Composition for promoting brain function development of infants and children

Abstract

And the influence of the NMN on the infant is clear. The subject of the invention is to provide a composition capable of promoting brain function development of infants and children. Provided is a composition for promoting brain function development in infants, comprising nicotinamide adenine dinucleotide (NAD)-related substances, or a food or pharmaceutically acceptable salt thereof. The brain function development is preferably a development in any field selected from the group consisting of communication, major exercises, fine exercises, solving problems, and personal / social components.

Description

Technical Field

[0001] The present invention relates to a composition for promoting the development of brain function in infants and children. The present invention is useful in the fields of development, health and nutrition of infants and young children, and in the fields of manufacturing food and beverages therefor. Background Art

[0002] Nicotinamide mononucleotide (NMN) is a precursor of nicotinamide adenine dinucleotide (NAD+) required for human life. As the amount of NAD in the body decreases with aging, it is believed that taking NMN, a precursor of NAD, is effective to cope with this.

[0003] For example, non-patent documents 1 and 2 disclose that based on the experimental results of administering NMN to aged mice, the recovery of the amount of NAD+ in the brain may promote the binding of brain nerves and blood vessels. Non-patent document 3 shows that with aging, NAD+ in the hippocampus of the mouse brain decreases, which is related to allergic behavior to fear and anxiety, and the administration of NMN may be able to alleviate allergic behavior to fear and anxiety. Non-patent document 4 reports that learning ability and memory ability are improved by administering melatonin and NMN to aged rats alone or in combination. In addition, non-patent document 5 shows that the administration of NMN to drug-induced depression model mice can improve drug-induced depression-like symptoms, which is related to mitochondrial energy metabolism in the brain. Patent document 1 describes an Alzheimer's disease-like symptom alleviator, characterized in that one selected from β-NMN, its pharmacologically acceptable salt, and their solvates is used as an active ingredient. The document states that the experimental results on Alzheimer's disease model mice suggest that β-NMN may be able to prevent spatial cognitive impairment and learning and memory impairment caused by β-amyloid protein.

[0004] On the other hand, the addition of NMN to infant food and drink has been studied. For example, Patent Document 2 describes a powdered milk composition for infants, comprising at least one of the nicotinamide riboside compounds selected from the group consisting of nicotinamide riboside (NR, I), nicotinic acid riboside (NAR, II), nicotinamide mononucleotide (NMN, III), reduced nicotinamide riboside (NRH, IV), reduced nicotinic acid riboside (NARH, V), nicotinamide riboside triacetate (NRTA, VI), nicotinic acid riboside triacetate (NARTA, VII), reduced nicotinamide riboside triacetate (NRH-TA, VIII) and reduced nicotinic acid riboside triacetate (NARH-TA, IX). The document also records that when piglets, which are models of infant intestinal development, ingest nicotinamide riboside, the level of short-chain fatty acids in feces increases. In addition, Patent Document 3 describes a food and drink for infants, characterized in that it contains an effective amount of NMN. The document also states that the IgM concentration, IgG concentration and CD8 positive T cell count in the blood of children aged 1.8 to 6.5 years who consumed milk powder supplemented with NMN for 30 consecutive days increased.

[0005] On the other hand, there are reports that the length of breastfeeding affects the intelligence of children (Non-patent Document 6). In addition, there are reports that mice raised by mothers supplemented with nicotinamide riboside (NR) have less fat and a tendency to have larger brains at weaning; NR stimulates lactation and stimulates the production of brain-derived neurotrophic factor (BDNF); due to NR supplementation, the BDNF content in breast milk is 2 times higher, which suggests that NR supplementation is a powerful mechanism for the development and health of newborns (Patent Document 4, Non-patent Document 7).

[0006] Prior art literature

[0007] Patent Literature

[0008] Patent Document 1: Japanese Patent Application Publication No. 2022-080787

[0009] Patent Document 2: Japanese Patent Application No. 2019-513385

[0010] Patent Document 3: International Publication No. WO2020 / 166527

[0011] Patent Document 4: International Publication WO2018 / 102426 (Japanese Patent Publication No. 2020-504168,

[0012] Japanese Patent No. 7136795)

[0013] Non-patent literature

[0014] Non-patent literature 1: Redox Biol. 2019Jun; 24: 101192

[0015] Non-patent literature 2: Geroscience. 2020Apr; 42(2): 527-546.

[0016] Non-patent literature 3: NPJ Aging Mech Dis. 2018 Nov 8; 4: 10.

[0017] Non-patent literature 4: Neuroscience. 2019 Dec 15; 423: 29-37.

[0018] Non-patent literature 5: J Affect Disord. 2020 Feb 15; 263: 166-174.

[0019] Non-patent literature 6: Breastfeed Med.2021; https: / / doi.org / 10.1089 / bfm.2020.0364

[0020] Non-patent literature 7: Cell Rep. 2019 Jan 22; 26(4): 969-983.e4. Summary of the invention

[0021] Problem that the invention aims to solve

[0022] Although NMN has been reported to act as an anti-aging substance, the effect of NMN contained in breast milk on the development of infant brain function is unclear.

[0023] Solutions for solving problems

[0024] The present invention provides the following contents.

[0025] [1] A composition for promoting the development of brain function in infants and children, comprising a nicotinamide adenine dinucleotide (NAD)-related substance, or a salt thereof that is acceptable as a food or a drug.

[0026] [2] The composition according to item 1, wherein the brain function development is development in any area selected from the group consisting of communication, gross motor skills, fine motor skills, problem solving, and personal / social skills.

[0027] [3] The composition according to 1 or 2, wherein the brain function development is development in any area selected from the group consisting of fine motor, problem solving, and personal / social.

[0028] [4] The composition according to any one of 1 to 3, wherein the brain function development is development in the personal / social domain.

[0029] [5] The composition according to any one of 1 to 4, wherein the brain function development is the brain function development of infants 23 months old and older.

