TW201438720A - Dietary oligosaccharides to enhance learning and memory - Google Patents

Abstract

Use of a nutritional composition comprising at least one human milk oligosaccharide in the manufacture of a medicament for enhancing learning and memory in an individual in need thereof where the human milk oligosaccharide is selected from lacto-N-neotetraose, lacto-N-tetraose, disialylated lacto-N-tetraose, 3'-fucosyllactose, and 3'-sialyllactose.

Description

Dietary oligosaccharides that enhance learning and memory Cross-reference to related applications

This application claims the benefit of U.S. Provisional Application No. 61/738,486, filed on December 18, 2012.

The present invention relates to the use of a nutritional composition comprising at least one breast milk oligosaccharide for the manufacture of a medicament for enhancing the learning and memory of an individual in need thereof. More specifically, the breast milk oligosaccharide is selected from the group consisting of lactose-N-neotetraose, lactose-N-tetraose, disialylated lactose-N-tetraose, 3'-trehalose lactose, and 3'-sialic acid. Lactose.

Infants experience rapid growth and development during their first year of life. During this period, the weight gain was about 190%, while the head circumference was increased by 1/3. Because the brain grows and develops fastest during early childhood and early childhood, supplying optimal nutrition during this period is critical for proper brain development. Currently, long-chain polyunsaturated fatty acids (LCPUFA), such as docosahexaenoic acid (DHA) and eicosatetraenoic acid, are added to all commercial infant formulas and many prenatal supplements for cognitive development purposes. (ARA). In addition, emerging research suggests that dietary supplementation with a 9-carbon compound sialic acid (a brain ganglioside component found in mammalian milk) can also enhance learning and memory.

The human visceral microbiome coexists with its host and can play a significant role in health and disease (Nicholson, 2012). This composite microbial community is collected from undigested The energy of carbohydrates, the promotion of host immune system maturation and the provision of key resistance to potential pathogens (Clemente et al., 2012). However, under some conditions, the visceral microbiome can also have a negative impact on human health. The undesired changes in visceral microbial phase composition are associated with the development of allergies, celiac disease, gastric cancer, autism, obesity, anorexia, inflammatory bowel disease (IBD), and type 2 diabetes (Clemente et al., 2012).

Although there is growing evidence that the composition of the intestinal microbial phase alters neuronal development and behavior (Diaz Heijtz et al., 2011), little is known about the relationship between diet, visceral microbial phase and central and peripheral nervous systems. . To date, it has been shown in animal models that oral administration of certain probiotics can alter brain lipid composition (Wall et al., 2012) and sensitivity to visceral pain (Kamiya et al., 2006; Duncker et al., 2011; McKernan et al., 2010), and anxiety-like behavior (Desbonnet et al., 2008). However, the interaction between indigestible dietary carbohydrates (such as breast milk oligosaccharides), intestinal microbial phase and neuronal development and function is virtually unknown.

references:

Clemente JC, Ursell LK, Wegener Parfrey L, et al . The impact of the gut microbiota on human health: an integrative view. Cell 2012;148:1258-70.

Desbonnet L, Garrett L, Clarke G, et al . The probiotic Bifidobacteria infantis: An assessment of potential antidepressant properties in the rat. J Psychiatr Res 2008;43:164-74.

Diaz Heijtz R, Wang S, Anuar F, et al . Normal gut microbiota modulates brain development and behavior. PNAS 2011;108:3047-52.

Duncker SC, Kamiya T, Wang L, et al . Probiotic Lactobacillus reuteri alleviates the response to gastric distension in rats. J Nutr 2011;141:1813-18.

Kamiya T, Wang L, Forsythe, P, et al . Inhibitory effects of Lactobacillus reuteri on visceral pain induced by colorectal distension in Sprague-Dawley rats. Gut 2006;55:191-96.

Mckernan DP, Fitzgerald P, Finan TG, et al . The probiotic Bifidobacterium infantis 35624 displays visceral antinociceptive effects in the rat. Neurogastroenterol Motil 2010;22:1029-36

Nicholson JK. Host-gut microbiota metabolic interactions. Science 2012; 336:1262-67.

Wall R, Marques TM, O' Sullivan O, et al . Contrasting effects of Bifidobacterium breve NCIMB 702258 and Bifidobacterium breve DPC 6330 on the composition of murine brain fatty acids and gut microbiota. Am J Clin Nutr 2012, Vol. 95, p. 1278-87.

The present invention provides the use of a nutritional composition comprising at least one breast milk oligosaccharide for the manufacture of a medicament for enhancing the learning and memory of an individual in need thereof, wherein the breast milk oligosaccharide is selected from the group consisting of lactose-N-neotetraose Lactose-N-tetraose, disialylated lactose-N-tetraose, 3'-trehalose lactose and 3'-sialyllactose.

definition

The terms "sterilizer" and "sterilizer" are used interchangeably herein and, unless otherwise stated, refer to filling a container with a nutrient solution (most commonly a metal can or other similar package), followed by filling with a liquid. The formulation of the package is subjected to the necessary heat sterilization steps to form a sterilized sterilizer-encapsulated nutrient solution product.

The term "aseptically packaged" as used herein, unless otherwise indicated, means that the packaged product is manufactured without relying on the above described sterilization step, wherein the nutrient solution and the package are filled. The sterilizing is separately performed separately, and then combined under sterile or aseptic processing conditions to form a sterilized aseptically packaged nutrient solution product.

The terms "fat" and "oil" as used herein, unless otherwise indicated, are used interchangeably and mean a lipid material derived from a plant or animal or processed from a plant or animal. These terms also include synthetic lipid materials as long as the synthetic materials are suitable for oral administration to humans.

The term "breast oligosaccharide" or "HMO" as used herein, unless otherwise indicated, generally refers to a plurality of complex carbohydrates found in human milk that may be in acidic or neutral form, and precursors thereof. Exemplary non-limiting breast milk oligosaccharides include 3'-sialyl lactose (3SL), 6'-sialyl lactose (6SL), lactose-N-neotetraose (LNnT), lactose-N-tetraose (LNT) ), disialylated lactose-N-tetraose (DSLNT), 3'-trehalosyl lactose (3FL) and 3'-sialyl lactose (3SL), and 2'-trehalosyl lactose (2FL).

The term "storage stable" as used herein, unless otherwise indicated, means that the nutritional product is packaged and then stored at 18-24 ° C for at least 3 months, including from about 6 months to about 24 months, and also includes It is still commercially stable from 12 months to about 18 months.

The terms "nutritional formulation" or "nutritional composition" as used herein are used interchangeably and, unless otherwise indicated, are meant to include nutrient solutions, nutritional powders, nutritional solids, nutrient semi-solids, nutrient semi-liquids, nutritional supplements. And synthetic formulations of any other nutraceutical product known in the art. The nutritional powder can be reconstituted to form a nutrient solution, which is suitable for human oral consumption. The term "nutritional formulation" or "nutritional composition" does not include human milk.

The term "nutrient solution" as used herein, unless otherwise indicated, refers to a ready-to-drink liquid form, a concentrated form of a nutritional product, and a nutrient solution made by restoring the nutritional powder described herein prior to use.

The term "nutritional powder" as used herein, unless otherwise indicated, refers to a nutritive product in a flowable or excavable form that can be reconstituted with water or another aqueous liquid prior to consumption. Both raw and spray-dried and dry blended/dry blended powders are included.

The term "nutritional semi-solid" as used herein, unless otherwise indicated, refers to a nutritional product having a property (such as rigidity) between a solid and a liquid. Some semi-solid examples include puddings, gelatin, and dough.

The term "nutritional semi-liquid" as used herein, unless otherwise indicated, refers to a nutritional product having a property (such as fluidity) between a liquid and a solid. Some semi-liquid examples include thick shakes and liquid gels.

