CN101766228B - 刺激免疫的婴儿营养品 - Google Patents
刺激免疫的婴儿营养品 Download PDFInfo
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- CN101766228B CN101766228B CN200910225789XA CN200910225789A CN101766228B CN 101766228 B CN101766228 B CN 101766228B CN 200910225789X A CN200910225789X A CN 200910225789XA CN 200910225789 A CN200910225789 A CN 200910225789A CN 101766228 B CN101766228 B CN 101766228B
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Abstract
本发明提供了一种含有脂肪成分、蛋白质成分和碳水化合物成分,并含有乳清和酪蛋白的营养或药物组合物。所述组合物的特征在于,酪蛋白与乳清的重量比例为1∶1至1∶2.4,并且该组合物含有:a)每100克蛋白质至少3克精氨酸;b)以总脂肪酸为基准,至少10重量%的亚油酸;c)以总脂肪酸为基准,至少1重量%的α亚麻酸;d)以总脂肪酸为基准,超过0.1重量%的量的至少一种长链多不饱和脂肪酸,所述长链多不饱和脂肪酸选自二十二碳六烯酸、花生四烯酸和二十碳五烯酸;e)以总脂肪酸为基准,5-25重量%的至少一种多不饱和脂肪酸;和f)每100克干重的组合物中,2-12克的聚合度为2-100的不能消化的低聚糖。本发明的组合物减少-尤其是-与喂养乳清为主的婴儿配方有关的风险。
Description
本申请是2005年8月19日提交的题目为“刺激免疫的婴儿营养品”的中国专利申请200580028171.4(对应国际申请PCT/EP2005/008999)的分案申请。
发明领域
本发明涉及含有脂肪成分、蛋白质成分和碳水化合物成分,并含有乳清和酪蛋白的营养或药物组合物,还涉及所述组合物的应用。
发明背景
母乳喂养是对婴儿发育和对抗感染的最佳支持。但是,不是所有的婴儿都处于能接受人乳的状况。因此,一个长久的目标是提供婴儿配方,它模仿了人乳的功能。婴儿配方和人乳之间,除了需要组成相似外,还特别需要模拟人乳的保护作用。人乳已显示,例如,人乳能够保护免受感染和过敏。
在目前的婴儿配方中,酪蛋白与乳清的比例与人乳尽可能接近地相似。据信该比例可使婴儿最佳成长。但是,仍有数个不利的方面与应用牛源性的、乳清为主的蛋白来源有关。这些乳清为主的配方奶不能进行最佳地保护以免受感染。与人乳喂养的婴儿相比,施用所述配方奶导致婴儿肠道菌群的发展受损,特别是在出生的前三至四周。但是,以乳清为主的、含有或多或少与人乳喂养的婴儿有同样菌属的配方奶所喂养的婴儿的菌群,其益生菌的量在接受乳清为主的配方奶的婴儿中比接受人奶的婴儿减少。此外,以含有乳清为主的牛蛋白来源的配方奶所喂养的婴儿的菌群,含有增量的致病菌,如梭状芽孢杆菌(clostridia)和肠细菌(enterobacteria)。因此,以乳清为主的配方奶喂养婴儿导致“不够理想的肠道菌群”形成。
由于婴儿免疫系统不成熟并且肠道不成熟,不够理想的肠道菌群的发展可导致感染、腹泻、过敏和炎症。尤其是0至30天的婴儿,用含有牛乳清为主的蛋白的配方奶喂养将遭受这些风险,因为他们的粪便菌群与人乳喂养的婴儿完全不同。
发明内容
本发明的目的是提供营养或药物组合物,其能降低与喂养乳清为主的婴儿配方有关的风险。
该目的通过权利要求1所述的组合物解决。
本发明组合物的特征在于
酪蛋白与乳清的重量比例为1∶1至1∶2.4,并且该组合物含有:
a)每100克蛋白至少3克精氨酸;
b)以总体脂肪酸为基准,至少10重量%的亚油酸(LA);
c)以总体脂肪酸为基准,至少1重量%的α亚麻酸(ALA);
d)以总体脂肪酸为基准,超过0.1重量%的量的至少一种长链多不饱和脂肪酸(LCPUFA),所述长链多不饱和脂肪酸(LCPUFA)选自二十二碳六烯酸(DHA),花生四烯酸(ARA)和二十碳五烯酸(EPA);
e)以总体脂肪酸为基准,5-25重量%的至少一种多不饱和脂肪酸;和
f)每100克该组合物干重中,2-12克的聚合度为2-100的不能消化的低聚糖。
本发明组合物刺激免疫系统成熟和肠道成熟。本发明的组合物特别适于预防和/或治疗婴儿的炎性病症,如感染、腹泻和过敏。本发明组合物:
·刺激“理想的肠道菌群”的发展(即菌群与人乳喂养产生的菌群相似);
·刺激胃肠道成熟,从而预防过敏原如致病菌、毒素和食物过敏原侵入体循环;
