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    • 专利摘要:
    nutritional composition for stimulation of muscle protein synthesis. The present invention relates to the use of an anabolic amino acid-derived stimulus acting in combination with vitamin D for the manufacture of a medicament or nutritional composition for preventing and / or treating a loss of any muscle mass, muscle strength, muscle function and physical function or any combination thereof in mammals.
    公开号:BR112013000446B1
    申请号:R112013000446-0
    申请日:2011-07-06
    公开日:2019-10-29
    发明作者:Verlaan George；Adeline Jourdan Marion-Eve；Ter Borg Sovianne；Charlotte Luiking Yvette
    申请人:Nutricia Nv；
    IPC主号:
    专利说明:

    Descriptive Report of the Invention Patent for USE OF VITAMIN D AND L-LEUCINE IN ITS FREE FORM FOR THE MANUFACTURE OF A MEDICINE FOR THE PREVENTION AND / OR TREATMENT OF A DISEASE OR CONDITION INVOLVING LOSS OF MUSCLE MASS IN A MAMMALIAN ADULT.
    FIELD OF THE INVENTION
    The present invention relates to the use of a stimulus derivative derived from an anabolic amino acid that acts in combination with vitamin D for the prevention and / or treatment of any loss of muscle mass, muscle strength, muscle function and physical function or any combination thereof in a mammal, especially an adult mammal, as well as specific nutritional compositions suitable for stimulating the synthesis of muscle proteins in a mammal, especially an adult mammal.
    BACKGROUND OF THE INVENTION
    Sarcopenia defines the loss of muscle mass, strength and function that occurs during aging [1]. Loss of muscle mass starts from the age of 30 at a rate of 3-8% per decade and accelerates from the age of 60. This loss reaches up to 35-40% in the elderly over 70, and, consequently, sarcopenia is especially prominent in the elderly.
    Preservation of muscle mass can only be achieved through adequate stimulation of protein synthesis and / or inhibition of proteolysis. Several factors contribute to muscle protein synthesis, among which the most important is the availability of amino acids (which serve as building blocks for newly synthesized proteins) and the activation signal generated by anabolic amino acids or derivatives of anabolic amino acids (for example, example, citrulline, leucine, essential amino acids (EAA) and creatine).
    However, protein intake is decreased in the elderly, which leads to inadequate postprandial availability of amino acids. In addition, aging is characterized by decreased muscle sensitivity to the anabolic effect of essential amino acids, especially leucine [2, 3]. This lower capacity to respond to leucine is associated with
    Petition 870190063502, of 07/08/2019, p. 7/14
    2/39 a decrease in the activation of intracellular pathways that control muscle protein synthesis [4, 5]. Consequently, in order to counteract the deleterious effect of aging on muscle protein synthesis, it is necessary to simultaneously target the bioavailability of amino acids, 5 especially essential amino acids, by increasing the intake of high quality protein (rich in essential amino acids, in particular leucine) and muscle response to anabolic amino acids improving muscle sensitivity to these amino acids.
    Of interest, aging is also characterized by a high prevalence of vitamin D deficiency (serum vitamin
    D below 25-50 nmol / L) and renal failure (serum vitamin D levels below 75 nmol / L) [6, 7]. Low serum concentrations of 25- (OH) D are associated with an increased risk of sarcopenia in the elderly [8].
    In the future, vitamin D deficiency may become a major health problem: only recently has it been declared [9] that between 40 and percent of the German population could have insufficient vitamin D, with an additional 15 to 30 percent deficient, thus, putting them at risk for a variety of health problems. In addition, current recommendations for daily vitamin D intake are 5 micrograms for adults 20 under 50 years of age and 10 micrograms for adults over 50 and are not adequate to ensure sufficient vitamin D (serum levels of vitamin D equal to or above 75 nmol / L) in the general population. Consequently, there is a need to significantly increase these recommendations (at least duplicate them) and, preferably, to increase them 25 to a daily dose of 25 micrograms or more, depending on sex, age, activity level and other factors.
    Vitamin D deficiency in adults is reported to precipitate or worsen osteopenia, osteoporosis, muscle weakness, sarcopenia [11], loss of physical function, fractures, common cancers, autoimmune diseases, 30 infectious diseases and cardiovascular diseases. There is also some evidence that vitamin D can reduce the incidence of various types of cancer and type-1 diabetes.
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    The science that supports the action of vitamin D on muscle strength, as well as the vitamin's role in immune health, is robust enough to have received a positive opinion from the European Food Safety Authority's (EFSA) Panei on Dietetic Products, Nutrition and Allergies ( NDA [10]).
    BACKGROUND OF THE PREVIOUS TECHNIQUE
    EP 1 712 140 B1 (Larena, December 18, 2006) describes a composition intended for the prevention and / or treatment of frailty syndrome in the elderly and sarcopenia which comprises a large number of components, including vitamin D (with a maximum 20 10 gg) and natural proteins, such as whey, rich in branched chain amino acids (including leucine). The composition does not contain free leucine, carbohydrates or fats.
    Document W02006 / 062273 (Kim, 15 June 2006) teaches a food supplement for health that consists essentially of 15 free branched amino acids (including leucine) and a number of antioxidants, including vitamin D3, referred to as aiding in the absorption and metabolism of branched amino acids to intensify the power of immediate impact under anaerobic conditions (for athletes under stress conditions).
    Document W02008 / 115563 (University of Florida Research
    Foundation, 25 September 2008) discloses a liquid food product composition suitable for - among a large number of medical applications - the treatment of a large number of age-related disorders, such as sarcopenia, comprising at least one vitamin in B , vitamin C, vitamin E, creatine, leucine, taurine, a carbohydrate, GABA, ribose, (acetyl) -carnitine and a source of fat and optionally comprising a source of protein (0.01 - 20 g) and vitamin D (0.01 to 1200 mg), the specific role of which is not disclosed.
    EP 2 036 552 (Kao Corporation, March 18, 30 2009) describes compositions for the treatment of muscle senescence, muscle dysfunction, muscle atrophy and related conditions containing catechin, optionally in combination with ramie chain amino acids
    4/39 and / or taurine as the active ingredient. Many different examples of useful formulations are disclosed. One of these examples concerns a standard multivitamin preparation including taurine and tea catechin. The standard multivitamin preparation includes vitamins according to the Japanese Recom5 mended Dietary Allowance. No specific function of any of the vitamins in the mixture is discussed or suggested in EP 2 036 552.
    Document W02009 / 143097 (Stokely-Van Camp Inc., November 26, 2009) teaches a milk-based drink comprising conjugated linoleic acid, milk proteins, carbohydrates, up to 1,000 IU of vita10 mine D and calcium to increase mass muscle and decrease in body fat in sedentary individuals and athletes submitted to strength training.
    EP 1 712 140 (Larena, October 18, 2006) proposes a composition comprising i) natural protein rich in branched-chain amino acids (Branched Chain Amino Acids - BCAA), ii) an amino acid selected from arginine and glutamine, iii) ginsenosides, iv) zinc, v) selenium, vi) a vitamin selected from B1, B2, B3, B5, B6, B8, B9, B12, C, D and E and vii) carotenoids. Most of the disclosed compositions contain a combination of whey and pea protein as the sources of natural protein rich in BCAA and arginine and / or glutamine.
    In addition, a number of prior art documents, including JP 2008237070 and US 2010/0124587, address the problem of reducing the risk of falls-related fractures in the elderly. Such compositions contain components designed to increase muscle mass or strength, thereby reducing the risk of falling, as well as a component designed to increase bone strength and / or density, thereby mitigating the consequences of falls. In these compositions, vitamin D is used to increase bone strength and / or density.
    None of the documents cited in the prior art describes the combined use of a stimulus derived from anabolic amino acid and vitamin D as active compounds working together, suitable for the prevention and / or treatment of any loss of muscle mass, strength
    5/39 muscle, muscle function and physical function or any combination thereof, in an adult mammal, as well as specific nutritional compositions suitable for stimulating the synthesis of muscle proteins in an adult mammal.
