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    • 专利摘要:
    composition and its uses for brain growth and / or cognitive and / or psychomotor development. the present invention relates to a composition comprising at least one long-chain polyunsaturated fatty acid, at least one probiotic and a mixture of oligosaccharides, said mixture containing at least one n-acetylated oligosaccharide, at least one sialylated oligosaccharide and at least one neutral oligosaccharide, for use in brain growth and / or cognitive and / or psychomotor development. this composition is particularly adapted for use in babies, notably premature babies. the present invention also relates to the use of said composition as a synthetic nutritional agent, for use in brain growth and / or cognitive and / or psychomotor development, as well as to the use of said composition to prepare a synthetic nutritional agent for promoting brain growth and / or cognitive and / or psychomotor development.
    公开号:BR112014008944B1
    申请号:R112014008944-2
    申请日:2012-10-12
    公开日:2020-09-15
    发明作者:Clara Garcia-Rodenas；Kurt Ornstein
    申请人:Société des Produits Nestlé S.A.；
    IPC主号:
    专利说明:

    FIELD OF THE INVENTION
    [001] The present invention relates to a composition for use in brain growth and / or cognitive and / or psychomotor development. This composition is for use in mammals, preferably in humans, more preferably in children. BACKGROUND OF THE INVENTION
    [002] During development, especially in the first years of life, children show interesting patterns of neural development and a high degree of neuroplasticity. The relationship between brain development and cognitive development is extremely complex and, since 1990, a growing area of research.
    [003] Some new developments are intended to prove a link between brain growth and cognitive development in children and, particularly, in premature babies or newborns with extremely low gestational age (ELGANs) (J. Pediatr. 2009; 155: 344 -9).
    [004] Therefore, there is a great interest in promoting brain growth, particularly in premature children, such that their cognitive and / or psychomotor development is favored.
    [005] Supplementation with long chain polyunsaturated fatty acids has been proposed to promote cognitive and psychomotor development and several clinical tests have investigated this hypothesis. However, a recent meta-analysis that combined these data did not show a significant effect of supplementation on neurodevelopment (Schulzke SM, Patole SK, Simmer K, Longchain polyunsaturated fatty acid supplementation in preterm infants (Review) The Cochrane Library 2011, Issue 2) .
    [006] Cognitive development can also be improved in premature children by greatly increasing the intake of protein and energy (I Brandt, EJ Sticker and MJ Lentze, catch-up growth of head circumference of vey low birth weight, smal gestacional age preterm infants and mental development to adulthood, J. Pediatr 2003; 142: 463-8). However, the large volumes of enteral feeding and / or the high protein / energy density of feeds can induce food intolerance. In addition, the large protein intake that leads to increased urea production, may increase the risk of renal failure and metabolic acidosis in premature children. In addition, the intake of a lot of protein / energy during childhood has been associated with long-term changes in metabolic health (increased risk of obesity, type II diabetes and cardiovascular disease) (KK ONG & RJF LOOS, Rapid infancy weight gain and subsequent obesity: Systematic reviews and hopeful suggestions Acta Paediatrica, 2006; 95: 904 908; J Rotteveel, MM van Weissenbruch, JWR Twisk, HA Delemarre-Van de Waal, Infant and Childhood Growth Patterns, Insulin Sensitivity, and Blood Pressure in Prematurely Born Young Adults Pediatrics 2008; 122: 313-321).
    [007] There is a need for a nutritional composition for use in brain growth and / or cognitive and / or psychomotor development, particularly in infants and young children, preferably infants, who were born premature or with low birth weight (LBW) or who have experienced intrauterine growth retardation (IUGR) or who have suffered growth retardation due to malnutrition, such as suboptimal uterine nutrition and / or disease.
    [008] There is a more general need for this nutritional intervention in young mammals, in particular infants and children, preferably children, but also young puppies. SUMMARY OF THE INVENTION
    [009] The present inventors have surprisingly found that administration of a mixture of specific oligosaccharides in combination with at least one long-chain polyunsaturated fatty acid (LC-PUFA) and at least one probiotic, is particularly effective in brain growth and / or cognitive and / or psychomotor development.
    Accordingly, the present invention provides a composition comprising at least one LC-PUFA, at least one probiotic and a mixture of oligosaccharides, said mixture containing at least one N-acetylated oligosaccharide, at least one sialylated oligosaccharide and at least one neutral oligosaccharide, for use in brain growth and / or cognitive and / or psychomotor development.
    [0011] The composition according to the invention is preferably a nutritional composition.
    [0012] LC-PUFA is preferably selected from arachidonic acid (ARA) and oicocosa-hexaenoic acid (DHA), more preferably LC-PUFA is a mixture of ARA and DHA.
    [0013] The probiotic is preferably selected from strains of probiotic bacteria, more preferably the probiotic is a lactobacillus or a bifidobacterium. In a preferred embodiment, the probiotic is Bifidobacterium lactis and Lactobacillus reuteri.
    [0014] The neutral oligosaccharide is preferably selected from fructo-oligosaccharides (FOS) and galactooligosaccharides (GOS), preferably GOS.
    [0015] In one embodiment, the oligosaccharide mixture can be derived from milk of animal origin, such as one or more from cow, goat, sheep or buffalo milk. For example, it was obtained by fractioning cow's milk and subsequent enzyme treatment.
    [0016] In a second embodiment, the oligosaccharide mixture can be prepared using enzymatic, chemo-enzymatic and / or chemical means.
    [0017] In a third modality, the oligosaccharide mixture can be prepared using yeast and / or bacterial fermentation technologies. For example, yeast and / or bacterial cells that express suitable enzymes such as glycosidases and / or glycosyltransferases after genetic modification or not, can be used for this purpose.