The term "infant" or "term infant" as used herein, unless otherwise indicated, refers to a person who is 12 months or less. The term "premature baby" as used herein refers to an individual born before 36 weeks of gestation.

The term "younger" as used herein, unless otherwise indicated, refers to an individual from greater than 1 year old to up to 3 years old.

The term "child" as used herein, unless otherwise indicated, refers to an individual that is older than 3 years old and up to 12 years old.

The term "neonatal" as used herein, unless otherwise indicated, refers to an individual who has been born for up to 4 weeks.

The terms "infant formula" or "synthetic infant formula" as used herein, unless otherwise indicated, are used interchangeably and refer to liquid, solid, semi-solid and semi-liquid breast milk substitutes or substitutes suitable for infant consumption. Synthetic formulations include components that are semi-purified or purified from origin. The term "semi-purified" or "purified" as used herein, unless otherwise indicated, means that the material has been prepared by purifying a natural material or by synthesis. The term "infant formula" or "synthetic infant formula" does not include human milk.

The term "synthetic pediatric formulation" as used herein, unless otherwise indicated, refers to liquid, solid, semi-solid and semi-liquid breast milk substitutes or substitutes suitable for infants or young children up to 36 months (3 years old). . Synthetic formulations include components that are semi-purified or purified from origin. The term "semi-purified" or "purified" as used herein, unless otherwise stated. It is meant that the material has been prepared by purifying the natural material or by synthesis. The term "synthetic pediatric nutritional formula" does not include human milk.

The term "synthetic child formula" as used herein, unless otherwise indicated, refers to liquid, solid, semi-solid and semi-liquid breast milk substitutes or substitutes suitable for consumption by children up to 12 years of age. Synthetic formulations include components that are semi-purified or purified from origin. The term "semi-purified" or "purified" as used herein, unless otherwise indicated, means that the material has been prepared by purifying a natural material or by synthesis. The term "synthetic child nutrition formula" does not include human milk.

The term "premature infant formula" as used herein, unless otherwise indicated, refers to liquid and solid nutritional products suitable for consumption by premature infants.

The term "mammal milk fortifier" as used herein, unless otherwise indicated, refers to a liquid and solid nutritional product suitable for mixing with a milk or premature infant formula or infant formula for preterm or term infant consumption.

The nutritional composition as described herein may be administered to an individual, including an infant and a pregnant woman with the infant or a mother breastfeeding the infant, or in some embodiments, may be Infant sub-categories; that is, the administration of specific babies (or pregnant women who have such babies or mothers who are breast-feeding) for the infant formula. For example, a particular infant may "need" an infant formula as described herein, if it is prone to occur (ie, has a genetic predisposition, has a family history, and/or has symptoms indicative of a neurological disease or condition), abnormal cognitive development, Mental illness or deficiency, cerebral palsy or other brain condition. In a particular embodiment, the infant in need of the nutritional composition disclosed herein is a premature infant.

All percentages, parts and ratios as used herein are by weight of the total composition, unless otherwise stated. Unless otherwise stated, all such weights are as far as the listed ingredients are, i.e., based on the active level, and thus do not include solvents or by-products that may be included in commercially available materials.

The numerical ranges as used herein are intended to include a In addition, such numerical ranges should be interpreted as providing support to the technical solutions for any value or subset of values within the range. For example, the disclosures 1 to 10 should be construed as supporting ranges of 2 to 8, 3 to 7, 5 to 6, 1 to 9, 3.6 to 4.6, 3.5 to 9.9, and the like.

All the individual features or limitations referred to in the present invention should include a corresponding plurality of features or limitations, and vice versa, unless otherwise stated or clearly indicated.

All combinations of methods or process steps as used herein may be performed in any order, unless otherwise stated or indicated to the contrary.

Both gamma-aminobutyric acid (GABA) and agmatine help improve learning, research and attention. GABA is the major inhibitory neurotransmitter of the central nervous system. It is believed to increase plasma growth hormone concentration and protein synthesis rate in the brain, which helps to promote brain development. Animal studies have shown that agmatine increases mental concentration in the synaptic terminals of rats undergoing spatial learning tasks by 85%. This suggests that agmatine plays a key role in this type of learning. These compounds can all be taken from food or produced endogenously by the host cell.

It has been found that GABA and agmatine can be produced in the human viscera of the already existing intestinal flora by supplying specific breast milk oligosaccharides (HMO). Feces obtained from breast-fed infants (BF) or formula-fed infants (FF) and incubated with HMO lactose-N-neotetraose (LNnT) as shown in Tables 1 and 2 and as described in Example 51 The anaerobic fermentation culture of the sample showed a dramatic increase in GABA and agmatine relative to the blank group. This in vitro study showed that consumption of selected HMOs would produce GABA and agmatine from human intestinal flora in vivo.

The present invention provides the use of a nutritional composition comprising at least one breast milk oligosaccharide for the manufacture of a medicament for enhancing the learning and memory of an individual in need thereof, wherein the breast milk oligosaccharide is selected from the group consisting of lactose-N-neotetraose Lactose-N-tetraose, disialylated lactose-N-tetraose, 3'-trehalose lactose and 3'-sialyllactose. Without being bound by a particular theory, Xianxin supplies the individual with lactose-N-neotetraose, lactose-N-tetraose, disialylated lactose-N-tetraose, 3'-trehalosyl lactose or 3'-sialic acid. The nutritional composition of lactose will cause the intestinal flora to consume such compounds and increase the amount of GABA, agmatine or both. GABA, agmatine or both will be absorbed into the bloodstream via the internal organs of the individual and then through the blood brain barrier. GABA, agmatine, or both will then improve the individual's learning, research capabilities, attention, or any combination thereof. Alternatively, GABA, agmatine, or both may not need to pass through the blood-brain barrier to produce the desired effect.

Specific non-limiting examples of HMOs which may be included alone or in combination in the compositions used in the methods of the invention include: lactose-N-neotetraose, lactose-N-tetraose, disialylated lactose-N-tetraose, 3 '- Trehalose lactose or 3'-sialyllactose. In one example, the nutritional composition for relieving the pressure of the individual in need comprises at least one breast milk oligosaccharide selected from the group consisting of lactose-N-neotetraose and lactose-N-tetraose. In another embodiment, the nutritional composition comprises lactose-N-neotetraose. In another embodiment, the nutritional composition comprises lactose-N-tetraose.

In one embodiment, the nutritional composition is a liquid and comprises from about 0.001 mg/mL to about 20 mg/mL, including from about 0.001 mg/mL to about 10 mg/mL, including from about 0.001 mg/mL to about 5 mg/mL, including about 0.01 mg/mL to about 20 mg/mL, including at least one selected from the group consisting of about 0.001 mg/mL to less than 2 mg/mL and including from about 0.01 mg/mL to less than 2 mg/mL, selected from the group consisting of lactose-N-neotetraose, Lactose-N-tetraose, disialylated lactose-N-four Sugar, 3'-trehalose lactose and 3'-sialyllactose lactose oligosaccharides.

In a particular embodiment, the nutritional composition is a liquid and comprises from about 0.001 mg/mL to about 20 mg/mL, including from about 0.001 mg/mL to about 10 mg/mL, including from about 0.001 mg/mL to about 5 mg/mL, including From about 0.001 mg/mL to less than 2 mg/mL, and including from about 0.01 mg/mL to about 20 mg/mL, including at least one selected from the group consisting of lactose-N-new four in an amount from about 0.01 mg/mL to less than 2 mg/mL Sugar and lactose-N-tetrasaccharide milk oligosaccharides.

In a particular embodiment, the nutritional composition is a liquid and comprises from about 0.001 mg/mL to about 20 mg/mL, including from about 0.001 mg/mL to about 10 mg/mL, including from about 0.001 mg/mL to about 5 mg/mL, including From about 0.001 mg/mL to less than 2 mg/mL, and including from about 0.01 mg/mL to about 20 mg/mL, including lactose-N-tetraose in an amount from about 0.01 mg/mL to less than 2 mg/mL.

