TW201316910A - Composition for use in brain growth and/or cognitive and/or psychomotor development - Google Patents

Abstract

The invention discloses 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 infants, notably preterm infants.

Description

Composition for brain growth and/or cognitive and/or psychomotor development

The present invention relates to compositions for brain growth and/or cognitive and/or psychomotor development. This composition is for mammals, preferably humans, and better babies.

During development, especially in the first few years of life, children show interesting neurodevelopmental patterns and high neuroplasticity. The relationship between brain development and cognitive development is extremely complex and has evolved into a research field since the 1990s.

Some new developments are intended to demonstrate the relationship between brain growth and cognitive development in infants, especially premature babies or very low gestational age newborns ( ELGAN ) ( J. Pediatr. 2009; 155:344-9 ).

Therefore, there is great interest in promoting the brain growth of especially premature babies to help their cognitive and/or mental development.

Long-chain polyunsaturated fatty acids have been proposed to promote cognitive and psychological development, and many clinical trials have investigated this hypothesis. However, recent integration analysis combining these data showed that supplementation had no significant effect on neurodevelopment (Schulzke SM, Patole SK, Simmer K, Longchain polyunsaturated fatty acid supplementation in preterm infants (Review) The Cochrane Library 2011, issue 2).

It is also possible to improve the cognitive development of premature babies by significantly increasing protein and energy intake (I Brandt, EJSticker and MJLentze, catch-up growth of head circumference of very low birth weight, small for gestational age preterm infants and mental development to adulthood , J Pediatr 2003; 142: 463-8). However, the large enteral feeding volume and/or high protein/energy density of the feeder can induce tolerance to feeding. In addition, high protein intake resulting in increased urea production may increase the risk of renal insufficiency and metabolic acidosis in premature infants. In addition, high protein/energy intake during infancy is associated with long-term changes in metabolic health (obesity, type 2 diabetes, and increased risk of cardiovascular disease) (KK ONG & RJF LOOS, Rapid infancy weight gain and subsequent obesity: Systematic reviews and Hopeful suggestions Acta P Diatrica, 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).

There is a need in the industry for nutritional compositions for the development of brain and/or cognitive and/or mental movements of infants and young children (preferred infants), which are premature or have low birth weight (LBW). Or undergoing intrauterine growth retardation (IUGR), or suffering from growth retardation due to malnutrition (such as poor intrauterine nutrition) and/or disease.

More generally, the industry needs to perform this nutritional intervention in young mammals, particularly infants and children, preferably infants and young pets.

The inventors have surprisingly discovered that a combination of a particular oligosaccharide mixture with at least one long chain polyunsaturated fatty acid (LC-PUFA) and at least one probiotic is administered. In particular, it can be effectively used for brain growth and/or cognitive and/or mental action development.

Accordingly, the present invention provides a composition comprising at least one LC-PUFA, at least one probiotic, and an oligosaccharide mixture, the mixture comprising at least one N-acetylated oligosaccharide, at least one sialylated oligosaccharide, and at least one Sexual oligosaccharides, which are used for brain growth and/or cognitive and/or psychomotor development.

The composition of the invention is preferably a nutritional composition.

The LC-PUFA is preferably selected from the group consisting of arachidonic acid (ARA) and docosahexaenoic acid (DHA), and more preferably, the LC-PUFA is a mixture of ARA and DHA.

The probiotic is preferably selected from a probiotic strain, more preferably, a probiotic strain lactobacillus or bifidobacterium . In a preferred embodiment, the probiotic strains are Bifidobacterium lactis and Lactobacillus reuteri .

The neutral oligosaccharide is preferably selected from the group consisting of fructooligosaccharides (FOS) and galactooligosaccharides (GOS), preferably GOS.

In one embodiment, the oligosaccharide mixture may be derived from animal milk, such as one or more of cow's milk, goat's milk, sheep's milk, or buffalo milk. For example, it is obtained by milk fractionation and further enzymatic treatment.

In a second embodiment, the oligosaccharide mixture can be prepared using enzymatic, chemical enzymatic and/or chemical means.

In a third embodiment, the oligosaccharide mixture can be prepared using yeast and/or bacterial fermentation techniques. For example, yeast and/or bacterial cells that exhibit suitable enzymes (eg, glycosidases and/or glycosyltransferases) can be used for this purpose either after genetic modification or without genetic modification.

The compositions of the present invention are preferably used in infants that are premature or have low birth weight (LBW) or undergo uterine growth retardation (IUGR) and/or are subject to growth delay due to disease and/or malnutrition.

The following terms as used herein have the following meanings.

The term "child" means a human being between the stage of birth and the stage of autism. Adults are older than children.

The term "infant" means a child who is within 12 months of age.