    The nutritional composition Resource® SeniorActiv (Nestle) commercially available since January 2010, is designed for malnourished elderly people, comprising a large number of components, including milk proteins (10 g / 100 ml, 7.5 g / 100 kcal) , vitamin D (250 IU / 100 ml) and 150 kcal / 100 ml of energy in a 200 ml serving and has a recommended dose of 2 servings / day for use to help minimize muscle breakdown and protein synthesis support. It does not contain derivatives of free amino acids, in particular free leucine.
    BRIEF DESCRIPTION OF THE INVENTION
    Surprisingly, no research has been done on the relationship between - on the one hand - protein deficiency (through inadequate protein intake) and the role of the activation signal generated by anabolic amino acids or stimuli derived from anabolic amino acids and - on the other hand - vitamin D deficiency, both of which are associated with age-related muscle loss in the elderly. It is postulated that 20 vitamin D, in particular high amounts of vitamin D, may play a crucial role in muscle sensitivity to the anabolic action of stimuli derived from amino acids. A nutritional product, rich in vitamin D, stimuli derived from anabolic amino acid and high quality protein would then lead to an adequate stimulation of muscle protein synthesis and thus muscle gain, especially in sarcopenic people, once that it would simultaneously address deficiencies in vitamin D and protein, as well as resistance to the anabolic action of amino acids on muscles.
    Surprisingly, the inventors found that vitamin D, in particular high amounts of vitamin D, as defined in the Vitamin D section below, enhances the stimulatory effect of stimuli derived from anabolic amino acid to stimulate muscle protein synthesis and
    6/39 subsequent gain in muscle mass. Without being limited by theory, it is likely that the level of activation of the intracellular signaling pathways that regulate muscle protein synthesis is higher when high amounts of vitamin D and a stimulus derived from an anabolic amino acid are delivered sequentially or simultaneously to a person.
    As a proof of concept that vitamin D enhances the stimulatory effect of anabolic amino acids on muscle protein synthesis, the activation of the intracellular signaling pathway that controls protein synthesis in the presence or absence of vitamin D and leucine in an in vitro model was studied.
    The combination is also useful to improve skeletal muscle health in adults, to reduce the decline in skeletal muscle health in adults, to increase mobility in adults, for recovery and / or restoration of skeletal muscle functionality in people adults after illness, surgery or injury, to reduce functional limitations in activities of daily living and, consequently, improve activities of daily living and reduce the risk of falls and injuries related to falls.
    DETAILED DESCRIPTION OF THE INVENTION
    The invention relates to the use of a stimulus derived from an anabolic amino acid that acts in combination with vitamin D, as well as to a composition comprising said mutually active components, for the manufacture of a nutritional composition or medication for the prevention and / or treating a loss of any one of muscle mass, muscle strength, muscle function and physical function or any combination thereof in a mammal, especially an adult mammal.
    In the context of the present application, the term at least also includes the starting point of the open band. For example, an amount of at least 95% by weight means any amount equal to 95% by weight or greater.
    In the context of this application, the term about means a deviation of 5% or less from the value provided, for example, 4%, 3%, 2%,
    7/39
    1% or less than 1%. For example, a value of about 12 g means any amount equal to 12 g ± 0.6 g, that is, any value in the range of 11.4 to 12.6 g. The reason for using the term about is to take into account the uncertainty associated with the analytical method to determine the specific component or the variability of the manufacturing process when it is related to the manufacture of a nutritional composition. According to a more preferred embodiment, about 0%. Thus, an amount of about 12 g means 12 g.
    In the context of this application, 1 IU of vitamin D is the biological equivalent of 0.025 pg. Therefore, 1,000 IU is the biological equivalent of 25 pg.
    By the term proteinaceous matter is meant a protein or any derivable part of a protein such as, but not limited to, non-hydrolyzed protein, native protein, hydrolyzed protein, peptides, such as oligopeptides and dipeptides and amino acids. Leucine is part of the proteinaceous matter and citrulline and creatine are not.
    Anabolic Amino Acid Derivatives
    The invention relates to the use of a stimulus derived from an anabolic amino acid, which is defined as a chemical compound derived from or which is a precursor to an amino acid (hence, derived from amino acid) which promotes (consequently, anabolic) growth muscle by increasing the net protein synthesis (hence, stimulation).
    Preferably, the stimulus derived from an anabolic amino acid is one or more selected from the group of L-leucine, citrulline and creatine. More preferably, the stimulus derived from an anabolic amino acid is an amino acid selected from the group of L-leucine and citrulline.
    L-leucine (hereinafter also called leucine, since the R form of leucine is not biologically relevant in the context of the present invention) is an essential amino acid, being part of a diverse number of proteins and, together with valine and isoleucine , belongs to the group of branched chain amino acids. Leucine can be used as
    8/39 a free amino acid or in a linked form, such as a dipeptide, an oligopeptide, a polypeptide or a protein. Common sources of leucine protein are milk proteins, such as whey, casein, micellar casein, caseinate and glycomacroprotein (GlycoMacroProtein - GMP) and vegetable proteins such as wheat, rice, pea, lupine and soy proteins. Said protein sources can provide intact proteins, hydrolysates or mixtures thereof, hereinafter called proteinaceous matter. Leucine is known as a potent activator of muscle protein synthesis.
    Citrulline is an α-arriino acid. Its name is derived from Citrullus, 10 the Latin word for watermelon, since it is naturally present in watermelons. Citrulline, in the form of citrulline malate, is sold as a dietary supplement to enhance athletic performance which has been suggested to promote aerobic energy production (human study) [12] and increase athletic performance and decrease muscle pain ( human study 15) [13]. In the human body, citrulline is produced from ornithine and carbamoyl phosphate in one of the central reactions in the urea cycle. It is also produced from arginine in the body as a by-product of the reaction catalyzed by the NOS family. Citrulline is also capable of promoting the synthesis of muscle proteins and has been described in human and 20 animal studies [see, for example, WO 2008/049984 by Université René Descartes-Paris, 2 May 2008], Citrulline is commercially available and can be obtained, for example, from Ajinomoto, Kyowa and Biocodex.
    Creatine (N- (amino-imino-methyl) -N-methyl-glycine; methylglycocyanine) is a nitrogenous organic acid that is produced in vertebrate animals, in particular the human body, from L-arginine, glycine and L- methionine and helps provide energy to the muscles. Creatine is commercially available and can be obtained, for example, from Sigma Aldrich, Alfa Aesar and Aminolabs.
    Preferably, the stimulus derived from an anabolic amino acid is provided in a daily dosage of 0.5 to 20 g, preferably 1 to 10 g. Preferably, the daily dosage is administered as a single portion.
    In one embodiment, leucine is supplied in a daily dose of
    9/39 to 10 g. When leucine is supplied as a proteinaceous material, it should comprise at least about 11% by weight of leucine. It has been found that about 11% by weight of total leucine, based on the total amount of proteinaceous matter, is a minimum amount present in the nutritional composition. Preferably, said proteinaceous material comprises at least about 12% by weight, preferably at least about 12.5% by weight, more preferably at least about 13% by weight of leucine.
    Preferably, the total leucine comprises at least about 20% by weight, preferably at least about 22.5% by weight, preferably at least about 25% by weight of leucine in free form with respect to the total amount of leucine. In the context of the present application, by free form is meant a peptide comprising 1 to 5 amino acids, preferably 1 to 3 amino acids, more preferably 1 amino acid. Preferably, leucine is a free amino acid, either as a base, a salt or a chelate.
    In one embodiment, citrulline is provided in a daily dose of 0.5 to 10 g.
    In one embodiment, creatine is supplied in a daily dose of 0.5 to 20 g.
    In one embodiment, any combination of leucine, citrulline, and creatine is provided in a daily dose of 0.5 to 20 g, preferably 1 to 10 g. Any combination is a selected combination from the group of leucine and citrulline; leucine and creatine; citrulline and creatine; leucine and citrulline and creatine.