In a particular embodiment, the nutritional composition is a liquid and comprises from about 0.001 mg/mL to about 20 mg/mL, including from about 0.001 mg/mL to about 10 mg/mL, including from about 0.001 mg/mL to about 5 mg/mL, including From about 0.001 mg/mL to less than 2 mg/mL, and including from about 0.01 mg/mL to about 20 mg/mL, including lactose-N-neotetraose in an amount from about 0.01 mg/mL to less than 2 mg/mL.

In one embodiment, the nutritional composition is a powder and comprises from about 0.0005% to about 5% by weight of the powder, including at least one selected from the group consisting of lactose-N-neotetraose, lactose, in an amount from about 0.01% to about 1%. N-tetrasaccharide, disialylated lactose-N-tetraose, 3'-trehalose lactose, and 3'-sialyl lactose, a milk oligosaccharide.

In a particular embodiment, the nutritional composition is a powder and comprises from about 0.0005% to about 5% by weight of the powder, such as from about 0.01% to about 1%, at least one selected from the group consisting of lactose-N-neotetraose and lactose. -N-tetrasaccharide milk oligosaccharide.

In a particular embodiment, the nutritional composition is a powder and comprises from about 0.0005% to about 5%, such as from about 0.01% to about 1%, by weight of the powder, of lactose-N-tetraose.

In a specific embodiment, the nutritional composition is a powder and comprises about a weight of the powder. Lactose-N-neotetraose in an amount of from 0.0005% to about 5%, such as from about 0.01% to about 1%.

In a specific embodiment, the nutritional composition is a bar and comprises from about 0.0005% to about 10% by weight of the bar, including at least one selected from the group consisting of lactose-N-new four in an amount of from about 0.01% to about 5% Sugar, lactose-N-tetraose, disialylated lactose-N-tetraose, 3'-trehalose lactose and 3'-sialyllactose lactose oligosaccharides.

In a specific embodiment, the nutritional composition is a strip and comprises from about 0.0005% to about 10% by weight of the strip, such as from about 0.01% to about 5%, at least one selected from the group consisting of lactose-N-neotetraose and lactose -N-tetrasaccharide milk oligosaccharide.

In a particular embodiment, the nutritional composition is a strip and comprises from about 0.0005% to about 10%, such as from about 0.01% to about 5%, by weight of the strip, of lactose-N-tetraose.

In a particular embodiment, the nutritional composition is a strip and comprises from about 0.0005% to about 10%, such as from about 0.01% to about 5%, by weight of the strip, of lactose-N-neotetraose.

Breast milk oligosaccharide (HMO)

Mammary oligosaccharide is a major component of human milk containing an average of 10 g of neutral oligosaccharides per liter and 1 g of acidic oligosaccharides per liter. The composition of breast milk oligosaccharides is very complex and more than 200 different oligosaccharide-like structures are known.

HMO alone or in some embodiments, including HMO in combination with other immune enhancing factors (eg, long chain polyunsaturated fatty acids, antioxidants, nucleotides, etc.) may be included. HMOs may be isolated or enriched from milk secreted by mammals including, but not limited to, human, bovine, ovine, porcine or goat species. HMO can also be produced via microbial fermentation, enzymatic processes, chemical synthesis, or a combination thereof.

In addition to the HMOs described above, the nutritional composition may comprise additional HMOs such as: acidic oligosaccharides, neutral oligosaccharides, n-acetyl glucosylated oligosaccharides, and HMO precursors. Specific non-limiting examples of HMOs that may be included alone or in combination in the compositions of the present invention include: sialic acid (i.e., free sialic acid, lipid-bound sialic acid, protein-bound sialic acid); D-glucose (Glc); D-galactose (Gal); N-ethyl glucosamine (GlcNAc); L- Trehalose (Fuc); trehalose-based oligosaccharide (ie, lactose-N-algae pentasaccharide I; lactose-N-algae pentasaccharide II; 2'-trehalosyl lactose; 3'-trehalose lactose; lactose -N-algae pentasaccharide III; lactose-N-di-algae hexasaccharide I; and lactose di-algae tetrasaccharide); non-fucosylated, unsialylated oligosaccharides (ie, lactose-N-tetraose and lactose) -N-neotetraose); sialic acid oligosaccharide (i.e., 3'-sialyl-3-trehalosyl lactate; disialyl-mono-fucosyl lactose-N-six hexose; single-trehalose Monosialyl lactose-N-octasaccharide (sialyl Lea); sialyl lactose-N-algae hexasaccharide II; disialyl lactose-N-algae pentasaccharide II; single trehalose disialic acid group Lactose-N-tetraose); and sialyl-based trehalose-based oligosaccharides (i.e., 2'-sialyl lactose; 2-sialyl lactosamine; 3'-sialyl lactose; 3'-sialic acid Lactosamine; 6'-sialyl lactose; 6'-sialyl lactosamine; sialyl lactose-N-neotetraose c; monosialyl lactose-N-hexaose; disialyl lactose N-hexasaccharide I; monosialyl lactose-N-six hexose I; monosialyl lactose-N-six hexose II Disialyl lactose-N-new hexasaccharide; disialyl lactose-N-tetraose; disialyl lactose-N-hexasaccharide II; sialyl lactose-N-tetraose a; disialyl group Lactose-N-hexasaccharide I; and sialyl lactose-N-tetraose b). A variant in which the glucose (Glc) at the reducing end is replaced by N-ethyl glucosamine (for example, 2'- trehalyl-N-ethyl glucosamine (2'FLNac) is 2'-trehalose Such variants of lactose are also suitable. Such HMOs are more fully described in U.S. Patent Application Serial No. 2009/0098240, which is incorporated herein in its entirety by reference. Other suitable examples of HMOs that may also be included in the compositions of the present invention include lactose-N-algae pentasaccharide V, lactose-N-hexaose, p-lactose-N-hexaose, lactose-N-hexasaccharide, p- Lactose-N-new hexasaccharide, mono-fucosyl lactose-N-hexasaccharide II, isomeric fucosylated lactose-N-hexaose (1), isomerized trehalosylated lactose-N-hexaose (3) Heteromeric fucosylated lactose-N-hexaose (2), di-trehalose-p-lactyl-N-hexaose, di-trehalose-p-lact-N-hexaose, 2-trehalose lactose-N-hexasaccharide, lactose-N-new octasaccharide, p-lactose-N-octasaccharide, iso-lactose-N-octasaccharide, lactose-N-octasaccharide, mono-fucosyl lactose- New octasaccharide, mono-fucosyl lactose-N-octasaccharide, di-trehalose lactose-N-octasaccharide I, di-trehalose lactose-N-octasaccharide II, di-trehalose lactose-N-new octasaccharide II, two trehalose Lactose-N-new octasaccharide I, lactose-N-decasaccharide, tri-trehalose lactose-N-new octasaccharide, tri-trehalose lactose-N-octasaccharide, tri-trehalose-iso-lactose-N - octasaccharide, lactose-N-dicoalhexaose II, sialyl-lactose-N-tetraose a, sialyl-lactose-N-tetraose b, sialyl-lactose-N-tetraose c, Sialyl-trehalose-lactose-N-tetraose I, sialic acid-trehalose-lactose-N-tetraose II and disialyl-lactose-N-tetraose, and combinations thereof. Particularly suitable nutritional compositions include at least one of the following HMO or HMO precursors: sialic acid (SA); 3'-sialyl lactose (3'SL); 6'-sialyl lactose (6'SL); 2'-trehalosyl lactose (2'FL); 3'-trehalosyl lactose (3'FL); lactose-N-tetraose and lactose-N-neotetraose (LNnT), and especially 6'SL Combination with 3'SL; combination of 3'FL and SA; combination of 2'FL and 3'FL; combination of 2'FL, 3'SL and 6'SL; combination of 3'SL, 3'FL and LNnT ; and a combination of 6'SL, 2'FL and LNnT.

