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    • 专利摘要:
    nutritional composition, use of nutritional composition, non-medical use of nutritional composition and non-medical use of an infant formula to feed a child the present invention relates to an improved balance of the essential branched chain amino acids leucine, isoleucine and valine in an infant formula .
    公开号:BR112012024102B1
    申请号:R112012024102
    申请日:2011-03-25
    公开日:2020-01-28
    发明作者:Marleen Van Der Beek Eline；Boehm Günther；Bernard Van Goudoever Johannes；Abrahamse Berkeveld Marieke
    申请人:Nutricia Nv；
    IPC主号:
    专利说明:

    CHILD FORMULA AND NON-MEDICAL USE OF THE CHILD FORMULA FIELD OF THE INVENTION
    The present invention is in the field of child nutrition and the content of essential branched-chain amino acids therein.
    HISTORY OF THE INVENTION
    Knowledge of the requirement for essential amino acids in children (preterm) is important, since excessive or deficient intake can lead to long-term morbidity, such as obesity (Singhal et al. (2002) Am J Clin Nutr 75: 993-9) or sub-ideal growth and the result of impaired neurodevelopment (Stephens et al (2009) Pediatrics 2009; 123: 1337-43).
    Branched-chain amino acids (BCAA branched-chain amino acids) leucine (Leu - leucine), isoleucine (Ile - isoleucine) and valine (Val - valine) represent 35 to 40% of the dietary amino acids indispensable in body protein and 14% of the total amino acids in skeletal muscle. Child nutrition was formulated using mother's milk, breast milk, as the most ideal composition. However, due to the different amino acid composition of protein sources used to produce infant nutrition, protein levels are generally higher, compared to those in breast milk, to ensure sufficient BCAA intake.
    It has now become increasingly clear that the early nutrition that is consumed by the child has metabolic effects on the child, also at a more advanced age, that is, metabolic imprinting. For example, WO 2008/054200 reveals that metabolic imprinting is an important mechanism in programming future health, and food is
    Petition 870190102628, of 10/11/2019, p. 10/271
    2/26 specifically designed to prevent obesity at an older age by providing low protein diets. Thus, diets with too much or too little protein can therefore be harmful to children. However, the exact requirement for essential amino acids for children born at term or premature children is not known.
    SUMMARY OF THE INVENTION
    Historically, descriptive or crude measures such as growth and nitrogen balance have been used to study amino acid requirements. No studies have been conducted using stable isotope techniques to adequately measure essential amino acid requirements for enteric-fed children. The inventors therefore investigated the requirement for essential amino acids using this preferred technique in enteric-fed children to determine the optimal ratio of amino acids in a nutritional composition and to determine the absolute requirements of the three essential amino acids BCAA, valine, isoleucine, and leucine. The results of these studies now radically change the known concepts of the requirement for amino acids. This is particularly relevant for formulas with a low protein concentration that aim to avoid adverse metabolic imprinting effects in children.
    The present inventors surprisingly found that the requirement for valine, which is currently set at 87 mg / kg / day, should be between 100 and 175 mg / kg / day, with a preferred range between 110 and 160 mg / kg / day. Also for isoleucine and leucine, higher requirements were established by the inventors. For isoleucine, 105 has been found to be between 100 and 160 mg / kg / day, preferably and 150 mg / kg / day. comparable
    Once at mg / kg / day; the current recommendation is that the leucine requirement seemed to be currently recommended values, be
    3/26 The most prominent consequence of the present discovery is that the relationships of these three branched chain amino acids must be adapted. Preferably, the Leu: Ile: Val weight ratio is between (1.1 to 1.5) :( 0.9 to 1.1): 1.0 instead of the currently recommended Leu: Ile: Val weight ratio 1.9: 1.0: 1.0. Thus, in one embodiment, the invention relates to a nutritional composition comprising protein, digestible carbohydrates and fat, in which the protein comprises the amino acids leucine, isoleucine and valine in a weight ratio of leucine: isoleucine: valine between (1.1 to 1.5) :( 0.9 to 1.1): 1.0. Preferably, the Leu: Ile: Val weight ratio is between (1.3 to 1.5) :( 0.9 to 1.1): 1.0, preferably between (1.3 to 1.5) :( 0.9 to 1.0): 1.0, preferably between 1.3: 1.0: 1.0 and 1.5: 0.9: 1.0
    A preferred composition according to the invention therefore comprises, per 10 ml, between 40 and 120 mg of valine, preferably between 55 and 120 mg of valine, preferably between 70 and 110 mg of valine and between 40 and 120 mg of isoleucine, preferably between 55 and 110 mg of isoleucine, preferably between 70 and 100 mg of isoleucine and between 70 and 180 mg of leucine, preferably between 90 and 170 mg of leucine. The composition according to the invention is intended for a child between 0 and 36 months. With a preferred energy content between 60 and 70 kcal per 100 ml, a preferred composition according to the invention comprises between 90 and 180 mg of valine per 100 kcal in the total composition, preferably between 100 and 150 valine per 100 kcal, preferably between 105 and 121 mg of valine per 100 kcal, and between 90 and 180 mg of isoleucine per 100 kcal in the total composition, preferably between 95 and 170 mg, preferably between 100 and 150 mg of isoleucine per 100 kcal and between 120 and 260 mg of leucine per 100 kcal in the total composition, preferably between 120 and 180 mg of leucine per 100 kcal,
    4/26 preferably between 130 and 160 mg of leucine per 100 kcal. Preferably, the leucine: isoleucine: valine ratio is between (1.3 to 1.5) :( 0.9 to 1.1): 1.0
    Compositions comprising the aforementioned ranges of amino acids are preferably used for enteric or parenteral feeding of a child. In particular, the compositions are used to prevent obesity during childhood or later in life, while maintaining optimal growth in the period when the child is mainly dependent on the protein intake composition.