[0030] [6] The composition according to any one of 1 to 5, which is for ingestion by infants 6 months old or younger.

[0031] [7] The composition according to any one of 1 to 6, which is in any form selected from the group consisting of formula milk powder, formula liquid milk, and breast milk substitute food.

[0032] [8] The composition according to any one of 1 to 7, wherein the concentration of the NAD-related substance or a salt thereof acceptable as a food or a drug when ingested is 1.9 μg / mL or more in terms of nicotinamide mononucleotide (NMN).

[0033] [9] The composition according to any one of 1 to 8, wherein the concentration of the NAD-related substance or a salt thereof acceptable as a food or a drug when ingested is 3.0 μg / mL or more in terms of NMN.

[0034]

[10] The composition according to any one of 1 to 9, which is in the form of a formula milk powder and contains 1.1 mg or more of an NAD-related substance or a salt thereof acceptable as a food or drug per 100 g, calculated as NMN.

[0035]

[11] The composition according to any one of 1 to 10, which is in the form of a formula milk powder and contains 1.8 mg or more of an NAD-related substance or a salt thereof acceptable as a food or drug per 100 g, calculated as NMN.

[0036]

[12] The composition according to any one of 1 to 11, wherein the NAD-related substance is NMN.

[0037]

[13] A method for promoting the development of brain function in infants, the method comprising the following steps: preparing an artificial nutritional composition containing NAD-related substances or salts thereof acceptable as food or medicine; and allowing an infant who needs to promote the development of brain function to ingest the prepared composition. A non-therapeutic method for promoting the development of brain function in infants, the method comprising the following steps: allowing an infant who wants to promote the development of brain function to ingest a composition containing NAD-related substances or salts thereof acceptable as food or medicine. A composition for use in a method for promoting the development of brain function in infants, the composition comprising NAD-related substances or salts thereof acceptable as food or medicine. Use of a composition containing NAD-related substances or salts thereof acceptable as food or medicine in the preparation of a composition for promoting the development of brain function in infants. Use of a composition containing NAD-related substances or salts thereof acceptable as food or medicine for promoting the development of brain function in infants.

[0038]

[14] The method, composition or use according to item 13, wherein the brain function development is development in any area selected from the group consisting of communication, gross motor skills, fine motor skills, problem solving and personal / social skills.

[0039]

[15] The method, composition, or use according to item 13 or 14, wherein the brain function development is development in any area selected from the group consisting of fine motor, problem solving, and personal / social.

[0040]

[16] The method, composition or use according to any one of 13 to 15, wherein the brain function development is development in the personal / social domain.

[0041]

[17] The method, composition or use according to any one of 13 to 16, wherein the brain function development is the brain function development of infants 23 months old and above.

[0042]

[18] The method, composition or use according to any one of 13 to 17, which is for ingestion by infants under 6 months old.

[0043]

[19] The method, composition or use according to any one of 13 to 18, which is in any form selected from the group consisting of formula milk powder, formula liquid milk and breast milk substitute food.

[0044]

[20] The method, composition or use according to any one of 13 to 19, wherein the concentration of the NAD-related substance or its salt acceptable as a food or medicine when ingested is 1.9 μg / mL or more in terms of NMN.

[0045]

[21] The method, composition or use according to any one of 13 to 20, wherein the concentration of the NAD-related substance or its salt acceptable as a food or medicine when ingested is converted into NMN, and the concentration of NMN is 3.0 μg / mL or more.

[0046]

[22] The method, composition or use according to any one of 13 to 21, which is in the form of formula milk powder and contains 1.1 mg or more of NAD-related substances converted to NMN per 100 g, or a salt thereof acceptable as a food or drug.

[0047]

[23] The composition according to any one of 13 to 22, which is in the form of a formula milk powder and contains 1.8 mg or more of an NAD-related substance converted to NMN, or a salt thereof acceptable as a food or drug, per 100 g.

[0048]

[24] The composition according to any one of 13 to 23, wherein the NAD-related substance is NMN.

[0049] The present invention also provides the following contents.

[0050]

[31] A composition for promoting the development of brain function in infants and children, comprising nicotinamide mononucleotide (NMN).

[0051]

[32] The composition according to 31, wherein the brain function development is development in any area selected from the group consisting of communication, gross motor, fine motor, problem solving and personal / social.

[0052]

[33] The composition according to 31 or 32, wherein the brain function development is development in any area selected from the group consisting of fine motor, problem solving, and personal / social.

[0053]

[34] The composition according to any one of 31 to 33, wherein the brain function development is development in the personal / social domain.

[0054]

[35] The composition according to any one of 31 to 34, wherein the brain function development is the brain function development of infants 23 months old and older.

[0055]

[36] The composition according to any one of 31 to 35, which is for ingestion by infants under 6 months old.

[0056]

[37] The composition according to any one of 31 to 36, which is in any form selected from the group consisting of formula milk powder, formula liquid milk and breast milk substitute food.

[0057]

[38] The composition according to any one of 31 to 37, wherein the concentration of NMN when ingested is 1.9 μg / mL or more.

[0058]

[39] The composition according to any one of 31 to 38, wherein the concentration of NMN when ingested is 3.0 μg / mL or more.

[0059]

[40] The composition according to any one of 31 to 39, which is in the form of formula milk powder and contains 1.1 mg or more of NMN per 100 g.

[0060]

[41] The composition according to any one of 31 to 40, which is in the form of formula milk powder and contains 1.8 mg or more of NMN per 100 g.

[0061]

[42] A method for promoting the development of brain function in infants, the method comprising the following steps: manufacturing an artificial nutritional composition containing NMN; allowing an infant who needs to promote brain function development to ingest the manufactured composition. A non-therapeutic method for promoting the development of brain function in infants, the method comprising the following steps: allowing an infant who wants to promote brain function development to ingest a composition containing NMN. A composition for use in a method for promoting the development of brain function in infants, the composition comprising NMN. Use of a composition containing NMN in the manufacture of a composition for promoting the development of brain function in infants. Use of a composition containing NMN for promoting the development of brain function in infants.