Other exemplary combinations include: SA, 3'SL, 6'SL, 3'FL, 2'FL, and LNnT; 3'SL, 6'SL, 3'FL, 2'FL, and LNnT; SA, 6'SL, 3'FL, 2'FL and LNnT; SA, 3'SL, 3'FL, 2'FL and LNnT; SA, 3'SL, 6'SL, 2'FL and LNnT; SA, 3'SL, 6' SL, 3'FL and LNnT; SA, 3'SL, 6'SL, 3'FL and 2'FL; SA and 3'SL; SA and 6'SL; SA and 2'FL; SA and LNnT; SA, 3'SL and 6'SL; SA, 3'SL and 3'FL; SA, 3'SL and 2'FL; SA, 3'SL and LNnT; SA, 6'SL and 3'FL; SA, 6' SL and 2'FL; SA, 6'SL and LNnT; SA, 3'FL and 2'FL; SA, 3'FL and LNnT; SA, 2'FL and LNnT; SA, 3'SL, 6'SL and 3'FL; SA, 3'SL, 6'SL and 2'FL; SA, 3'SL, 6'SL and LNnT; SA, 3'SL, 3'FL and 2'FL; SA, 3'SL, 3'FL and LNnT; SA, 3'SL, 2'FL and LNnT; SA, 6'SL, 3'FL and 2'FL; SA, 6'SL, 2'FL and LNnT; SA, 6'SL, 3'FL and LNnT; SA, 3'FL, 2'FL and LNnT; SA, 6'SL, 2'FL and LNnT; SA, 3'SL, 3'FL, 2'FL and LNnT; SA, 6' SL, 3'FL, 2'FL and LNnT; SA, 3'SL, 6'SL, 3'FL and LNnT; SA, 3'SL, 3'FL, 2'FL and LNnT; SA, 3'SL, 6'SL, 2'FL and LNnT; 3'SL, 6'SL, 3'FL and 2'FL; 3'SL, 6'SL 2'FL and LNnT; 3'SL, 3'FL, 2'FL and LNnT; 3'SL, 6'SL, 3'FL and LNnT; 3'SL, 6'SL and 3'FL; 3'SL, 3'FL and 2'FL; 3'SL, 2'FL and LNnT; 3'SL, 6'SL and 2'FL; 3'SL, 6'SL and LNnT; 3'SL and 3'FL; 3' SL and 2'FL; 3'SL and LNnT; 6'SL and 3'FL; 6'SL and 2'FL; 6'SL and LNnT; 6'SL, 3'FL and LNnT; 6'SL, 3' FL, 2'FL and LNnT; 3'FL, 2'FL and LNnT; 3'FL and LNnT; and 2'FL and LNnT.

Long-chain polyunsaturated fatty acids (LCPUFA)

In addition to the HMOs described above, the nutritional composition can include an LCPUFA. LCPUFA is included in the nutritional composition to provide nutritional support, as well as to reduce oxidative stress and to enhance the growth and functional development of the intestinal epithelium and related immune cell populations. In some embodiments, the nutritional composition includes a combination of one or more HMOs with one or more LCPUFAs such that the composition provides synergistic benefits to the end user, such as synergistic benefits in modulating antiviral immune responses and inhibiting inflammation. In some embodiments, the HMO used in combination with the LCPUFA to provide synergy is an acidic HMO.

Exemplary LCPUFAs for use in nutritional compositions include, for example, omega-3 LCPUFAs and omega-6 LCPUFAs. Specific LCPUFAs include docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), arachidonic acid (ARA), linoleic acid, sub- Linoleic acid (alpha linoleic acid) and gamma-linolenic acid derived from oil sources such as vegetable oil, marine plankton, fungal oil and fish oil. In a particular embodiment, the LCPUFA is derived from fish oil such as salmon oil, salmon oil, salmon oil, salmon oil, halibut oil, salmon oil or salmon oil. Particularly preferred LCPUFAs for use in nutritional compositions with HMO include DHA, ARA, EPA, DPA, and combinations thereof.

In order to reduce the potential side effects of high dose LCPUFA in the nutritional composition, the LCPUFA content is preferably no more than 3% by weight of the total fat content of the nutritional composition, including less than 2% by weight of the total fat content, and includes Less than 1% by weight of total fat content.

The LCPUFA may be provided in the form of a free fatty acid, a triglyceride, a diglyceride, a monoglyceride, a phospholipid, an esterified form or a mixture of one or more of the foregoing, preferably a triglyceride. form.

The nutritional composition can comprise a total concentration of LCPUFA from about 0.01 mM to about 10 mM and including from about 0.01 mM to about 1 mM. Alternatively, the nutritional composition may comprise a total concentration of LCPUFA from about 0.001 g/L to about 1 g/L.

In one embodiment, the nutritional composition comprises a total long chain omega-6 fatty acid at a concentration of from about 100 to about 425 mg/L or from about 12 to about 53 mg/100 kcal, and/or additionally comprising from about 40 to about 185 mg/L or from about 5 to about A total long chain omega-3 fatty acid at a concentration of about 23 mg/100 kcal. In a particular embodiment, the ratio of long chain omega-6 fatty acids to long chain omega-3 fatty acids in the nutritional composition is in the range of from about 2:1 to about 3:1, preferably about 2.5:1.

In a particular embodiment, the nutritional composition comprises DHA at a concentration of from about 0.025 mg/mL to about 0.130 mg/mL or from about 3 to about 16 mg/100 kcal. In another embodiment, the nutritional composition comprises ARA at a concentration of from about 0.080 mg/mL to about 0.250 mg/mL or from about 10 to about 31 mg/100 kcal. In another embodiment, the nutritional composition comprises a combination of DHA and ARA such that the ratio of DHA to ARA is in the range of from about 1:4 to about 1:2.

Antioxidants

In addition, the nutritional composition may comprise one or more antioxidants in combination with HMO (and optionally LCPUFAs and/or nucleotides) to provide nutritional support and to reduce oxidative stress. In some embodiments, the nutritional composition includes a combination of HMO and antioxidant such that the composition provides synergistic benefits to the end user, such as synergistic benefits in modulating antiviral immune responses and inhibiting inflammation. In some embodiments, the HMO system is used in combination with carotenoids (and in particular lutein, beta-carotene, zeaxanthin, and/or lycopene) to provide synergy.

Any antioxidant suitable for oral administration may be included for use in the nutritional compositions of the present invention, including, for example, vitamin A, vitamin E, vitamin C, retinol, tocopherol, and the like. Carotenes, for example, include lutein, beta-carotene, zeaxanthin, and lycopene, and combinations thereof.

The antioxidants used in the nutritional compositions can be used with HMO alone or in combination with HMO and LCPUFA and/or nucleotides. In one embodiment, the antioxidants used in the nutritional composition include carotenoids. In one embodiment, the carotenoid is lutein, lycopene, zeaxanthin, and/or beta-carotene. Nutritional compositions containing such combinations as selected and defined herein can be used to modulate the levels of inflammation and/or C-reactive protein in preterm and term infants.