The term "preterm infant or premature infant" means an infant born less than 37 weeks of gestational age.

The term "low birth weight infant" means an infant having a live birth weight of less than 2,500 g.

The term "young child" means a child between the ages of 1 and 3.

The term "infant formula" means a food intended for the specific nutritional use of an infant during the period from 4 months to 6 months prior to life and which satisfies the nutritional requirements of such person (May 14, 1991 regarding infant formula and larger) European Commission Directive of the follow-on formula 91/321/EEC Article 1.2).

The term "premature infant formula" means an infant formula intended for use in a premature infant.

The term "human milk fortifier" means a supplement for calorie, protein, minerals and vitamins in breast milk that is fed to a premature infant or a baby with a low birth weight.

The term "larger infant formula" means intended for use over 4 months of age. A food for a particular nutritional use of an infant and which constitutes a major liquid element in the diet in which such persons are increasingly diversified.

The term "starter infant formula" means a food intended for a particular nutritional use of an infant during the first 4 months of life.

The term "child food" means a food intended for the specific nutritional use of an infant during the first year of life.

The term "baby cereal composition" means a food intended for the particular nutritional use of an infant during the first year of life.

The term "growth milk" means a milk-based beverage that is adapted to the specific nutritional needs of young children.

The term "weaning period" means the period of time during which a portion of a baby's diet partially or completely replaces breast milk or an infant formula.

The term "brain growth and/or cognitive and/or mental action development" means supporting brain growth and/or cognitive and/or mental action development.

The term "nutritional composition" means a composition that is administered to an individual for nutrition. This nutritional composition is usually administered orally, transgastrically or intravenously, and it typically includes a source of lipid or fat and a source of protein.

The term "synthetic mixture" means a mixture obtained by chemical and/or biological means which is chemically identical to a mixture naturally occurring in mammalian milk.

The term "hypoallergenic composition" means a composition that is less likely to cause an allergic reaction.

The term "probiotic" means a microbial cell preparation or a microbial cell component or a microbial cell metabolite having a beneficial effect on the health or wellness 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).

The term "oligosaccharide" means a carbohydrate having a degree of polymerization (DP) in the range of 2 to 20 (including 2 and 20), but excluding lactose.

The term "neutral oligosaccharide" means an oligosaccharide that is uncharged and does not have an N-acetinyl residue.

The term "sialylated oligosaccharide" means an oligosaccharide having a residue of a sialic acid (eg, N-ethyl thioneamine and/or N-hydroxyethyl thioglycolic acid).

The term "N-acetylated" oligosaccharide means an oligosaccharide having at least one hexose having an N-acetinyl residue.

All percentages are by weight unless otherwise indicated.

In one aspect, the invention provides a composition comprising at least one LC-PUFA, at least one probiotic, and a mixture of oligosaccharides, the mixture comprising at least one N-ethyl fluorenyl group selected from the group consisting of Oligosaccharides: GalNAcα1,3Galβ1,4Glc (=3'GalNAc-lac=N-acetamido-aminogalactosyl-lactose), Galβ1,6GalNAcα1,3Galβ1,4Glc(=6'Gal-3GalNAc-lac=half Lactosyl-N-ethinyl-aminogalactosyl-lactose, Galβ1,4GlcNAcβ1,3Galβ1,4Glc (milk-N-neotetraose or LNnT) and Galβ1,3GlcNAcβ1,3Galβ1 (milk-N-tetraose or LNT); at least one selected from the group consisting of sialylated oligosaccharides comprising: NeuAcα2, 3Galβ1, 4Glc (=3'-sialyl lactose) and NeuAcα2,6Galβ1,4Glc (=6'-sialyllactose) And at least one The group consisting of the following neutral oligosaccharides: 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-di Gal-lac), Galβ1,6Galβ1,3Galβ1,4Glc(=6',3 -Gal-lac), Galβ1,3Galβ1,6Galβ1,4Glc(=3',6-di-Gal-lac), Galβ1,3Galβ1,3Galβ1,4Glc(=3',3-di-Gal-lac), Galβ1,4Galβ1 , 4Glc (=4'Gal-lac) and Galβ1,4Galβ1,4Galβ1,4Glc (=4',4-di Gal-lac) and Fucα1,2Galβ1,4Glc (=2'fucosyllactose or FL), The composition is used for brain growth and/or cognitive and/or mental action development.