·刺激免疫系统的成熟,一旦过敏原、病原体或毒素越过肠屏障和/或进入体循环,能产生更好的防卫;
·同时为婴儿提供最佳的营养。
人们相信,“低危肠道菌群”发展潜在的生理过程、肠的成熟和免疫系统的成熟是高度内在关联并且互相依赖的。因此,婴儿配方应当以适当的平衡包括所有那些配料,其刺激肠的成熟、免疫系统的成熟和低危肠道菌群的发展。伴随最佳的配料组合,将更好地保护婴儿免受过敏原。本发明组合物提供了所述的最佳配料组合。由于配料通常以不同机制起作用,本发明组合物的配料协同作用,为婴儿提供了改善的抵抗力,并降低了炎性病症的发生率,特别是过敏。
本发明组合物包含低度聚合的低聚糖。低聚糖刺激低危肠道菌群的形成,尤其是降低(潜在)致病肠道菌,如梭状芽孢杆菌、肠细菌和/或肠球菌(enterococci)的数量;并刺激由双歧杆菌(bifidobacteria)和乳酸菌(lactobacilli)的建群。双歧杆菌(bifidobacteria)和乳酸菌(lactobacilli)刺激刺激肠道的成熟是通过,例如,由肠上皮细胞刺激岩藻低聚糖(fuco-oligosaccharides)的合成。包含不同低聚糖的混合物可达到最佳刺激,尤其是包括中性和酸性低聚糖的低聚糖混合物。低聚糖通过降低Th2反应并增加Th1反应,也对免疫系统有“直接”作用。已发现包含低聚糖的本发明组合物能有利地用于恢复Th1/Th2反应的失衡,并用于治疗和预防与Th1/Th2失衡有关的病症,如自身免疫和过敏。
但是,即使在低聚糖与非人类乳清为主的蛋白相结合时,接受该组合物的婴儿要遭受出生第一个月期间的感染风险增加。因此,需要进一步改善免疫系统和/或肠道成熟度。
已经令人吃惊地发现,LCPUFA能有效降低上皮的细胞旁渗透性。与Usami等人(Clinical Nutrition 2001,20(4):351-359)所报告的相对照,已发现C18和C20多不饱和脂肪酸,特别是二十碳五烯酸(EPA;C20:5n3)、二十二碳六烯酸(DHA;C22:56n3)和花生四烯酸(AA;C20;4)能有效降低肠紧密连接的渗透性,从而刺激肠的成熟。因此,本发明组合物有利地包括LCPUFA。另外,必需的脂肪酸,亚油酸(C18:2n6)和α亚麻酸(C18:3n3)对于免疫系统的成熟以及对于肠道的成熟二者都是不可缺少的。在另一个特别优选实施方案中,本发明组合物还包含γ-亚麻酸(GLA;C18:3(n-6))。因此,本发明组合物含有亚油酸和α亚麻酸。
任选地,但高度优选地,本发明组合物还包含核苷酸和/或核苷。核苷酸刺激肠道的成熟,降低腹泻的发生率并刺激免疫系统。婴儿以添加核苷酸的配方奶喂养,相对于不添加核苷酸的配方奶喂养,暴露在抗原下之后,抗体的效价增加,并刺激抗原自然杀伤细胞的活性(Carver等人,Acta Paediatrica,(1999)第88卷,增补430期,第83-88页)。
发明详述
本发明的组合物包含乳清为主的非人类蛋白源、长链多不饱和脂肪酸和低聚糖。
如上所述,本发明提供了含酪蛋白与乳清的重量比例为1∶1至1∶2.4的酪蛋白和乳清婴儿配方,和每100克蛋白至少3克精氨酸的组合物。
酪蛋白/乳清比例的1∶1至1∶2.4的范围,包括了该范围内含的所有数值,因此例如,下列酪蛋白与乳清的比例:1∶1,1∶1.1,1∶1.2,1∶1.3,1∶1.4,1∶1.5,1∶1.6,1∶1.7,1∶1.7,1∶1.9,1∶1.2,1∶1.3,1∶1.4,1∶1.5,1∶1.6,1∶1.7,1∶1.8,1∶1.9,1∶2.0,1∶2.1,1∶2.2,1∶2.3和1∶2.4。在优选实施方案中,酪蛋白∶乳清比例为1∶1.4-1.6,甚至更优选大约1∶1.5(40∶60)。
优选精氨酸以每100克蛋白成分3-8克精氨酸的量存在。该范围公开了所有的值,特别是该范围内存在的所有整数值,如3、4、5、6、7和8克。所述组合物优选每100克蛋白质含有4-5克精氨酸。
在所述组合物中存在的LCPUFA选自DHA、AA和EPA。这意味着可以存在一种或两种或三种所述长链多不饱和脂肪酸。
给出的多不饱和脂肪酸的5-25重量%的范围,公开了落在该范围内的所有值。
本发明组合物不包括由人乳组成的组合物。本发明方法不包括含有施用由人乳组成的组合物的方法。因此,优选本发明方法包括施用含有非人源物质的组合物,优选非人源的纤维碳水化合物、脂肪和/或蛋白质,优选来自植物、动物、细菌或合成的来源。优选制备本发明组合物所用的所有成份和组分,源出于非人类的来源。
常量营养物
本发明组合物能有利地用作婴儿配方。所述婴儿配方优选含有脂肪成分、蛋白质成分和碳水化合物成分,并优选以液体形式给婴儿施用。