[0062]

[43] The method, composition or use according to item 12, wherein the brain function development is development in any area selected from the group consisting of communication, gross motor, fine motor, problem solving and personal / social.

[0063]

[44] The method, composition, or use according to item 12 or 13, wherein the brain function development is development in any area selected from the group consisting of fine motor, problem solving, and personal / social.

[0064]

[45] The method, composition or use according to any one of 12 to 14, wherein the brain function development is development in the personal / social domain.

[0065]

[46] The method, composition or use according to any one of 12 to 15, wherein the brain function development is the brain function development of infants 23 months old and above.

[0066]

[47] The method, composition or use according to any one of 12 to 16, which is for ingestion by infants under 6 months old.

[0067]

[48] ​​The method, composition or use according to any one of 12 to 17, which is in any form selected from the group consisting of formula milk powder, formula liquid milk and breast milk substitute food.

[0068]

[49] The method, composition or use according to any one of 12 to 18, wherein the concentration of NMN when ingested is 1.9 μg / mL or more.

[0069]

[50] The method, composition or use according to any one of 12 to 18, wherein the concentration of NMN during ingestion is 3.0 μg / mL or more.

[0070]

[51] The method, composition or use according to any one of 12 to 18, which is in the form of formula milk powder and contains 1.1 mg or more of NMN per 100 g.

[0071]

[52] The composition according to any one of 12 to 18, which is in the form of formula milk powder and contains 1.8 mg or more of NMN per 100 g.

[0072] Effects of the Invention

[0073] The composition of the present invention can contribute to the future healthy growth of infants by promoting the development of their brain functions.

[0074] Since NMN, which is an active ingredient of the composition of the present invention, is originally contained in breast milk, the composition of the present invention can safely exert the target effect on infants and children.

[0075] A composition can be provided that can promote brain function development in the same manner as breast milk nutrition even when breast milk nutrition is not available.

[0076] According to the present invention, information on the correlation between NMN ingested during infancy and brain function development is provided.

[0077] The composition of the present invention is expected to be applied to the treatment of diseases or conditions related to brain function in infants and children. In addition, the composition of the present invention is expected to be applied not only to infants, but also to promote brain function development, improve nutritional status, and maintain / enhance health in infants, children, adults, and the elderly. BRIEF DESCRIPTION OF THE DRAWINGS

[0078] Figure 1 Mean ± standard error of the inter-group comparison with a critical value of 1.922 μg / ml, *p<0.05 by Mann-Whitney U, lowNMN: n=22, highNMN: n=128

[0079] Figure 2Mean ± SEM of the inter-group comparison with a critical value of 3.089 μg / ml, *p<0.05 by Mann-Whitney U, lowNMN: n=76, highNMN: n=74

[0080] Figure 3 The distribution of NMN, NAD, NR and NA concentrations in breast milk for one month For the horizontal lines representing the distribution of NMN, NAD, NR and NA concentrations in the figure, from the lowest concentration, they represent: minimum value (NMN is 0.058μg / ml, NAD is 0.154μg / ml, NR is 0.006μg / ml, and NA is 0.000μg / ml), first quartile (NMN is 2.352μg / ml, NAD is 1.069μg / ml, NR is 0.050μg / ml, and NA is 0.000μg / ml), second quartile (NMN is 2.352μg / ml, NAD is 1.069μg / ml, NR is 0.050μg / ml, and NA is 0.000μg / ml), Quartiles (median, 3.075 μg / ml for NMN, 1.481 μg / ml for NAD, 0.119 μg / ml for NR, and 0.000 μg / ml for NA), third quartile (3.758 μg / ml for NMN, 1.958 μg / ml for NAD, 0.422 μg / ml for NR, and 0.002 μg / ml for NA), maximum value (8.043 μg / ml, 4.657 μg / ml for NAD, 1.532 μg / ml for NR, and 0.002 μg / ml for NA). DETAILED DESCRIPTION

[0081] [Active ingredients]

[0082] The composition of the present invention comprises a nicotinamide adenine dinucleotide (NAD)-related substance, such as nicotinamide mononucleotide (NMN), as an effective ingredient.

[0083] NMN has two optical isomers, α-type and β-type, but in the present invention, when expressed as NMN, it refers to β-NMN (β-Nicotinamide mononucleotide) unless otherwise specified. NMN is an intermediate metabolite of NAD+. It should be noted that the active ingredient refers to the ingredient that is beneficial to the target, and for functional labeled foods, it is sometimes called a functional-related ingredient.

[0084] In one embodiment, NMN may be contained in the composition in the form of a salt acceptable as a food or a drug. In the present invention, when it is stated that the composition contains NMN, it also includes the case where NMN is contained in the form of a salt acceptable as a food or a drug.

[0085] Salts acceptable as food or medicine refer to any salt selected from the group consisting of nitrates, sulfates, carbonates, bicarbonates, halogen salts, formates, acetates, citrates, tartrates, oxalates, fumarates, salts of saturated or unsaturated fatty acids having 3 to 20 carbon atoms, salts of carnitine and its derivatives, salts of hydroxycitric acid and its derivatives, salts of ascorbic acid and its derivatives, salts of ascorbic acid phosphate and its derivatives, sodium salts, potassium salts, calcium salts, magnesium salts, zinc salts and ammonium salts.

[0086] In one embodiment, NMN can be included in the composition in the form of an NAD-related substance or a salt thereof acceptable as a food or medicine. Regarding the present invention, when it is stated that the composition contains NMN, it also includes the case where NMN is included in the form of an NAD-related substance or a salt thereof acceptable as a food or medicine.