    D vitamin
    Vitamin D is a group of fat-soluble secosteroids, the two main physiologically relevant forms of which are vitamin D2 (ergocalciferol) and vitamin D 3 (cholecalciferol). These are known collectively as calciferol. Vitamin D without a subscript refers to all forms of vitamin D, whether D1, D 2 , D 3 , D 4 or D 2 in particular and D 3 or any mixture thereof.
    10/39
    When ingested, vitamin D is hydroxylated in the liver (endoplasmic reticulum) in 25-hydroxycholecalciferol (25 (OH) D), also known as calcidiol, by the enzyme 25-hydroxylase produced by hepatocytes. Once done, the product is stored in hepatocytes until necessary and can be released into the plasma where it will bind to an α-globulin. 25-hydroxycholecalciferol is then transported to the kidney's proximal tubules where it can be hydroxylated by one of two enzymes in different forms of vitamin D, one of which is active vitamin D (1.25 (OH) D) and the other a which is inactive vitamin D (24.25 (OH) D). The enzyme 1a-hydroxylase, which is activated by the parathyroid hormone (and, additionally, by low level of calcium or phosphate), constitutes the main biologically active vitamin D hormone, with a hydroxylation in C1 forming 1.25-di- hydroxycholecalciferol (1.25 (OH) 2 D, also known as calcitriol). A distinct enzyme hydroxylates the C24 atom, forming 24R, 25 (OH) 2 D3 when 1a-hydroxylase is not active, inactivating the molecule from any biological activity.
    Vitamin D can be supplied in an active (1.25 (OH) 2 D) or inactive (Vit D 3 or D 2 ).
    According to one embodiment, vitamin D is used in an amount of 800 IU or more per daily dosage such as, for example, 1,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000 or 10,000 IU or any other value between any of the two mentioned values or more, but not so high as to cause toxicity to the individual to whom it is administered.
    According to one embodiment, vitamin D is used in an amount of 20 pg or more per daily dosage such as, for example, 25, 50, 75, 100, 125, 150, 175, 200, 225 or 250 pg per daily dosage or any value between any of the two mentioned values or more. Currently, the maximum tolerable intake level (UL) in Europe and the USA is 2,000 International Units (International Units - IU), equivalent to 50 pg per day. However, recent research, particularly from clinical trials, suggests that this should be increased to 10,000 IU (250 micrograms per day), as this dosage was not associated with side effects.
    11/39 adverse or toxic.
    Specifically preferred is a daily dose of vitamin D of more than 1000 IU (25 pg).
    Protein Matter
    According to one embodiment, the stimulus derived from anabolic amino acid in combination with vitamin D is used to manufacture a medicine. In the context of the present application, a medicament is an embodiment of the invention, which contains or does not contain substantially caloric components, such as carbohydrates, proteinaceous material and fat, in addition to the components according to the invention. The medicament can be administered sequentially or simultaneously with said calorie components, in particular a source of protein. Said caloric components can be supplied separately, in the form of a meal, a food supplement, a drink or in any other form.
    According to an alternative modality, the stimulus derived from anabolic amino acid in combination with vitamin D is used for the manufacture of a nutritional composition. In the context of the present application, a nutritional composition is a modality of the invention which contains or contains substantially caloric components, such as carbohydrates, fat and proteinaceous matter, with the exception of the components according to the invention.
    According to one embodiment, the stimulus derived from anabolic amino acid in combination with vitamin D is used in combination with a source of proteinaceous material to provide the amino acids necessary to prevent and / or treat a loss of muscle mass, a loss of muscle function or both in an adult mammal. The source of proteinaceous matter can be provided separately, in the form of a meal, a food supplement, a drink or any other form, or can be combined into a single nutritional composition.
    Preferably, the proteinaceous material is derived from high quality protein, such as milk proteins, such as whey or ca
    12/39 seine. Amino acids are essentially L-amino acids, since only L-amino acids are metabolically relevant in the context of the present invention.
    Preferably, the nutritional composition according to the invention comprises at least about 12 g of proteinaceous matter per 100 kcal.
    Preferably, the composition comprises at least about 12.5 g, at least about 13 g, at least about 13.5 g and, more preferably, about 14 g of proteinaceous matter per 100 kcal.
    According to another embodiment, the nutritional composition according to the invention comprises at least about 45% proteinaceous matter per 100 kcal. Preferably, the composition comprises at least about 48%, at least about 50%, at least about 52%, at least about 54% and, more preferably, at least about 56% proteinaceous per 100 kcal.
    According to a preferred embodiment, the proteinaceous material according to the invention comprises at least about 80% by weight of whey protein, preferably at least about 85% by weight of whey protein, preferably at least about 90% by weight and, more preferably, about 95% by weight of whey protein.
    Whey protein is considered a fast protein in reference to the rate of appearance in the circulation of amino acids after ingestion of whey. The whey protein can be an intact whey protein, a hydrolyzed whey protein, a microparticle whey protein, a nanoparticle whey protein, a micellar whey protein and the like. Preferably, the whey protein is an intact whey protein, that is, an intact whey protein, as present in fresh milk.
    As a source of whey protein to be used in the present invention, any available source of whey protein
    13/39 can be used commercially, that is, whey obtained by any process for the preparation of whey known in the art, as well as fractions of whey protein prepared from it or proteins that make up the whey. bulk of whey proteins, with β-lactoglobulin, α-lactalbumin and whey albumin, such as liquid whey or whey in powder form, such as whey protein isolate (Whey Protein Isolate - WPI) or whey protein concentrate (Whey Protein Concentrate - WPC). Whey protein concentrate is rich in whey proteins, but it also contains other components, such as fat, lactose and glycomacroprotein (GlycoMacroProtein - GMP), a non-globular casein-related protein. Typically, whey protein concentrate is produced by means of membrane filtration. On the other hand, the whey protein isolate consists mainly of whey proteins with a minimal amount of fat and lactose. The whey protein isolate generally requires a more rigorous separation process, such as a combination of microfiltration and ultrafiltration or ion exchange chromatography. It is generally accepted that an isolated whey protein re ere f _ To a mixture wherein at least 90% by weight of the solids are whey proteins. A whey protein concentrate is accepted as having a percentage of whey protein between the starting amount in the by-product (about 12% by weight) and a whey protein. In particular, sweet whey, obtained as a by-product in the manufacture of cheese, acid whey, obtained as a by-product in the manufacture of acid casein, native whey, obtained through microfiltration of milk or whey curd, obtained as a by-product in the manufacture of curdled casein, can be used as a source of whey proteins.
    In addition, whey proteins can originate from all types of mammalian animal species such as, for example, cows, sheep, goats, horses, buffalo and camels. Preferably, the whey protein is of bovine origin.
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    Preferably, the source of whey protein is available as a powder, preferably, the source of whey protein is a WPC or WPL
    According to another embodiment, the proteinaceous material according to the invention comprises at least about 45% by weight of essential amino acids (EAA), preferably at least about 47% by weight and, more preferably, at least about 50% % by weight of EAA. The essential amino acids are amino acids selected from the group of isoleucine (He), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), threonine (Thr), tryptophan (Trp) and valine (Vai). Since native whey protein and casein protein comprise (depending on the source) at most about 45 and 41% by weight of EAA, respectively, it may be necessary to add EAA to the nutritional composition, for example in the form of amino acids or peptides, to reach the preferred amount of at least 45% by weight.
    According to another embodiment, the proteinaceous material according to the invention comprises total leucine, total valine and total isoleucine in a leucine: valine: total isoleucine ratio of about 1.73: 1: 1. Alternatively, the weight ratio of leucine: (valine + isoleucine) is about 0.9 or greater, preferably 1.0 or greater. Adequate levels of valine and isoleucine can be provided by whey protein or can be provided by added amino acids, either in the free form as bases or salts or in the form of peptides.