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, the mixture comprising: 0.25 wt% relative to the total weight of the oligosaccharide mixture At least one N-acetylated oligosaccharide to 20 wt%, preferably 0.3 wt% to 10 wt%, more preferably 0.3 wt% to 5 wt%, and even more preferably about 0.5 wt%, relative to the oligosaccharide At least one sialylated oligosaccharide of from 0.5 wt% to 30 wt%, preferably from 0.75 wt% to 15 wt%, more preferably from 0.75 wt% to 10 wt% and even more preferably from about 1 wt%, based on the total weight of the mixture, And ̇ in at least one of 50 wt% to 99.3 wt%, preferably 20 wt% to 80 wt%, more preferably 10 wt% to 50 wt%, and even more preferably about 50 wt%, relative to the total weight of the oligosaccharide mixture. Sexual oligosaccharides, which are used for brain growth and/or cognitive and/or psychomotor development.

According to a preferred embodiment, the oligosaccharide mixture is present in an amount of from 0.5% to 70%, more preferably from 1% to 20%, even more preferably from 2% to 5%, relative to the total weight of the composition.

The oligosaccharide compound is defined by its structure, wherein GalNAc is N-acetyl galactosamine, GlcNAc is N-acetyl glucosamine, Gal galactose, NeuAc N-ethyl thione, Glc Glucose and Fuc are fucose.

The oligosaccharide mixture of the compositions of the invention may be the sole source of oligosaccharides in the composition.

In the first embodiment, the neutral oligosaccharide is preferably selected from the group consisting of FOS and GOS, preferably GOS, such as those described above.

In the second embodiment (independent or not from the first embodiment), the neutral oligosaccharide is preferably 2'-fucosyllactose (FL). In this case, FL is preferably included in the population of neutral oligosaccharides in the oligosaccharide mixture during the manufacture of the oligosaccharide mixture.

Neutral oligosaccharides can be prepared as a mixture by purchasing and mixing the individual components. For example, synthetic galactooligosaccharides such as the following are commercially available under the trade names Vivinal® (from Friesland Campina, Netherlands) and Elix'or®: Galβ1,6Gal, Galβ1,6Galβ1,4Glc, Galβ1,6Galβ1,6Glc, Galβ1,3Galβ1, 3Glc, Galβ1, 3Galβ1, 4Glc, Galβ1, 6Galβ1, 6Galβ1, 4Glc, Galβ1, 6Galβ1, 3Galβ1, 4Glc, Galβ1, 3Galβ1, 6Galβ1, 4Glc, Galβ1, 3Galβ1, 3Galβ1, 4Glc, Galβ1, 4Galβ1, 4Glc and Galβ1,4Galβ1, 4Galβ1, 4Glc and mixtures thereof. Other oligosaccharide suppliers are Dextra Laboratories, Sigma- Aldrich Chemie GmbH and Kyowa Hakko Kogyo Ltd. Alternatively, specific glycosyltransferases and/or glycosidases (such as galactosyltransferase and/or fucosyltransferase and/or galactosidase and/or fucosidase) can be used to generate Galactose oligosaccharides and/or fucosylated oligosaccharides.

Fucosyl lactose is a fucosylated oligosaccharide (i.e., an oligosaccharide having a fucose residue). Fucosylated oligosaccharides can be isolated from natural sources (eg, animal milk) by chromatography or filtration techniques. Alternatively, it can be produced by biotechnological means using a specific fucosyltransferase and/or fucosidase via the use of enzyme-based fermentation techniques (recombinant or native enzymes) or microbial fermentation techniques. In the latter case, the microorganism can express its natural enzymes and substrates or can be engineered to produce individual receptors and enzymes. Single microbial cultures and/or mixed cultures can be used. Fucosylated oligosaccharide formation can be initiated by receptor acceptor, starting from any degree of polymerization (DP), starting from DP=1. Alternatively, fucosylated oligosaccharides can be produced by chemical synthesis from lactose and free fucose. Fucosylated oligosaccharides are also commercially available, for example, from Kyowa, Hakko, Kogyo, Japan.

According to the present invention, the sialylated oligosaccharide may be selected from the group consisting of 3'-sialyl lactose and 6'-sialyl lactose. Preferably, the sialylated oligosaccharide comprises both 3'-sialyl lactose and 6'-sialyl lactose. In this embodiment, the ratio between the 3'-sialyl lactose and the 6'-sialyl lactose is preferably in the range of between 5:1 and 1:2.

The 3'- and 6'-forms of sialic lactose can be obtained by addition to the composition from natural sources such as animal milk, or can be isolated from this natural source by chromatography or filtration techniques. Alternatively, it can be used by biotechnological methods using specific sialyltransferases or sialidases (neurases), by enzyme-based fermentation techniques. (recombinant or natural enzyme), produced by chemical synthesis or by microbial fermentation techniques. In the latter case, the microorganism can express its natural enzymes and substrates or can be engineered to produce individual receptors and enzymes. A single microbial culture or mixed culture can be used. Sialyl oligosaccharide formation can be initiated by receptor acceptor, starting from any degree of polymerization (DP), starting from DP=1. Alternatively, sialyllactose can be produced by chemical synthesis from lactose and free N'-ethylmercapto-neuraminic acid (sialic acid). Sialyl lactose is also commercially available, for example, from Kyowa Hakko Kogyo, Japan.