    [0018] The composition of the invention is preferably used for children who were born premature or with low birth weight (LBW) or who experienced intrauterine growth retardation (IUGR) and / or who suffered growth retardation due to illness and / or malnutrition . DETAILED DESCRIPTION OF THE INVENTION
    [0019] As used here, the following expressions have the following meanings.
    [0020] The expression "child" means a human being between the stages of birth and puberty. An adult is a human being older than a child.
    [0021] The term "infant" means a child under the age of 12 months.
    [0022] The term "premature baby" (or "premature child") means a child born at less than 37 weeks of gestational age.
    [0023] The expression "child with low birth weight" means a child born alive who weighs less than 2500 g.
    [0024] The expression "small child" means a child aged between one and three years.
    [0025] The term "infant formula" means a foodstuff intended for a nutritional use in particular by babies during the first four to six months of life and which satisfies the nutritional needs of that category of person by itself (Article 1.2 of the European Commission Directive 91/321 / EEC of 14 May 1991 on infant formulas and transition formulas).
    [0026] The expression "infant formula for premature" means an infant formula intended for a premature baby.
    [0027] The expression "fortifier for human milk" means a supplement used to increase the calories, proteins, minerals and vitamins in breast milk for premature babies or babies with low birth weight.
    [0028] The expression "transitional formula" means a food intended for particular nutritional use by babies over four months and which constitutes the main liquid element in the progressively diversified diet of this category of person.
    [0029] The expression "initial infant formula" means a food intended for nutritional use in particular by babies during the first four months of life.
    [0030] The expression "baby food" means a food intended for nutritional use, in particular by children, during the first years of life.
    [0031] The term "infant cereal composition" means a food intended for nutritional use, in particular by children, during the first years of life.
    [0032] The term "growth milk" means a milk-based drink adapted to the specific nutritional needs of young children.
    [0033] The term "weaning period" means the period during which breast milk or infant formula is partially or totally replaced by another food in a child's diet. The term "brain growth and / or cognitive and / or psychomotor development" means support for brain growth and / or cognitive and / or psychomotor development.
    [0034] The term "nutritional composition" means a composition that nourishes an individual. This nutritional composition is usually to be given orally, intragastrically or intravenously and usually includes a lipid or fat source and a protein source.
    [0035] The term "synthetic mixture" means a mixture obtained by chemical and / or biological means, which can be chemically identical to the mixture that occurs naturally in mammalian milks.
    [0036] The term "hypoallergenic composition" means a composition that is unlikely to cause allergic reactions.
    [0037] The term "probiotic" means preparations of microbial cells or components of microbial cells or metabolites of microbial cells with a beneficial effect on the health or well-being of the host. (Salminen S, Ouwehand A. Benno Y. et al. "Probiotics: how should they be defined" Trends Food Sci. Technol. 1999: 10 107-10).
    [0038] The expression "oligosaccharide" means a carbohydrate that has a degree of polymerization (DP) that varies between 2 and 20 inclusive, but that does not include lactose.
    [0039] The term "neutral oligosaccharide" means an oligosaccharide that has no charge and no N-acetyl residue.
    [0040] The term "sialylated oligosaccharide" means an oligosaccharide that has a sialic acid residue (such as N-acetylneuraminic acid and / or N-glycolylneuraminic acid).
    [0041] The term "N-acetylated" oligosaccharide means an oligosaccharide that has at least one hexose that carries an N-acetyl residue.
    [0042] All percentages are by weight unless otherwise stated.
    [0043] In one aspect, the invention provides a composition comprising at least one LC-PUFA, at least one probiotic, and a mixture of oligosaccharides, said mixture containing at least one N-acetylated oligosaccharide selected from the group comprising GalNAccrt, 3Galβ1, 4Glc (= 3'GalNAc-lac = N-acetyl-galactosaminyl-lactose), Galβ1, 6GalNAcα1,3Galβ1,4Glc (= 6'Gal-3GalNAc-lac = galactosyl-N-acetyl-galactosaminyl-lactose), Galβ1, 4GlcNAcβ1, 3Galβ1,4Glc (lacto-N-neotetraose or LNnT) and Galβ1, 3GlcNAcβ1,3Galβ1 (lacto-N-tetraose or LNT), at least one sialylated oligosaccharide selected from the group comprising NeuAcα2,3Galβ1,4Glc (= 3'-sialylose) and NeuAcα2,6Galβ1,4Glc (= 6'-sialylactose), and at least one neutral oligosaccharide selected from the group comprising Galβ1,6Gal (= β1,6-digalactoside); Galβ1, 6Galβ1,4Glc (= 6'Gal-lac); Galβ1, 6Galβ1,6Glc; Galβ1, 3Galβ1,3Glc; Galβ1, 3Galβ1,4Glc (= 3'Gal-lac); Galβ1, 6Galβ1,6Galβ1,4Glc (= 6 ', 6-diGal-lac); Galβ1, 6Galβ1,3Galβ1,4Glc (= 6 ', 3-diGal-lac); Galβ1, 3Galβ1,6Galβ1,4Glc (= 3 ', 6-diGal-lac); Galβ1, 3Galβ1,3Galβ1,4Glc (= 3 ', 3-diGal-lac); Galβ1, 4Galβ1,4Glc (= 4'Gal-lac) and Galβ1, 4Galβ1,4Galβ1,4Glc (= 4 ', 4-diGal-lac); and Fucαl, 2Galβ1,4Glc (= 2 'fucosylactose or FL), for use in brain growth and / or cognitive and / or psychomotor development.