    Surprisingly, the inventors found that essential amino acids, in particular leucine, show an enhanced bioavailability of amino acids to stimulate muscle protein synthesis and subsequent muscle mass when essential amino acids were administered using a hypocaloric nutritional composition ((defined as not exceeding 100 kcal) / 100 ml.) Without being limited by theory, amino acids are likely to reach circulation faster and reach higher blood levels when dietary protein is provided in a low calorie composition compared to a
    15/39 high calorie, preferably using whey, although the effect is the same, but less so for casein. This so-called low-energy effect could be beneficially used for the treatment of people suffering from any disease, the prevention and treatment of which are related to the synthesis of muscle proteins, in particular sarcopenia, a disease which involves muscle decline with synthesis insufficient (liquid) muscle protein and muscle decline associated with aging.
    Fat and Carbohydrates
    According to a preferred embodiment, the nutritional composition according to the invention comprises at least one from a fat source and a carbohydrate source. The presence of one or both of these components effectively prohibits the excessive use of protein as an energy source, rather than to stimulate muscle protein synthesis.
    The total amount of energy provided by fat and / or carbohydrates (digestible and indigestible) should correspond to the total energy provided by proteinaceous matter. Therefore, the total amount of fat and / or carbohydrates should be at most about 55%, preferably at most about 52%, preferably at most about 48%, preferably at most about 44%.
    The amount of energy supplied, respectively, by fat and / or carbohydrates can vary within wide limits, as long as both components are present. More specifically, the amount of fat can vary between 10 and 35%, preferably between 15 and 30%. More specifically, the amount of carbohydrate can vary between 10 and 35%, preferably between 15 and 30%. Consequently, the relative amounts of the sum of fat and carbohydrates fluctuate between 30 and 60%.
    In a preferred embodiment, the nutritional composition according to the invention comprises a fat source and a carbohydrate source, preferably in an amount of about 2 g of fat and about 6.4 g of digestible carbohydrates per 100 kcal.
    With regard to the type of fat, a wide choice is
    16/39 possible, as long as the fat is food grade.
    Fat can be either animal fat or vegetable fat, or both. Although animal fats, such as lard or butter, have essentially equal caloric and nutritional values and can be used alternatively, vegetable oils are highly preferred in the practice of the present invention due to their readiness, ease of formulation, absence of cholesterol and lower concentration of saturated fatty acids. In one embodiment, the composition of the present invention comprises rapeseed oil, corn oil and / or sunflower oil. Fat may include a source of medium chain fatty acids, such as medium chain triglycerides (MCT, mainly 8 to 10 carbon atoms in length), a source of long chain fatty acids, such as long chain triglycerides (LCT ) and phospholipid-linked fatty acids, such as phospholipid-bound EPA or DHA or any combination of the two types of sources. MCTs are beneficial because they are easily absorbed and metabolized in a metabolically stressed patient. In addition, the use of MCTs will reduce the risk of malabsorption of nutrients. Sources of LCT, such as canola oil, rapeseed oil, sunflower oil, soy oil, olive oil, coconut oil, palm oil, linseed oil, marine oil or corn oil, are beneficial because it is known that LCTs can modulate the immune response in the human body.
    Regarding the type of carbohydrates, a wide choice is possible, as long as the carbohydrates are of food quality. Digestible carbohydrates positively influence an individual's energy level and add to the advantageous effect of the nutritional composition according to the invention. The digestible carbohydrate can comprise simple or complex carbohydrates or any mixture thereof. Suitable for use in the present invention are glucose, fructose, sucrose, lactose, trehalose, palatinose, corn syrup, malt, maltose, isomaltose, partially hydrolyzed corn starch, maltodextrin, oligo- and glucose polysaccharides. Dietary Fibers
    The liquid enteral nutritional composition according to the invention
    17/39 tion can optionally be reinforced with dietary fibers (or prebiotic fibers), such as non-digestible carbohydrates, such as galacto-oligosaccharides, fructo-oligosaccharides, inulin and pectin (pectin hydrolyzate, low viscosity pectin (a product degradation of pectin with a DP of 2 - 250) or other products of degradation of pectin). In one embodiment of the present invention, the composition according to the invention comprises 0.5 g / 100 kcal to 6 g / 100 kcal of nondigestible carbohydrates. Dietary fibers include nondigestible oligosaccharides having a DP of 2 to 20, preferably 2 to 10. More preferably, these oligosaccharides do not contain substantial amounts (less than 5% by weight) of saccharides outside these DP ranges and are soluble. These oligosaccharides can include fructo-oligosaccharides (Fructo-OligoSaccharides - FOS), transgalactooligosaccharides (Transgalacto-OligoSaccharides - TOS), xylooligosaccharides (Xylo-OligoSaccharides - XOS), soy oligosaccharides and the like. Optionally, also higher molecular weight compounds, such as inulin, soy polysaccharides, acacia polysaccharides (acacia fiber or gum arabic), cellulose, resistant starch and the like can be incorporated into the composition according to the invention. The amount of insoluble fiber, such as cellulose, is preferably less than 20% by weight of the dietary fiber fraction of the composition according to the invention and / or less than 0.6 g / 100 kcal. The amount of thickened polysaccharides, such as carrageenan, xanthans, pectins, galactomannans and other high molecular weight (DP> 50) nondigestible polysaccharides is preferably low, ie less than 20% of the weight of the fiber fraction or less than 1 g / 100 kcal. Before, hydrolyzed polysaccharides, such as hydrolyzed pectins and galactomannans, can be advantageously included.
    A preferred fiber component is a nondigestible oligosaccharide with a chain length (DP) of 2 to 10, for example, Fibersol® (resistant oligoglycosis), in particular hydrogenated Fibersol® or a mixture of oligosaccharides with a DP of 2 to 10 , such as fructo-oligosaccharides or galacto-oligosaccharides (Galacto-OligoSaccharides - GOS), which may also contain a small amount of higher saccharides
    18/39 (for example, with a DP of 11 to 20). Such oligosaccharides preferably comprise 50% by weight to 90% by weight of the fiber fraction or 0.5 g / 100 kcal to 3 g / 100 kcal of the composition according to the invention. Other suitable fiber components include saccharides that have only partial digestibility.
    In a particular embodiment, the composition according to the invention comprises one or more of fructo-oligosaccharides, inulin, acacia polysaccharides, soy polysaccharides, cellulose and resistant starch.
    In another embodiment of the present invention, the composition according to the invention may comprise a mixture of neutral and acidic oligosaccharides, as described in WO 2005/039597 (N.V. Nutricia), which is incorporated herein by reference in its entirety.
    More particularly, the acid oligosaccharide has a degree of polymerization (Degree of Polymerization - DP) between 1 and 5000, preferably between 1 and 1,000, more preferably between 2 and 250, even more preferably between 2 and 50, more preferably between 2 and 10. If a mixture of acidic oligosaccharides with different degrees of polymerization is used, the average SD of the mixture of acidic oligosaccharides is preferably between 2 and 1000, more preferably between 3 and 250, even more preferably between 3 and 50. The acidic oligosaccharide can be a homogeneous or heterogeneous carbohydrate. Acid oligosaccharides can be prepared from pectin, pectate, alginate, chondroitin, hyaluronic acids, heparin, heparan, bacterial carbohydrates, sialoglycans, fucoidan, oligosaccharide or carrageenan and are preferably prepared from pectin or alginate. Acid oligosaccharides can be prepared using the methods described in WO 01/60378, which is incorporated herein by reference. The acid oligosaccharide is preferably prepared from highly methoxylated pectin, which is characterized by a degree of methoxylation above 50%. As used here, degree of methoxylation (also referred to as DE or degree of esterification) is intended to mean the extent to which free carboxylic acid groups contained in the polygalacturonic acid chain have been esterified (for example, through methyl19 / 39 tion). The acidic oligosaccharides are preferably characterized by a degree of methoxylation above 20%, preferably above 50%, even more preferably above 70%. Preferably, the acidic oligosaccharides have a methylation degree above 20%, preferably above 50%, even more preferably above 70%. The acid oligosaccharide is preferably administered in an amount of between 10 mg and 100 grams per day, preferably between 100 mg and 50 grams per day.
