.5
脂肪/黄油 20.5
全蛋(液) 18.0
柠檬香料 足够量
烘焙剂 足够量
在搅拌条件下将所有组分缓慢加入,制成甜酥点心团(sweet shortpastry)。
之后,将所述点心团冷藏(4℃)至少2小时,之后将其抹平成厚度为大约5mm。烘焙前切成小块,在表面刷上蛋黄。
烘焙:
烤箱: 鼓风式烤箱(fan oven)
烘焙温度: 180℃
烘焙时间: 15分钟
实施例7 吐司面包
活性组分:该食物产品中加入了生物素以及一种或多种额外成分,所述额外成分选自泛硫乙胺、EGCG、植烷酸、硫辛酸和普利醇。
生物素:每份0.03mg-50mg
泛硫乙胺:每份20mg-800mg
EGCG:每份5mg-500mg
植烷酸:每份20mg-2000mg
硫辛酸:每份5mg-500mg
普利醇:每份0.1mg-20mg
典型份量:100g
[%]
小麦面粉,550型 55.4
水 33.2
酵母 2.8
盐 1.1
脂肪/黄油 5.5
麦芽 0.6
乳化烘焙剂 1.4
所述酵母被溶于一部分水中。所有组分被混合到一起,形成面团。在揉捏过程结束时加入盐。之后,对所述面团进行再次处理,将其分开,放置于烘焙用烤模上以发酵。烘焙之后,所述的块直接从模子里取出。
工艺参数:
揉捏:
螺旋揉捏系统: 第一档5-6分钟,第二档3-4分钟
面团发酵: 无
面团温度: 22℃-24℃
发酵时间 40分钟
烘焙:
烤箱: 荷兰式烤箱
烘焙温度: 220℃
烘焙时间: 35-40分钟
实施例8 酸奶-凝固型(set type),3.5%的脂肪
活性组分:该食物产品中加入了生物素以及一种或多种额外成分,所述额外成分选自泛硫乙胺、EGCG、植烷酸、硫辛酸和普利醇。
生物素:每份0.03mg-50mg
泛硫乙胺:每份20mg-800mg
EGCG:每份5mg-500mg
植烷酸:每份20mg-2000mg
硫辛酸:每份5mg-500mg
普利醇:每份0.1mg-20mg
典型份量:225g
[%]
全脂奶(3.8%的脂肪) 90.5
脱脂奶粉 2.0
糖 5.0
培养物 2.5
所述的奶被加热至35℃,然后加入奶粉、稳定剂、糖和活性组分。该混合物被加热至65℃以溶解所有组分。然后在高压均质机中(p1=150bar,p2=50bar)于65℃下对将所述混合物进行均质。再在80℃下对该乳状物进行20分钟的巴氏消毒。冷却到45℃后,加入天然酸奶/培养物,混匀。再将该混合物装入若干杯子,在45℃下发酵3-4小时,直到pH达到4.3,然后将其贮藏在4℃下。
实施例9 酸奶-搅拌型,3.5%的脂肪
活性组分:该食物产品中加入了生物素以及一种或多种额外成分,所述额外成分选自泛硫乙胺、EGCG、植烷酸、硫辛酸和普利醇。
生物素:每份0.03mg-50mg
泛硫乙胺:每份20mg-800mg
EGCG:每份5mg-500mg
植烷酸:每份20mg-2000mg
硫辛酸:每份5mg-500mg
普利醇:每份0.1mg-20mg
典型份量:225g
[%]
全脂奶(3.8%的脂肪) 90.2
脱脂奶粉 2.0
稳定剂 0.3
糖 5.0
培养物 2.5
所述的奶被加热至35℃,然后加入奶粉、稳定剂、糖和活性组分。该混合物被加热至65℃以溶解所有组分,然后在高压均质机中(p1=150bar,p2=50bar)于65℃下对所述混合物进行均质。再在80℃下对该乳状物进行20分钟的巴氏消毒。冷却到45℃后,加入天然酸奶/培养物,混匀,接着在45℃下发酵3-4小时,直到pH达到4.3。经过冷却及有力的搅拌之后,所述酸奶被装进若干杯子,在4℃贮藏。
实施例10 冰淇淋,8%的脂肪
活性组分:该食物产品中加入了生物素以及一种或多种额外成分,所述额外成分选自泛硫乙胺、EGCG、植烷酸、硫辛酸和普利醇。
生物素:每份0.03mg-50mg
泛硫乙胺:每份20mg-800mg
EGCG:每份5mg-500mg
植烷酸:每份20mg-2000mg
硫辛酸:每份5mg-500mg
普利醇:每份0.1mg-20mg
典型份量:85g
[g]
全脂奶(3.7%的脂肪) 600.00
鲜奶油(35%的脂肪) 166.00
脱脂奶粉 49.10
糖 109.00
80%的葡萄糖浆 70.00