    [0044] In a second aspect, the invention relates to a composition comprising at least one long-chain polyunsaturated fatty acid, at least one probiotic and an oligosaccharide mixture comprising: 0.25 to 20% by weight, preferably 0.3 to 10% by weight, more preferably 0.3 to 5% by weight and even more preferably about 0.5% by weight, with respect to the total weight of the oligosaccharide mixture, of at least one N- oligosaccharide acetylated, 0.5 to 30% by weight, preferably 0.75 to 15% by weight, more preferably 0.75 to 10% by weight and even more preferably about 1% by weight, with respect to the total weight of the mixture of oligosaccharide, of at least one sialylated oligosaccharide and 50 to 99.3% by weight, preferably 20 to 80% by weight, more preferably 10 to 50% by weight and even more preferably about 50% by weight, with respect to the total weight of the oligosaccharide mixture, of at least one neutral oligosaccharide, for use in brain growth and / or development cognitive and / or psychomotor.
    [0045] According to a preferred embodiment, the oligosaccharide mixture is present in an amount of 0.5 to 70%, more preferably 1 to 20%, even more preferably 2 to 5% with respect to the total weight of the composition.
    [0046] Oligosaccharide compounds are defined by their structures, where GalNAc is N-acetyl galactosamine, GlcNAc is N-acetyl glucosamine, Gal is galactose, NeuAc is N-acetyl neuraminic acid, Glc is glucose and Fuc is fucose.
    [0047] The oligosaccharide mixture of the composition according to the invention may be the only source of oligosaccharide in the composition.
    [0048] In a first embodiment, the neutral oligosaccharide is preferably selected from FOS and GOS, preferably GOS such as those mentioned above.
    [0049] In a second embodiment, independent or not of the first embodiment, the neutral oligosaccharide is preferably 2'-fucosylactose (FL). In that case, FL is preferably included in the group of neutral oligosaccharides in the oligosaccharide mixture during its manufacture.
    [0050] The neutral oligosaccharide can be prepared as a mixture by acquiring and mixing the individual components. For example, synthesized galacto-oligosaccharides such as Galβ1, 6Gal, Galβ1,6Galβ1,4Glc, Galβ1,6Galβ1,6Glc, Galβ1,3Galβ1,3Glc, Galβ1, 3Galβ1,4Glc, Galβ1, 6Galβ1,6Galβ1,4Glc1al, , 4Glc, Galβ1, 3Galβ1,6Galβ1,4Glc, Galβ1, 3Galβ1,3Galβ1,4Glc, Galβ1, 4Galβ1,4Glc, and Galβ1, 4Galβ1,4Galβ1,4Glc and mixtures of these are commercially available under the trade name Vivinal® of Friesland Campina, Holland and Elix'or®. Other oligosaccharide suppliers are Dextra Laboratories, Sigma-Aldrich Chemie GmbH and Kyowa Hakko Kogyo Co., Ltd. Alternatively, specific glycosyltransferases and / or glycosidases, such as galactosyltransferases and / or fucosyltransferases and / or galactosidases and / or fucosidases can be used for produce galactooligosaccharides and / or fucosylated oligosaccharides.
    [0051] Fucosylactose is a fucosylated oligosaccharide (meaning an oligosaccharide that has a fucose residue). This fucosylated oligosaccharide can be isolated by chromatography or filtration technology from a natural source such as animal milk. Alternatively, it can be produced by biotechnological means using specific fucosyltransferases and / or fucosidase through the use of enzyme-based fermentation technology (recombinant or natural enzymes) or microbial fermentation technology. In the latter case, microbes can express their natural enzymes and substrates or they can be manipulated to produce the respective substrates and enzymes. Isolated microbial cultures and / or mixed cultures can be used. The formation of fucosylated oligosaccharide can be initiated by the accepting substrates starting from any degree of polymerization (DP), from DP = 1 onwards. Alternatively, fucosylated oligosaccharides can be produced by chemical synthesis from lactose and free fucose. Fucosylated oligosaccharides are also available, for example, from Kyowa, Hakko, Kogyo of Japan.
    [0052] According to the invention, the sialylated oligosaccharide can be selected from the group comprising 3'-sialylactose and 6'-sialylactose. Preferably, the sialylated oligosaccharide comprises both 3'-sialylactose and 6'-sialylactose. In that embodiment, the ratio of 3'-sialylactose to 6'-sialylactose is preferably between 5: 1 and 1: 2.
    [0053] The 3 'and 6' forms of sialylactose can be obtained by adding to the composition a natural source such as milk of animal origin or can be isolated by chromatography or filtration technology from such natural source. Alternatively, they can be produced by biotechnological means using sialyltransferases or sialidases, specific neuraminidases by enzyme-based fermentation technology (recombinant or natural enzymes), by chemical synthesis or microbial fermentation technology. In the latter case, microbes can express their natural enzymes and substrates or they can be manipulated to produce the respective substrates and enzymes. Isolated microbial cultures and / or mixed cultures can be used. The formation of sialyl-oligosaccharide can be initiated by the accepting substrates starting from any degree of polymerization (DP), from DP = 1 onwards. Alternatively, sialylactoses can be produced by chemical synthesis from lactose and N'-acetylneuraminic acid (sialic acid). Sialylactoses are also commercially available, for example, from Kyowa Hakko Kogyo of Japan.