[0087] NAD-related substances refer to NAD or substances that can be converted into NAD in vivo. NAD acts as a coenzyme for various dehydrogenases in vivo and can form oxidized forms (NAD + ) and reduced form (NADH). NAD-related substances include: NMN, nicotinamide riboside (NR), NAD, nicotinamide (NAM) (sometimes also called niacinamide), nicotinic acid (NA), NaAD (nicotinic acid adenine dinucleotide), NaMN (nicotinic acid mononucleotide). Regarding the present invention, when expressed as NAD, unless otherwise specified, it includes oxidized NAD + The case of and the case of reduced NADH.

[0088] NAD-related substances include compounds represented by general formula (I), namely, nicotinamide mononucleotide derivatives.

[0089]

[0090] In the formula, R 1 and R 2 Each independently is an acyl group having 6 to 16 carbon atoms, and the hydrocarbon group bonded to the carbonyl carbon in the acyl group is a straight-chain or branched saturated or unsaturated hydrocarbon group. Such a compound can be manufactured by: in a solvent containing 20% ​​by mass or more of a strongly acidic liquid having a pKa of 2.0 or less, NMN is subjected to an acylation reaction using an acylating agent, wherein the acylating agent is any one selected from the group consisting of the following substances: a carboxylic acid having an acyl group having 6 to 16 carbon atoms obtained by combining a straight-chain or branched saturated or unsaturated hydrocarbon group with a carbonyl carbon, a halide of the carboxylic acid, and an anhydride of the carboxylic acid (see WO2017 / 110317).

[0091] In a preferred embodiment, the composition comprises, as an active ingredient, any one selected from NMN, NAD, NR, NA, and NAM, NaAD and NaMN; preferably, it comprises any one selected from NMN, NAD, NR and NA; more preferably, it comprises NMN.

[0092] NMN, NAD-related substances, and salts thereof that are acceptable as foods or medicines can be produced by various methods, either by synthesis or by extraction from natural products containing the substance or cultures of yeast or the like.

[0093] [use]

[0094] (Function / Role)

[0095] The composition of the present invention can be used to promote the development of brain function in infants. Brain function development includes those that can be evaluated through various existing tests. Examples of existing tests include: developmental screening (questionnaires), such as: Ages & Stages Questionnaires (registered trademark), Third Edition (ASQ (registered trademark) -3), its translated version, Tojoji-style infant analysis developmental examination method, Denver developmental screening test (DDST), its Japanese version (JDDST); individual developmental examination, such as the new version of the K-style developmental examination, etc.

[0096] In a preferred embodiment, the composition is used to promote any of the five developmental areas. The five developmental areas refer to communication (babbling, vocalization, listening and understanding), gross motor (movement of arms, legs and the whole body), fine motor (movement of fingertips and fingers), problem solving (learning and playing with toys), and personal / social (single-player games that embody sociality, playing with toys or other children). For example, the promotion of the developmental field of communication is specifically embodied in the form of promoting babbling / vocalization and improving the understanding based on listening. Therefore, in a more specific manner, the composition is used to promote any ability selected from the group consisting of babbling, vocalization, and listening and understanding based thereon; for promoting the motor ability of any one selected from the group consisting of arms, legs and the whole body; for promoting the movement of fingertips and fingers; for promoting learning ability; for promoting sociality.

[0097] In one embodiment, the composition is used to promote the development of any area selected from the group consisting of communication, gross motor skills, fine motor skills, problem solving, and personal / social skills; preferably, it is used to promote the development of all of these areas. In addition, in another embodiment, the composition is used to promote the development of any area in the five areas, including at least the development of the personal / social area. In addition, in another embodiment, the composition is used to promote the development of any area selected from the group consisting of fine motor skills, problem solving, and personal / social skills; preferably, it is used to promote the development of all areas of fine motor skills, problem solving, and personal / social skills.

[0098] The development of 5 areas can be evaluated by Ages & Stages Questionnaires (registered trademark), Third Edition (ASQ (registered trademark) -3) and its Japanese version. When using ASQ (registered trademark) -3, the questionnaire is selected according to the exact age / age of the target infant. As a Japanese version, questionnaires for 6 months, 12 months, 18 months, 24 months, 30 months, 36 months, 42 months, 48 ​​months, 54 months, and 60 months are prepared. If the target infant is an infant born before 37 weeks and 0 days of gestation, if he is less than 2 years old at the time of evaluation, the questionnaire is selected according to the corrected age. The questionnaire is usually filled out by the guardian or caregiver. The scores after filling out are statistically analyzed, and the scores are corrected as needed. A chart showing the cutoff values ​​of each area is used to evaluate the development status of each area.

[0099] In one embodiment, the composition is used to promote brain function development in infants aged 23 months and above. According to the research of the present inventors, it was found that the amount of NMN in breast milk ingested at 1 to 6 months of age was highly correlated with the development evaluated by the Japanese version of the ASQ-3 24-month basic information filling sheet (target age: 23 months 0 days to 25 months 15 days).

[0100] A composition that promotes the development of brain function means that, in addition to the situation where any of the five areas develops rapidly (higher scores calculated by ASQ (registered trademark)-3) compared to when a composition without NMN or containing a lower concentration of NMN is ingested, it also includes the following situations: helping any of the five areas to develop normally; bringing the degree of development of any of the five areas close to normal development when the degree of development is within the range that requires observation; etc.

[0101] The composition of the present invention can also be used to treat diseases or conditions related to brain function, which are expected to improve by promoting brain function development. Examples of such diseases or conditions include developmental disorders. Developmental disorders are disorders related to brain function development. Developmental disorders include pervasive developmental disorders such as autism, Asperger's syndrome, learning disabilities, attention deficit hyperactivity disorder, Tourette syndrome, and stuttering.

[0102] In addition, the composition of the present invention can be used to maintain healthy brain function, maintain good brain function development, and assist these.