    DETAILED DESCRIPTION OF THE INVENTION
    Protein content: The term protein content, as used in this document, can be calculated from the nitrogen content using the formula: Nitrogen content x 6.25. The nitrogen content can be measured according to standard procedures known to the person skilled in the art.
    Child: The term child, according to the present invention, means a human aged between 0 and months, preferably between 0 and 18 months and even more preferably between 0 and 6 months. The younger the child, the more dependent the child is on the infant formula for protein intake. Therefore, the formula is preferred for the age group of less than 12 months or children who, digestive problems or allergies, depend on the infant for their protein intake.
    Pre-mature and / or small children due to the formula of gestational age: A child born before the end of the period, before or in 37 weeks of pre-mature child is related to a pattern of pregnancy and pregnancy of the mother, this from the beginning of the latter is, before or in 3 7 weeks from the mother's menstrual period. SGA children are your weight
    5/26 is below the 10th percentile for gestational age. They have generally been subject to intrauterine growth restriction (IUGR). Premature or SGA children include low birth weight children (LBW children), very low birth weight children (VLBW children), and extremely low birth weight children (children ELBW - extremely low birth weight infants). LBW children are defined as children weighing less than 2500 g. VLBW children are children weighing less than 1500 g, and ELBW children as children weighing less than 1000 g.
    Infant formula is a nutritionally complete formula comprising protein, fat, carbohydrates, and micronutrients such as vitamins and minerals. Preferably, the infant formula comprises dietary fiber, nucleotides and the fatty acids arachidonic acid (AA - arachidonic acid) and docosahexaenoic acid (DHA docosahexaenoic acid). The term infant formula excludes breast milk.
    Good nutrition is essential for optimal growth and development in the pre-mature and full-term child. Protein is an important component of adequate nutrition, as it provides essential amino acids required for critical protein synthesis and growth. Nutrition is especially important during the early stages of life, as protein intake in the first 4 weeks of life can have a major influence on cognitive function and blood pressure later on.
    The alarming increase in both the prevalence and severity of obesity in children has renewed interest in childhood eating patterns. The high initial weight gain, in the first 1 to 2 years of life, is associated with
    6/26 adverse later health outcomes, such as high blood pressure, high overweight and body fat deposition and increased risk of diabetes. The increased intake of the infant formula, protein in children fed with can develop a role compared to breastfed children, since children fed with the formula reach a higher body weight and weight by length at one year of age. The reduction of protein content in baby food could contribute to protein reduction, that is, it can be a strategy for these adverse effects.
    the right quantities that
    One of the available, becomes more of good quality amino acids than critical.
    Classically, nine amino acids as essential; if these amino acids in the correct proportions, the synthesis of
    These amino acid requirements are nutritionally considered not to be administered protein will be reduced.
    indispensable were determined by a number of different methods.
    Historically, descriptive or crude measures, such as growth and nitrogen balance, have been used. No studies have been conducted using stable isotope techniques to adequately measure essential amino acid requirements for enteric-fed children.
    For vulnerable populations, such as newly maintaining a deficient diet for one born, a long period is unacceptable.
    Brunton et al.
    (1998) Curr
    Opin Clin
    Nutr Metab
    Care, 1 (5): p. 449-53 validated a minimally invasive oxidation indicator protocol to use the (IAAO - indicator amino acid oxidation) technique in infants and children amino acids.
    This protocol was recently used to determine the total requirements for branched-chain amino acids in healthy school-age children. Estimates of requirements in children were similar to those
    7/26 estimates in adult humans, which suggests that the experimentally derived values reflect maintenance requirements, and do not take into account all growth needs.
    Current recommendations for children aged 0 to 6 months are based on the amino acid content of human milk, which may be inappropriate, since breastfed children have very variable milk intake and breastfed children themselves largely regulate the intake they need. European Food and Safety guidelines
    Authority (EFSA) require that the infant formula contains 88 mg of valine, 92 mg of isoleucine and 167 mg of leucine per 100 kcal with a minimum of 60 and a maximum of 70 kcal / 100ml of the formula, ie between 52.5 and 62.0 mg of valine per 100 ml, 55 and 64.9 mg of isoleucine and between 100 and 118 mg of leucine per 100 ml of the formula. According to the present invention, these bands are unsuitable.
    According to the total protein in the formula between 1.3 and 1.9 g of the present invention, the infantile content is preferably protein / 100kcal, even more and 1.8 g of protein / 100 kcal, preferably between 1.3 resulting in an infant formula comprising between 5.2 and the protein's total, based on the calorie composition. A preferred composition comprises between 180 mg of valine and between 90 and 180 mg of isoleucine per kcal and between 130 and 260 mg of leucine per 100 kcal. For composition based on amino acids or based on protein hydrolysates, the preferred ranges according to
    7.6 and
    100 to 100 of the present inventions are between 105 and 120 mg of valine and between 100 and 120 mg of isoleucine per 100 kcal and between 130 and 160 mg of isoleucine per 100 kcal, since these are bands that come closest to the average amino acid requirement experimentally determined (see examples 1 and 2).