N-acetylated oligosaccharides can be obtained by adding a natural source such as animal milk to the composition. Alternatively, it can be prepared by the action of an aglycosidase and/or an aminogalactosidase on N-ethylidene-glucose and/or N-ethylmercaptogalactose. Likewise, N-ethinyl-galactosyltransferase and/or N-ethinyl-glycosyltransferase can be used for this purpose. N-acetylated oligosaccharides can also be produced by fermentation using individual enzymes (recombinant or natural) and/or microbial fermentation using fermentation techniques. In the latter case, the microorganism can express its natural enzymes and substrates or can be engineered to produce individual receptors and enzymes. A single microbial culture or mixed culture can be used. N-acetylated oligosaccharide formation can be initiated by receptor acceptor starting from any degree of polymerization starting from a degree of polymerization (DP)=1. Another option is the chemical conversion of oligosaccharides (such as lactulose) or ketohexoses (such as sugars) bound to the oligosaccharides to N-acetyl hexosamine or N-acetyl hexose hexoses containing oligosaccharides. Amines are described, for example, in Wrodnigg, TM; Stutz, AE (1999) Angew. Chem. Int. Ed. 38: 827-828.

LNnT and LNT can be synthesized by enzymatic transfer of a sugar unit from a donor moiety to a receptor moiety using a glycosyl hydrolase and/or a glycosyltransferase, such as, for example, U.S. Patent No. 5,288,637 and WO 96/10086. Alternatively, LNnT can be freed or bound to an oligosaccharide (e.g., lactone) as set forth in Wrodnigg, TM; Stutz, AE (1999) Angew. Chem. Int. Ed. 38: 827-828. The hexose saccharide (eg, fructose) of the sugar) is chemically converted to N-acetyl hexosamine or an oligosaccharide containing N-acetyl hexosamine. The N-ethinyl-lactosamine produced in this manner can then be transferred to the lactose as part of the receptor.

Preferably, the N-acetylated oligosaccharide is selected from the group consisting of milk-N-neotetraose (or LNnT) and milk-N-tetraose (or LNT). Preferably, LNnT and/or LNT are included in the sialylated oligosaccharide in the oligosaccharide mixture during the manufacture of the oligosaccharide mixture.

The probiotic strains present in the compositions of the present invention may be selected from any strain that meets the probiotic definition and has an acceptable shelf life for the composition to be incorporated therein. For example, if the composition is included in an infant formula, the infant formula is required to remain stable and effective for up to 12 months. The probiotic strain is preferably Lactobacillus or Lactobacillus bifidum.

Examples of preferred Bifidobacterium lactis include Lactobacillus lactis, Bifidobacterium longum , Bifidobacterium breve , and Bifidobacterium infantis , especially strains. Lactobacillus acidophilus CNCM I-3446 sold by Christian Hansen (Denmark) under the trade name Bb12, Lactobacillus longiflorum ATCC BAA-999 sold by Morinaga Milk Industry Co., Ltd. (Japan) under the trade name BB536, by Danisco Lactobacillus brevis strains sold under the trade name Bb-03, Lactobacillus brevis strains sold under the trade name M-16V by Morinaga, Lactobacillus bifidus strains sold under the trade name Bifantis by Procter & Gamble and A strain of Lactobacillus brevis that sold by Institut Rosell (Lallemand) under the trade name R0070.

Examples of preferred Lactobacillus are Lactobacillus rhamnosus , Lactobacillus paracasei and Lactobacillus reuteri. The preferred strains are Lactobacillus rhamnosus ATCC 53103, Lactobacillus rhamnosus CGMCC 1.3724, Lactobacillus reuteri DSM 17938 and Lactobacillus paracasei CNCM I-2116. Even more preferably, the probiotic strain is Lactobacillus reuteri DSM 17938.

Lactobacillus reuteri DSM 17938 is sold by BioGaia A.B under the trade name Reuteri.

According to the present invention, the probiotic strain is selected from the group of probiotic bacteria, and the probiotic is preferably Lactobacillus or Lactobacillus bifidum, and the probiotic is more preferably Lactobacillus lactis or Lactobacillus reuteri.

Probiotics can be present in the composition in a wide range of percentages, provided that the probiotics deliver the effect. Preferably, however, the probiotic strain is present in a combination of a probiotic strain equivalent to 10e2 cfu (=colony forming unit) to 10e12 cfu per gram of composition, more preferably between 10e6 cfu and 10e9 cfu. In. This expression includes the possibility that the bacteria are viable, inactive or dead or even present as fragments (eg DNA, cell wall material, intracellular material or bacterial metabolite). In other words, if all bacteria are alive (whether they are actually alive, inactivated or dead, fragmented, or a mixture of any or all of these states), the amount of bacteria contained in the composition Take The colony forming ability of this amount of bacteria is expressed.