[0103] It should be noted that, with regard to the present invention, when it is expressed as treating a disease or condition, it includes: reducing the risk of disease; delaying, preventing, and treating the disease; terminating and delaying progression. Treatment includes: medical actions performed by doctors for the purpose of treating diseases; and non-medical actions performed by people other than doctors, such as nutritionists, registered dietitians, health workers, midwives, nurses, clinical examination technicians, food manufacturers, and food sellers. In addition, treatment includes: recommending the administration or intake of specific foods, guiding feeding methods, health guidance, nutritional guidance (nutritional guidance required for the recuperation of the injured and the sick, and nutritional guidance for maintaining and improving health), eating management, and guidance required for nutritional improvement of eating. The treatment objects of the present invention include humans (individuals) and non-human mammals (companion animals, etc.).

[0104] (Target)

[0105] The composition of the present invention is suitable for being taken by an object that desires to promote brain function development, or an object that needs to promote brain function development. Such objects include: infants (less than 1 year old, including 1-month-old newborns), toddlers (over 1 year old and less than 6 years old), children (over 6 years old and less than 15 years old), adults (over 15 years old), middle-aged and elderly people (over 40 years old and less than 65 years old), elderly people (over 65 years old), pregnant women, parturient women, people in and after illness, men, and women.

[0106] In one embodiment, the composition is for ingestion by infants (babies, toddlers and children), preferably for ingestion by infants or toddlers, more preferably by infants (e.g., under 6 months old). In another embodiment, the composition is suitable for ingestion by a subject who desires artificial nutrition instead of breast milk nutrition, or a subject who needs artificial nutrition.

[0107] [Composition]

[0108] (Dosage form / form)

[0109] The composition of the present invention can be prepared in any form such as solid, liquid, mixture, suspension, emulsion, gel, sol, etc. The composition of the present invention can be prepared as a synthesized nutritional composition prepared by mixing various components.

[0110] In a particularly preferred embodiment, the composition of the present invention is in the form of formula milk powder, formula liquid milk or breast milk substitute food. Formula milk powder refers to raw milk, milk or special milk or food made from these as raw materials, or using them as the main raw materials, adding nutrients required by infants and young children to make it into a powder. Formula liquid milk refers to raw milk, milk or special milk or food made from these as raw materials, or using them as the main raw materials, adding nutrients required by infants and young children to make it into a liquid.

[0111] Formula milk powder, formula liquid milk or breast milk substitute food can be for infants, follow-up use, low birth weight infants, children, adults, the elderly, allergic people, lactose intolerance, and inborn errors of metabolism. Follow-up use means that it is used to take the nutrients needed from infancy to early childhood in a balanced manner after the weaning period starting from about 9 months of age until about 3 years of age.

[0112] In one embodiment, the formula milk powder is dissolved and used at 5-17%, preferably 8-16%, more preferably 12-15%. The formula milk powder can be made into a stick or cube shape in a single amount (for example, the amount used to dissolve in hot water and prepare 200 ml of milk).

[0113] The composition of the present invention can be made into a composition in the form of food or medicine other than formula milk powder, formula liquid milk or breast milk substitute food. Except for special records, food or medicine includes not only food or medicine for humans, but also food or medicine for animals other than humans. Except for special records, food includes: general food, functional food, food suitable for young children, nutritional composition, and also includes: therapeutic food (food to achieve therapeutic purposes. Food cooked based on a menu prescribed by a doctor and prepared by a nutritionist, etc. according to the recipe), diet therapy food, formula food, nursing food, and therapeutic auxiliary food. Except for special records, food includes not only solid objects, but also liquid foods, such as beverages, drinking agents, liquid food and soup. Functional food refers to food that can impart specified functionality to an organism, including, for example, specific health foods (including: special protection [specific health foods] with additional conditions), functional labeling foods, health functional foods including nutritional functional foods, special purpose foods, nutritional supplements, health supplements, nutritional enhancers (for example, tablets, coated tablets, sugar-coated tablets, capsules, liquid preparations and other food), beauty foods (for example, weight loss foods) and other health foods. In addition, in the present invention, "functional foods" include: health foods that apply health claims (Healthclaim) based on food standards of the Codex (FAO / WHO Joint Food Standards Commission). Cosmetics include: medicinal cosmetics.

[0114] When the composition is a food, it can be made into any form such as a nutritional enhancer, candy, beverage, beverage, flavoring, dairy product, processed food, side dish, soup, etc. Specifically, the composition of the present invention can be made into a soft candy, tablet, beverage, fermented milk, milk beverage, milk beverage, refreshing drink, ice cream, cheese, bread, biscuits, crackers, pizza crust, formula milk powder, liquid food, patient food, nutritional food, frozen food, processed food, etc., and can also be made into a form such as granules, powder, paste, concentrated liquid, etc. for mixing in beverages, foods, or for diluting and preparing beverages, etc. Specifically, it can be made into a slurry form for adding to milk.

[0115] When the composition is a drug, specific examples include chewable tablets, sublingual tablets, tablets, pills, capsules, granules, powders, liquids, suspensions, emulsions, slurries, liniments, lotions, gels, aerosols, sprays, ointments, creams, tapes, patches, eye drops, nasal drops, and suppositories.

[0116] (NMN content / dosage)

[0117] The content and concentration of NMN in the composition can be appropriately set as long as it is an amount that can exert the target effect, taking into account various factors such as the age, age, weight, and target effect of the subject. It should be noted that, with respect to the present invention, when the amount or concentration of NMN in the composition is shown, the amount / concentration in NMN is indicated unless otherwise specified. In other words, with respect to the present invention, when the amount or concentration of NAD-related substances or salts thereof acceptable as food or medicine in the composition is shown, the amount / concentration converted to NMN is indicated unless otherwise specified. That is, when a salt of NMN acceptable as food or medicine, or an NAD-related substance other than NMN is used as an active ingredient instead of NMN, it can be designed to use an equimolar amount / equimolar concentration of NMN acceptable as food or medicine, or an NAD-related substance other than NMN. For those skilled in the art, this conversion can be easily performed.