    8/26
    For compositions based on non-hydrolyzed (intact) protein, these latter narrow bands are preferably about 10% lower, preferably between 10 and 20% lower. Thus, in one embodiment, for compositions based on non-hydrolyzed (intact) protein, the preferred ranges according to the present invention are between 105 and 120 mg of valine and between 100 and 120 mg of isoleucine per 100 kcal and between 130 and 160 mg of isoleucine per 100 kcal.
    In another preferred embodiment of the present invention, a nutritional composition comprises a component of lipid, protein and digestible carbohydrate, where the protein component provides between 5.0 and 7.6% of the total calories, the lipid component provides 3 5 at 55% of the total calories, and the digestible carbohydrate component provides 30 to 60% of the total calories for the production of a nutritional composition, and where the composition comprises, per 100 ml, between 40 and 110 mg of valine, preferably between 40 and 70 mg of valine, and between 40 and 110 mg of isoleucine. Preferably, the leucine: valine weight ratio is in the range of 1.1: 1.0 to 1.5: 1.0, more preferably in the range of 1.3: 1.0 and 1.5: 1.0 and the isoleucine: valine weight ratio is in the range of 0.9: 1.0 to 1.1: 1.0, preferably about 1.0: 1.0, which means that the quantities of Ileu and Vai are not they necessarily have to be exactly the same, but they are within the rounded margin of the second decimal place. Thus, preferably, the leucine: isoleucine: valine weight ratio is in the range (1.1 to 1.5) :( 0.9 to 1.1): 1.0, preferably in the range (1.1 to 1.5) 1.5): 1.0: 1.0.
    Preferably, the composition according to the invention is used to feed children who largely depend on their protein intake from the nutritional composition according to the present invention. These children are preferably aged between 0 and 36 months,
    9/26 preferably between 0 and 18 months and even more preferably between 0 and 6 months. The compositions can also be used for children suffering from (multiple) food allergies that would normally restrict their intake of intact protein when using hydrolyzed protein formulas or formulas based on amino acids. In addition, the composition can be used for the dietary management of diseases such as Phenylketonuria (PKU
    Phenylketonuria), maple syrup urine diseace (MSUD) disease or Tyrosinemia.
    Typically, children ingest 150 ml of a baby milk formula per kg of body weight per day. Preferably, with this diet, a child ingests the amounts of leucine, isoleucine and valine now established. Thus, in one embodiment, the invention relates to a non-medical use of an infant formula to feed a child, or a non-medical method to feed a child comprising administering an infant formula, wherein the infant formula comprises protein that provides leucine, isoleucine and valine in a ratio of (1.1 to
    1.5) :( 0.9 to 1.1): 1.0, and the infant formula provides between 100 and 175 mg of valine per kg of body weight per day, and between 100 and 160 mg of isoleucine per kg of body weight per day when the child ingests 150 ml of the nutritional composition per kg of body weight per day.
    PROTEIN
    The protein is preferably present in the composition below 8% based on the total calories in the composition. Preferably, the nutritional composition comprises between 5.0 and 8.0% protein based on total calories, more preferably between 5.5 and 8.0% even more preferably between 5.7 and 7.6% protein based in total calories. As total calories in the composition,
    10/26 the sum of calories delivered by the digestible fats, proteins and carbohydrates of the composition is taken. A low protein concentration ensures a low insulin response, thus preventing the proliferation of adipocytes, especially visceral adipocytes in children. The concentration of protein in a nutritional composition is determined by the sum of protein, peptides and free amino acids. The protein concentration is determined by determining the amount of nitrogen, multiplying this by a factor of 6.25. One gram of protein is equal to 4 kcal. Based on dry weight, the composition preferably comprises less than 12% by weight of protein, more preferably from 6% to 11% by weight, even more preferably from 7% to 11% by weight. Based on a ready-to-drink liquid or reconstituted powder product, the composition Preferably comprises less than 1.5 g of protein per 100 ml, more preferably between 0.8 and 1.35 g per 100 ml.
    The source of the protein is preferably selected in such a way that the minimum requirements for essential amino acid content are met and satisfactory growth is guaranteed. Thus, protein sources based on cow's milk protein, such as whey, casein and mixtures thereof, and soy proteins, are preferred. If whey proteins are used, the protein source is preferably based on acidic whey or sweet whey, isolated from whey protein or mixtures thereof and may include lactalbumin and β-lactoglobulin. Most preferably, the protein source is based on acidic whey or sweet whey, from which the casein-glyco-macropeptide (CGMP - caseino-glyco-macropeptide) was removed. Removing CGMP from sweet whey protein or using acid whey advantageously reduces the threonine content.
    11/26
    Preferably, whey protein enriched with a-lactalbumin is used to optimize the amino acid profile. The use of protein sources with an optimized amino acid profile closer to that of breast milk allows all essential amino acids to be provided in a reduced protein concentration, below 8%, based on the total energy content, preferably between 5.5 and 8.0%, based on the total energy content provided by the protein, fat and digestible carbohydrate and still guarantees a satisfactory growth.
    To ensure that low levels of protein can be achieved, nutritional compositions according to the present invention preferably comprise a protein source, wherein the sum of leucine, isoleucine and valine provides at least 20% by weight of the amino acid content totals.
    If the modified sweet whey is used as a protein source, it is preferably supplemented by free arginine in an amount of 0.1 to 3 s by weight and / or free histidine in an amount of 0.1 to 1.5% by weight, based on total proteins.