在优选实施方案中,本发明涉及包含30-60en%脂肪、5-15en%蛋白质和25-75en%碳水化合物的组合物,特别是婴儿配方。优选所述组合物包含5-15en%蛋白质、30-60en%脂肪和25-65en%碳水化合物。更优选本发明组合物含有43-53en%脂肪、7-11en%蛋白和43-53en%碳水化合物(en%是能量百分比的简称,并代表每种成分贡献给本制品总热量值的相对量)。
本发明的婴儿配方的蛋白质成分含有上述重量比例的酪蛋白和乳清。所述酪蛋白和/或乳清优选来自非人类的哺乳动物乳汁。为了给婴儿提供最佳营养,所述组合物含有特定量的精氨酸。术语“蛋白质”或蛋白质成分在本本文中是蛋白质、多肽、肽和氨基酸的集合。精氨酸在本发明组合物中是不可缺少的。它减少肠道炎性疾病的发病率(Amin等人,Journal of Pediatrics,(2002)第140卷,第4期,第425-431页)。此外,精氨酸刺激免疫系统,并且是维持健康的免疫系统所需要的(Niever等人,Biomedicine&Pharmacotherapy,(2002)第56卷,第10期,第471-482页)。酪蛋白和乳清含有精氨酸,但是对于多数奶源(如牛乳清和酪蛋白),酪蛋白和乳清提供的精氨酸不充分。优选补充到组合物中的精氨酸至少部分是游离氨基酸的碱,如L-精氨酸的形式,或以其盐或酯的形式,其中优选游离氨基酸。本发明组合物优选每100克干婴儿配方包含75至500mg的以游离氨基酸形式的精氨酸,更优选每100克干婴儿配方有150至400mg的以游离氨基酸形式的精氨酸。
本发明组合物的碳水化合物优选主要由乳糖提供,即优选总体可消化的碳水化合物中,至少75重量%是由乳糖提供的,优选至少90重量%。
低苏氨酸蛋白质
非人类蛋白来源的乳清为主的婴儿配方,与人乳相比,典型地具有高含量的生物可利用的苏氨酸。人乳含有相对少量的生物可利用苏氨酸。因而,现有技术中提供了减少乳清为主的配方奶中苏氨酸含量的方法(参见例如EP1048226,WO0111990和EP741522)。施用苏氨酸减少的乳清为主的配方奶给出了体内苏氨酸分布,其与母乳喂养婴儿的分布类似。本发明组合物优选是低苏氨酸的组合物,即每100克蛋白质含2-6克苏氨酸的组合物。低苏氨酸含量可以通过,例如,使用超滤法制备的乳清产物或某些酸性乳清产物来达到。
必需脂肪酸含量
以总体脂肪酸为基准,本发明组合物含有至少10重量%的亚油酸(LA),优选在11至20重量%之间,更优选12至15重量%之间。以总体脂肪酸为基准,本发明组合物优选含有至少1重量%的α亚麻酸(ALA),优选1.5至4重量%之间的ALA,甚至更优选2至2.5重量%之间。为了减少肠应激,LA/ALA的重量比例优选在2至10之间,优选在5至7.5之间。
以总体脂肪酸为基准,本发明的组合物优选包括0.05至5重量%之间的γ-亚麻酸(GLA),优选在0.1至1重量%之间。
长链多不饱和脂肪酸含量
本发明组合物含有至少一种具有20或22个碳原子的长链多不饱和脂肪酸(LCPUFA),以总体脂肪酸为基准,其量超过0.1重量%,选自二十二碳六烯酸(DHA)、花生四烯酸(ARA)和二十碳五烯酸(EPA)。优选该组合物以总体脂肪酸为基准,含有超过0.1重量%的DHA;以总体脂肪酸为基准,有超过0.1重量%的AA。
优选该组的至少一种LCPUFA,以所述组合物的总体脂肪酸含量为基准,所包含的量在0.15至1重量%之间。以所述组合物的总体脂肪酸含量为基准,优选这些LCPUFA中的至少两种存在的量在0.15至1重量%之间。优选所述组合物含有AA和DHA,甚至更优选AA、DHA和EPA。
AA含量优选不超过总脂肪酸的5重量%,更优选不超过1重量%,最优选在0.1至0.6重量%之间。在本发明组合物中,有利地加入EPA和/或DHA以平衡了AA的作用,如减少了AA代谢的潜在促炎性作用。AA的过度代谢可导致炎症。因此,本发明组合物优选包含AA、EPA和/或DHA,其中AA/DHA的重量比例优选0.25以上,优选0.5以上,甚至更优选1以上。AA/DHA的比例优选在25以下,优选10以下。AA/EPA的重量比例优选在1至100之间,更优选5至20之间。EPA/DHA的重量比例优选为1或更低,更优选0.5以下。
在优选实施方案中,LCPUFA的含量不超过总脂肪酸的3重量%,因为它令人满意地尽可能接近地模拟人乳。出于同样的原因,本发明组合物优选每100克脂肪酸含有少于1克的ω-3LCPUFA,更优选每100克脂肪酸在0.1至0.75克之间。ω-6LCPUFA含量优选每100克脂肪酸不超过2克,并且优选每100克脂肪酸在0.1至0.75克之间。