The composition contains at least one LC-PUFA, which is typically an n-3 or n6 LC-PUFA. The n-3 LC-PUFA can be a C20 or C22 n-3 fatty acid. Preferably, the C20 or C22 n-3 LC-PUFA is present in an amount of at least 0.1 wt% 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 n-6 fatty acid. Preferably, the C20 or C22 n-6 LC-PUFA is present in an amount of at least 0.1 wt% 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 fat, fungal oil, low EPA fish oil or algae oil. The LC-PUFA of the composition of the present invention can be provided in a small amount of oil (e.g., fish oil or microbial oil) containing a large amount of pre-formed arachidonic acid and docosahexaenoic acid.

The composition of the present invention is preferably a nutritional composition, more preferably a synthetic nutritional composition. In this case, it may be a premature infant formula, a human milk fortifier, a neonatal formula, a larger infant formula, a toddler food formula, a baby cereal formula, a growing milk, a medical food for clinical nutrition, or usually during hospitalization. Supplements for use and/or intended to be used after discharge. Supplements can be used for premature babies or children or adults. Preferably, the composition is for use in preterm delivery of a product, such as a premature infant formula, a human milk fortifier or a premature infant supplement. According to an embodiment, the composition is preferably a premature infant formula, a human milk fortifier or a supplement. The composition of the invention may also be a product for children or adults (such as yogurt or medical food) as well as pet food.

According to a particularly preferred embodiment, the composition of the invention is for use in infants who have premature birth or who have LBW or who have experienced IUGR or have been delayed due to disease and/or malnutrition and Young children, preferably premature babies.

The compositions of the invention may be used before and/or during and/or after the weaning period.

The invention also encompasses the use of a composition of the invention as a synthetic nutrient for brain growth and/or cognitive and/or psychomotor development.

In the case of humans, all of the uses described above are particularly intended for use in infants and young children, preferably infants. However, such uses are also intended for younger pets. The compositions and uses of the present invention are particularly useful in infants and children (preferably infants) who are premature or have LBW or who experience IUGR or are particularly resistant to growth due to disease and/or malnutrition during infancy.

Without wishing to be bound by theory, the inventors believe that the combination of oligosaccharide mixtures in the above compositions in brain growth and/or cognitive and/or psychomotor development may be effected by probiotic strains and LC-PUFAs via The result of a synergistic combination of immunomodulator effects triggered by stimulation of a particular oligosaccharide mixture.

The oligosaccharide mixture, LC-PUFA and probiotic strain can be administered in the same composition or can be administered sequentially.

If it is desired to cope with the preterm and LBW infants, the composition is preferably a nutritional composition that is consumed, for example, in liquid form. It can be a nutritionally complete formula such as a (premature) infant formula, a supplement, a human milk fortifier, a larger infant formula or a growing milk. Alternatively, for young mammalian groups, the composition can be a pet food.

The compositions of the invention may also contain a source of protein. I believe that the type of protein is not important to the invention, provided that it is satisfied for the essential amine groups. The minimum requirements for acid and ensure satisfactory growth. Thus, protein sources based on whey, casein, and mixtures thereof, as well as soy-based protein sources can be used. In the case of whey proteins, the protein source may be based on acid whey or sweet whey or mixtures thereof and may include alpha-lactalbumin and beta-lactoglobulin in any desired ratio. The protein can eventually be partially hydrolyzed to enhance oral tolerance to allergens, especially food allergens. In this case, the composition is a hypoallergenic composition.

In addition to the oligosaccharide mixture, the compositions of the invention may also contain a source of carbohydrates. This is especially preferred in the case where the composition of the invention is an infant formula. In this case, although any carbohydrate source commonly found in infant formulas, such as lactose, sucrose, maltodextrin, starch, and mixtures thereof, may be used, the preferred carbohydrate source is lactose. In either case, the oligosaccharide mixture is preferably a single source of prebiotics in the compositions of the invention.

In addition to LC-PUFA, the compositions of the invention may also contain a source of lipids. This is especially suitable if the nutritional composition of the invention is an infant formula. In this case, the lipid source can be any lipid or fat suitable for use in an infant formula. Preferred fat sources include palmitoleic acid, high oleic sunflower oil, and high oleic safflower oil. The essential fatty acids linoleic acid and alpha-linolenic acid can also be added. In the composition, the fat source (including LC-PUFA, such as ARA and/or DHA) preferably has an n-6 to n of from about 1:2 to about 10:1, preferably from about 3:1 to about 8:1. -3 fatty acid ratio.