    The proteins may be intact or hydrolyzed or a mixture of intact and hydrolyzed proteins, although intact proteins are generally preferred. Preferably, the composition comprises hydrolyzed casein and / or hydrolyzed whey protein. It has been found that administration of a composition in which the protein comprises hydrolyzed casein and hydrolyzed whey results in reduced postprandial levels of both insulin and glucose compared to administration of a composition comprising intact casein and intact whey protein. Increased levels of both insulin and glucose indicate a form of insulin insensitivity and / or
    12/26 resistance in children fed by the formula. The present composition preferably comprises at least 25% by weight of peptides with a chain length of 2 to 30 amino acids, based on the dry weight of the protein. The amount of peptides with a chain length between 2 and 30 amino acids can, for example, be determined as described by de Freitas et al. (1993), J. Agric. Food Chem. 41: 1432-1438. The present composition can include casein hydrolyzate or the present composition can include whey protein hydrolyzate or both. The present composition preferably includes both casein hydrolyzate and whey protein, because the amino acid composition of bovine casein is more similar to the amino acid composition found in human milk protein, and whey protein is easier to separate. digest and is found in greater proportions in human milk. The composition preferably comprises at least 50% by weight, preferably at least 80% by weight, more preferably about 100% by weight of a protein hydrolyzate, based on the total weight of the protein. The present composition preferably comprises a protein with a degree of protein hydrolysis between 5 and 25%, more preferably between 7.5 and 21%, more preferably between 10 and 20%. The degree of hydrolysis is defined as the percentage of peptide bonds that have been broken by enzymatic hydrolysis, with 100% being the total of potential peptide bonds present. A suitable way of preparing a hydrolyzate is described in WO 01/41581.
    When using the protein source based on amino acids, the amount of amino acids that will actually become available to the child will be more predictable. Therefore, a preferred composition according to the invention comprises amino acids as a protein source. In a
    In the embodiment of the composition according to the present invention, the protein consists essentially of free amino acids. A preferred embodiment is shown in example 3.
    DIETARY FIBERS
    Early differences in the composition of fecal microbiota in children can predict overweight (Kalliomaki et al. (2008) Am J Clin Nutr 87 (3): 534-538). They showed that Bifidobacterium spp affecting both the quantity and quality of the microbiota during the first year of life was higher in number in children exhibiting normal weight at 7 years than in children developing overweight. Without adhering to the theory, the inventors believe that in addition to a low protein intake, the use of dietary fiber capable of stimulating bifid flora will have an additional effect in preventing or treating obesity in children. Dietary fibers are selected from the group consisting of fibers that can stimulate the growth of
    Bifidobacterium spp.
    Preferably, non-digestible oligosaccharides have a DP between 2 and 60. The non-digestible oligosaccharide is preferably selected from the group consisting of fructo-oligosaccharides (including insulin), xylogalacto-oligosaccharides (including transgalactooligosaccharides), glyco-oligosaccharides (including gentio- , nigero- and ri clodextrin-oligosaccharides, arabinooligosaccharides, oligosaccharides, oligosaccharides, oligosaccharides, oligosaccharides Preferably, cyclodextrin-oligosaccharides, oligosaccharides, oligosaccharides, oligosaccharides, oligosaccharides, oligosaccharides the present invention comprises fructogalacto-oligosaccharides galacturonic acid, more preferably oligosaccharides, and / or oligosaccharides
    14/26 galactooligosaccharides, more preferably beta-binding galactooligosaccharides. In a preferred embodiment, the composition comprises a mixture of β-binding galactooligosaccharides and fructooligosaccharides, more preferably in a weight ratio of 20 to 2: 1 to 3, more preferably 12 to 7: 1. Preferably, the present invention comprises galacto-oligosaccharides with a DP of 2 to 10 and / or fructo-oligosaccharides with a DP of 2 to 60. Galacto-oligosaccharides are preferably selected from the group consisting of beta-linked galacto-oligosaccharides, transgalacto-oligosaccharides, galactooligosaccharides , lacto-N-tetraose (LNT - lacto-N-tetraose), lacto-N-neotetraose (neo-LNT - lacto-N-neotetraose), fucosillactose, fucosylated LNT and fucosylated neo-LNT. Β-binding galactooligosaccharides are, for example, sold under the brand name Vivinal ™ (Borculo Domo Ingredients, Netherlands). Preferably, the saccharides of the galacto-oligosaccharides have β bond, since this is also the case in the galacto-oligosaccharides of human milk. The fructooligosaccharide is an NDO comprising a chain of fructose units beta-linked with an average DP or DP of 2 to 250, more preferably 10 to 100. The fructo-oligosaccharide includes inulin, levan and / or a mixed type of polyfructan. An especially preferred fructooligosaccharide is inulin. Fructooligosaccharides suitable for use in the compositions are also already commercially available, for example, Raftiline®HP (Orafti). Uronic acid oligosaccharides are preferably obtained from the degradation of pectin, more preferably apple pectin, beet pectin and / or citrus pectin. Preferably, the composition comprises 0: fructooligosaccharide-binding galactooligosaccharide: uronic acid oligosaccharide in a weight ratio of 20 to 2: 1: 1 to 3, more preferably
    15/26 to 7: 1: 1 to 2.