The nutritional composition can comprise at least one of lutein, lycopene, zeaxanthin, and beta-carotene to provide a total amount of carotenoids from about 0.001 [mu]g/mL to about 10 [mu]g/mL. In one embodiment, the nutritional composition may comprise from about 0.001 μg/mL to about 10 μg/mL, including from about 0.044 μg/mL to about 5 μg/mL lutein, and from about 0.001 μg/mL to about 5 μg/mL, including Lutein is present in an amount from about 0.001 μg/mL to about 0.0190 μg/mL, including from about 0.001 μg/mL to about 0.0140 μg/mL. In another embodiment, the nutritional composition comprises from about 0.001 μg/mL to about 10 μg/mL, including from about 0.0185 μg/mL to about 5 μg/mL and from about 0.001 μg/mL to about 5 μg/mL, including about 0.001 μg/ The mL is from about 0.0130 μg/mL, including from about 0.001 μg/mL to about 0.0075 μg/mL lycopene. In another embodiment, the nutritional composition comprises from about 1 μg/mL to about 10 μg/mL, including from about 0.034 μg/mL to about 5 μg/mL and from about 1 μg/mL to about 5 μg/mL, including from about 0.001 μg/mL to About 0.025 μg/mL, including from about 0.001 μg/mL to about 0.011 μg/mL β-carotene. Any combination of such amounts of beta-carotene, lutein, zeaxanthin, and lycopene can be included in the nutritional composition. Other carotenoids may be included in the nutritional composition as appropriate. Any or all of the carotenoids included in the nutritional composition may be derived from natural sources or artificially synthesized.

Each of the carotenoids in the selected combination can be obtained from any known or otherwise suitable source of material suitable for use in the nutritional composition, and each of which can be provided individually or together, or in any combination and from a number of sources, Including, for example, other vitamins or A source of a multivitamin premix of minerals in combination with one or more carotenoids as described herein. Non-limiting examples of some suitable sources of lutein, lycopene, beta-carotene or combinations thereof include LycoVit® lycopene (available from BASF, Mount Olive, NJ); in the form of oil, powder or beads Lyc-O-Mato® tomato extract (available from LycoRed Corp., Orange, NJ); beta-carotene, lutein or lycopene (available from DSM Nutritional Products, Parsippany, NJ); FloraGLO® Lutein (available from Kemin Health, Des Moines, IA); Xangold® natural lutein ester (available from Cognis, Cincinnati, OH); and Lucarotin® beta-carotene (available from BASF, Mount Olive, NJ).

Nucleotide

In addition to HMO, the nutritional composition may additionally comprise nucleotide and/or nucleotide precursors selected from the group consisting of nucleosides, purine bases, pyrimidine bases, ribose and deoxyribose. The nucleotide can be in the form of a monophosphate, diphosphate or triphosphate. The nucleotide can be a ribonucleotide or a deoxyribonucleotide. Nucleotides can be monomeric, dimeric or multimeric (including RNA and DNA). The nucleotide may be present in the nutritional composition in free acid form or in the form of a salt, preferably in the form of a monosodium salt. In some embodiments, the nutritional composition comprises a combination of HMO and nucleotide such that the composition provides synergistic benefits to the end user, such as in modulating an antiviral immune response and inhibiting inflammation and/or improving intestinal barrier integrity. Synergy benefits.

Incorporation of nucleotides in the nutritional compositions of the present invention improves intestinal barrier integrity and/or maturation, which is beneficial for preterm and term infants with less developing intestinal flora and thus slower intestinal barrier maturation.

Suitable nucleotides and/or nucleosides for use in the nutritional composition include 5'-monophosphate cytidine, 5'-monophosphate uridine, 5'-monophosphate adenosine, 5'-1-monophosphate guanosine And/or one or more of 5'-monophosphate monophosphate, such as 5'-monophosphate cytidine, 5'-monophosphate uridine, 5'-monophosphate adenosine, 5'-monophosphate guanosine and 5'-monophosphate glucoside.

The nucleotide system is at least about 5 mg/L, including at least about 10 mg/L, including about 10 mg/L. To a total of about 200 mg/L, including from about 42 mg/L to about 102 mg/L, and the total amount of nucleotides comprising at least about 72 mg/L of the nutritional product is present in the nutritional composition.

In a particular embodiment, when the nutritional composition is a nutritional powder, the nucleotides can be at least about 0.007%, including from about 0.0078% to about 0.1556%, and include about 0.056% (by weight of the nutritional powder), or per 100 g of the nutritional powder is at least about 0.007 g, including from about 0.0078 g to about 0.1556 g, and is present in an amount comprising about 0.056 g of nucleotide.

In another specific embodiment, when the nutritional composition is a ready-to-feed nutrient solution, the nucleotides are at least about 0.001%, including from about 0.001% to about 0.017%, and include about 0.0071% (by weight of the nutritional powder) Or at least about 0.001 g per 100 g of ready-to-feed nutrient solution, including from about 0.001 g to about 0.017 g, and is present in an amount comprising about 0.0071 g of nucleotide.

In another specific embodiment, when the nutritional composition is a concentrated nutrient solution, the nucleotides are at least about 0.0019%, including from about 0.0019% to about 0.0382%, and include about 0.0138% (by weight of the nutritional powder) Or at least about 0.0019 g per 100 g of concentrated nutrient solution, including from about 0.0019 g to about 0.0382 g, and is present in an amount comprising about 0.0138 g of nucleotides.

Mass of nutrients

The nutritional composition can be formulated to include at least one of protein, fat, and carbohydrate. In many embodiments, the nutritional composition will contain one or more HMOs and comprise at least one of a fat, a protein, and a carbohydrate.

Although the total concentration or total amount of fat, protein and carbohydrate may depend on the type of product (ie, breast milk fortifier, premature infant formula, infant formula, etc.), product form (ie, nutritive solids, powder, ready-to-drink liquid, The concentrate or nutrient strip) and the intended user's target dietary requirements vary, but such concentrations or amounts are most typically within one of the following specific ranges, including any other essential fats, proteins, and/or as described herein. Carbohydrate ingredients.

For liquid formulations, the carbohydrate concentration is most typically from about 5% to about the weight. Within 40%, including from about 7% to about 30%, including from about 10% to about 25%; the fat concentration is most typically from about 1% to about 30% by weight, including from about 2% to about 15%, Also included is from about 3% to about 10%; and the protein concentration is most typically in the range of from about 0.5% to about 30% by weight, including from about 1% to about 15%, and also including from about 2% to about 10%.

For liquid human milk fortifier products, the carbohydrate concentration is most typically in the range of from about 10% to about 75% by weight of the breast milk fortifier, including from about 10% to about 50%, including from about 20% to about 40%; Typically in the range of from about 10% to about 40% by weight of the breast milk fortifier, including from about 15% to about 37%, and also including from about 18% to about 30%; and the protein concentration is most often at the weight of the breast milk fortifier It ranges from about 5% to about 40%, including from about 10% to about 30%, and also includes from about 15% to about 25%.

The amount of carbohydrate, fat and/or protein in any of the liquid nutritional compositions described herein may additionally or alternatively be characterized as a percentage of total calories in the liquid nutritional composition, as described in the following table. These macronutrients of the liquid nutritional compositions used in the method of the present invention are most commonly formulated in any of the calorie ranges (Examples A-F) described in the table below (each value is preceded by the term "about").

In one embodiment, the liquid infant formula (ie, the food liquid and concentrate) comprises a protein component which may comprise from about 7.5% to about 25% of the calorie content of the formula; the carbohydrate component may comprise a total calorie content of the infant formula of about 35%; % to about 50%; and the fat component can account for the baby The formulations have a total calorie content of from about 30% to about 60% of their examples. These ranges are provided by way of example only and are not intended to be limiting. The other suitable ranges are noted in the table below (each value is preceded by the term "about").

When the nutritional product is in the form of a powdered adult, child, young child, neonatal, pediatric, preterm or term infant formula, the protein component is from about 5% to about 35% by weight of the preterm or term infant formula, including From 8% to about 12%, and including from about 10% to about 12%; the fat component is from about 10% to about 35% by weight of the preterm or term infant formula, including from about 25% to about 30% And comprising from about 26% to about 28%; and the carbohydrate component is from about 30% to about 85%, including from about 45% to about 60%, including about 50% by weight of the preterm or term infant formula % to about 55% is present.