LCPUFA和其它脂肪酸可以提供以游离脂肪酸,以甘油三酯形式、以磷脂形式或以上的一种或多种混合物。本发明组合物有利地含有至少一种磷脂形式的AA和DHA,因为这些可以减少肠炎性病症的发生率。本发明组合物优选每克总脂肪含有0.1至5mg的来自磷脂的AA,和每克总脂肪0.1至5mg的来自磷脂的DHA。优选AA和/或DHA至少部分以磷脂酰胆碱(PC)和/或磷脂酰乙醇胺(PE)的形式存在,如含有PE和/或PC的AA和/或DHA。
单不饱和脂肪酸
本发明营养组合物优选还含有ω-9(n-9)脂肪酸(优选油酸,18:1),以提供充分的营养。以总脂肪酸的重量为基准,优选本发明组合物提供至少15重量%的n=9脂肪酸,更优选至少25重量%。以总脂肪酸的重量为基准,n-9脂肪酸的含量优选在80重量%以下。为了提供充分的营养,本发明组合物优选具有重量比例在2至5之间的饱和脂肪酸/多不饱和脂肪酸。单不饱和脂肪酸/饱和脂肪酸的重量比例优选在0.5至2之间。
本发明组合物以总脂肪酸为基准,优选含有5至25重量%之间的多不饱和脂肪酸,优选在10至20重量%之间。
本发明组合物能通过包含十八碳四烯酸(C18:4n3)更进一步得到改进。以总脂肪酸为基准,该组合物优选含有0.05至2重量%之间的十八碳四烯酸,甚至更优选在0.1至1重量%之间。
低聚糖
本发明组合物每100克组合物的干重含有聚合度(DP)为2至100之间的不能消化的低聚糖2-12克,优选3至8克之间,更优选5至7.5克之间。奶粉在液体中重构并给婴儿施用该液体配方奶之后,这些不能消化的低聚糖的量提供了所需的作用,而不导致肠不适。合适的不能消化的低聚糖,在肠内不被或仅部分被酸或存在于人类上消化道(小肠和胃)的消化酶的作用所消化,但可被人类肠道菌群发酵。该低聚糖优选是水溶性的(超过每升水1克低聚糖的溶解度)。本发明低聚糖的平均DP优选40以下,甚至更优选20以下。本发明组合物最好含有2至12克之间的DP为2-60,更优选DP为2-10(即,DP为2,3,4,5,6,7,8,9和10的那些低聚糖的重量和)的低聚糖。
根据另外的实施方案,至少一种本发明组合物的低聚糖选自菊粉、低聚果糖、不能消化的糊精、低聚半乳糖(包括反式低聚半乳糖[transgalactooligosaccharides])、低聚木糖、低聚阿拉伯糖(arabinooligosaccharides)、寡葡萄糖、寡甘露糖、乳-N-新丁糖、岩藻低聚糖(含有至少一个岩藻糖单位)、酸性低聚糖(见下,如,糖醛酸低聚糖如果胶水解产物)及其混合物。
优选本发明组合物含有选自菊粉和低聚果糖的至少一种,和选自低聚半乳糖(包括反式低聚半乳糖)和果胶水解产物的至少一种。在特别优选的实施方案中,本发明组合物含有2-12克DP为2-10的低聚糖和β-连接的半乳糖和葡萄糖,更优选反式低聚半乳糖(即[gal]n-glu,其中n为2-10)。在特别优选的实施方案中,本发明组合物含有反式低聚半乳糖(即[gal]n-glu,其中n为2-10),果胶水解产物,以及至少选自低聚果糖和菊粉中的一种。本发明低聚糖也能是源自动物乳汁的低聚糖、源自动物乳汁的低聚糖混合物或岩藻糖基化的(fucosylated)低聚糖(含有至少一个岩藻糖单位的低聚糖)。
为了进一步改进整个结肠部位的肠道成熟,优选本发明组合物中至少10重量%的低聚糖具有DP为2-5(即2,3,4和/或5)和至少5重量%具有DP为10-100。优选至少50重量%,更优选至少75%重量%的低聚糖具有DP为2-10(即2,3,4,5,6,7,8,9和/或10),因为它们被认为可以在整个回肠和结肠的近段和中段发挥作用,还因为需要合并在所述组合物中达到所需作用的低聚糖的重量百分率被降低了。
优选重量比例:
(DP为2-5的低聚糖)∶(DP为6-9的低聚糖);和(DP为10-100的低聚糖)∶(DP为6-9的低聚糖)二者均超过1。
优选二者的重量比例超过2,更甚优选超过5。
本发明组合物每100克该组合物干重优选含有0.5-10克DP在2至10之间的低聚半乳糖,更优选在1至5克之间。优选的低聚半乳糖为反式低聚半乳糖,因为这是最佳模拟人类乳汁的低聚糖。本发明优选每100克所述组合物干重含有0.5-10克DP在10至60之间的果糖多糖(fructopolysaccharide),更优选1至5克之间。术语“果糖多糖”指含有至少10个β-连接的果糖单位的链的多糖碳水化合物。
酸性低聚糖
为了进一步改进屏障完整性,本发明组合物优选包括DP在2至100,优选2-60之间的酸性低聚糖。术语酸或酸性低聚糖指低聚糖含有选自N-乙酰神经氨酸、N-乙醇酰神经氨酸、游离或酯化的羧酸、硫酸基和磷酸基的至少一个酸性基团。所述酸性低聚糖优选含有糖醛酸单位(即糖醛酸聚合物),更优选半乳糖醛酸单位。本发明组合物的每100克本发明组合物干重,优选含有0.1至10克之间的酸性低聚糖,更优选每100克干重1至6克之间。
结构I:聚合的酸性低聚糖
其中:
R优选选自氢、羟基或酸性基团,优选羟基;并且