    Preferably, the composition comprises from 80 mg to 2 g of nondigestible oligosaccharides per 100 ml, more preferably 150 mg to 1.50 g, even more preferably 300 mg to 1 g. Based on dry weight, the composition preferably comprises from 0.25% by weight to 5.5% by weight, more preferably from 0.5% by weight to 4% by weight, even more preferably 1.5% by weight to 3% by weight. A smaller amount of non-digestible oligosaccharides will be less effective in stimulating the beneficial bacteria in the microbiota, while a very high amount will result in side effects of abdominal bloating and discomfort.
    A study has been carried out determining the stimulation of bifid flora in children fed by the formula showing an improved bifidogenic effect of galactooligosaccharides and long chain inulin when supplied in combination, compared to a formula with only one dietary fiber.
    Children from 9 to 10 months of age ingested 500 ml per day of a milk formula comprising 1.2 g of betagalacto-oligosaccharides plus long-chain inulin for 1 month (group A). A control group received the formula of milk without beta-galact and long-chain inulin (group B). In total, 138 children participated in the study. Fecal flora was examined before and after this period by FISH analysis.
    After the intervention time, the proportion of total Bifidobacteria / bacteria was significantly higher in group A than in group B. A preferred composition according to the invention, therefore, comprises a combination of beta-galacto-oligosaccharides and long-chain inulin .
    FAT
    As explained above, the protein content of the infant formula has effects on lipid metabolism and
    16/26 in fat deposition in children. In addition, the composition of fat lipids in infant formula has been shown to have an important impact on obesity prevention, and in particular on central obesity or visceral adiposity, see, for example, W02008 / 054208. The term visceral adiposity refers to a condition with an increased visceral fat mass. The term visceral adiposity is also called central obesity. Visceral adiposity is typically caused (by the accumulation of) excessive visceral fat mass. Visceral fat, also known as organ fat, intra-abdominal fat, peritoneal fat or central fat is usually located within the peritoneal cavity, unlike subcutaneous fat, which is found under the skin and intramuscular fat, which is found intercalated in skeletal muscles. Visceral fat includes mesenteric fat, perirenal fat and retroperitoneal fat.
    Previous research, revealed in W02008 / 054208, has shown that Medium chain fatty acids (MCFA) contribute to a reduced fat mass at an older age. Therefore, in addition to the specific protein and amino acid content according to the present claims, the composition advantageously comprises MCFA.
    The effect on visceral fat deposition was specifically demonstrated using a nutritional composition comprising (i) a ratio of LA / ALA between 2 and 6 and (ii) a low LA content (<14.5% by weight based on fatty acids total) and optionally LC-PÜFA (particularly DHA). Such a composition resulted in a reduction in visceral adiposity at an older age.
    A preferred nutritional composition, therefore, comprises protein, digestible carbohydrates and fat, in
    17/26 that the protein comprises the amino acids leucine, isoleucine and valine in a ratio of leucine: isoleucine: valine in the range (1.1 to 1.5) :( 0.9 to 1.1): 1.0, and the fat comprises linoleic acid and alpha linoleic acid in a proportion between 2 and 6 and the content of linoleic acid is less than 14.5% by weight based on the total fatty acids. This composition could preferably be used for enteric feeding of a child to prevent obesity at a later age.
    APPLICATIONS
    The present nutritional composition should advantageously be ingested or administered to preterm children or small children for gestational age and, therefore, it is intended for the enteral or parenteral treatment of preterm or small children for gestational age. In addition, the present nutritional composition, and preferably the form in which the protein essentially consists of free amino acids, is advantageously used for the treatment of children with a metabolic disease selected from the group PKU, MSUD and tyrosinemia, or for the treatment of children with a food allergy. Preferably, the present nutritional composition should advantageously be ingested or administered to a child aged 0 to 36 months, preferably between 0 and 24 months.
    The invention also relates to the use of the nutritional composition according to the present invention for the manufacture of a medicament for the treatment of a) children aged 0 to 24 months and / or b) preterm children or c) children small for gestational age or d) children with a metabolic disease selected from the group consisting of PKU, MSUD and tyrosinemia or e) children with a food allergy.
    18/26
    In a preferred embodiment, the present invention relates to the use of the nutritional composition according to the present invention for the manufacture of a medicament for preventing obesity at a later age.
    In addition, the present invention relates to the non-medical use of the nutritional composition according to the present invention for the manufacture of a composition to feed a child aged 0 to 36 months.
    In addition, the present invention relates to the non-medical use of an infant formula to feed a child, wherein the infant formula comprises protein that provides leucine, isoleucine and valine in a ratio of (1.1 to 1.5) :( 0.9 to 1.1): 1.0, and the infant formula provides between 100 and 175 mg of valine per kg of body weight per day, and between 100 and 160 mg of isoleucine per kg of body weight per day, when the child ingests 150 ml of nutritional composition per kg of body weight per day.
    EXAMPLES
    EXAMPLE 1. Valine and isoleucine requirements in a child
    EXPERIMENTAL PROJECT
    Male children born at term (n = 28) were enrolled in this study. They had a gestational age of 37 to 43 weeks, a birth weight of more than 2500 grams and their postnatal ages were less than or equal to 28 days.
    The IAAO technique (Zello et al. (1993) Am J Physiol 264: E677-85) was used to determine the requirement for valine and, in a separate experiment, to determine the requirement for isoleucine. This method uses an indicator that is oxidized when an essential amino acid is limiting, since there is no storage of amino acids and the amino acids must be partitioned between incorporation into protein or
    19/26 oxidation. If the tested amino acid is deficient in the diet, this will limit protein synthesis, and the indicator amino acid will be oxidized. If the dietary intake of the test amino acid increases, the oxidation of the indicator will decrease, until the test amino acid requirement is met. When the intake corresponds to the requirement, then the protein synthesis occurs in ideal capacity and the oxidative degradation of all other essential amino acids is stabilized. The test amino acid requirement is identified by this breakpoint.