    The term neutral oligosaccharides, as used in the present invention, refers to saccharides which have a degree of polymerization of 10 units of monose which exceeds 2, more preferably above 3, even more preferably above 4, more preferably above 10, which are not or are only partially digested in the intestine by the action of digestive acids or enzymes present in the human upper digestive tract (small intestine and stomach), but which are fermented by the human intestinal flora 15 and, preferably, have no acid groups. The neutral oligosaccharide is structurally (chemically) different from the acid oligosaccharide. The term neutral oligosaccharides, as used in the present invention, preferably refers to saccharides which have a degree of polymerization of the oligosaccharide below 60 monose units, preferably below 40, even more preferably below 20, more preferably below 10. The term monose units refers to units having a closed ring structure, preferably hexose, for example, pyranose or furanose forms. The neutral oligosaccharide preferably comprises at least 90%, more preferably at least 95% of monose units selected from the group consisting of mannose, arabinose, fructose, fucose, rhamnose, galactose, α-D-galactopyranose, ribose, glucose, xylose and derivatives thereof, calculated on the total number of monose units contained therein. Suitable neutral oligosaccharides are preferably fermented by the intestinal flora. Preferably, the oligosaccharide is selected from the group consisting of: cellobiosis (4-Ο-βD-glucopyranosyl-D-glucose), cellodextrins ((4-OpD-glucopyranosyl) n -D-glucose), B-cyclodextrins (molecules cyclic a-1-4-linked D-glucose; a-cycle
    20/39 dextrin-hexamer, β-cyclodextrin-heptamer and γ-cyclodextrin-octamer), indigestible dextrin, gentile-oligosaccharides (mixture of linked β-1-6 glucose residues, some 1-4 bonds), gluco-oligosaccharides ( aD-glucose mixture), isomalto-oligosaccharides (a-1-6 linear glucose residues linked with some 1-4 bonds), isomaltose (6-OaD-glucopyranosyl-D-glucose); isomaltriosis (6-OaD-glucopyranosyl- (1-6) -aD-glucopyranosyl-Dglycosis), panose (6-OaD-glucopyranpsil- (1 -6) -aD-glucopyranosyl- (1 -4) -Ducrosis), leukosis ( 5-OaD-glucopyranosyl-D-fructopyranoside), palatinose or isomaltulose (6-OaD-glucopyranosyl-D-fructose), teanderose (OaD-glucopyranosyl- (1 -6) -OaD-glucopyranosil- (1 -2) -BD- fructofuranoside), D-agatosis, D-lyxo-hexulose, lacto-sucrose (O ^ -D-galactopyranosil- (1 -4) -OaD-glucopyranosyl- (1 -2) ^ - D-fructofuranoside), α-galacto- oligosaccharides, including raffinose, stachyose and other soy oligosaccharides (OaD-galactopyrosil- (1-6) -aD-glucopyranosyl-pD-fructofuranoside), β-galacto-oligosaccharides or transgalacto-oligosaccharides $ -D-galactopyrosyl- ) - ^ - D-glucopyranosyl] n - (1-4) α-D glucose), lactulose (4-O ^ -D-galactopyranosyl-D-fructose), 4'galate-silactose (OD-galactopyranosil- (1 - 4) -OpD-glucopyranosyl- (1 -4) -D-glucopyranose), synthetic galacto-oligosaccharide (neogalactobiosis, isogalactobiose, gal-sucrose, isolactose I, II and III), fruit - type Levana (β-ϋ- (2-> 6) fructofuranosyl) n α-D-glucopyranoside), fruit - type Inulin (β-ϋ - ((2-> 1) fructofuranosyl) n aD -glucopyranoside), 1 fp-fructofuranosylnistose (β-ϋ - ((2- »1) -frutofuranosyl) n BD-fructofuranoside), xylo-oligosaccharides (BD - ((1-> 4) xylose) n , lymphose, lacto- sucrose and arabino-oligosaccharides.
    According to another preferred embodiment, the neutral oligosaccharide is selected from the group consisting of fruits, fructo-oligosaccharides, indigestible dextrin galacto-oligosaccharides (including transgalacto-oligosaccharides), xylo-oligosaccharides, arabino-oligosaccharides, gluco-oligosaccharides, gluco-oligosaccharides -oligosaccharides, sniff-oligosaccharides and mixtures thereof. More preferably, the neutral oligosaccharide is selected from the group consisting of fructo-oligosaccharides, galacto-oligosaccharides and transgalacto-oligosaccharides.
    Suitable oligosaccharides and their production methods are
    21/39 further described in Laere K.J.M. (Laere, Degradation of Structurally Different Non-Digestible Oligosaccharides by Intestinal Bacteria: Glycosylhydrolases of Bi. Adolescentis. PhD-thesis (2000), Wageningen Agricultural University, Wageningen, The Netherlands), all the content of which is incorporated here by reference. Transgalacto-oligosaccharides (TransgalactoOligoSaccharide - TOS), for example, are sold under the trademark Vivinal ™ (Borculo Domo Ingredients, Netherlands). Indigestible dextrin, which can be produced by means of corn starch pyrolysis, comprises glycosidic bonds to (1- »4) and (1-» 6), as present in native starch and contains 10 bonds 1-> 2 and 1-> 3 and levoglucosan. Due to these structural characteristics, non-digestible dextrin contains well-developed branched particles, which are partially hydrolyzed by human digestive enzymes. Many other commercial sources of nondigestible oligosaccharides are readily available and are known to those skilled in the field. For example, transgalacto-oligosaccharide is available from Yakult
    Honsha Co., Tokyo, Japan. Soy oligosaccharide is available from Calpis Corporation distributed by Ajinomoto U.S.A. Inc., Teaneck, NJ.
    In another preferred embodiment, the composition according to the invention comprises an acid oligosaccharide with a DP between 2 and 20 250, prepared from pectin (such as hydrolyzed pectin (an acid oligosaccharide (Acid OligoSaccharide - AOS)) and pectin from low viscosity), alginate and mixtures thereof and a neutral oligosaccharide selected from the group of fruits, fructo-oligosaccharides, indigestible dextrins, galactooligosaccharides, including transgalacto-oligosaccharides, xyl-oligosaccharides, oligosaccharides, oligosaccharides, gluco-oligosaccharides, oligosaccharides, gluco-oligosaccharides snuff-oligosaccharides and mixtures thereof.
    In another preferred embodiment, the composition according to the invention comprises two chemically distinct neutral oligosaccharides. It has been found that the administration of acidic oligosaccharides 30 combined with two chemically different neutral oligosaccharides provides an optimal synergistic immune stimulatory effect. Preferably, the composition according to the invention comprises:
    22/39
    - an acidic oligosaccharide as defined above (preferably low viscosity pectin);
    - a galactose-based neutral oligosaccharide (of which more than 50% of the monose units are galactose units), preferably selected from the group consisting of galactose and transgalactooligosaccharide; and
    - a neutral oligosaccharide based on fructose and / or glucose (of which more than 50% of the monose units are fructose and / or glucose units, preferably fructose), preferably inulin, fructan and / or fructo-oligosaccharides, more preferably long-chain fructooligosaccharide (with an average SD of 10 to 60).
    Preferably, the nutritional composition further includes one or more dietary fibers selected from the group of short-chain GOS, long-chain FOS, inulin and low-viscosity pectin.
    Particular Modalities of Nutritional Composition
    In a particularly preferred embodiment, the nutritional composition comprises, per 100 kcal:
    (i) about 14 g of proteinaceous matter, which comprises about 95% by weight of whey protein, with respect to the total proteinaceous matter and comprises at least about 14% by weight of leucine, with respect to the matter total proteinaceous, of which at least about 26% by weight is in free form, relative to total leucine, (ii) about 2 g of fat and about 6.4 g of digestible carbohydrates, and (iii) about 532 IU (13.3 mg) of vitamin D, for the manufacture of a medicine for the prevention or treatment of a disease which involves muscle decline in an adult mammal, in which the nutritional composition is administered as 1 to 2 servings daily, each serving containing about 150 kcal.