选自R2、R3、R4和R5的至少一个代表了N-乙酰神经氨酸、N-乙醇酰神经氨酸、游离或酯化的羧酸、硫酸基和磷酸基,而且其余的R2、R3、R4和R5代表羟基和/或氢。选自R2、R3、R4和R5的之一优选表示N-乙酰神经氨酸、N-乙醇酰神经氨酸、游离或酯化的羧酸、硫酸基或磷酸基,其余代表羟基和/或氢。甚至更优选选自R2、R3、R4和R5的之一代表游离或酯化的羧酸,其余的R2、R3、R4和R5代表羟基和/或氢;并且
n是整数,指己糖单位的数目(还参见下文的聚合度部分),可以是任何的己糖单位。适当的n是1-5000之间的整数。优选的己糖单位是糖醛酸单位。
最优选R1、R2和R3代表羟基,R4代表氢,R5代表羧酸,n是1至250之间的任一数,优选在1至10之间,并且己糖单位是半乳糖醛酸。
本发明方法所用的优选酸性低聚糖的检测、测定和分析,在申请人较早的涉及酸性低聚糖的专利申请,即WO 0/160378中给出。
优选地,所述酸性低聚糖具有一个,优选两个,末端糖醛酸单位,其可以是游离或酯化的。优选末端糖醛酸单位选自半乳糖醛酸、葡糖醛酸、古罗糖醛酸、艾杜糖醛酸、甘露糖醛酸、rib糖醛酸(riburonicacid)和alt糖醛酸(altruronic acid)。这些单位可以是游离或酯化的。在一个甚至更优选的实施方案中,末端己糖单位有双键,其优选位于末端己糖单位的C4和C5位之间。优选末端己糖单位之一含有双键。所述末端己糖(如糖醛酸)优选具有依照下面结构II的结构:
结构II:优选的末端己糖酸基
其中:
R优选选自氢、羟基或酸基,优选羟基(见上);并且
选自R2、R3、R4和R5的至少一个代表N-乙酰神经氨酸、N-乙醇酰神经氨酸、游离或酯化的羧酸、硫酸基和磷酸基,其余的R2、R3、R4和R5代表羟基和/或氢。优选选自R2、R3、R4和R5的之一代表着N-乙酰神经氨酸、N-乙醇酰神经氨酸、游离或酯化的羧酸、硫酸基和磷酸基,其余的R2、R3、R4和R5代表羟基和/或氢。甚至更优选选自R2、R3、R4和R5的之一代表游离或酯化的羧酸,其余的R2、R3、R4和R5代表羟基和/或氢;并且n是整数,指己糖单位的数目(还参见下文的聚合度部分),其可以是任何的己糖单位。适当的n是1-5000之间的整数,代表己糖单位的数目,所述己糖单位优选是糖醛酸,甚至更优选半乳糖醛酸单位。所述单位上的羧酸基可以为游离的或(部分)酯化的,并且优选是至少部分甲基化的。
更优选R2和R3代表羟基,R4代表氢,和R5代表游离或酯化的羧酸。
本发明所用的酸性低聚糖优选以果胶、果胶酸酯、藻酸盐、软骨素、透明质酸、肝素、乙酰肝素、细菌碳水化合物、涎多糖(sialoglycans)、岩藻多糖、岩藻低聚糖或卡拉胶来制备,更优选果胶和/或藻酸盐。优选用果胶水解产物。
核苷酸
本发明组合物还优选每100克该组合物的干重中,含有5至100mg之间的核苷和/或5至100mg之间的核苷酸,更优选5至50mg之间。所述核苷酸和/或核苷与本发明组合物的其他配料协同作用,进一步刺激免疫系统。
锌
锌是免疫功能生长和发育的必需微量营养素。缺锌削弱整体免疫功能和对感染的抵抗力。因此本发明组合物有利地包含锌,优选每100克本发明组合物的干重中,锌的量为2-100mg,甚至更优选每100克本发明组合物的干重至少有4-25mg锌。锌的重量是按元素锌计算的。
液体
本发明组合物优选是粉末或液态或片剂形态,其中所述片剂的重量在5至25克之间。优选本发明组合物是粉末形态,因为这可以增加保存期。本发明组合物优选以液体形态口服。在施用本发明组合物之前,其优选与液体,优选水混合。由于液体组合物优选在35-40℃(优选大约37℃)的温度下施用,所述液体配方奶优选以下列方法制备:
方法a:将温度低于30℃的水与根据权利要求1-10的任一项的组合物混合,水∶组合物的重量比例为1-10∶1;并加热步骤a)得到的混合物至温度达35至50℃之间;或者
方法b:将温度低于60℃的水与根据权利要求1-10的任一项的组合物混合,水∶组合物的重量比例为1-10∶1;冷却步骤a)得到的混合物至温度达35至40℃之间。方法a)更适合用粉末制备液体配方,而步骤b)更适合从片剂制备ta液体配方。
在接受液体食品的很多婴幼儿和生病的对象中,大便不规律(如大便硬,便量少,腹泻)是主要问题。已发现施用以液态形式的本发明组合物可以减少大便的问题,所述组合物的重量摩尔渗透压浓度在50至500mOsm/kg之间,更优选100至400mOsm/kg之间,最优选220至300mOsm/kg之间。
考虑到上述腹泻问题,液体食品没有过高的热量密度也是很重要的,因为这导致了明显的肠应激。但是,配方奶需要提供充分的热量喂养婴儿。因此,液体食品优选热量密度在0.5至0.9kcal/ml之间,优选在0.6至0.8kcal/ml之间。