[0118] In the case where the composition is a liquid, such as a formula liquid milk, from the viewpoint of promoting the development of any of the above five areas, the NMN concentration of the composition is preferably 0.05 μg / mL or more, more preferably 1.0 μg / mL or more. From the viewpoint of more clearly promoting the development of any of the above five areas, including at least the personal / social field, the concentration of NMN is preferably 1.9 μg / mL or more, more preferably 2.3 μm / mL or more, further preferably 2.5 μm / mL or more, and further preferably 3.0 μm / mL or more. From the viewpoint of more clearly promoting the development of any area selected from the group consisting of fine motor, problem solving and personal / social; preferably fine motor, problem solving and development of all areas of personal / social, the concentration of NMN is preferably 3.0 μg / mL or more, and can also be set to 3.5 μg / mL or more, and can also be set to 3.7 μg / mL.

[0119] When the composition is a liquid, such as a formula liquid milk, the upper limit of the NMN concentration of the composition can be appropriately set, for example, it can be set to 50 μg / mL or less, it can be set to 40 μg / mL or less, it can be set to 30 μg / mL or less, it can be set to 20 μg / mL or less, and it can be set to 10 μg / mL or less. From the perspective of the amount usually contained in breast milk, the concentration of NMN is preferably 8.1 μg / mL or less, and can also be set to 6.0 μg / mL or less.

[0120] In the case where the composition is solid, such as formula milk powder, from the viewpoint of promoting the development of any of the above five areas, the amount of NMN per 100g of the composition is preferably 0.03mg or more, more preferably 1.0mg or more. From the viewpoint of more clearly promoting the development of any of the above five areas, including at least the personal / social field, the amount of NMN per 100g of the composition is preferably 1.1mg or more, more preferably 1.3mg or more, further preferably 1.4mg or more, and further preferably 1.8mg or more. From the viewpoint of more clearly promoting the development of any area selected from the group consisting of fine motor skills, problem solving, and personal / social development; preferably fine motor skills, problem solving, and development of all areas of personal / social development, the amount of NMN per 100g of the composition is preferably 1.8mg or more, and can also be set to 2.0mg or more, and can also be set to 2.2mg or more.

[0121] When the composition is solid, such as formula milk powder, the upper limit of the amount of NMN per 100g of the composition can be appropriately set, for example, it can be set to 60mg or less, or 50mg or less, or 40mg or less, or 30mg or less, or 20mg or less. From the viewpoint of being within the range of the amount normally contained in breast milk, the amount of NMN per 100g of the composition is preferably 16.1mg or less, or 13mg or less.

[0122] The content of NMN in the composition can also be designed in consideration of the amount of NMN per day. The daily amount of NMN can be set to 0.50 mg or more, or it can be set to 1.0 mg or more. From the viewpoint of more clearly promoting the development of any field selected from the group consisting of fine motor skills, problem solving, and personal / social, the daily amount of NMN is preferably 1.9 mg or more, and more preferably 2.5 mg or more. From the viewpoint of more clearly promoting the development of personal / social fields, the daily amount of NMN is more preferably 3.0 mg or more, and further preferably 6.0 mg or more.

[0123] The upper limit of the daily amount of NMN can be appropriately set, for example, it can be set to 50 mg or less, it can also be set to 40 mg, it can also be set to 30 mg or less, it can also be set to 20 mg or less, and it can also be set to 10 mg or less. From the point of view of the amount usually contained in breast milk, the daily amount of NMN is preferably 8.1 mg or less, and it can also be set to 6.0 mg or less. Such a daily amount can also be divided into multiple portions, such as 3 to 7 portions, to be suitable for intake 3 to 7 times a day.

[0124] The composition can be taken at any time of the day. When the composition is a formula milk powder, a formula liquid milk, or a breast milk substitute food, the composition of the present invention can be used for breastfeeding in the same manner as during breastfeeding.

[0125] It is considered that the NAD concentration in the body used varies throughout the day, and from the viewpoint of increasing during the active period, it is considered that in one embodiment, it is preferable to ingest a larger amount of the composition in the morning when the active period begins.

[0126] (Other ingredients, additives)

[0127] In addition to NMN, the composition of the present invention may also include other nutrients that are acceptable as food or medicine. For example, when the composition is in the form of formula milk powder, formula liquid milk or breast milk substitute food, as ingredients other than NMN, it may include: protein, lipid, cholesterol, carbohydrate, niacin, pantothenic acid, biotin, vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, folic acid, zinc, sodium, potassium, calcium, selenium, iron, copper, magnesium, phosphorus, lactadhesin, α-lactalbumin, β-lactoglobulin, ARA (arachidonic acid), DHA (docosahexaenoic acid), linoleic acid, α-linolenic acid, phospholipids, oligofructose, inositol, β-carotene, chlorine, carnitine, taurine, nucleotides, etc.

[0128] In addition, the composition may contain, in addition to NMN, other active ingredients and nutrients that are acceptable as food or medicine.

[0129] In addition, the composition may further include additives acceptable as food or medicine. Examples of such additives are: inactive carriers (solid or liquid carriers), excipients, surfactants, binders, disintegrants, lubricants, dissolution aids, suspending agents, coating agents, colorants, preservatives, buffers, pH regulators, emulsifiers, stabilizers, sweeteners, antioxidants, spices, acidulants, natural products.

[0130] (usage)

[0131] The composition of the present invention can be used orally. For parenteral administration, for example, it can be administered via a tube (gastrostomy fistula, enterotomy fistula) or via the nose, but is preferably used orally.