The compositions of the present invention may also contain all of the vitamins and minerals deemed necessary in the daily diet in a nutritionally significant amount. Minimum requirements for certain vitamins and minerals have been established. Minerals, dimensions, depending on the situation in the composition of the invention Examples of vitamins and other nutrients include vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin E, vitamin K, vitamin C, vitamin D, folic acid, inositol, nicotinic acid, biotin, pantothenic acid, gallbladder Alkali, 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 a salt. The presence and amount of specific minerals and other vitamins will vary depending on the intended population.

If desired, the compositions of the present invention may contain emulsifiers and stabilizers such as soy lecithin, citric acid esters of mono- and diglycerides, and the like.

The compositions of the present invention may also contain other substances which may have beneficial effects, such as lactoferrin, nucleotides, nucleosides, gangliosides, polyamines, and the like.

The preparation of the compositions of the invention will now be illustrated by way of example.

The formulation can be prepared in any suitable manner. For example, it can be prepared by blending a protein source, a carbohydrate source (as opposed to an oligosaccharide mixture), and a fat source (including LC-PUFA) in an appropriate ratio. If used, an emulsifier can be included at this time. Vitamins and minerals can be added at this time, but are usually added later to avoid thermal degradation. Any lipophilic vitamins, emulsifiers, and the like can be dissolved in the fat source prior to blending. Water can then be mixed, preferably water that has been reverse osmosis, to form a liquid mixture. The water temperature is conveniently in the range of between about 50 ° C and about 80 ° C to aid in the dispersion of the ingredients. Commercially available liquefiers can be used to form the liquid mixture. If the final product is to be in liquid form, the oligosaccharide mixture is added at this stage. If the final product is a powder, the oligosaccharides may be added at this stage if desired. Then in, for example, two phases The liquid mixture is homogenized.

The liquid mixture can then be heat treated to reduce the bacterial load by, for example, rapidly heating the liquid mixture to a temperature in the range between about 80 ° C and about 150 ° C for between about 5 seconds and about 5 minutes. This can be carried out by steam injection, autoclave or heat exchangers such as plate heat exchangers.

The liquid mixture can then be cooled to between about 60 ° C and about 85 ° C by, for example, flash 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 further cooled to add any heat sensitive components such as vitamins and minerals. At this time, the pH and solid content of the homogenized mixture can be conveniently adjusted.

The homogenized mixture is transferred to a suitable drying device (eg, a spray dryer or freeze dryer) and converted to a powder. The moisture content of the powder should be less than about 5% by weight. The oligosaccharide mixture can be added at this stage by dry mixing with the probiotic strain or by blending it with the probiotic strain in the form of a crystalline syrup, and spray dried (or freeze dried).

If the liquid composition is preferred, the homogenized mixture can be sterilized and then aseptically filled into a suitable container, or it can be first filled into a container and then processed through a sterilizer.

In another embodiment, the compositions of the invention may be in an amount sufficient to achieve the desired effect in the individual. This form of administration is generally more suitable for preterm or LVR or IUGR infants, older children and adults.

Will be included in the supplement according to the way you want to invest in supplements. The amount of oligosaccharide, LC-PUFA and probiotic strains.

The supplement may be in the form of, for example, a powder, a lozenge, a capsule, a soft lozenge or a liquid. Supplements may further contain protective hydrocolloids (eg, gums, proteins, modified starches), binders, film formers, encapsulants/materials, wall/shell materials, matrix compounds, coatings, emulsifiers, surfactants , solubilizer (oil, fat, wax, lecithin, etc.), adsorbent, carrier, filler, co-compound, dispersant, wetting agent, processing aid (solvent), flow agent, taste mask, weight gain Agent, gelling agent and gel former. Supplements may also contain customary pharmaceutical additives and adjuvants, excipients and diluents including, but not limited to, water, gelatin of any origin, vegetable gums, sulfonic acid lignin, talc, sugar, starch, gum arabic ( Gum arabic), vegetable oils, polyalkylene glycols, flavoring agents, preservatives, stabilizers, emulsifiers, buffers, lubricants, colorants, wetting agents, fillers, and the like.

The supplement may be added to a product acceptable to the consumer (which is a human or animal) (for example, an ingestible carrier or carrier, respectively). Examples of such carriers or carriers are pharmaceutical or food or pet food compositions. Non-limiting examples of such compositions are milk, yogurt, curd, cheese, fermented milk, milk based fermentation products, fermented cereal based products, milk based powders, human milk, preterm formula, infant formula, oral supplements And tube feeding.

In addition, supplements may contain organic or inorganic carrier materials suitable for enteral or parenteral administration, as well as vitamins, trace mineral elements, and other micronutrients, as recommended by government agencies such as USRDA.