应用
本发明组合物有利地施用于0至2岁之间的婴儿。本发明组合物也能有利地用在为早产儿(妊娠37周之前出生的婴儿)提供营养需求的方法中。在优选的实施方案中,本发明提供了喂养0至30天之间婴儿的方法。
本发明组合物能有利地用于治疗或预防疾病,其中所包括的免疫系统和/或肠屏障的不成熟是病程发展的基础。本发明组合物因此能有利地用于治疗或预防腹泻或过敏,尤其在0至2岁之间的婴儿。本发明组合物特别适合用于治疗和/或预防过敏性鼻炎、过敏性结膜炎、过敏性皮炎、遗传过敏性皮炎和/或食物过敏。
本发明组合物优选以包装的粉末或包装好的即食配方奶提供。为了防止产品腐坏,即食配方奶的包装规格不超过一次用量,如优选不超过500ml;粉末状本发明组合物的包装规格优选不超过250次用量。适当的粉末包装规格为2000克或以下,优选每个1000克或以下。
包装的产品贴有标签,明确或含蓄地指导消费者依照上下文的一个或多个目的,应用所述产品,这包括在本发明中。所述标签可以,例如,包括文字如“刺激肠和/或免疫系统的成熟”,“减少过敏反应”,“应激少”,“改善抵抗力”或“减少敏感性”或者类似的文字。
因此,本发明的一个主题是,应用本文描述的组合物制造配方食品或药物,施用于哺乳动物,用于炎性疾病、腹泻、湿疹和/或遗传过敏性皮炎的治疗和/或预防。
本发明另外的一个主题是,应用本文描述的组合物制造药物,用在治疗和/或预防炎性疾病、腹泻、湿疹和/或遗传过敏性皮炎的方法中,所述方法包括经肠道或口服给哺乳动物,特别是人类的婴儿施用所述组合物。在优选的实施方案中,本发明方法提供了治疗和/或预防感染的方法,所述方法包括施用本发明组合物。
本发明通过下面的实施例进一步描述:
实施例1:婴儿营养品
液体婴儿营养品,通过将13.9g粉末和水混合而制备,产生100ml终产品,所述液体产品每100ml包括:
能量: 66kcal
蛋白质: 8en%
1.3g(含有0.6g酪蛋白;0.8g乳清;0.072g L-精氨
酸)
可消化的碳水化合物: 44en%
7.4g(含有7.3g乳糖)
脂肪: 48en%
3.5g(含有0.41g亚油酸;0.08g α-亚麻酸;0.012g花生四烯酸;0.002g二十碳五烯酸;0.006g二十二碳六烯酸;1.4g油酸;)
纤维: 0.8g(含有0.05g果糖多糖(Raftiline HPTM,
Orafti,Tienen,比利时);0.55g反式低聚半乳糖
(Vivinal-GOSTM(Borculo Domo Ingredients,荷兰);
0.20g果胶水解产物,依照EP1373543的实施例1所
描述制备。
核苷酸: 0.89mg胞苷-5-单磷酸盐;
0.55mg尿苷-5-单磷酸盐;
0.82mg腺苷-5-单磷酸盐;
0.20mg鸟苷-5-单磷酸盐;
0.34mg肌苷-5-单磷酸盐;
摩尔渗透压浓度: 300mOsmol/l
该组合物还含有胆碱(6mg/100ml)和牛磺酸(6.3mg/100ml);矿物质和痕量元素(包括2mg锌/100ml)以及维生素,其量依照婴儿配方的国际指南。
实施例2:
包装的实施例1的婴儿配方,其中包装上贴有标签,说明所述配方奶能适用于预防或治疗过敏。
实施例3:
试验计划
检验含有酸性低聚糖、任选与中性低聚糖组合的食品对延迟型过敏(DTH)反应的作用,这是Th1免疫反应的参数,并通过在局部抗原攻击后,测定耳朵肿胀的增加度来测定。
所用的酸性低聚糖(AcOl),平均DP在2-10之间,通过WO02/42484(见实施例1)所描述的方法获得。以食物的总重量为基准,检验含有1重量%、2.5重量%、5重量%和10%重量%AcOl的食物。含有低聚半乳糖(GOS)(Vivinal-GOSTM(Borculo Domo Ingredients,荷兰)和低聚果糖(FOS)(Raftiline HPTM,Orafti,Tienen,比利时)的中性低聚糖混合物(GF)中,GOS∶FOS的重量比例为9∶1。以食物的总重量为基准,检验含有1、2.5和5重量%GF的食物。以食物的总重量为基准,在含有1重量%GF和1重量%AcOl的食物中,检验酸性和中性低聚糖(GF和AcOl)的组合的作用。
所有数据以相对于对照数值的百分数来表示,即低聚糖添加组与接受对照食物(不含低聚糖)的组比较的相对数值。
动物和食物