    During this study period, patients were randomly assigned to receive graduated valine intakes ranging from 5 to 236 mg / kg day or graduated isoleucine intakes ranging from 5 to 216 mg / kg day. After adapting to the study diet for 24 hours, baseline breath samples were obtained and a tracer protocol was started. Patients were weighed daily, before and at the end of the tracer protocol, and a head circumference was measured on the study day.
    STUDY FORMULA
    We use a study formula identical to the regular Neocate, an amino acid based formula designed to meet the amino acid requirements of children (SHS, Liverpool, UK) but without the test amino acid and with a reduced amount of phenylanine. The amount of valine was adjusted separately as L-valine. The amount of isoleucine was adjusted separately as L-isoleucine. L-phenylanine was provided during the adaptation time and during the [ 13 C] bicarbonate infusion to obtain a stable total intake of 166 mg / kg / d throughout the study. To make the formula isonitrogenated, we add L-alanine separately. Since phenylanine was used as an indicator and phenylanine is hydroxylated to tyrosine before
    20/26 oxidation can occur, we made sure that the tyrosine intake was well above current requirements. A very limited tyrosine intake could reduce the recovery of 13 C labeled in respiratory air. To minimize the effect of feeding on the [ 13 C] bicarbonate plateau, continuous drop feeding was provided during the [ 13 C] bicarbonate infusion. To minimize discomfort for patients, they could drink a bottle every hour during the infusion of [ 1-13 C] phenylanine.
    TRACER PROTOCOL
    On the study day, patients received a prepared enteric infusion (15 pmol / (kg) continuous (10 pmol / (kg-h)) of [ 13 C] bicarbonate (sterile pyrogen free, 99% 13 C atom per percent excess (APE); Cambridge Isotopes, Woburn, United States) for 3 hours to quantify individual CO2 production.The labeled sodium bicarbonate infusion was directly followed by a prepared enteric infusion (30 pmol / (kg), continuous (30 pmol / (kg-h)) of [ 1-13 C] phenylanine (99% 13 C APE; Cambridge Isotopes, Woburn, United States) for five hours by an infusion pump, through the nasogastric tube. with tracers were weighed before and after the infusion to determine the exact amount of tracer given during the study.
    SAMPLE COLLECTION
    Breath samples were collected on the day of adaptation in the first 8 patients to determine the time required to obtain a stable background enrichment, using the direct sampling method described by Van der Schoor et al. (2004) Pediatr Res 55: 50-4. On the study day, baseline samples were obtained 15 and 5 minutes before the tracer infusion started. During the duplicate of the experiment, breath samples enriched with C were
    21/26 collected every 10 minutes during the isotopic steady state of the [ 13 C] bicarbonate infusion, starting after 1.75 hours, and every 15 minutes during the isotopic steady state of the [1- 13 C] phenylanine infusion starting after 3 hours.
    ANALYSIS AND CALCULATIONS
    The isotope enrichment of 13 CO 2 in exhaled air was measured by isotopic ratio mass spectrometry (ABCA; Europe Scientific, Van Loenen Instruments, Leiden, Netherlands) and expressed as APE above the baseline. The steady state was defined as three or more consecutive points with a slope not different from zero (p <0.05). Body CO 2 production (mmol / kg.h) was calculated for each child as previously described (Riedijk et al. (2005) Pediatr Res 58: 861-4). The oxidation rate of fractional [ 1-13 C] phenylanine was calculated using the following equation:
    fractional phenylanine oxidation (%) = [IE PH ex Íb] / [ipHE x ΙΕβ] X 100-s where ΙΕρηε θ isotopic enrichment of C in expired air during the infusion of [1 - 13 C] phenylanine (APE), iB is the infusion rate of [ 13 C] bicarbonate (pmol / (kg · h)), Íphe is the infusion rate of [1- 13 C] phenylanine (pmol / (kg ^ h)) and IEB is the enrichment 13 C isotope in expired air during the [ 13 C] bicarbonate infusion (van der Schoor et al. (2004) Gut 53: 38-43).
    STATISTICAL ANALYSIS
    Descriptive data were expressed as mean ± SD. The 13 CO 2 steady state on exhalation during [1 13 C] phenylanine was reached when the linear tilt factor proved not to be significantly different from zero (p <0.05). The valine requirement was determined by applying a two-phase linear regression crossover model (Ball and Bayley (1984) J Nutr 114: 1741-6; Seber GAF. Linear Regression Analysis. New York: John Wiley, 1977) on
    22/26 fractional oxidation rates. The safe level of intake (above 95% Cl) was determined using Fieller's theorem (Seber GAF. Ibid.). All statistical analyzes were performed using SPSS (SPSS version 15.0, Chicago, IL, United States).
    RESULTS
    All patients reached an isotopic steady state (plateau) in both [ 13 C] bicarbonate and [1- 13 C] phenylanine infusion defined by the absence of a significant slope between the data points on each plateau.