    In another particularly preferred embodiment, the nutritional composition comprises, per 100 kcal:
    (i) about 12 g of proteinaceous matter, which comprises
    23/39 about 90% by weight of whey protein, in relation to the total proteinaceous matter and comprises at least about 16% by weight of leucine, in relation to the total proteinaceous matter, of which at least about 45% in weight are in free form, relative to total leucine, (ii) about 1.5 g of fat and about 8.3 g of digestible carbohydrates, and (iii) about 640 IU (16 pg) of vitamin D, for the manufacture of a medicine for the prevention or treatment of a disease which involves muscle decline in an adult mammal, in which the nutritional composition is administered as 1 to 2 servings daily, each serving containing about 125 kcal.
    Micronutrients
    Elderly people are at risk for micronutrient deficiencies, which is partly due to the fact that their energy consumption is often reduced, while many micronutrient recommendations increase [14]. As a result, 25-60% of older people do not comply with recommendations for micronutrient intake and vitamin deficiencies, such as A, C, D, E, B6, folic acid, vitamin B12, calcium, magnesium and zinc, are commonly reported [15-17]. In addition, micronutrients are associated with fragility. Low intake of vitamin D, E, C and folic acid was associated with frailty [18] and low serum levels of carotenoids, vitamin E, vitamin D, selenium and zinc were observed in elderly people with frailty versus without frailty [19].
    Of the micronutrients, selenium, zinc, carotenoids, vitamin C and vitamin E have antioxidant properties. Regarding the published observation on reversion, through supplementation with antioxidants, of reduced leucine capacity to stimulate muscle protein synthesis in elderly rats [20], a mixture of antioxidants is included in the nutritional composition.
    B vitamins from folic acid, vitamin B6 and vitamin B12 are involved in the homocysteine metabolic pathway, a known risk factor for common diseases in the elderly [21] and are, in general, deficient in the elderly
    24/39 [17]. Due to the beneficial effect of folic acid, vitamin B6 and vitamin B12 in reducing homocysteine levels in the blood, these vitamins are present in the nutritional composition.
    Consequently, the nutritional composition according to the invention can optionally further comprise one or more micronutrients, defined as minerals, residual elements and vitamins, selected from the group of sodium, potassium, chloride, calcium, phosphorus, magnesium, carotenoids, vitamin A , vitamin E, vitamin K, vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, folic acid, vitamin B12, biotin, vitamin 10 C, zinc, iron, copper, manganese, molybdenum, selenium, chromium, fluoride and iodide. Preferably, micronutrients are selected from the group of carotenoids, vitamin A, vitamin B6, vitamin B12, vitamin C, vitamin E, folic acid, calcium, phosphorus, magnesium, zinc and selenium. Preferably, the nutritional composition according to the invention may further comprise carotenoids, vitamin B6, vitamin C, vitamin E, folic acid, vitamin B12, selenium and zinc. Preferably, the nutritional composition according to the invention may further comprise, per 100 kcal, 10 to 500 mg of carotenoids, 8 to 750 pg of vitamin B6, 2.25 to 25 mg of vitamin C, 0.5 to 10 mg vitamin E, 10 to 150 mg of folic acid, 0.07 to 5 mg of vitamin B12, 2.5 to 20 20 pg of selenium and 0.5 to 2.0 mg of zinc.
    Medical Use
    The nutritional composition according to the invention can advantageously be used for the manufacture of a medicament for the prevention or treatment of a disease or condition that involves muscle decline in a mammal, especially an adult mammal. Alternatively, the nutritional composition according to the invention can advantageously be used to manufacture a medicament for the prevention or treatment of a disease or condition selected from the group of sarcopenia, loss of muscle mass, insufficient synthesis of muscle proteins, muscle breakdown, muscle proteolysis, muscle atrophy, muscle dystrophy, muscle catabolism, loss of muscle mass, loss of muscle strength, loss of muscle mass, loss of muscle function, loss of
    25/39 physical capacity, loss of physical performance, reduced mobility, fragility, surgery, disability, risk of falling and risk of fractures related to falls.
    Preferably, said mammal is an elderly adult human. In this regard, it is claimed that, in the context of this application, an elderly human is a person 50 years of age or older, in particular 55 years of age or older, more particularly of 60 years of age or older, more protein 65 years of age or older. This rather broad definition takes into account the fact that the average age varies between different populations, on different continents, countries, etc. Most developed countries accept the chronological age of 65 as a definition of 'older' person or more old (associated with the age at which you can start receiving pension benefits), but, like many Western concepts, it does not adapt well, for example, to the situation in Africa. At the moment, there is no standard United Nations (UN) numerical criterion, but the cut accepted by the UN is 60+ years to refer to the elderly population in the western world. The most traditional African definitions of an elderly person or 'elderly' person correlate with the chronological ages of 50 to 65 years, depending on the environment, region and country.
    The nutritional composition according to the invention can advantageously be used for the prevention or treatment of muscle decline, that is, loss of muscle mass, during or after maintenance of body weight, during or after energy restriction, during or after rest in bed or during or after recovery from physical trauma. In a particularly preferred embodiment, the compositions of the present invention are used in the treatment of an individual, for example, an individual suffering from excessive weight or obesity, said individual being following a weight loss program, an energy restriction program and / or an exercise program. Said isolation can be a child, a teenager, an adult or an elderly person. In one embodiment, said individual is a child, teenager or adult.
    26/39
    Dosage
    The nutritional composition is administered as 1 to 2 servings per day, each serving containing between 80 and 200 kcal, preferably about 125 kcal, preferably about 150 kcal. Preferably, the nutritional composition is administered as a daily portion. Using a nutritional composition in liquid form or for serving with a spoon, the portion can comprise 30 to 250 ml of nutritional composition according to the invention, more preferably 200 ml per serving. Using a nutritional composition in a solid form, such as a powder, the portion can comprise 20 to 100 g of nutritional composition according to the invention, more preferably 30 to 70 g per serving, even more preferably about 40 g per serving .
    Nutritional Compositions
    The present invention also relates to a composition comprising at least one combination of stimulus derived from anabolic amino acid with vitamin D, preferably in an amount of 800 IU or more per daily dosage.
    The present invention also relates to nutritional compositions with a high content of specific low-calorie protein (defined as not exceeding 100 kcal / 100 ml) suitable for stimulating muscle protein synthesis, either in liquid form, to be served with a spoon or solid.
    According to one embodiment, the invention relates to a liquid or spoon serving nutritional composition comprising:
    (i) no more than about 100 kcal of energy per 100 ml of liquid nutritional composition or to serve with a spoon, (ii) at least about 10 g of proteinaceous matter per 100 ml of liquid nutritional composition or to serve with a spoon , comprising at least about 80% by weight of whey protein, based on the total proteinaceous matter, (iii) at least about 1 g of leucine per 100 ml of liquid nutritional composition or to be served with a spoon, of which at least about
    27/39 of 20% by weight are in free form, relative to the total amount of leucine, (iv) at least about 400 IU of vitamin D per 100 ml of liquid nutritional composition or to be served with a spoon, and (v) a source of fat and a source of digestible carbohydrates.
    According to another embodiment, the invention relates to a liquid nutritional composition that comprises:
    (i) about 100 kcal of energy per 100 ml of the liquid nutritional composition, (ii) about 12 g of proteinaceous matter per 100 ml of the liquid nutritional composition which comprises about 10.8 g of whey protein per 100 ml of the liquid nutritional composition, (iii) about 2 g of leucine per 100 ml of the liquid nutritional composition, of which about 1 g per 100 ml of the liquid nutritional composition is in a free form, (iv) at least about 640 IU of vitamin D per 100 ml of the liquid nutritional composition, (v) about 2 g of fat per 100 ml of the liquid nutritional composition, which comprises a total of 400 mg of DHA and EPA, per 100 ml of the liquid nutritional composition and about 8 , 3 g of digestible carbohydrates per 100 ml of the liquid nutritional composition, (vi) optionally a source of dietary fiber, and, (vii) optionally additional micronutrients.