    [0054] N-acetylated oligosaccharides can be obtained by adding to the composition a natural source such as milk of animal origin. Alternatively, they can be prepared by the action of glycosaminidase and / or galactosaminidase on N-acetyl-glucose and / or N-acetyl-galactose. Likewise, N-acetyl-galactosyl transferases and / or N-acetyl-glycosyl-transferases can be used for this purpose. N-acetylated oligosaccharides can also be produced through the use of fermentation technology using the respective enzymes (recombinant or natural) and / or microbial fermentation. In the latter case, microbes can express their natural enzymes and substrates or they can be manipulated to produce their respective substrates and enzymes. Isolated microbial cultures and / or mixed cultures can be used. The formation of N-acetylated oligosaccharide can be initiated by the acceptor substrates starting from any degree of polymerization (DP), from DP = 1 onwards. Another option is the chemical conversion of keto-hexoses (eg, fructose) free or attached to an oligosaccharide (eg, lactulose) into N-acetylhexosamine or an oligosaccharide containing N-acetylhexosamine as described in Wrodnigg, TM ; Stutz, A.E. (1999) Angew. Chem. Int. Ed. 38: 827-828.
    [0055] LNnT and LNT can be synthesized by the enzymatic transfer of saccharide units from donor moieties to acceptor moieties using glycosyl hydrolases and / or glycosyl transferases as described, for example, in US Patent No. 5,288,637 and WO 96/10086. Alternatively, LNnT can be prepared by the chemical conversion of ketohexoses (eg, fructose) free or attached to an oligosaccharide (eg, lactulose) to N-acetylhexosamine or an oligosaccharide containing N-acetylhexosamine as described in Wrodnigg , TM; Stutz, A.E. (1999) Angew. Chem. Int. Ed. 38: 827-828. N-acetyl-lactosamine produced in this way can then be transferred to lactose as the acceptor portion.
    [0056] Preferably, the N-acetylated oligosaccharide is selected from the group comprising lacto-N-neotetraose (or LNnT) or lacto-N-tetraose (or LNT). Preferably LNnT and / or LNT are included in the group of sialylated oligosaccharides in the oligosaccharide mixture during their manufacture.
    [0057] The probiotic bacterial strain present in the composition of the invention can be selected from any strain that satisfies the definition of a probiotic and has an acceptable life span for the composition in which it will be incorporated. For example, if the composition is incorporated in an infant formula, the infant formula must remain stable and effective for up to 12 months. The probiotic bacterial strain is preferably a lactobacillus or a bifidobacterium.
    [0058] Examples of preferred Bifidobacterium species include Bifidobacterium lactis, Bifidobacterium longum, Bifidobacterium breve and Bifidobacterium infantil. Particularly preferred strains are Bifidobacterium lactis CNCM 1-3446 sold, inter alia, by the Christian Hansen company in Denmark under the trade name Bb12, Bifidobacterium longum ATCC BAA-999 sold by Morinaga Milk Industry Co. Ltd. of Japan under the trade name BB536, the Bifidobacterium brevis strain sold by Danisco under the trade name Bb-03, the Bifidobacterium brevis strain sold by Morinaga under the trade name M-16V, the Bifidobacterium pediatric strain sold by Procter & Gamble Co. under the trade name of Bifantis and a strain of Bifidobacterium breve sold by Institut Roseli (Lallemand) under the trade name R0070.
    [0059] Examples of Lactobacillus species Lactobacillus rhamnosus, Lactobacillus paracasei and Lactobacillus reuteri. Particularly preferred strains are Lactobacillus rhamnosusATCC 53103, Lactobacillus rhamnosus CGMCC 1.3724, Lactobacillus reuteri DSM 17938, and Lactobacillus paracasei CNCM 1-2116. Even more preferably the probiotic is Lactobacillus reuteri DSM 17938.
    [0060] Lactobacillus reuteri DSM 17938 is sold by BioGaia A.B. under the trade name Reuteri.
    [0061] According to the invention, the probiotic is selected from the probiotic bacterial strains, preferably the probiotic is a lactobacillus or a bifidobacterium, more preferably the probiotic is Bifidobacterium lactis or Lactobacillus reuteri.
    [0062] The probiotic can be present in the composition in a wide range of percentages for the probiotic to release the described effect. However, preferably, the probiotic is present in the composition in an amount equivalent to between 10e2 to 10e12 cfu (= colony-forming unit) of a probiotic bacterial strain, more preferably between 10e6 and 10e9 cfu, for each gram of the composition. This expression includes the possibilities that the bacteria are alive, inactivated or dead or even present as fragments such as DNA, cell wall materials, intracellular materials or metabolites of bacteria. In other words, the amount of bacteria that the composition contains is expressed in terms of the colony-forming ability of that amount of bacteria if all the bacteria were alive, regardless of whether they are, in fact, alive, inactivated or dead, fragmented or a mixture of any or all of these states.
    [0063] The composition contains at least one LC-PUFA, which is usually an n-3 or n-6 LC-PUFA. The n-3 LC-PUFA can be a n-3 C20 or C22 fatty acid. The n-3 LC-PUFA C20 or C22 is preferably present in an amount of at least 0.1% by weight of all fatty acids in the composition. Preferably, n-3 LC-PUFA is docosahexaenoic acid (DHA, C22: 6, n-3). The n-6 LC-PUFA can be a C20 or C22 fatty acid. The n-6 LC-PUFA C20 or C22 is preferably present in an amount of at least 0.1% by weight of all fatty acids in the composition. Preferably n-6 LC-PUFA is arachidonic acid (ARA, C20: 4, n-6). The source of LC-PUFA can be, for example, egg lipids, fungus oil, low EPA fish oil or seaweed oil. The LC-PUFA of the composition of the invention can be supplied in small amounts of oils containing high amounts of arachidonic acid and docosahexaenoic acid such as fish oils or microbial oils.