Advantages, properties, and various other features of the present invention will become more fully apparent from the <RTIgt;

Instance

Experiments were carried out on the addition of an oligosaccharide mixture (which is a galactooligosaccharide-rich bovine milk oligosaccharide (CMOS) mixture (demineralized lactose whey permeate or DDWP), LC-PUFA (arachidonic acid- ARA- and docosahexaenoic acid-DHA-) and Lactobacillus lactis (BL) and optionally 2'-fucosyllactose (FL) or 2'-fucosyllactose (FL) The effect of a combination of milk N-neotetraose (LNNT) on pups.

Method Experimental program

The experiment was performed in accordance with the Swiss Animal Protection Law and approved by Office Vétérinaire Cantonal (Lausanne, Switzerland, Grant No. 2028). Reproductor male and unmarried female Long-Evans Hooded rat lines were purchased from Janvier (France) and the rats arrived at the animal care facility two weeks prior to mating.

Pregnant females receive food (Kliba 3437) and water ad libitum, kept in constant temperature and humidity, and maintained at 12:12 dark: bright cycle. Captive conditions maintain the full duration of the program. On the second day after birth (B) after birth (B), the mother is removed from the maternity cage and the sex of the cub is determined. After randomization of body weight, 8 standardized litters of male pups were allocated for rearing. One of two breeding conditions is assigned to the mother and its young: 1) maternal deprivation group, which is isolated from the mother for 180 min (MS) per day from PND2 to PND14, or 2) untreated control (NS).

MS pups were weaned (W) at PND15. By weight and breastfeeding mothers The machine was assigned and assigned to a group of 16 animals that received the following feeding until PND26: control diet (modified AIN 93G, MS control group) or suitable for LC-PUFA, Lactobacillus lactis CNCMI-3446 (BL) And a similar diet of oligosaccharides (DDWP). MS animals (MS control group) were housed in groups of 8 pups up to PND21 to reduce the stress load of premature weaning, and then individually housed until the end of the experiment. Animals in the NS group were weaned to a control diet (NS control group) at PND21 and individually housed until the end of the experiment.

Exposed to PND26 or PND26 by thorough bleeding under isoflurane anesthesia ( )animal. Record brain weight: Brain was collected after craniotomy and weighed in Libra.

2. Treatment and diet

The following functional ingredients for the experimental tube feeding and dietary compositions contained 98.8% dry matter DDWP ingredients, the composition of which is detailed in Table 1 below.

DDWP is generally obtained according to the disclosure of WO 2007/101675 or WO 2007/090894 and usually contains a mixture of about 30 wt% of GalNAcα1,3Galβ1,4Glc and Galβ1,6GalNAcα1,3Galβ1,4Glc; 50 wt% of Galβ1,6Galβ1 , 4Glc and Galβ1, 3Galβ1, 4Glc; 20 wt% NeuAcα2, 3Galβ1, 4Glc and NeuAcα2, 6Galβ1, 4Glc.

Animals were weaned from the time of weaning until the end of the experiment: a semi-synthetic diet for nutritional adaptation (modified AIN 93 G), the composition of which is shown in Tables 2, 3 and 4.

The fatty acid profiles of the four diets are balanced to provide similar n-6/n-3 ratios and Similar ratios of saturated, monounsaturated, and polyunsaturated fatty acids. Therefore, the fatty acid composition of the four diets is nearly identical in terms of fatty acid profile.

Animals were sacrificed on the 26th or 35th day after birth (PND).

3. Brain weight

Based on the results of Figures 2 and 3, it appears that the first composition of the present invention, PUFA-BL-DDWP, exhibited brain weight superior to that obtained from the control of the control MS control.

Furthermore, the third composition of the present invention, PUFA-BL-DDWP-FL-LNNT, exhibited a brain weight superior to the composition PUFA-BL-DDWP at PND 26. In fact, it seems that if DDWP-BL-PUFA is effective at PND26, a longer supplement at PND35 shows a more significant effect. DDWP-BL-PUFA-FL-LNNT showed a significant effect on PND26.

All compositions of the invention demonstrated greater brain weight than the MS control group. This is a true advantage of the compositions of the invention.

Figure 1 is a diagram illustrating the experimental protocol.

Figure 2 is a bar graph plotting experimental results on brain weight (g) on day 35 of birth (=PND).

Figure 3 is a bar graph plotting experimental results on brain weight (g) on day 26 of birth (=PND).