冰淇淋稳定剂 5.00
香料 足够量
颜料 足够量
将糖、脱脂奶粉和稳定剂加入到奶和鲜奶油中,混匀,加热至45℃。然后将活性组分以及葡萄糖浆和贮存液形式的颜料加进去。该混合物被加热进行巴氏消毒(80℃,20分钟)。然后进行均质步骤。之后,该混合物在持续搅拌下被冷却,在5℃下加入香料。将该混合物在5℃下成熟至少4小时,再通过冰淇淋机(膨胀率overrun为100%)。所述冰淇淋被装入若干杯子,贮藏于-20℃至-30℃。
实施例11 酒胶糖(wine gum)
活性组分:该食物产品中加入了生物素以及一种或多种额外成分,所述额外成分选自泛硫乙胺、EGCG、植烷酸、硫辛酸和普利醇。
生物素:每份0.03mg-50mg
泛硫乙胺:每份20mg-800mg
EGCG:每份5mg-500mg
植烷酸:每份20mg-2000mg
硫辛酸:每份5mg-500mg
普利醇:每份0.1mg-20mg
典型份量:30g
[g]
明胶,200 Bloom 80.0
水I 125.0
冰糖 290.0
水II 120.0
葡萄糖浆DE 38 390.0
柠檬酸 10.0
香料 2.0
颜料 足够量
预产量(yield ca.) 1000.0
将明胶分散于水I中,搅拌,通过蒸气浴加热或使用微波炉令其溶解。将糖和水II混合,煮沸直到获得澄清溶液。从热源上移开。趁着溶解有糖的溶液还是热的,将其与糖浆混合。缓慢加入明胶溶液。保持静置,直至表面泡沫能被除去,并达到60℃-65℃。在搅拌下加入香料、柠檬酸和颜料溶液以及活性组分。将其倒入淀粉盘(starch tray)上印制的模子中,在室温放置至少48小时。移走淀粉粉末,用油或蜡抛光。在室温干燥并装入密封小袋中。
实施例12
在C57BLKS/J db/db小鼠(n=7-8/组)中开展了5周的实验,检测了生物素和植烷酸的组合清除葡萄糖的功效以及其各自单独清除葡萄糖的功效。该2型糖尿病晚期模型具有严重的高血糖,其被广泛用于测定抗糖尿病化合物的功效。
从Jackson实验室(Bar Harbor,ME,USA)获得了雄性的db/db小鼠。8周龄的成年小鼠被用于本实验。小鼠被单只培养于带垫子的塑料笼中,其可获得充足的标准啮齿动物食物和自来水。对所述动物居所进行温度控制(24℃)、湿度控制(55%)和光线控制(12小时的亮-暗循环)。所述动物被随机分为四组。生物素和植烷酸作为混合添加饲料(feed-ad-mix)施予所述动物。(占膳食1%的)玉米油作为生物素和植烷酸的载体物质,单独使用时其作为安慰剂。第1组被施予安慰剂,第2组被施予剂量为8mg/kg体重(BW)/天的生物素,第3组获得剂量为300mg/kg BW/天的植烷酸,第4组则获得剂量分别为8mg/kg BW/天和300mg/kg BW/天的生物素和植烷酸。处理四周之后,对口服葡萄糖负荷(1g/kg体重)之后90分钟、120分钟、150分钟及180分钟时的葡萄糖清除情况进行检测。从尾部血管获得90分钟、120分钟、150分钟、180分钟时的血样,以测定血液中的葡萄糖水平。血液中的葡萄糖是用葡萄糖分析仪(Glucotrend Premium,Roche Diagnostics,Rotkreu,Switzerland)来测量的。所有数据都以每个膳食组内动物数据平均值的形式来展示。膳食组间平均差异的统计显著性通过单向方差分析(analysis of variance,ANOVA)来检测。如果发现了显著性差异,则用Dunnett’s的多重比较法(multiple comparison)来进行每个组与对照组的比较。P值小于0.05就被认为是有显著性的。所有分析采用Statistica(ver.5.5A,StatSoft,Inc)来开展。
葡萄糖负荷(1g/kg体重)期间,经过生物素和植烷酸的组合处理的动物血液葡萄糖水平在所有时间点都比对照组低。不管是用生物素还是用植烷酸进行单一治疗,都无法引起葡萄糖水平的显著性降低。