    [0064] The composition according to the invention is preferably a nutritional composition, more preferably a synthetic nutritional composition. In this case, it can be a formula for premature baby, a human milk fortifier, an initial infant formula, a transition formula, a baby food formula, a baby cereal formula, a growth milk, a medical food product for clinical nutrition or a supplement, typically to be used while in the hospital or after the hospital pantry. A supplement can be for a premature baby or a child or an adult. Said composition is preferably a product for feeding a premature baby such as a formula for a premature child, a human milk fortifier or a supplement for a premature child. According to one embodiment, the composition is preferably a formula for premature infants, a human milk fortifier or a supplement. The composition according to the invention can also be a product for children and adults such as a yogurt or medical food, as well as pet food.
    [0065] According to a particularly preferred embodiment, the composition according to the invention is for use in infants and young children who were born premature or with LBW or who experienced IUGR or who suffered from growth failure due to illness and / or bad nutrition, preferably premature babies.
    [0066] The composition according to the invention can be for use before and / or during and / or after the weaning period.
    [0067] The invention also includes the use of a composition according to the invention, as a synthetic nutritional agent, for use in brain growth and / or cognitive and / or psychomotor development.
    [0068] All the uses set out above are particularly intended for babies and young children, preferably babies, in the case of humans. But these uses are also intended for young animals. The compositions or uses of the present invention are particularly suitable for babies and children, preferably babies, who were born premature or with LBW or experienced IUGR or who suffered growth retardation due to illness and / or malnutrition, particularly during childhood.
    [0069] Without wishing to be bound by theory, the inventors believe that the effectiveness of the combination of oligosaccharide mixture in the composition described above in brain growth and / or cognitive and / or psychomotor development may be the result of the synergistic combination of the modulating effects of immunity triggered by the probiotic bacterial strain and the LC-PUFA through its stimulation with the specific oligosaccharide mixture.
    [0070] The oligosaccharide mixture, LC-PUFA and the probiotic bacterial strain can be administered in the same composition or can be administered sequentially.
    [0071] If the group of premature babies and children with LBW is to be reached, the composition is preferably a nutritional composition, for example, consumed in liquid form. It can be a nutritionally complete formula such as a baby formula (premature), a supplement, a human milk fortifier, a transition formula or a growth milk. Alternatively, for the group of puppies of mammals, the composition may be a puppy food.
    [0072] The composition according to the invention can also contain a source of protein. The type of protein is not considered to be critical to the present invention as long as the minimum requirements for the content of essential amino acids are met and satisfactory growth is guaranteed. Therefore, sources of whey-based protein, casein and their mixtures can be used as well as sources of soy-based protein. As far as whey proteins are of interest, the protein source can be based on acidic whey or sweet whey or mixtures thereof and can include alpha-lactalbumin and beta-lactoglobulin in any desired proportions. Proteins can be partially hydrolyzed in order to enhance oral tolerance to allergens, especially food allergens. In this case, the composition is a hypoallergenic composition.
    [0073] The composition according to the present invention can also contain a carbohydrate source in addition to the oligosaccharide mixture. This is particularly preferable in the case where the composition of the invention is a baby formula. In that case, any carbohydrate source conventionally found in baby formulas such as lactose, sucrose, maltodextrin, starch and mixtures thereof can be used although the preferred carbohydrate source is lactose. In any case, the oligosaccharide mixture is preferably a single source of prebiotic in the composition according to the invention.
    [0074] The composition according to the present invention can also contain a source of lipids in addition to LC-PUFA. This is particularly relevant if the nutritional composition of the invention is a baby formula. In that case, the source of lipids can be any lipid or fat that is suitable for use in infant formulas. Preferred fat sources include palm oil, high oleic sunflower oil and high oleic safflower oil. Linoleic and α-linolenic fatty acids can also be added. In the composition, the fat source (including LC-PUFA such as ARA and / or DHA) preferably has a ratio of n-6 to n-3 fatty acids from about 1: 2 to about 10: 1, preferably about 3: 1 to about 8: 1.
    [0075] The composition of the invention may also contain all vitamins and minerals understood to be essential in the daily diet and in nutritionally significant amounts. Minimum requirements have already been established for certain vitamins and minerals. Examples of minerals, vitamins and other nutrients optionally present in the composition of the invention include vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin E, vitamin K, vitamin C, vitamin D, folic acid, inositol, niacin, biotin , pantothenic acid, choline, calcium, phosphorus, iodine, iron, magnesium, copper, zinc, manganese, chlorine, potassium, sodium, selenium, chromium, molybdenum, taurine, and L-carnitine. Minerals are usually added in the form of salt. The presence and amounts of specific minerals and other vitamins will vary depending on the intended population. If necessary, the composition of the invention can contain emulsifiers and stabilizers such as soy, lecithin, esters of mono citric acid and diglycerides and the like.
    [0076] The composition of the invention can also contain other substances that can have a beneficial effect such as lactoferrin, nucleotides, nucleosides, gangliosides, polyamines and the like.
    [0077] The preparation of the composition according to the invention will now be described by way of example.
    [0078] The formula can be prepared in any suitable way. For example, it can be prepared by mixing a protein source, a carbohydrate source (other than the oligosaccharide mixture) and a fat source including LC-PUFA in appropriate proportions. If used, emulsifiers can be included at this point. Vitamins and minerals can be added at this point, but are usually added later to prevent thermal degradation. Any lipolytic vitamins, emulsifiers and the like can be dissolved in the fat source before mixing. The water, preferably the water that has been subjected to reverse osmosis, can then be mixed into a liquid mixture form. The water temperature is conveniently in the range of about 50 ° C to about 80 ° C to help disperse the ingredients. Commercially available liquefying agents can be used to form the liquid mixture. The oligosaccharide mixture can be added at this stage if the final product is to be in liquid form. If the final product is to be a powder, oligosaccharides can also be added at this stage if desired. The liquid mixture is then homogenized, for example, in two stages.