    According to another embodiment, the invention relates to a liquid nutritional composition that comprises:
    (i) about 100 kcal of energy per 100 ml of the liquid nutritional composition, (ii) about 12 g of proteinaceous matter per 100 ml of the liquid nutritional composition which comprises about 10.8 g of whey protein per 100 ml of the liquid nutritional composition, (iii) about 2 g of leucine per 100 ml of the liquid nutritional composition, of which about 1 g per 100 ml of the liquid nutritional composition
    28/39 are in a free form and about 1 g of citrulline per 100 ml of liquid nutritional composition, (iv) at least about 640 IU of vitamin D per 100 ml of liquid nutritional composition, (v) about 2 g of fat per 100 ml of the liquid nutritional composition, which comprises a total of 400 mg of DHA and EPA, per 100 ml of the liquid nutritional composition and about 8.3 g of digestible carbohydrates per 100 ml of the liquid nutritional composition, (vi) optionally a source of dietary fiber, and, (vii) optionally additional micronutrients.
    Preferably, the liquid or spoonable nutritional composition according to the invention comprises less than 90 kcal, preferably less than 80 kcal of energy per 100 ml of liquid nutritional composition.
    According to another embodiment, the invention relates to a liquid nutritional composition that comprises:
    (i) about 75 kcal of energy per 100 ml of the liquid nutritional composition, (ii) about 10.5 g of proteinaceous matter per 100 ml of the liquid nutritional composition which comprises about 10 g of whey protein per 100 ml of the liquid nutritional composition, (iii) about 1.5 g of leucine per 100 ml of the liquid nutritional composition, of which about 0.4 g per 100 ml of the liquid nutritional composition are in a free form, (iv) at least about 400 IU of vitamin D per 100 ml of the liquid nutritional composition, (v) about 1.5 g of fat per 100 ml of liquid nutritional composition and about 4.8 g of digestible carbohydrates per 100 ml of the liquid nutritional composition, (vi) optionally a source of dietary fiber, and, (vii) optionally additional micronutrient (s).
    According to another embodiment, the invention relates to a
    29/39 liquid nutritional composition comprising:
    (i) about 75 kcal of energy per 100 ml of the liquid nutritional composition, (ii) about 10.5 g of proteinaceous matter per 100 ml of the liquid nutritional composition which comprises about 10 g of whey protein per 100 ml of the liquid nutritional composition, (iii) about 1 g of leucine per 100 ml of the liquid nutritional composition, about 0.5 g of citrulline per 100 ml of liquid nutritional composition and about 2.5 g of creatine per 100 ml of liquid nutritional composition, (iv) at least about 400 IU of vitamin D per 100 ml of the liquid nutritional composition, and (v) about 1.5 g of fat per 100 ml of liquid nutritional composition and about 4.8 g of digestible carbohydrates per 100 ml of the liquid nutritional composition, (vi) optionally a source of dietary fiber, and (vii) optionally additional micronutrient (s).
    According to another embodiment, the invention relates to a liquid nutritional composition that comprises:
    (i) about 75 kcal of energy per 100 ml of the liquid nutritional composition, (ii) about 10.5 g of proteinaceous matter per 100 ml of the liquid nutritional composition which comprises about 10 g of whey protein per 100 ml of the liquid nutritional composition, (iii) about 1 g of leucine per 100 ml of the liquid nutritional composition and about 1 g of citrulline per 100 ml of the liquid nutritional composition, (iv) at least about 400 IU of vitamin D per 100 ml of the liquid nutritional composition, (v) about 1.5 g of fat per 100 ml of liquid nutritional composition and about 4.8 g of digestible carbohydrates per 100 ml of the liquid nutritional composition,
    (Vi) optionally a source of dietary fiber, and (vii) optionally additional micronutrient (s).
    According to another embodiment, the invention relates to a liquid nutritional composition that comprises:
    (i) about 75 kcal of energy per 100 ml of the liquid nutritional composition, (ii) about 10.5 g of proteinaceous matter per 100 ml of the liquid nutritional composition which comprises about 10 g of whey protein per 100 ml of the liquid nutritional composition, (iii) about 1 g of leucine per 100 ml of liquid nutritional composition and about 2.5 g of creatine per 100 ml of liquid nutritional composition, (iv) at least about 400 IU of vitamin D per 100 ml of the liquid nutritional composition, (v) about 1.5 g of fat per 100 ml of liquid nutritional composition and about 4.8 g of digestible carbohydrates per 100 ml of the liquid nutritional composition, (vi) optionally a source of dietary fiber, and (vii) optionally additional micronutrient (s).
    According to another embodiment, the invention relates to a nutritional composition for serving with a spoon comprising:
    (i) about 75 kcal of energy per 100 ml of nutritional composition to serve with a spoon, (ii) about 10.5 g of proteinaceous matter per 100 ml of nutritional composition to serve with a spoon comprising about 10 g of protein whey per 100 ml of nutritional composition to serve with spoon, (iii) about 1.5 g of leucine per 100 ml of nutritional composition to serve with spoon, of which about 0.4 g per 100 ml of nutritional composition to serve with spoon are in a free form, (iv) at least about 400 IU of vitamin D per 100 ml of nutritional composition to serve with spoon,
    31/39 (v) about 1.5 g of fat per 100 ml of nutritional composition to serve with a spoon and about 4.8 g of digestible carbohydrates per 100 ml of nutritional composition to serve with a spoon, (vi) optionally a source of dietary fiber, and, (vii) optionally additional micronutrient (s).
    When a source of dietary fiber is added to the composition described above, it is preferable to add an amount of about 0.83 g of dietary fiber comprising 0.63 g of GOS, 0.07 g of FOS / inulin and 0.14 g of low viscosity pectin.
    When additional micronutrient (s) are added to the above compositions, one or more micronutrients are preferably selected from the group of sodium, potassium, chloride, calcium, phosphorus, magnesium, carotenoids, vitamin A, vitamin E, vitamin K , vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, folic acid, vitamin B12, biotin, vitamin C, zinc, iron, copper, manganese, molybdenum, selenium, chromium, fluoride and iodide.
    Said high amounts of whey protein can be obtained using inventive processes, as described in WO 2009/113858, the content of which is incorporated herein by reference.
    According to one embodiment, the nutritional composition is packaged as a 30 ml to 300 ml portion, more preferably as a 200 ml portion.
    According to one embodiment, the invention relates to a solid nutritional composition comprising:
    (i) less than about 500 kcal of energy per 100 g of dry weight, (ii) at least about 49 g of proteinaceous matter per 100 g of dry weight, comprising at least about 80% by weight of whey protein of milk, in relation to total proteinaceous matter, (iii) at least about 5 g of leucine per 100 g of dry weight, of which at least about 20% by weight are in free form, in relation to total leucine, ( iv) at least about 50 μg of vitamin D per 100 g of dry weight, and
    32/39 (v) a source of fat and a source of digestible carbohydrates.
    The solid nutritional composition according to the invention comprises, per 100 g, less than 445 kcal, preferably less than 395 kcal of energy.
    According to one embodiment, the invention relates to a solid nutritional composition comprising:
    (i) about 375 kcal of energy per 100 g of dry weight, (ii) about 53 g of proteinaceous matter per 100 g of dry weight, which comprises about 50 g of whey protein per 100 g of dry weight , (iii) about 7.5 g of leucine per 100 g of dry weight, of which about 2 g per 100 g is in a free form, (iv) at least about 50 pg of vitamin D per 100 g of dry weight, (v) about 7.5 g of fat per 100 g of dry weight and about 24 g of digestible carbohydrates per 100 grams of dry weight, (vi) optionally a source of dietary fiber, and (vii) optionally additional micronutrient (s).