生物素和植烷酸组合的处理对葡萄糖清除速率(glucose removal rate,GRR)施加了出人意料的协同效应。GRR被定义为葡萄糖被从血液中清除并被指引到外周组织的速度。应用葡萄糖负荷之后90分钟、120分钟、150分钟和180分钟,对经过生物素和植烷酸的组合处理的动物而言,其血液葡萄糖水平降低的程度比预测的要高,所述预测是通过由生物素或植烷酸单一疗法引起的降低来进行的。上述事实表明,在经过生物素和植烷酸的组合处理的动物中,GRR被协同性提高。为对GRR做出评估,所述的葡萄糖水平被表示作每组葡萄糖水平较之对照组的百分比变化。表1中给出了GRR的值。预测的GRR被定义为用生物素和植烷酸进行单一治疗时获得的GRR值的和。
表1
OGTT 90分钟、120分钟、150分钟和180分钟时,db/db小鼠的葡萄糖清除速率(葡萄糖较之对照减少的%),所述小鼠经过了生物素处理、植烷酸处理或两种化合物的组合的处理。
葡萄糖清除速率(%) | ||||
90分钟 | 120分钟 | 150分钟 | 180分钟 | |
生物素(8mg/kg BW/天) | 11.6 | 10.2 | 15.3 | 15.0 |
植烷酸(300mg/kg BW/天) | 9.7 | 12.5 | 14.6 | 15.2 |
预测的:生物素(8mg/kg BW/天)+植烷酸(300mg/kg BW/天) | 21.3 | 22.7 | 29.9 | 30.2 |
发现的:生物素(8mg/kg BW/天)+植烷酸(300mg/kg BW/天) | 25.9* | 31.0* | 35.1* | 33.2* |
*与对照有显著性差异(p值小于0.05)
表1显示,对补充有生物素和植烷酸的组合的组而言,其效果比单独服用生物素及植烷酸的组的效果之和要高。因此,生物素和植烷酸的组合对葡萄糖代谢具有协同效果。
实施例13
在肝葡萄糖代谢相关基因的协同调控上,对生物素与EGCG及半胱胺组合的效果进行了研究。选用Affymetrix GeneChip高密度寡核苷酸微阵列技术,对H-4-II-E大鼠肝细胞中的总体基因表达情况进行测定。在一种组合处理条件下其调控模式显示出协同作用的基因被筛选出来,葡萄糖内稳定(homeostasis)标志基因被选出,以进行进一步的分析。肝脏的碳水化合物代谢受严格的调节。两种特殊的酶,葡糖激酶(glucokinase,GK)和葡糖-6磷酸酶(glucose-6 phosphatase,Glc-6-Pase),使肝脏在葡萄糖内稳定中发挥了极其重要的作用。因为葡萄糖的过量产生是导致人类糖尿病和空腹高血糖的重要因素,所以,通过Glc-6-Pase对葡糖-6-磷酸水解的调节,就成了葡萄糖释放到循环系统中这一过程远端决定速度的酶步骤。在糖尿病动物模型中已有肝Glc-6-Pase mRNA水平显著增加的报道。因此,能够令Glc-6-Pase催化亚基减少表达的化合物或化合物的组合可以被认为能令高血糖回复正常及预防糖尿病状态。以前就有显示,EGCG能降低H-4-II-E细胞中Glc-6-Pase mRNA的水平。生物素能诱导GK在大鼠肝细胞中的表达也是已知的。
细胞培养
H-4-II-E细胞是从American Type Culture Collection(ATCC)获得的,其被培养于培养基199(Invitrogen,Basel,Switzerland)中,所述培养基中补充有10%的胎牛血清,所述培养在37℃下于潮湿的含5%CO2的空气中进行。对在亚汇合状态(subconfluence)的细胞进行有规律地传代,使用具有低传代数的细胞。为进行最后的试验,对细胞进行胰蛋白酶化,以1×106细胞/孔的密度将其接种至6孔细胞培养板中,并在培养基199及0.1%的BSA(Invitrogen)中再培养6小时,之后加入化合物。EGCG被应用于DMSO中;半胱胺先溶于1M的HCl中,再应用到刺激培养基中;生物素则直接溶解到培养基中。24小时的处理后,获取总RNA。
高密度寡核苷酸阵列杂交