For powdered breast milk fortifiers, the protein component is present from about 1% to about 55% by weight of the breast milk fortifier, including from about 10% to about 50%, and includes from about 10% to about 30%; The fraction is present from about 1% to about 30% by weight of the breast milk fortifier, including from about 1% to about 25%, and includes from about 1% to about 20%; and the carbohydrate component is a breast milk fortifier The weight ranges from about 15% to about 75%, including from about 15% to about 60%, including from about 20% to about 50%.

The total or total concentration of fat, carbohydrate and protein in the powdered nutritional composition used in the method of the invention may vary significantly depending on the selected composition and the intended user's dietary or medical need. Other suitable examples of large nutrient concentrations are set forth below. In this case, the total or total concentration refers to all sources of fat, carbohydrate and protein in the powdered product. For powdered nutritional compositions, these total or total concentrations are most commonly and preferably formulated in any of the specific ranges described in the table below (each value is preceded by a term "approximately").

When the nutritional product is a nutritional bar, the protein component is from about 5% to about 45% by weight of the nutritional bar, including from about 15% to about 35%, and includes from about 20% to about 30%; The fraction is present in an amount from about 2% to about 25%, including from about 5% to about 20%, and including from about 10% to about 15% by weight of the nutritional bars; and the carbohydrate component is based on the weight of the nutritional bars From about 2% to about 25%, including from about 5% to about 20%, including from about 5% to about 15%.

fat

The nutritional composition used in the methods of the invention may comprise one or more sources of fat. Suitable fat sources for use herein include any fat or fat source suitable for use in oral nutritional products and compatible with the essential ingredients and characteristics of such products. For example, in one particular embodiment, the other fat is derived from a long chain polyunsaturated fatty acid and/or a short chain fatty acid.

Other non-limiting examples of suitable fats or sources thereof for use in the nutritional products described herein include coconut oil, fractionated coconut oil, soybean oil, corn oil, olive oil, safflower oil, high oleic safflower oil, oleic acid ( EMERSOL 6313 OLEIC ACID, Cognis Oleochemicals, Malaysia), MCT oil (medium chain triglyceride), sunflower oil, high oleic sunflower oil, palm oil and palm kernel oil, palm oil, rapeseed oil, aquatic animal oil, fish oil , fungal oil, algae oil, cottonseed oil and combinations thereof.

protein

The nutritional composition used in the method of the invention may additionally comprise a protein. Any protein that is suitable for use in an oral nutritional composition and that is compatible with the essential ingredients and characteristics of such products Sources are all suitable for use in nutritional compositions.

Non-limiting examples of suitable proteins or sources thereof for use in a nutritional product include hydrolyzed, partially hydrolyzed or unhydrolyzed protein or protein sources, which may be derived from any known or otherwise suitable source, such as milk (eg, casein, Whey), animals (eg meat, fish), cereals (eg rice, corn), vegetables (eg soybean) or combinations thereof. Non-limiting examples of such proteins include milk protein isolates, milk protein concentrates as described herein, casein isolates, extensively hydrolyzed casein, whey proteins, casein sodium or casein calcium, whole fat milk , partially or completely skim milk, soy protein isolate, soy protein concentrate, and the like. In a particular embodiment, the nutritional composition comprises a protein source derived from milk proteins of human and/or bovine origin.

Carbohydrate

The nutritional product used in the methods of the present invention may additionally comprise any carbohydrate suitable for use in an oral nutritional product and compatible with the essential ingredients and characteristics of such products.

Non-limiting examples of suitable carbohydrates or sources thereof for use in the nutritional products described herein can include maltodextrin, hydrolyzed or modified starch or corn starch, glucose polymer, corn syrup, corn syrup solids, derived from Carbohydrate, pea-derived carbohydrates, potato-derived carbohydrates, tapioca starch, sucrose, glucose, fructose, lactose, high fructose corn syrup, honey, sugar alcohols (eg maltitol, erythritol, sorbus) Sugar alcohols), artificial sweeteners (such as sucralose, potassium sulfonate, stevia) and combinations thereof. A particularly desirable carbohydrate is low dextrose equivalent (DE) maltodextrin.

Other ingredients that exist as the case may be

The nutritional composition used in the method of the present invention may additionally comprise other components as appropriate, which may improve the physical, chemical, aesthetic or processing characteristics of the product, or be used as a pharmaceutical or other nutritional component when used in a target population. Many of such optional ingredients are known or otherwise suitable for use in a medical food or other nutritional product or pharmaceutical dosage form, and may also be used in the compositions herein, with the proviso that the ingredients present as the case may be Oral vote It is safe and compatible with the basic and other ingredients in the selected product form.

Non-limiting examples of such optional ingredients include preservatives, emulsifiers, buffers, fructooligosaccharides, galactooligosaccharides, polydextrose, and other probiotics (eg, other neutral or acidic HMOs, Inulin, oligofructose, polydextrose, pectin hydrolysate and gel), probiotics (eg B. animalis subsp. lactis BB-12), Leiter B-bacteria HN019 ( B.lactis HN019), B-bacteria Bi07, Lactobacillus rhamnosus GG ( L. rhamnosus GG), Lactobacillus rhamnosus HN001, Lactobacillus acidophilus LA-5 ( L.acidophilus LA -5), Lactobacillus acidophilus NCFM, Lactobacillus brevis CECT5716 ( L. fermentum CECT5716), Rhizopus BB536 ( B. longum BB536), Rhizopus AH1205, Rhizopus AH1206, Bifidobacterium breve M-16V ( B.breve M-16V), Lactobacillus reuteri ATCC 55730 ( L. reuteri ATCC 55730), Lactobacillus reuteri ATCC PTA-6485, Lactobacillus reuteri DSM 17938), postbiotics (probiotics) Metabolites), long-chain polyunsaturated fatty acids (DHA, ARA, DPA, EPA, etc.), nucleotides, antioxidants/anti-inflammatory compounds including tocopherols, carotenoids , ascorbate/vitamin C, ascorbyl palmitate, polyphenols (eg curcumin), glutathione and superoxide dismutase (melon), human and/or bovine origin milk proteins, soy protein, pea protein, human And/or other biologically active factors of bovine origin (eg growth hormone, cytokines, TFG-β), glyceryl tributyrate or other monoglycerides containing SCFA, diglycerides or triglycerides, sources of breast milk Lipids, free amino acids or peptides (eg HMB, arginine, leucine and/or glutamic acid), lactose, other water-soluble vitamins and fat-soluble vitamins, minerals and trace elements, pharmaceutically active substances Other nutrients, colorants, flavoring agents, thickening agents and stabilizers, emulsifiers, lubricants, and the like as described herein.

The nutritional composition may additionally comprise a sweetener, preferably at least one sugar alcohol such as maltitol, erythritol, sorbitol, xylitol, mannitol, isomalt and lactitol, and is also preferred. Including at least one artificial or high-potency sweetener, such as acesulfame Potassium, aspartame, sucralose, saccharin, stevia and tagatose. Such sweeteners, especially combinations of sugar alcohols and artificial sweeteners, are particularly suitable for formulating liquid beverage embodiments of the present invention having the desired flavor characteristics. Such sweetener combinations are particularly effective in masking occasionally undesired flavors associated with the addition of vegetable proteins to liquid beverages. The concentration of sugar alcohol in the nutritional product as the case may be at least 0.01% by weight of the nutritional product, including from about 0.1% to about 10%, and also including from about 1% to about 6%. The concentration of the artificial sweetener, as appropriate, may range from about 0.01% by weight of the nutritional product, including from about 0.05% to about 5%, and also from about 0.1% to about 1.0%.

Glidants or anti-caking agents can be included in the nutritional compositions as described herein to delay agglomeration or agglomeration of the powder over time and to facilitate the flow of the powder embodiment from its container. Any of the known glidants or anti-caking agents known or otherwise suitable for use in nutritional powders or product forms are suitable herein, non-limiting examples of which include tricalcium phosphate, citrate, and combinations thereof. The concentration of the flow aid or anti-caking agent in the nutritional composition will vary depending on the form of the product, other selected ingredients, the desired flow characteristics, and the like, but is most typically from about 0.1% to about 4% by weight of the nutritional composition. Within the range, including from about 0.5% to about 2%.