    [0079] The liquid mixture can then be thermally treated to reduce bacterial loads, by rapidly heating the liquid mixture to a temperature in the range between about 80 ° C and about 150 ° C for a duration between about 5 seconds and about 5 minutes, for example. This can be done by means of a steam injection, an autoclave or a heat exchanger, for example, a heat exchange plate.
    [0080] Then, the liquid mixture can be cooled to between about 60 ° C and about 85 ° C, for example, by rapid cooling. The liquid mixture can then be homogenized, for example, in two stages between about 10 MPa and about 30 MPa in the first stage and between about 2 MPa and about 10 MPa in the second stage. The homogenized mixture can then be cooled to add any heat-sensitive components, such as vitamins and minerals. The pH and solids content of the homogenized mixture are conveniently adjusted at this point.
    [0081] The homogenized mixture is transferred to a suitable drying apparatus such as a spray dryer or lyophilizer and converted into powder. The powder must have a moisture content of less than about 5% by weight. The oligosaccharide mixture can be added at this stage by dry mixing together with the strains of probiotic bacteria or mixing it in a syrup to form crystals, along with the probiotic bacterial strains and spray drying (or lyophilizing).
    [0082] If the liquid composition is preferred, the homogenized mixture can be sterilized and then aseptically filled in suitable containers or it can be filled first in the containers and then sterilized.
    [0083] In another embodiment, the composition of the invention can be a supplement in an amount sufficient to obtain the desired effect on an individual. This form of administration is generally more suitable for premature babies or those with LBW or IUGR, older children and adults.
    [0084] The amount of oligosaccharides, LC-PUFA and probiotic bacterial strain to be included in the supplement will be selected according to the way in which the supplement will be administered.
    [0085] The supplement can be, for example, in the form of powder, tablets, capsules, lozenges or a liquid. The supplement may additionally contain protective hydrocolloids (such as gums, proteins, modified starches), binders, film forming agents, encapsulating agents / materials, wall / shell agents, matrix compounds, coatings, emulsifiers, surface active agents, solubilizing agents (oils, fats, waxes, lecithins, etc.), absorbents, vehicles, fillers, co-compounds, dispersing agents, wetting agents, processing aids (solvents), flow agents, flavor masking agents, agents weighting, gelling agents and gel forming agents. The supplement may also contain conventional pharmaceutical additives and adjuvants, excipients and diluents including, but not limited to, water, gelatin of any origin, vegetable gums, lignin sulfonate, talc, sugars, starch, gum arabic, vegetable oils, polyalkylene glycols, agents flavoring, preservatives, stabilizers, emulsifying agents, buffers, lubricants, dyes, wetting agents, fillers and the like.
    [0086] The supplement can be added in a product acceptable to the consumer (which is a human or animal), such as a vehicle or ingestible support, respectively. Examples of such vehicles or carriers are a pharmaceutical composition or a food or animal feed. Non-limiting examples for such compositions are milk, yogurt, curd, cheese, fermented milk, fermented milk-based products, fermented cereal-based products, milk-based powders, human milk, formula for premature infants, infant formula, oral supplement and tube feeding.
    [0087] In addition, the supplement may contain an organic or inorganic carrier material suitable for enteral or parenteral administration as well as vitamins, mineral trace elements and other micronutrients in accordance with the recommendations of government agencies such as USRDA.
    [0088] The advantages, nature and several additional aspects of the invention will appear more fully after consideration of the illustrative experiment which will now be described in detail together with the attached figures. In the figures:
    [0089] FIG. 1 is a diagram to illustrate the experiment protocol.
    [0090] FIG. 2 is a bar graph showing the results of the experiments, in terms of brain weight (g) on the postnatal day (= PND) 35.
    [0091] FIG. 3 is a bar graph showing the results of the experiments, in terms of brain weight (g) on the postnatal day (= PND) 26. EXAMPLE
    [0092] The experiments were carried out with regard to the effect of supplementing a mixture of oligosaccharides, which is a mixture of oligosaccharides from cow's milk (CMOS) enriched with galacto-oligosaccharides (permeated with demineralized whey, without lactose or DDWP) , LC-PUFA (arachidonic acid - ARA - and docosahexaenoic acid - DHA -) and Bifidobacterium lactis (BL), and optionally 2'-fucosylactose (FL) or the combination of 2'-fucosylactose (FL) and N- neotetraose (LNNT) on puppies. 1. METHODOLOGY EXPERIMENTAL PROTOCOL
    [0093] The experiments were carried out with the approval of the Swiss Animal Protection Law (severity level 1) and were approved by the Office Vétèrinaire Cantonal (Lausanne, Switzerland, authorization n ° 2028). Virgin male and female breeding Long-Evans Hooded rats were purchased from Janvier (France), arriving at the animal housing facility two weeks prior to breeding.
    [0094] The pregnant females received food (Kliba 3437) and water ad libitum, were housed under constant temperature and humidity and maintained in a 12:12 dark: clear cycle. Accommodation conditions were maintained throughout the duration of the protocol. On the postnatal day (= PND) 2 after birth (B), the calves were removed from their maternity cages and the sex of the chicks was determined. Standardized litters of 8 male puppies were assigned for adoption, after randomizing by body weight. Breeding stock and chicks were assigned to one of two breeding conditions: 1) groups with maternal deprivation, exposed to a period of 180 min of daily maternal separation from PND2 to PND14 (MS) or 2) unhandled controls (NS).
    [0095] MS puppies were weaned (W) in the PND15. They were randomized by weight and care and distributed in groups of 16 animals that were fed a controlled diet (modified AIN 93G, group MS-cont) or a similar diet adapted to contain LC-PUFA, Bifidobacterium lactis CNCM I-3446 (BL ) and oligosaccharides (DDWP). The MS animals (MS-Cont group) were housed in groups of 8 offspring until PND21 to reduce the stress burden of early weaning and then individually sheltered until the end of the experiment. NS group animals were weaned with a controlled diet (NS-Cont group) in PND21 and individually hosted until the end of the experiment.