[0132] The subject can repeatedly ingest the composition, and the subject can continue to ingest it for a long time. The time is not particularly limited, and in order to fully manifest the effect, it is preferably ingested for a long time, such as more than 1 week, more than 2 weeks, more than 1 month, more than 3 months, more than 6 months, more than 1 year. Since NMN as an active ingredient is a substance with long-term consumption experience, and NMN is originally contained in breast milk, the composition of the present invention is particularly suitable for long-term ingestion.

[0133] (other)

[0134] The composition of the present invention can be used together with the intake of other ingredients, the intake of health foods / nutritional supplements, exercise, regular diet, etc. In addition, the composition of the present invention can also be used in combination with a therapy that promotes the development of brain function. Examples of therapies that promote the development of brain function include: inclusive therapy, music therapy, occupational therapy, social skills training, cognitive behavioral therapy, and rehabilitation therapy.

[0135] Those skilled in the art can appropriately produce the composition of the present invention using existing equipment, etc. In the production of the composition, the stage of mixing NMN is not particularly limited as long as the properties of NMN are not significantly impaired.

[0136] The composition of the present invention can also be manufactured according to conventional methods when it is in the form of formula milk powder, formula liquid milk or breast milk substitute food. For example, in the case of formula milk powder, it can be manufactured as follows. The processed material of whey protein, casein, processed material of soy protein, sugars (lactose, oligosaccharides), minerals, vitamins, and oils (as fatty acids, including: ARA, DHA, linoleic acid, α-linolenic acid, etc.) are mixed, and after dissolution, mixing, and purification, sterilization, concentration, and homogenization are carried out, and a drying process such as spray drying can be obtained. Formula milk powder. In this case, as long as the characteristics of NMN are not significantly damaged, the stage of NMN mixing is not particularly limited.

[0137] The product containing the composition of the present invention can be marked with functions and purposes (purposes), and can also be marked with the meaning of recommending that a specific object be administered / ingested. It can be marked directly or indirectly, and examples of direct marking are: records of tangible objects such as the product itself, packaging, containers, labels, and hangtags, and examples of indirect marking include: websites, stores, manuals, exhibitions, media seminars and other seminars, books, newspapers, magazines, television, radio, mail, email, sound and other advertising / promotional activities based on places or means. As examples of the functions and purposes (purposes) marked, it can be cited: "Helping brain function development", "Helping to maintain brain function", "Giving to babies before 6 months of age", "Giving to infants", "Giving to young children", etc.

[0138] Hereinafter, the present invention will be described in more detail using examples.

[0139] Example

[0140] [NMN promotes infant and child development]

[0141] Method 1

[0142] The effect of the amount of nicotinamide adenine dinucleotide (NAD)-related substances ingested by infants on their future brain function development was evaluated. The specific method is as follows.

[0143] 150 infants who were completely breastfed from 1 to 6 months old were selected as subjects, and the concentration of NAD-related substances in the breast milk consumed by the infants for 1 month was measured by LC-MS / MS. As NAD-related substances, NAD, nicotinamide riboside (NR), nicotinic acid (NA), nicotinamide (NAM), and nicotinamide mononucleotide (NMN) were evaluated.

[0144] The determination of NAD-related substances in breast milk was performed as follows. The frozen breast milk was dissolved and ultrasonically treated at 40°C for 10 minutes. 1460 μL of 82.2% (v / v) methanol was added to 40 μL of breast milk, stirred, and then ultrasonically treated for 30 seconds. 100 μL of internal standard solution (80 ng / mL β-Nicotinamide-d4 Mononucleotide adjusted with 80.0% (v / v) methanol solution) was added, stirred, and centrifuged at 17,900g and 4°C for 10 minutes. 50 μL of the supernatant was concentrated by centrifugation, dissolved in 525 μL of 0.1 mg / mL citric acid aqueous solution, filtered with a 0.22 μm filter, and the resulting substance was supplied to a liquid chromatography mass spectrometer (LC-MS / MS) and analyzed under the following conditions to determine the NMN concentration.

[0145] (LC-MS / MS analysis conditions)

[0146] Detector: Xevo TQ-XS (manufactured by Waters)

[0147] HPLC system: Waters

[0148] Column: ACQUITY PREMIER HSS T3 1.8μm 2.1mm×150mm Column

[0149] Mobile phase

[0150] Solution A: 5 mM ammonium formate aqueous solution

[0151] Solution B: Acetonitrile solution

[0152] The ratio of liquid A to liquid B: the flow of mobile phase begins → 0 minutes: liquid A 100 v / v% - liquid B 0 v / v%; 0 minutes → 3.0 minutes: liquid A 90 v / v% - liquid B 10 v / v%; 3.0 minutes → 3.5 minutes: liquid A 90 v / v% - liquid B 10 v / v%; 3.5 minutes → 8.0 minutes: liquid A 10 v / v% - liquid B 90 v / v%; 8.0 minutes → 11.5 minutes: liquid A 100 v / v% - liquid B 0 v / v%

[0153] Column temperature: 45°C

[0154] Flow rate: 0.3mL / min

[0155] Injection volume: 2 μL

[0156] Ionization: ESI positive mode

[0157] m / z of NMN

[0158] Precursor ion (Q1 Mass, (Da)): 335.2

[0159] Product ion (Q3 Mass, (Da)): 123.0.

[0160] At 24 months of age, the development of infants and children was evaluated using ASQ (registered trademark)-3 (Japanese version of ASQ (registered trademark)-3 Infant Development Screening Questionnaire, Medical College, 2021). The relationship between the amount of each NAD-related substance ingested by infants and children's development was evaluated based on the Spearman rank correlation coefficient.

[0161] Method 2

[0162] We are conducting research on whether the difference in the amount of NMN that infants and children take will lead to differences in the future development of their brain functions. The specific method is as follows.