Stabilizers may also be included in the nutritional compositions. Any stabilizer known or otherwise suitable for use in a nutritional composition is also suitable for use herein, some non-limiting examples of which include gums such as xanthan gum. The stabilizer may comprise from about 0.1% to about 5.0% by weight of the nutritional composition, including from about 0.5% to about 3%, including from about 0.7% to about 1.5%.

The nutritional composition may additionally comprise any of a variety of other vitamins or related nutrients, non-limiting examples of which include vitamin A, vitamin D, vitamin E, vitamin K, thiamine, riboflavin, pyridoxine, vitamin B. ₁₂ , carotenoids (such as β-carotene, zeaxanthin, lutein, lycopene), niacin, folic acid, pantothenic acid, biotin, vitamin C, choline, inositol, its salts and derivatives, And their combinations.

The nutritional composition may additionally comprise any of a variety of other additional minerals, non-limiting examples of which include calcium, phosphorus, magnesium, iron, zinc, manganese, copper, sodium, potassium, molybdenum, chromium, chlorine Compounds and combinations thereof.

Production method

The nutritional compositions used in the methods of the present invention can be prepared by any known or otherwise effective manufacturing technique for preparing the solid or liquid form of the selected product. Many of these techniques are known to be useful in any established product form (such as nutrient solutions, nutritional powders, and nutritional bars) and are readily applied by a person of ordinary skill to the nutritional compositions described herein.

Thus, the nutritional compositions used in the methods of the present invention can be prepared by any of a variety of known or otherwise effective methods of formulation or manufacture. In a suitable manufacturing process, for example, at least three separate pastes are prepared, including a fat-packed protein (PIF) slurry, a carbohydrate-mineral (CHO-MIN) slurry, and a water-in-package (PIW) slurry. The PIF slurry is formed by heating and mixing an oil (such as rapeseed oil, corn oil, etc.), followed by adding an emulsifier (such as lecithin), a fat-soluble vitamin, and a part of all proteins under continuous heating and stirring. (eg milk protein concentrate, etc.). CHO-MIN slurry is formed by adding the following substances to water under heating and stirring: minerals (such as potassium citrate, dipotassium phosphate, sodium citrate, etc.), traces and ultra-trace minerals (TM/UTM) Premix), thickener or suspending agent (eg crystalline avermectin, gellan gum, carrageenan). The resulting CHO-MIN slurry is held under continuous heating and stirring for 10 minutes, followed by the addition of other minerals (such as potassium chloride, magnesium carbonate, potassium iodide, etc.), and/or carbohydrates (eg, HMO, fructooligosaccharides, sucrose, corn). Syrup, etc.). The PIW slurry is then formed by mixing the remaining protein, if any, with heating and stirring.

The resulting slurry is then blended under heating and the pH is adjusted to 6.6-7.0, after which the composition is subjected to high temperature short time (HTST) processing during which the composition is heat treated, emulsified and homogenized. Then it is allowed to cool. Water-soluble vitamins and ascorbic acid are added, pH is adjusted to the desired range if necessary, flavoring is added, and water is added to achieve the desired total solids content. The composition is then aseptically packaged to form a sterile encapsulated nutritional emulsion. The emulsion can then be further diluted, heat treated and packaged to form a ready-to-eat or concentrate solution. Or it may be heat treated and subsequently processed and packaged in the form of a recoverable powder (eg, spray dried, dry blended, coalesced powder).

Nutritional solids, such as spray-dried nutritional powders or dry-mixed nutritional powders, can be prepared by any known or otherwise effective collection of techniques suitable for the preparation and formulation of nutritional powders.

For example, when the nutritional powder is a spray dried nutritional powder, the spray drying step can likewise include any spray drying technique known or otherwise suitable for use in the manufacture of nutritional powders. Many different spray drying methods and techniques are known for use in the field of nutrition, all of which are suitable for use in the manufacture of spray dried nutritional powders herein.

A method of preparing a spray-dried nutritional powder comprises forming and homogenizing an aqueous slurry or liquid comprising pre-digested fat, and optionally protein, carbohydrate and other fat sources, followed by spray drying the slurry or liquid to produce Spray dried nutritional powder. The method can further comprise the steps of spray drying, dry mixing, or otherwise adding other nutrients, including any one or more of the ingredients described herein, to the spray dried nutritional powder.

The nutritional composition can be in the form of a strip. In a suitable manufacturing process, for example, safflower oil, lecithin, glycerin, water and flavoring agents are added to the mixer. A dry powder component and a vitamin and mineral premix were added to the mixer and mixed for 1 minute. Corn syrup (heated to 95-105 °F) was added to the mixer and mixed for 2 minutes. Soy chips and marshmallow pieces were added to the mixer and mixed for 2 minutes. Cool chocolate candy balls were added to the mixer and mixed for 1 minute. The mixture is formed into a strip. Apply a coating (preheated to 95-100 °F). Nutrient bars can be made using a number of different ingredients and mixing procedures.

Other suitable methods for preparing a nutritional product are described, for example, in U.S. Patent No. 6,365,218 (Borschel et al.), U.S. Patent No. 6,589,576 (Borschel et al.), U.S. Patent No. 6,306,908 (Carlson et al.), U.S. Patent Application No. 20030118703 A1 In Nguyen et al., the description of which is incorporated herein by reference. degree.

Product form

The compositions used in the methods of the invention may be formulated and administered in the form of known or otherwise suitable oral products. Any solid, liquid, semi-solid, semi-liquid or powder product form, including combinations or variations thereof, is suitable herein for the purpose of allowing the ingredients (also as defined herein) to be safely and effectively The mouth is delivered to the individual.

The compositions used in the methods of the present invention are desirably formulated in the form of a dietary product, which is defined herein as embodiments comprising the ingredients of the present invention which comprise at least one of a fat, a protein and a carbohydrate and are preferably It also contains product forms of vitamins, minerals or a combination thereof.

The nutritional composition may be formulated with sufficient variety and amount of nutrients to provide a unique, primary or supplemental source of nutrition, or to provide an individual nutritional product for a particular condition or a nutritional product having the desired nutritional benefits as described below.

Some illustrative, non-limiting examples of particular products suitable for use in accordance with the present invention include premature infant formula, term infant formula, breast milk fortifier, pediatric formulation, adult nutritional formula, elderly nutritional formula, medical formula, aged nutritional formula, diabetes Nutritional formulas, nutritional bars and their analogues.

Nutrient solution

The nutrient solution includes both a concentrated nutrient solution and an instant nutrient solution. Such nutrient solutions are most often formulated as suspensions or emulsions, although other liquid forms are within the scope of the invention.

Suitable nutritional emulsions can be aqueous emulsions containing proteins, fats and carbohydrates. Such emulsions are generally in the form of a flowable or drinkable liquid at a temperature of from about 1 ° C to about 25 ° C and are typically in the form of oil-in-water, water-in-oil or complex aqueous emulsions, although such emulsions most typically have a continuous aqueous phase and A continuous oil phase in the form of an oil-in-water emulsion.

The nutritional emulsion can be and is generally stable to storage. The nutritional emulsion typically contains up to about 95% water by weight, based on the weight of the nutritional emulsion, including from about 50% to 95%, and also includes about From 60% to about 90%, and also from about 70% to about 85% water. The nutritional emulsion can have a variety of product densities, but most typically has greater than about 1.03 g/mL, including greater than 1.04 g/mL, including greater than 1.055 g/mL, including from about 1.06 g/mL to about 1.12 g/mL, and also includes A density of from 1.085 g/mL to about 1.10 g/mL.