    The Spearmen classification correlation coefficient between isoleucine intake and fractional oxidation was 0.63 (p = 0.000). Using two-phase regression analysis with leucine intake as the independent variable and fractional oxidation of the [1-13C] phenylanine tracer as the dependent variables, the stopping point was determined to be 110 mg / kg / d. Ingestion of the safe population determined by the upper 95% of Cl was 164.6 mg / kg / d.
    The Spearmen classification correlation coefficient between isoleucine intake and fractional oxidation was 0.74 (p = 0.000). From the two-phase regression analysis with isoleucine intake as the independent variable and fractional oxidation of the [1- 13 C] phenylanine tracer as the dependent variable, the stopping point was determined to be 105 mg / kg / d. The safe population intake determined by the upper 95% of Cl was
    152 mg / kg / d.
    EXAMPLE 2. Leucine requirement of children
    Following the same procedure as in Example 1, children's leucine requirement was determined.
    Male children born at term (n = 33) were enrolled in this study. They were of an age
    23/26 gestational age of 37 to 43 weeks, a birth weight of more than 25 00 grams and their postnatal ages were less than or equal to 28 days.
    RESULTS
    All patients reached an isotopic steady state (plateau) in both [ 13 C] bicarbonate and [1- 13 C] phenylanine infusion defined by the absence of a significant slope between the data points on each plateau.
    Using two-phase regression analysis with leucine intake as the independent variable and fractional oxidation of the [1- 13 C] phenylalanine tracer as the dependent variables, the stopping point was determined to be 140 mg / kg / d . The intake of the safe population determined by the 95% higher Cl was 245 mg / kg / d.
    EXAMPLE 3. Amino acid-based nutrition suitable for the treatment of allergic children
    NUTRIENT'S NAME PER 100 kcal PROTEIN EQUIVALENT (N x 6.25) 1.36 g NITROGEN 0.22 g CARBOHYDRATE 12.94 g FATS 4.75 g (MCT) 0.19 g (LCT) 4.28 g
    MINERALSSODIUM 24.98 mg POTASSIUM 138.45 mg CHLORIDE 106.96 mg CALCIUM 96.47 mg PHOSPHOR 70.2 mg MAGNESIUM 5.11 mg Ca: P RATIO 1.37 _
    TRACE ELEMENTS IRON 1.48 mg ZINC 1.03 mg IODINE 14.22 μγ
    24/26
    MANGANESE 0.08 mg COPPER 0.08 mg MOLYBDENUM 2.97 μγ SELENIUM 2.28 μγ CHROMIUM 2.06 μγ
    VITAMINS VITAMIN A 151.24 μγ VITAMIN E 1.12 UI L-ASCORBIC ACID 21.9 mg TIAMINE 0.11 mg RIBOFLAVINE 0.15 mg PYRIDOXIN 0.13 mg NIACINA 1.16 mg PANTOTHENIC ACID 0.6 mg MYO-INOSITOL 25.05 mg HILL 12.42 mg VITAMIN D3 1.94 μγ CYANOCOBALAMINE 0.31 μγ FOLACIN 10.33 μγ d-BIOTIN 6.82 μγ VITAMIN Kl 7.23 μγ NIACINA (equivalent) 1.64 mg
    AMINO ACIDSL-ALANINE 55.4 mg L-ARGININE 98.3 mg L-ASPARTIC ACID 91.7 mg L-CYSTINE 36.3 mg L-GLUTAMIC ACID 0 mg GLYCIN 86.5 mg L-HYSTIDINE 56.2 mg L-ISO LEUCINA 108.5 mg L-LEUCINA 148.4 mg L-LYSINE 100.9 mg L-METHIONINE 23.7 mg L-PROLINA 105.2 - mg L-PHENYLALANINE 66.1 mg L-SERINA 64.7 mg L-TREONINA 72.8 mg L-TRYPTOPHAN 29.1 mg L-TYROSINE 66.1 mg L-VALINA ________ 109.7 mg
    25/26
    L-ASPARAGIN 0 mg L-CITRULIN 0 mg L-CARNITINA 1.2 mg TAURINA 3.3 mg L-GLUTAMINE 134.4 mg TOTAL AMINO ACIDS 1.46 g
    EXAMPLE 4. Infant formula comprising intact milk protein amino acids according to the invention
    COMPONENTS1. Proteins (equivalents) UNITY Per 100 kcal g 1.42. Carbohydrates g 11.7- Sugars g 11.53. Fats g 5.12- Saturated g 2.224. Fiber, dietary g 0.8565. Sodium g 25.8D. NUTRITIONAL PROPERTIES Energy percentages 1. Proteins (equivalents) En% 5.62. Carbohydrates En% 46.4 _ * 3. Fats En% 46.34. Fibers En% 1.7Total En% 100* Including organic acids and polyols 11
    E. COMPOSITION 1. Proteins (equivalents), total g 1.4 - Nitrogen (Protein) g 0.224 - Animal protein g 1,428 • Whey protein g 0.861 • Casein g 0.574 • isoleucine and valine, each mg 25g 11.7 2. Carbohydrates - Sugars g 11.5 • Glucose g 0.4 • Fructose g• Galactose g 0.026 • Lactose--------- g 11.1
    26/26
    3. Fats g 5.12 - Vegetables g 5.02 - Animals g 0.11 • milk g 0.06 - Saturated g 2.22 • MCT g- Monounsaturated g 2.06 - Polyunsaturated g 0.84 4. Fiber, dietary g 0.856 - Soluble g 0.86 - Insoluble g 5. Moisture / water g 136
    F. COMPOSITION OF AMINO ACIDS L-Alanine mg 65.8L-Arginine mg 46.9L-Aspartic acid / L-Asparagine mg 116.2L-Cist (e) ina mg 25.2L-Glutamic acid / L-Glutamine mg 263.2Glycine mg 29.4L-Histidine mg 33.6L-Isoleucine mg 109.7 (84.7 protein) L-Leucine mg 158.2L-Lysine mg 136.5L-Methionine mg 37.1L-Phenylanine mg 63.7L-Proline mg 110.6L-Serina mg 86.8L-Threonine mg 86.8L-Tryptophan mg 23.1L-Tyrosine mg 5 9.5L-Valina mg 114.6 (89.6 protein) relationshipleucine: isoleucine: valine = 1.4: 1.0: 1.0
    1/2
    权利要求:
    Claims (9)
    [1]
    1. CHILD FORMULA, characterized by comprising protein, digestible carbohydrates and fats, in which the protein comprises the amino acids leucine, isoleucine and valine in a weight ratio leucine: isoleucine: valine between (1.1 to 1.5) :( 0 , 9 to 1.1): 1.0, where the sum of leucine, isoleucine and valine provides at least 20% by weight of the total amino acid content, where the total protein content is between 1.3 and 1.9 g of protein / 100 kcal, and where the protein comprises between 120 and 180 mg of leucine per 100 kcal in the total composition, between 90 and 180 mg of isoleucine per 100 kcal in the total composition and between 90 and 180 mg of valine per 100 kcal in the total composition.