    [0096] The animals were sacrificed (t) in PND26 or PND26 for exhaustive bleeding under anesthesia with isofluorane. The weight of the brain was recorded: the brain was collected after opening the skull and weighed on a scale. 2. TREATMENT AND DIETS
    [0097] Below, functional ingredients used for experimental gavage and the composition of the diet comprised by the ingredient DDWP in 98.8% of the dry matter, whose composition is detailed in Table 1 below. Table 1. Composition of the DDWP mixture

    [0098] DDWP is typically obtained according to the descriptions of W02007 / 101675 or WO 2007/090894 and generally contains a mixture of about 30% by weight of GalNAcα1,3Galβ1,4Glc and Galβ1,6GalNAcα1,3Galβ1,4Glc; 50% by weight of Galβ1, 6Galβ1,4Glc and Galβ1,3Galβ1,4Glc; 20% by weight of NeuAcα2,3Galβ1,4Glc and NeuAcα2,6Galβ1,4Glc.
    [0099] The animals were fed from weaning until the end of the experiment with nutritionally adapted semi-synthetic diets (modified AIN 93G) whose composition is shown in Tables 2, 3 and 4. TABLE 2: Diet recipes (per 100 g of diet)


    [00100] 1DDWP (demineralized, delactated whey permeate); 2LNNT = Lacto-N-neo Tetraose; 3FL = 2-Fucosyl-Lactose; 4B. lactis = BL = B. lactis CNCM I-3446, spray dried. Table 3: Fat mix (g / 100 g of fat mix)
    Table 4: Nutritional composition of diets

    [00101] 5 predicted from the nutritional composition (1 g of digestible carbohydrate = 4 Kcal; 1 g of oligosaccharide = 2 Kcal; 1 g of protein = 4 Kcal; 1 g of fat = 9 Kcal); 6analyzed by Kjeldhal; 7 analyzed by Soxhlet; 8AA = arachidonic acid, 9DHA = docosahexaenoic acid; 10analyzed by standardized culture method and PCR; NA = Not analyzed; ND = below the detection limits (less than 1.00E + 03).
    [00102] The fatty acid profile of the four diets was balanced to provide a similar proportion of n-6 / n-3 and a similar proportion of saturated, monounsaturated and polyunsaturated fatty acids. Therefore, the fatty acid composition of the four diets was approximately the same in terms of the fatty acid profile.
    [00103] The animals were sacrificed on the postnatal day, PND, 26 or 35. 3. WEIGHT OF THE BRAIN
    [00104] From the results of Figures 2 and 3, it appears that the first PUFA-BL-DDWP composition, according to the invention, shows a better brain weight than the brain weights obtained by the MS- control composition CONT.
    [00105] Additionally, the third composition according to the invention PUFA-BL-DDWP-FL-LNNT showed a higher brain weight than the PUFA-BL-DDWP composition in PND 26. In reality, it appears that DDF-BL-PUFA was efficient in PND26, longer supplementation in PND35 showed a more significant effect. DDWP-BL-PUFA-FL-LNNT showed a significant effect already in the PND26.
    [00106] All compositions according to the invention proved to result in a heavier brain than that of the MS-CONT group. This is the real advantage of the compositions according to the invention.
    权利要求:
    Claims (9)
    [0001]
    1. Composition for use in brain growth and / or cognitive and / or psychomotor development, characterized by the fact that it comprises: at least 0.1% by weight of a long-chain polyunsaturated fatty acid (LC-PUFA), of 10e2 to 10e12 cfu (colony forming unit) of at least one probiotic, and from 0.5 to 70% by weight of a mixture of oligosaccharides, said mixture containing at least one N-acetylated oligosaccharide, at least one sialylated oligosaccharide and at least one neutral oligosaccharide; the N-acetylated oligosaccharide being selected from the group comprising lacto-N-neotetraose (or LNnT) and lacto-N-tetraose (or LNT); and the neutral oligosaccharide being 2'-fucosylactose (or FL).
    [0002]
    2. Composition, according to claim 1, characterized by the fact that, in addition to FL, the neutral oligosaccharide is selected from fructo-oligosaccharides (FOS) and / or galactooligosaccharides (GOS), preferably GOS.
    [0003]
    3. Composition according to claim 1 or 2, characterized by the fact that, in addition to LNnT, LNT and FL, said oligosaccharide mixture contains at least one N-acetylated oligosaccharide selected from the group comprising GalNAccrt, 3Galβ1,4Glc (= 3'GalNAc-lac = N-acetyl-galactosaminyl-lactose), Galβ1, 4GlcNAcβ1,3Galβ1,4Glc, Galβ1, 3GlcNAcβ1,3Galβ1, 4Glc and Galβ1,6GalNAcα1,3Galβ1,4Glc (= 6'Gal-3GAL galactosil-N-acetyl-galactosaminyl-lactose), Galβ1, 4GlcNAcβ1,3Galβ1,4Glc (lacto-N-neotetraose or LNnT) and Galβ1, 3GlcNAcβ1,3Galβ1,4Glc (lacto-N-tetraose or LNT), at least one oligalate selected from the group comprising NeuAcα2,3Galβ1,4Glc (= 3-sialylactose) and NeuAcα2,6Galβ1,4Glc (= 6'-sialylactose), and at least one neutral oligosaccharide selected from the group comprising Galβ1,6Gal (= β1,6- digalactoside); Galβ1,6Galβ1,4Glc (= 6'Gal-lac); Galβ1,6Galβ1,6Glc; Galβ1, 3Galβ1,3Glc; Galβ1, 3Galβ1,4Glc (= 3'Gal-lac); Galβ1, 6Galβ1,6Galβ1,4Glc (= 6 ’, 6-diGal-lac); Galβ1, 6Galβ1,3Galβ1,4Glc (= 6 ', 3-diGal-lac); Galβ1,3Galβ1,6Galβ1,4Glc (= 3 ’, 6-diGal-lac); Galβ1, 3Galβ1,3Galβ1,4Glc (= 3 ', 3-diGal-lac); Galβ1, 4Galβ1,4Glc (= 4'Gal-lac) and Galβ1, 4Galβ1,4Galβ1,4Glc (= 4 ', 4-diGal-lac); and Fucαl, 2Galβ1,4Glc (= 2 'fucosylactose or FL).