遵循Affymetrix GeneChip阵列方案(Affymetrix,Santa Clara,Ca,USA),制备了总共24个样品。简言之,通过使用Qiagen RNeasy MiniKit和柱上无RNase的DNase I消化(Qiagen,Basel,Switzerland)来提取细胞中的总RNA。对T7-(T)24引物(5’-GGCCAGTGAATTGTAATACGACTCACTATAGGGAGGCGG-(dT)24-3’)和10μg总RNA进行退火,并在DTT、dNTPs和1x的反应缓冲液存在的情况下,用Superscript II反转录酶(400U)来合成第一链cDNA。在dNTPs存在的情况下,通过向含有1x第二链缓冲液的最终反应体系中加入E.coli DNA聚合酶(40U)、E.coli连接酶(10U)和RNase H(2U)来合成第二链。最后用T4 DNA聚合酶(10U)(SuperscriptTM MicroarrayCustomized Kit,Invitrogen,Basel,CH)来补平链末端。通过苯酚/氯仿抽提来纯化cDNA,随后用T7 RNA聚合酶(MegascriptTM T7 Kit,Ambion,Texas,USA),加上bio-16-UTPs和bio-11-CTPs(RocheMolecular Biochemicals,Penzberg,Germany),来开展3小时的体外转录。RNeasy纯化后,用40mM Tris醋酸(pH 8.1)、100mM醋酸钾和30mM的醋酸镁在95℃下对10μg获得的cRNA进行35分钟的片段化。按照Affymetrix GeneChip表达分析技术手册(Expression Analysis TechinicalManual)所述来制备杂交混合液,其中含有100mM的MES缓冲液、1M的NaCl、20mM的EDTA、0.01%的Tween 20、样品cRNA、片段化的细菌对照spikes、生物素化oligo 984、鲱鱼精DNA(0.5μg/μl;Invitrogen)和乙酰化BSA(0.25μg/μl;Promega,Madison,WI,USA)。然后在45℃下将样品杂交到Affymetrix GeneChipRat 230(SubA)上,所述杂交持续16小时。最后,用EukGE-WS2v3程序在GeneChipFluidics 400工作站(Affymetrix)中对阵列进行洗涤,采用抗体扩增方案,用链霉抗生物素蛋白R-藻红蛋白(streptavidinR-phycoerythrin,SAPE)进行两次染色。
数据分析
通过共焦激光扫描(Hewlett Packard,Palo Alto,Ca,USA)收集原始的荧光数据,用Affymetrix Microarray Suite(MAS 4.0)对其进行分析。用RACE-A分析工具(Roche,Basel,Switzerland)来开展数据加工。对所有阵列进行标准化,所述标准化针对所有用到的阵列的平均差异(Average Difference,AvgDiff)值总和的平均数来进行。标准化后的AvgDiff值低于4的,被自动赋予4这个值。从重复的样品中计算得到平均差异的平均值(mean average difference values,MeanAvgDiff)和标准差(SD)。处理组给予赋形剂(V;0.1%DMSO),作为单种化合物应用的50μM EGCG(A)、1μM生物素(B)、50μM半胱胺(C),以及EGCG/生物素的组合(D)和半胱胺/生物素的组合(E);每项实验都开展三次。最大协同因子(SF)>+/-1并在p<0.05的不成对t检验中具有显著性水平的基因被筛选出,以作全面分析。处理组内的相对基因表达等于平均差异的平均值(MeanAvgDiff)。当所述实验重复进行时,相应的平均值为
X、
Y、
M、
V;其中赋形剂处理条件是V,单种化合物是X或Y,多元组合为M。协同因子(SF)被认为是多元的基因表达减去赋形剂比上附加(additive)基因表达减去赋形剂的比率,因此SF=(
M-V)/((
X-
V)+(
Y-
V))。
结果
用赋形剂(0.1%DMSO),作为单种化合物给予的50μM EGCG、1μM生物素、50μM半胱胺,或者EGCG/生物素的组合和半胱胺/生物素的组合对H-4-II-E大鼠肝细胞进行24小时的刺激。总RNA样品被加工成cRNA探针,并与Affymetrix rat 230(SubA)阵列杂交。用AffymetrixMAS 4.0程序进行对原始荧光数据的计算。从RACE-A程序产生的基因筛选列表中获得葡糖-6-磷酸酶基因表达的MeanAvgDiff表达水平、标准差(SD)和SF值。