6周龄的雌性C57BI/6小鼠(Harlan Nederland BV,Horst,荷兰)以定期12小时明/暗的方式群养。组规模为每组10只动物,阴性对照组3只动物。动物给予半合成的食物(Research Diet Services,Wijk bijDuurstede,荷兰)。对照食物的制作按照AIN93G规范(Reeves等人(1993)Development and Testing of the AIN93 purified diets for rodents:results on growth kidney calcification and bone mineralisation in rats andmice.J Nutrition 123(11):1923-31),添加低聚糖的食物以这些规范为基础。通过以重量为基础,总碳水化合物与低聚糖交换,添加食物的碳水化合物含量保持恒定。个别碳水化合物成分相应于其在食物中的正常比例被取代。正常食物中的碳水化合物由玉米淀粉(总重量的40%)、糊精化的玉米淀粉(13.2%)、蔗糖(10%)和纤维素(5%)组成。
接种方案
在适应新居和食物的二至四周后,开始接种。在第0天,接种前采集血样。第1天,进行第一次皮下接种。三周后,采集血样(21天)并给予加强接种(22天)。加强注射后9天(31天),用数显外径千分尺(Digimatic outside micrometer)(Mitutoyo,Veenendaal,荷兰)测量基础耳朵厚度,并通过在小鼠耳翼中i.c.(皮内)注射抗原溶液诱发延迟型过敏(DTH)反应。24小时后(32天),测定DTH反应,采集血样并处死小鼠。分离脾脏并制备用于离体(ex-vivo)再刺激。
所述接种包括由抗原溶液和Stimune佐剂(Specol,Cedi-diagnosticsBV,Lelystad,荷兰)1∶1混合的100μl i.c.(皮内)注射。该抗原溶液是流感疫苗(Influvac)2002/2003(Solvay Pharmaceuticals,Weesp,荷兰)在PBS中1∶100的稀释液。流感疫苗是三价蛋白疫苗,含有3×30μg/ml三种不同流感病毒株的血凝素。
为了DTH反应,小鼠在双侧耳朵i.c注射25μl渗析流感疫苗作为DTH攻击。
细胞培养
脾细胞用细筛孔细胞过滤器(Becton Dickinson,Erembodegem,比利时)从脾脏分离。用5分钟冰孵溶解血红细胞。用不带酚红的培养液清洗后,进行细胞计数(Coulter Counter,Beckman Coulter,荷兰),并保留在冰上。培养细胞用0.1μg/ml渗析的流感疫苗作为刺激物来建立。细胞以每孔1*106细胞种植到96孔培养板上。培养基由具有HEPES缓冲液的RPMI-1640和具有10%胎牛血清(FCS)的2mM L-谷氨酰胺(Invitrogen,Merelbeke,比利时)组成。培养细胞在37℃的5%CO2中孵育5天。之后收集上清液,冷冻在-80℃直至分析。通过结合3H-胸苷,在平行培养细胞中测定细胞增殖,所述3H-胸苷在最后18小时以0.4μCu/孔加入到培养细胞中。5天后,用Filtermate收集器(PerkinElmer,Zaventem,比利时)收集细胞,在Micro-Beta计数器(Perkin Elmer,Zaventem,比利时)上计数。放射活性的衰减每孔测定1分钟,并且记录每分钟的计数(cpm),作为增殖速度的测定。
在流感疫苗刺激的培养细胞的上清中分析细胞因子。IL-2、IL-5、IL-10和IFN-γ,用带有用于所述细胞因子的定制混合的beadset(custommixed beadset)的Bio-Plex系统(Bio-Rad,Veenendaal,荷兰)测定。细胞因子根据生产商的说明书测定。IL-4用Pharmingen OptEIA小鼠IL-4试剂盒(Becton Dickinson,Erembodegem,比利时),根据生产商的说明书,以ELISA测定。
结果
DTH反应的酸性低聚糖
含有1重量%、2.5重量%和5重量%AcOl剂量的食物,诱发DTH反应的统计学显著性增加,表现出剂量依赖性增加(见表1)。观察到的作用指示了酸性低聚糖在本发明方法中的有利应用。
表1
重量%食物中的酸性低聚糖 | DTH反应(%) |
0(对照) | 100 |
1 | 122 |
2.5 | 136* |
5 | 140* |
*指示相对于对照有显著性差异(P<0.05)
DTH反应的酸性和中性低聚糖
1重量%GF、2.5重量%GF和1重量%GF与1重量%AcOl的混合物的组合,诱发DTH统计学显著性增加(见表2)。所观察到的作用指示了不能消化的低聚糖,特别是酸性和中性低聚糖的组合在本发明方法中的有利应用。
表2
重量%食物中的低聚糖 | DTH反应(%) |
0(对照) | 100 |
1重量%GF | 132* |
1重量%AcOl | 122 |
2.5重量%GF | 129* |
2.5重量%AcOl | 136* |
1重量%GF和1重量%AcOl | 159* |
*指示相对于对照有显著性差异(P<0.05)
酸性低聚糖的流感疫苗特异性增殖