    [0004]
    Composition according to any one of claims 1 to 3, characterized in that the oligosaccharide mixture comprises: 0.25 to 20% by weight, preferably 0.3 to 10% by weight, more preferably 0, 3 to 5% by weight, and even more preferably, 0.5% by weight, with respect to the total weight of the oligosaccharide mixture, of at least one N-acetylated oligosaccharide, preferably 0.5 to 30% by weight 0.75 to 15% by weight, more preferably 0.75 to 10% by weight, and even more preferably 1% by weight, with respect to the total weight of the oligosaccharide mixture, of at least one sialylated oligosaccharide, and 50 to 99.3% by weight, preferably 20 to 80% by weight, more preferably 10 to 50% by weight, and even more preferably 50% by weight, with respect to the total weight of the oligosaccharide mixture, according to at least one neutral oligosaccharide.
    [0005]
    Composition according to any one of claims 1 to 4, characterized in that the mixture of oligosaccharides comprises from 1 to 20%, even more preferably, 2 to 5%, with respect to the total weight of the composition.
    [0006]
    6. Composition according to any one of claims 1 to 5, characterized by the fact that LC-PUFA is selected from arachidonic acid (ARA) and docosahexaenoic acid (DHA), preferably LC-PUFA is a mixture of ARA and DHA.
    [0007]
    7. Composition according to any one of claims 1 to 6, characterized in that the probiotic is selected from probiotic bacterial strains, preferably the probiotic is a lactobacillus or a bifidobacterium, more preferably, the probiotic is Bifidobacterium lactis or Lactobacillus reuteri .
    [0008]
    Composition according to any one of claims 1 to 7, characterized in that the sialylated oligosaccharide is selected from the group comprising 3'-sialylactose and 6'-sialylactose, and preferably the sialylated oligosaccharide comprises both 3 ' -sialylactose and 6'-sialylactose, the ratio between 3'-sialylactose and 6'-sialylactose being preferably in the range between 5: 1 and 1: 2.
    [0009]
    9. Composition according to any one of claims 1 to 8, characterized by the fact that it is a formula for premature babies, a human milk fortifier, an initial infant formula, a transitional infant formula, a baby food formula , a formula of infant cereal, a growth milk, a medical food product for clinical nutrition or a supplement and preferably, said composition is a formula for premature babies, a human milk fortifier or a supplement.
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    同族专利:
    公开号 | 公开日
    AU2012325060A1|2014-03-13|
    PL2775852T3|2017-02-28|
    WO2013057049A1|2013-04-25|
    RU2607458C2|2017-01-10|
    EP2775852B1|2016-08-17|
    BR112014008944A2|2017-05-02|
    AU2012325060B2|2015-11-19|
    US20140271562A1|2014-09-18|
    EP2775852A1|2014-09-17|
    CN103889238A|2014-06-25|
    CL2014000759A1|2014-08-22|
    ZA201403591B|2016-01-27|
    IN2014DN01468A|2015-05-22|
    MX2014004716A|2015-02-05|
    ES2601891T3|2017-02-16|
    MX350435B|2017-09-06|
    EP3095331A1|2016-11-23|
    CN103889238B|2017-10-13|
    PT2775852T|2016-11-08|
    RU2014119844A|2015-11-27|
    MY170185A|2019-07-09|
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    法律状态:
    2018-01-16| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2018-03-27| B15K| Others concerning applications: alteration of classification|Ipc: A61K 35/741 (2015.01), A23L 33/105 (2016.01), A23L |
    2018-03-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2018-08-28| B07G| Grant request does not fulfill article 229-c lpi (prior consent of anvisa) [chapter 7.7 patent gazette]|Free format text: NOTIFICACAO DE DEVOLUCAO DO PEDIDO POR NAO SE ENQUADRAR NO ART. 229-C DA LPI. |
    2019-07-16| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|
    2019-07-16| B15K| Others concerning applications: alteration of classification|Free format text: AS CLASSIFICACOES ANTERIORES ERAM: A61K 35/741 , A23L 33/105 , A23L 33/12 , A23L 33/135 , A23L 33/21 , A23L 33/00 , A61K 31/202 , A61K 31/702 , A61K 35/744 , A61K 35/00 Ipc: A23L 33/00 (2016.01), A23L 33/12 (2016.01), A23L 3 |
    2019-10-15| B25A| Requested transfer of rights approved|Owner name: SOCIETE DES PRODUITS NESTLE S.A. (CH) |
    2019-12-03| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|
    2020-04-07| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2020-09-15| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 12/10/2012, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    EP11185600|2011-10-18|
    EP11185600.1|2011-10-18|
    PCT/EP2012/070281|WO2013057049A1|2011-10-18|2012-10-12|Composition for use in brain growth and/or cognitive and/or psychomotor development|
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