[0163] Regarding the data on the content of NMN in breast milk and the developmental scores of infants shown in Method 1, the subject infants were divided into two groups according to the NMN concentration in breast milk, and the Mann-Whitney U test was used for inter-group comparison. Here, the critical concentration of the two groups was set to 1.922μg / ml (average value of NMN concentration in breast milk for 1 month - 1× standard deviation) or 3.089μg / ml (average value of NMN concentration in breast milk for 1 month). That is, inter-group comparisons were made between the two groups of the group with NMN concentration in breast milk ≥1.922μg / ml (high NMN group) and <1.922μg / ml (low NMN), or the group with ≥3.089μg / ml (high NMN) and <3.089μg / ml (low NMN).

[0164] Method 3

[0165] The maximum amount of NMN in the composition that can be ingested by infants and children is estimated using the following method.

[0166] A box plot showing the distribution of NMN concentration in breast milk was prepared based on the NMN content in breast milk described in Method 1. Based on the obtained distribution, the maximum NMN concentration in breast milk was estimated as the maximum amount of NMN in the composition ingested by the infant.

[0167] Result 1

[0168] The correlation between the five developmental indicators (communication, gross motor, fine motor, problem solving, and social-personal) in ASQ3 at 24 months of age and the concentrations of each NAD-related substance in breast milk was evaluated, and the results are shown in Tables 1 and 2.

[0169] The concentration of NMN in breast milk consumed by infants showed a significant positive correlation with all five developmental areas at 24 months (p < 0.05). Among the NAD-related substances in breast milk other than NMN, the infant developmental areas that showed a positive correlation with their concentrations in breast milk were: NR for problem solving, NA for gross motor skills, and NAD concentration for communication (p < 0.05) (Table 1). In addition, among the correlations between NAD-related substances that showed a significant positive correlation and developmental areas, it was confirmed that the correlation with NMN concentration in breast milk was stronger among all the correlation coefficients (r) (Table 2).

[0170] The above shows that among NAD-related substances, NMN is most effective in promoting brain development in infants and children.

[0171] [Table 1]

[0172] Table 1. Correlation analysis between NAD-related substances and developmental domains based on Spearman rank correlation coefficient

[0173]

[0174] [Table 2]

[0175] Table 2. Comparison of correlation coefficients between NMN and developmental domains, and between other NAD-related substances and developmental domains

[0176]

[0177] Result 2

[0178] The results of the inter-group comparison showed that in the inter-group comparison with a critical value of 1.922 μg / ml, the high NMN group significantly promoted the development of infants and children in personal / social projects ( Figure 1 ). In the inter-group comparison with a critical value of 3.089 μg / ml, the high NMN group significantly promoted the development of infants and children in fine motor skills, problem solving, and personal / social projects ( Figure 2 ). This indicates that when the NMN in the composition consumed is at least ≥1.922 μg / ml, it will significantly promote the brain function of infants and children.

[0179] Result 3

[0180] The distribution of NMN, NAD, NR and NA concentrations in breast milk of 150 subjects for one month is shown in Figure 3 The maximum concentration was 8.043 μg / ml. Therefore, it was confirmed that the upper limit of NMN concentration for infants to ingest is preferably 8.043 μg / ml.

[0181] Summarize

[0182] (1) Through our epidemiological study, we discovered that the concentration of NAD-related substances in milk consumed by infants is related to the development of brain function in infants.

[0183] (2) It was found that the effect of promoting brain function development was effective when the NMN concentration in the composition was 1.922 to 8.043 μg per 1 ml when consumed (equivalent to 1.131 to 16.09 mg / 100 g of the composition when the dry powder was dissolved at a concentration of 5 to 17% (w / v)).

[0184] (3) It was found that: It is further preferred that the NMN concentration in the composition is effective when it is 3.089 to 8.043 μg per 1 ml when consumed (equivalent to 1.817 to 16.09 mg / 100 g of the composition when the dry powder is dissolved at a concentration of 5 to 17% (w / v)).

[0185] Industrial Applicability

[0186] According to the present invention, a medicine or food composition, a method for manufacturing a medicine or food that can promote the development of children's brain function can be provided. In addition, through the present invention, it is expected to improve the nutrition of many children, ensure healthy life, and promote welfare.

Claims

1. A composition for promoting the development of brain function in infants and children, comprising a nicotinamide adenine dinucleotide (NAD)-related substance or a salt thereof that is acceptable as a food or medicine.

2. The composition according to claim 1, wherein Brain function development is development in any area selected from the group consisting of communication, gross motor, fine motor, problem solving, and personal / social.

3. The composition according to claim 1, wherein Brain function development is development in any area selected from the group consisting of fine motor, problem solving, and personal / social.

4. The composition according to claim 1, wherein Brain function development is development in the personal / social domain.

5. The composition according to claim 1, wherein Brain function development refers to the brain function development of infants and children aged 23 months and above. The composition according to claim 1 , which is intended for ingestion by infants under 6 months of age.

7. The composition according to claim 1, which is in any form selected from the group consisting of formula milk powder, formula liquid milk and breast milk substitute food.

8. The composition according to any one of claims 1 to 7, wherein The concentration of the NAD-related substance or a salt thereof acceptable as a food or a drug when ingested is 1.9 μg / mL or more in terms of nicotinamide mononucleotide (NMN).

9. The composition according to any one of claims 1 to 7, wherein The concentration of the NAD-related substance or a salt thereof acceptable as a food or a drug when ingested is 3.0 μg / mL or more in terms of NMN.

10. The composition according to any one of claims 1 to 7, which is in the form of a formula milk powder and contains 1.1 mg or more of an NAD-related substance or a salt thereof acceptable as a food or a drug per 100 g, calculated as NMN.

11. The composition according to any one of claims 1 to 7, which is in the form of a formula milk powder and contains 1.8 mg or more of an NAD-related substance or a salt thereof acceptable as a food or a drug per 100 g, calculated as NMN.

12. The composition according to any one of claims 1 to 7, wherein NAD-related substance is NMN.

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