施用含有2.5重量%和5重量%酸性低聚糖(AcOl)的食物,导致对离体法流感疫苗特异性增殖作用的显著降低(见表3)。观察到的作用指示了酸性低聚糖在本发明方法中的有利应用。
酸性和中性低聚糖组合物的流感疫苗特异性增殖作用
施用1重量%GF与1重量%AcOl的组合,诱导对抗原特异性增殖作用的显著降低(见表3)。由于所述作用比单独含有酸性或中性低聚糖食物的DTH反应有明显改善,所述结果指示了使用酸性和中性低聚糖所提供的协同作用。观察到的作用指示了酸和中性低聚糖在本发明方法中的有利应用。增殖作用降低指示了Th2反应的减少,和本发明方法的Th1/Th2平衡作用。
表3
重量%食物中的低聚糖 | 流感疫苗特异性增殖作用(%) |
0(对照) | 100 |
1重量%GF | 100 |
1重量%AcOl | 92 |
2.5重量%AcOl | 61* |
5重量%AcOl | 54* |
1重量%GF和1重量%AcOl | 50* |
*指示相对于对照有显著性差异(P<0.05)
Th1/Th2平衡:施用酸性低聚糖后的细胞因子分布
在流感疫苗特异性脾细胞的培养上清液中测定细胞因子分布。数据以相对于接种对照组数值(即没有接受低聚糖)的百分数表示。与对照比较,含有2.5重量%和5重量%AcOl的食物导致Th2相关的细胞因子IL-4、IL-5和IL-10降低,而Th1相关的细胞因子IL-2则增加,IFN-γ不显著性降低(见表4)。所述结果指示了酸性低聚糖的Th1/Th2平衡作用,并指示了本发明方法中酸性低聚糖的有利应用,如治疗和/或预防Th1免疫性相对低下的疾病。
Th1/Th2平衡:施用酸性和中性低聚糖后的细胞因子分布
与对照比较,施用1重量%GT和1重量%AcOl的组合导致Th2相关的细胞因子IL-4、IL-5和IL-10降低,而Th1相关的细胞因子IL-2和IFN-γ不降低(见表4,其中数据以相对于接种对照组数值(即没有接受低聚糖)的百分数表示)。所述结果指示了酸性和中性低聚糖组合的Th1/Th2平衡作用,并指示了酸性低聚糖在本发明方法中的有利应用,如治疗和/或预防Th1免疫性相对低下的疾病。特别是IL-4/IFN比例反映了Th2/Th1平衡。换句话说,降低的比例指示了Th1刺激和/或Th2抑制,并且在任何情况下都指示了本发明低聚糖的Th1-Th2平衡作用。
表4
*指示相对于对照有显著性差异(P<0.05)
Claims (13)
1.被配制成婴儿配方并含有脂肪成分、蛋白质成分和碳水化合物成分,以及包含乳清和酪蛋白的营养和药物组合物,
其特征在于,
酪蛋白与乳清的重量比例为1∶1至1∶2.4,并且所述组合物含有:
a)每100克蛋白质至少3克精氨酸;
b)以总脂肪酸为基准,至多25重量%的至少一种多不饱和脂肪酸,其包含:
以总脂肪酸为基准,至少10重量%的亚油酸;
以总脂肪酸为基准,至少1重量%的α亚麻酸;以及
以总脂肪酸为基准,超过0.1重量%的量的至少一种长链多不饱和脂肪酸,所述长链多不饱和脂肪酸选自二十二碳六烯酸、花生四烯酸和二十碳五烯酸;
c)每100克干重的该组合物中2-12克的聚合度为2-60的不能消化的低聚糖,其包含中性和酸性低聚糖,其中的酸性低聚糖含有糖醛酸单位。
2.根据权利要求1的组合物,其特征在于能消化的低聚糖包含反式低聚半乳糖、果胶水解产物以及选自低聚果糖和菊粉中的至少一种。
3.根据权利要求1的组合物,其特征在于所述组合物含有二十二碳六烯酸、花生四烯酸和二十碳五烯酸。
4.根据权利要求1的组合物,其特征在于蛋白质成分占5-15en%;脂肪成分占30-60en%;以及碳水化合物成分占25-75en%。
5.根据权利要求1的组合物,其特征在于所述组合物进一步包括每100克干重的该组合物5至100mg的核苷酸和/或5至100mg的核苷。
6.根据权利要求1的组合物,其特征在于所述组合物含有每100克蛋白质成分2-6克的苏氨酸。
7.根据权利要求1的组合物,其特征在于所述组合物含有以总脂肪酸为基准,超过0.1重量%的量的二十二碳六烯酸,和以总脂肪酸为基准,超过0.1重量%的量的花生四烯酸,并且花生四烯酸/二十二碳六烯酸的重量比在0.25和25之间。
8.权利要求1-7的任一项所限定的组合物在制备施用于人类婴儿用于治疗和/或预防炎性疾病的配方食品或药物中的应用。
9.根据权利要求8所述的应用,其中所述的炎性疾病是过敏。
10.根据权利要求8所述的应用,其中所述的炎性疾病是湿疹。
11.根据权利要求8所述的应用,其中所述的炎性疾病是遗传过敏性皮炎。
12.根据权利要求8的应用,其中所述组合物经肠道施用。
13.根据权利要求8所述的应用,其中所述组合物经口施用。
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