Claims (13)

A composition comprising at least one long chain polyunsaturated fatty acid (LC-PUFA), at least one probiotic and an oligosaccharide mixture, the mixture comprising 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 mental motor development. The composition of claim 1, wherein the neutral oligosaccharide is selected from the group consisting of fructooligosaccharides (FOS) and/or galactooligosaccharides (GOS), preferably GOS. The composition of claim 1 or 2, wherein the oligosaccharide mixture contains at least one N-acetylated oligosaccharide selected from the group consisting of GalNAcα1, 3Galβ1, 4Glc (=3'GalNAc-lac=N-B Mercapto-aminogalactosyl-lactose, Galβ1,4GlcNAcβ1,3Galβ1,4Glc, Galβ1,3GlcNAcβ1,3Galβ1,4Glc and Galβ1,6GalNAcα1,3Galβ1,4Glc(=6'Gal-3GalNAc-lac=galactosyl-N -Ethyl-aminogalactosyl-lactose), Galβ1,4GlcNAcβ1,3Galβ1,4Glc (lacto-N-neotetraose or LNnT) and Galβ1,3GlcNAcβ1,3Galβ1,4Glc (milk-N-tetraose) Or LNT); at least one selected from the group consisting of sialylated oligosaccharides: NeuAcα2, 3Galβ1, 4Glc (=3'-sialyl lactose) and NeuAcα2,6Galβ1,4Glc (=6'-sialyl lactose And at least one group consisting of a group of intermediate oligosaccharides consisting of: 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-di Gal-lac), Galβ1,6Galβ1,3Galβ1,4Glc( =6',3-di Gal-lac), Galβ1,3Galβ1,6Galβ1,4Glc(=3',6-di Gal-lac), Galβ1,3Galβ1,3Galβ1,4Glc(=3',3-di Gal-lac), Galβ1,4Galβ1,4Glc(=4'Gal -lac) and Galβ1,4Galβ1,4Galβ1,4Glc (=4',4-di Gal-lac), and Fucα1,2Galβ1,4Glc (=2'fucosyllactose or FL). The composition of claim 1 or 2, wherein the oligosaccharide mixture comprises: 0.25 wt% to 20 wt%, preferably 0.3 wt% to 10 wt%, more preferably 0.3 wt%, based on the total weight of the oligosaccharide mixture Up to 5 wt% and even more preferably about 0.5 wt% of at least one N-acetylated oligosaccharide, from 0.5 wt% to 30 wt%, preferably from 0.75 wt% to 15 wt%, based on the total weight of the oligosaccharide mixture %, more preferably 0.75 wt% to 10 wt% and even more preferably about 1 wt% of at least one sialylated oligosaccharide, and 50 wt% to 99.3 wt%, preferably relative to the total weight of the oligosaccharide mixture. 20 wt% to 80 wt%, more preferably 10 wt% to 50 wt%, and even more preferably about 50 wt% of at least one neutral oligosaccharide. The composition of claim 1 or 2, wherein the oligosaccharide mixture comprises from 0.5% to 70%, more preferably from 1% to 20%, even more preferably from 2% to 5% by total weight of the composition. The composition of claim 1 or 2, wherein the LC-PUFA is selected from the group consisting of arachidonic acid (ARA) and docosahexaenoic acid (DHA), and the LC-PUFA is preferably a mixture of ARA and DHA. The composition of claim 1 or 2, wherein the probiotic strain is selected from a probiotic bacterial strain, preferably a lactobacillus or a bifidobacterium , the probiotic being more preferred Bifidobacterium lactis or Lactobacillus reuteri . The composition of claim 1 or 2, wherein the N-acetylated oligosaccharide is selected from the group consisting of milk-N-neotetraose (or LNnT) and milk-N-tetraose (or LNT). The composition of claim 1 or 2, wherein the sialylated oligosaccharide is selected from the group consisting of 3'-sialyl lactose and 6'-sialyl lactose, and the sialylated oligosaccharide is preferably Containing both 3'-sialyl lactose and 6'-sialyl lactose, the ratio between 3'-sialyl lactose and 6'-sialyl lactose is preferably between 5:1 and 1:2 Within the range. The composition of claim 1 or 2, wherein the neutral oligosaccharide is 2'-fucosyllactose (or FL). The composition of claim 1 or 2, wherein the composition is a premature infant formula, a human milk fortifier, a starter infant formula, a follow-on formula, a toddler food formula, a baby cereal A formula, a growing milk, a medical food or supplement for clinical nutrition, preferably a premature infant formula, a human milk fortifier or a supplement. A composition according to claim 1 or 2 for use in infants and children having premature birth or having low birth weight or undergoing intrauterine growth retardation or growth stunting due to malnutrition and/or disease, preferably infants . Use of a composition comprising at least one long chain polyunsaturated fatty acid (LC-PUFA), at least one probiotic and an oligosaccharide mixture, the mixture comprising at least one N-acetylated oligosaccharide, at least one sialylation Oligosaccharides and at least one neutral oligosaccharide for use in the manufacture of synthetic nutrients for brain growth and/or cognitive and/or psychomotor development.