表2
化合物 | MeanAvgDiff(平均相对表达) | SD | SF |
V(赋形剂) | 535.01 | 96.24 | - |
A(EGCG) | 484.8 | 34.36 | - |
B(生物素) | 516.66 | 60.82 | - |
C(半胱胺) | 447.42 | 18.69 | - |
D(EGCG/生物素) | 332.46 | 87.21 | 2.95* |
E(半胱胺/生物素) | 343.91 | 59.85 | 1.80* |
*p<0.05(不成对学生t检验)
用Affymetrix GeneChip方法来测定葡糖-6-磷酸酶催化亚基的表达水平(Affymetrix Id:1370725_a_at)。通过对重复样品进行两两比较,计算出平均差异的平均值(MeanAvgDiff)。
Glc-6-Pase使肝脏产生葡萄糖的活性,在短期空腹阶段增加,这与肝中葡萄糖异生的增加一致。另一方面,使肝细胞可以利用葡萄糖的GK活性会在空腹期间降低。在进食状态下,对这两种酶活性短期调节的机制会在餐后阶段发生。肝对葡萄糖的过量生产是胰岛素依赖型糖尿病和非胰岛素依赖型糖尿病中空腹高血糖的主要诱因。葡萄糖产生过程的远端酶步骤由葡糖-6-磷酸酶复合物催化。从表2中可见,经过EGCG/生物素或半胱胺/生物素处理的H-4-II-E细胞中显示,葡糖-6-磷酸酶催化亚基的信使RNA出人意料地协同降低。因此,表2中的数据显示,令人惊奇地,生物素以与EGCG或与泛硫乙胺代谢物半胱胺协同的方式发挥作用,对大鼠肝细胞中的葡萄糖代谢主要限速酶中的一种的表达进行负调节。因而,此类组合治疗会减少葡萄糖的产生,因此将减轻高血糖及预防糖尿病。
Claims (22)
1.一种组合物,所述组合物包含生物素和EGCG,所述生物素的数量足以给予服用者每kg体重0.01mg至每kg体重3mg的每日剂量。
2.如权利要求1所述的组合物,其中含有的EGCG的数量足以给予服用者每kg体重0.3mg至每kg体重30mg的每日剂量。
3.如权利要求1或2所述的组合物,其中还存在泛硫乙胺。
4.如权利要求3所述的组合物,其中含有的泛硫乙胺的数量足以给予服用者每kg体重1mg至每kg体重50mg的每日剂量。
5.如权利要求1或2所述的组合物,其中还存在植烷酸。
6.如权利要求5所述的组合物,其中含有的植烷酸的量足以给予服用者每kg体重1mg至每kg体重100mg的每日剂量。
7.如权利要求1或2所述的组合物,其中还存在硫辛酸。
8.如权利要求7所述的组合物,其中存在的硫辛酸的量足以给予服用者每kg体重0.3mg至每kg体重30mg的每日剂量。
9.如权利要求1或2所述的组合物,其中还存在普利醇。
10.如权利要求9所述的组合物,其中存在的普利醇的量足以给予服用者每kg体重0.002mg至每kg体重1.5mg的每日剂量。
11.如权利要求1或2所述的组合物,其为剂量单位形式。
12.如权利要求11所述的组合物,其中,所述剂量单位形式是固体剂量单位形式。
13.如权利要求12所述的组合物,其中所述的剂量单位形式中含有0.35mg至200mg的生物素。
14.如权利要求11所述的组合物,其中所述的剂量单位形式是液体剂量单位形式。
15.如权利要求14所述的组合物,其中所述的剂量单位形式中含有0.35mg至200mg的生物素。
16.如权利要求1所述的组合物,其为食物,或是用于食物的补充剂组合物。
17.如权利要求16所述的组合物,其中所述食物是饮料。
18.一种食物,其中包含每份0.03mg至50mg的生物素以及EGCG。
19.如权利要求18所述的食物,其为饮料。
20.生物素和EGCG在制造营养药物性组合物中的用途,其中用到的所述生物素的数量足以提供每kg体重0.01mg至每kg体重3mg的每日剂量。
21.如权利要求20所述的用途,其中所述的营养药物性组合物是食物,或是用于食物的补充剂组合物。
22.如权利要求21所述的用途,其中,所述食物是饮料。
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