The nutritional emulsion can have a calorie density tailored to the nutritional needs of the end user, although in most cases the emulsion typically comprises at least 19 kcal/fl oz (660 kcal/l), more typically about 20 kcal/fl oz (675-680 kcal). /l) to about 25 kcal/fl oz (820 kcal/l), even more typically about 20 kcal/fl oz (675-680 kcal/l) to about 24 kcal/fl oz (800-810 kcal/l). In general, the 22-24kcal/fl oz formula is more commonly used in preterm or low birth weight infants, and the 20-21kcal/fl oz (675-680 to 700 kcal/l) formula is more commonly used in term infants. In some embodiments, the emulsion can have a caloric density of from about 50 to 100 kcal/l to about 660 kcal/l, including from about 150 kcal/l to about 500 kcal/l. In some embodiments, the emulsion can have a caloric density of 25, or 50, or 75, or 100 kcal/l.

The nutritional emulsion can have a pH range of from about 3.5 to about 8, but most advantageously ranges from about 4.5 to about 7.5, including from about 5.5 to about 7.3, including from about 6.2 to about 7.2.

While the serving component of the nutritional emulsion may vary depending on a variety of variables, a typical edible component will generally be at least about 1 mL, or even at least 2 mL, or even at least 5 mL, or even at least 10 mL, or even at least 25 mL, including 1 mL. To a range of about 300 mL, including from about 4 mL to about 250 mL, and including from about 10 mL to about 240 mL.

Nutritional solid

The nutritive solid can be in any solid form, but is typically a flowable or substantially flowable particulate composition, or at least a particulate composition. Particularly suitable nutritional solid product forms include spray dried, coalesced and/or dry blended powder compositions. The compositions are easily excavated and measured with a spoon or other similar device, and it is contemplated that the user will readily reconstitute it with an aqueous liquid (usually water) to form a nutritional composition for immediate oral or enteral use. In this case, "immediately" use generally means about 48 hours, most usually about 24 hours. In time, it is better to recover.

The nutritional powder can be reconstituted with water to a calorie density tailored to the end user's nutritional needs prior to use, although in most cases the powder is reconstituted with water to form at least 19 kcal/fl oz (660 kcal/l), more typically about 20 kcal. /fl oz (675-680 kcal/l) to about 25 kcal/fl oz (820 kcal/l), even more typically about 20 kcal/fl oz (675-680 kcal/l) to about 24 kcal/fl oz (800-810 kcal/l) Compositions. In general, the 22-24kcal/fl oz formula is more commonly used in preterm or low birth weight infants, and the 20-21kcal/fl oz (675-680 to 700 kcal/l) formula is more commonly used in term infants. In some embodiments, the reconstituted powder can have a caloric density of from about 50 to 100 kcal/l to about 660 kcal/l, including from about 150 kcal/l to about 500 kcal/l. In some embodiments, the emulsion can have a caloric density of 25, or 50, or 75, or 100 kcal/l.

Instance

Exemplary compositions are shelf stable nutritional compositions prepared according to the methods of manufacture described herein, and thus, unless otherwise indicated, each exemplary composition includes examples of aseptic processing and embodiments of the autoclave package.

Example 1-5

Predictive Examples 1-5 illustrate ready-to-eat nutritional emulsions, the ingredients of which are listed in the table below. Unless otherwise stated, all listed ingredients are in kilograms.

AN=when needed

Example 6-10

Predictive Examples 6-10 illustrate the ready-to-eat nutritional emulsions of the present invention, the ingredients of which are listed in the table below. Unless otherwise stated, all listed ingredients are in kilograms.

AN=when needed

Example 11-15

Predictive Examples 11-15 illustrate concentrated liquid emulsions, the ingredients of which are listed in the table below. Unless otherwise stated, all listed ingredients are in kilograms.

AN=when needed

Example 16-20

Predictive Examples 16-20 illustrate ready-to-eat nutritional emulsions whose ingredients are listed in the table below. Unless otherwise stated, all listed ingredients are in kilograms.

AN=when needed

Example 21-25

Predictive Examples 21-25 illustrate concentrated liquid emulsions, the ingredients of which are listed in the table below. Unless otherwise stated, all listed ingredients are in kilograms.

AN=when needed

Example 26-30

Predictive Examples 26-30 illustrate breast milk fortifier liquids, the ingredients of which are listed in the table below. Unless otherwise stated, all listed ingredients are in kilograms.

Example 31-35

Predictive Examples 31-35 illustrate spray dried nutritional powders whose ingredients are listed in the table below. Unless otherwise stated, all listed ingredients are in kilograms.

AN=when needed

Example 36-40

Predictive Examples 36-40 illustrate nutritional bars whose ingredients are listed in the table below. Unless otherwise stated, all listed ingredients are in kilograms.

Example 41-45

Predictive Examples 41-45 illustrate liquid formulations, the ingredients of which are listed in the table below. Unless otherwise stated, all listed ingredients are in kilograms.

Example 46-50

Predictive Examples 46-50 illustrate liquid formulations whose ingredients are listed in the table below. Unless otherwise stated, all listed ingredients are in kilograms.

Example 51

A stool sample from eight human infants (a group of four breast-fed infants and another group of four formula-fed infants) was used as an inoculum for lactose-N-neotetraose (LNnT) anaerobic fermentation (37 ° C) . The supernatant from the fermentation broth was sampled at 0 hours, 3 hours, and 6 hours. A culture in which no HMO was added was used as a control group. A sample of the fermentation medium (blank group) was also analyzed, which constituted approximately 90% of the starting culture volume.

Samples were extracted and divided into aliquots for analysis on GC/MS and LC/MS/MS platforms. GABA and agmatine ions were identified in the chromatogram and the peak area was integrated for quantitative analysis. The data in Tables 1 and 2 obtained show the relative ratio of GABA and agmatine compared to the blank group in breastfed and formula-fed infants.

The present invention has been described by way of illustration of several embodiments, and the invention is not limited by the scope of the accompanying claims. Other advantages and modifications will be apparent to those skilled in the art.

Claims (13)

Use of a nutritional composition comprising at least one breast milk oligosaccharide for the manufacture of a medicament for enhancing the learning and memory of an individual in need thereof, wherein the breast milk oligosaccharide is selected from the group consisting of lactose-N-neotetraose, lactose -N-tetraose, disialylated lactose-N-tetraose, 3'-trehalosyl lactose and 3'-sialyl lactose. The use of claim 1, wherein the at least one breast milk oligosaccharide comprises lactose-N-neotetraose or lactose-N-tetraose. The use of claim 2, wherein the at least one breast milk oligosaccharide comprises lactose-N-neotetraose. The use of claim 2, wherein the at least one breast milk oligosaccharide comprises lactose-N-tetraose. The use of claim 1, wherein the nutritional composition is a liquid and comprises from about 0.001 mg/mL to about 20 mg/mL of the breast milk oligosaccharide. The use of claim 5, wherein the nutritional composition is a liquid and comprises from about 0.001 mg/mL to about 10 mg/mL of the breast milk oligosaccharide. The use of claim 6, wherein the nutritional composition is a liquid and comprises from about 0.001 mg/mL to about 5 mg/mL of the breast milk oligosaccharide. The use of claim 1, wherein the nutritional composition is a powder and comprises from about 0.0005% to about 5% of the breast milk oligosaccharide by weight of the powder. The use of claim 8, wherein the nutritional composition is a powder and comprises from about 0.01% to about 1% by weight of the powder of the breast milk oligosaccharide. The use of claim 1, wherein the nutritional composition further comprises at least one of a fat, a protein or a carbohydrate. The use of claim 10, wherein the nutritional composition further comprises a protein. The use of claim 1, wherein the nutritional composition is an infant formula. The use of any one of claims 1 to 4 and 10 to 12, wherein the nutritional composition is a nutritional bar, a nutrient solution or a nutritional powder.