    [2]
    2. CHILD FORMULA, according to claim 1, characterized by the leucine: isoleucine: valine weight ratio being between (1.3 to 1.5) :( 0.9 to 1.1): 1.0.
    [3]
    CHILDREN'S FORMULA, according to either of claims 1 or 2, characterized in that the protein comprises between 130 and 160 mg of leucine per 100 kcal in the total composition, between 100 and 120 mg of isoleucine per 100 kcal in the total composition and between 105 and 121 mg of valine per 100 kcal in the total composition.
    [4]
    CHILD FORMULA according to any one of claims 1 to 3, characterized in that the protein is present between 5 and 8%, based on the total calories of the composition.
    [5]
    CHILDREN'S FORMULA according to any one of claims 1 to 4, characterized in that it additionally comprises at least one bifidogenic dietary fiber
    Petition 870190102628, of 10/11/2019, p. 11/271
    2/2 selected from the group consisting of beta-linked galacooligosaccharides, transgalactooligosaccharides, galacto-oligosaccharides, lacto-N-tetraose (LNT), lacto-N-neotetraose (neo-LNT), fucosyl-lactose, fucosylated LNT 5, neo -Fucosylated LNT and xylooligosaccharides.
    [6]
    6. CHILD FORMULA according to any one of claims 1 to 5, characterized in that it additionally comprises at least one PUFA selected from the group consisting of ARA, DHA and EPA.
    10
    [7]
    CHILD FORMULA according to any one of claims 1 to 6, characterized in that the protein consists essentially of free amino acids.
    [8]
    8. CHILD FORMULA, according to any one of claims 1 to 7, characterized by the total protein content
    15 be between 1.3 and 1.8 g of protein / 100 kcal.
    [9]
    9. NON-MEDICAL USE OF THE CHILD FORMULA, as defined in claims 1 to 8, characterized by being for the manufacture of a composition to feed a child aged between 0 and 36 months.
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    同族专利:
    公开号 | 公开日
    EP2984942A1|2016-02-17|
    DK2552242T3|2015-12-21|
    ES2555257T3|2015-12-30|
    DK2552242T4|2021-11-01|
    PL2552242T5|2021-11-08|
    US20170181460A1|2017-06-29|
    PL2552242T3|2016-03-31|
    EP2984942B1|2020-04-22|
    CN107821606A|2018-03-23|
    DK2984942T3|2020-06-15|
    EP2552242A1|2013-02-06|
    CN102892309A|2013-01-23|
    CN107821606B|2021-09-14|
    WO2011119023A1|2011-09-29|
    US9492498B2|2016-11-15|
    US10136668B2|2018-11-27|
    EP2552242B1|2015-09-09|
    US20130079276A1|2013-03-28|
    RU2559432C2|2015-08-10|
    RU2012145528A|2014-05-20|
    CN102892309B|2016-01-27|
    PT2552242E|2016-01-08|
    BR112012024102A2|2015-09-01|
    WO2011119033A1|2011-09-29|
    US8987196B2|2015-03-24|
    ES2555257T5|2022-02-25|
    HUE025633T2|2016-04-28|
    EP2552242B2|2021-09-01|
    MY160552A|2017-03-15|
    US20150352178A1|2015-12-10|
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    法律状态:
    2017-10-24| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2018-03-27| B15K| Others concerning applications: alteration of classification|Ipc: A23L 33/10 (2016.01), A23L 33/12 (2016.01), A23L 3 |
    2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2018-05-02| B07G| Grant request does not fulfill article 229-c lpi (prior consent of anvisa) [chapter 7.7 patent gazette]|
    2019-07-16| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|
    2020-01-07| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2020-01-28| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 25/03/2011, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    PCT/NL2010/050156|WO2011119023A1|2010-03-26|2010-03-26|Low protein infant formula with increased essential amino acids|
    PCT/NL2011/050207|WO2011119033A1|2010-03-26|2011-03-25|Low protein infant formula with increased essential amino acids|
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