    According to one embodiment, the invention relates to a solid nutritional composition comprising:
    (i) about 375 kcal of energy per 100 g of dry weight, (ii) about 51 g of proteinaceous matter per 100 g of dry weight, which comprises about 50 g of whey protein per 100 g of dry weight , (iii) about 5.5 g of leucine per 100 g of dry weight, about
    2.5 g of citrulline per 100 g of dry weight and about 12.5 g of creatine per 100 g of dry weight, (iv) at least about 50 pg of vitamin D per 100 g of dry weight, (v) about 7.5 g of fat per 100 g of dry weight and about 24 g of digestible carbohydrates per 100 grams of dry weight, (vi) optionally a source of dietary fiber, and
    33/39 (vii) optionally additional micronutrient (s).
    According to one embodiment, the invention relates to a solid nutritional composition comprising:
    (i) about 375 kcal of energy per 100 g of dry weight, (ii) about 51 g of proteinaceous matter per 100 g of dry weight, which comprises about 50 g of whey protein per 100 g of dry weight , (iii) about 5.5 g of leucine per 100 g dry weight and about
    2.5 g of citrulline per 100 g of dry weight, (iv) at least about 50 gg of vitamin D per 100 g of dry weight, (v) about 7.5 g of fat per 100 g of dry weight and about 24 g of digestible carbohydrates per 100 grams of dry weight, (vi) optionally a source of dietary fiber, and (vii) optionally additional micronutrient (s).
    According to one embodiment, the invention relates to a solid nutritional composition comprising:
    (i) about 375 kcal of energy per 100 g of dry weight, (ii) about 51 g of proteinaceous matter per 100 g of dry weight, which comprises about 50 g of whey protein per 100 g of dry weight , (iii) about 5.5 g of leucine per 100 g of dry weight and about 5 g of citrulline per 100 g of dry weight, (iv) at least about 50 pg of vitamin D per 100 g of dry weight , (v) about 7.5 g of fat per 100 g of dry weight and about 24 g of digestible carbohydrates per 100 grams of dry weight, (vi) optionally a source of dietary fiber, and (vii) optionally micronutrient ( additional s.
    According to one embodiment, the invention relates to a solid nutritional composition comprising:
    (i) about 375 kcal of energy per 100 g dry weight,
    34/39 (ii) about 51 g of proteinaceous matter per 100 g of dry weight, which comprises about 50 g of whey protein per 100 g of dry weight, (iii) about 5.5 g of leucine per 100 g dry weight and about
    12.5 g of creatine per 100 g of dry weight, (iv) at least about 50 pg of vitamin D per 100 g of dry weight, (v) about 7.5 g of fat per 100 g of dry weight and about 24 g of digestible carbohydrates per 100 grams of dry weight, (vi) optionally a source of dietary fiber, and (vii) optionally additional micronutrient (s).
    When a source of dietary fiber is added to the compositions described above, it is preferable to add a total amount of 4.13 g of dietary fiber comprising about 3.1 g of GOS, 0.34 g of FOS / inulin and 0.19 g of low viscosity pectin.
    When additional micronutrient (s) are added to the above compositions, one or more micronutrients are preferably selected from the group of sodium, potassium, chloride, calcium, phosphorus, magnesium, carotenoids, vitamin A, vitamin E, vitamin K , vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, folic acid, vitamin B12, biotin, vitamin C, zinc, iron, copper, manganese, molybdenum, selenium, chromium, fluoride and iodide.
    Preferably, the solid nutritional composition according to the invention is formed as a powder, capable of being dissolved in an aqueous solution.
    Preferably, the solid nutritional composition according to the invention is presented as a portion of about 20 to 70 g, more preferably about 40 g.
    The powder can be presented as a sachet, a cup and the like, about the size of a portion size or it can be presented in a container comprising several portions, such as 10 to 25 portions, optionally accompanied by a measuring device , such as a spoon.
    35/39
    With respect to the liquid nutritional composition, to serve with a spoon and solid according to the invention, one or more of the following specifications apply:
    - the amount of fat can vary between 10 and 35%, preferably between 15 and 30%;
    - the amount of carbohydrate can vary between 10 and 35%, preferably between 15 and 30%;
    - the relative amounts of the sum of fat and carbohydrates vary between 30 and 60%;
    the proteinaceous matter comprises at least about 85% by weight of whey protein, preferably at least about 90% by weight and, more preferably, about 95% by weight of whey protein;
    - the proteinaceous material comprises at least 45% by weight, preferably at least 47% and, more preferably, at least about 50% by weight of essential amino acids (EAA);
    the proteinaceous matter comprises at least about 12% by weight, preferably at least about 12.5% by weight, more preferably at least about 13% by weight of leucine;
    the proteinaceous material comprises at least about 22.5% by weight, preferably at least about 25% by weight of leucine in free form, in relation to the total amount of leucine;
    - proteinaceous matter comprises total leucine, total valine and total isoleucine in a ratio of leucine: valine: total isoleucine of about 1.7-3: 1: 1;
    - the nutritional composition also includes one or more dietary fibers selected from the group of short-chain GOS, long-chain FOS, inulin and low-viscosity pectin;
    - the nutritional composition still comprises one or more micronutrients selected from the group of sodium, potassium, chloride, calcium, phosphorus, magnesium, carotenoids, vitamin A, vitamin E, vitamin K, vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, folic acid, vitamin
    36/39
    Β12, biotin, vitamin C, zinc, iron, copper, manganese, molybdenum, selenium, chromium, fluoride and iodide.
    The compositions according to the invention can be prepared by methods as disclosed in WO 2009/113858, which is incorporated herein by reference in its entirety. Powders can be prepared by methods generally known in the art to those skilled in the field, such as spray drying the liquid composition.
    EXPERIMENT SUMMARY
    An experimental in vitro study is carried out to evaluate the synergistic or additional action of leucine and vitamin D on intracellular pathways that regulate protein synthesis in muscle cells.
    Mouse C2C12 myoblasts are obtained from the American Type Culture Source Collection (No. CRL-1772). Myoblasts are grown at 37 ° C in an atmosphere of 5% CO 2 in growth medium consisting of Dulbecco's modified Eagle's medium (Dulbecco's Modified Eagle's Medium - DMEM) supplemented with 10% fetal calf serum and antibiotics. C2C12 myotube differentiation is induced by removing fetal calf serum from confluent cells and adding 10 gg / ml insulin, 5 pg / ml transferrin and 2% horse serum.
    Confluent C2C12 myotubes are treated with vehicles only or with different doses of D 3 1,25 (OH) 2 . Subsequently, the cells are deprived of horse serum by incubation in serum-free medium for the remaining two hours. During this deprivation period, different amounts of leucine and insulin are added to the medium before cell collection.
    Medium with or without leucine supplementation is used to assess the synergistic or additional action of leucine and vitamin D on intracellular pathways that regulate protein synthesis (Akt, mTOR) and / or in direct measurement of protein synthesis.
    The protein synthesis rate (FSR) in C2C12 myotubes after 72h pretreatments with 0, 1 or 10 nm of vitamin D3 1.25 (OH) 2 is re
    37/39 shown in figure 1. The change (%) in the rate of protein synthesis versus no pretreatment with vitamin D 3 is summarized in Table 1.
    As shown in figure 1, vitamin D 3 (dose of 1 or 10 nM) can stimulate the synthesis of muscle proteins, regardless of the presence of leucine (without stimulation). More importantly, when myotubes are treated with leucine and vitamin D 3 , the increase in the rate of muscle protein synthesis (26.4%) is greater than the sum of the response obtained when cells are treated with vitamin D 3 alone ( 14.3%) or with leucine only (10.7%).
    Taken together, these results clearly support the synergistic action of leucine and vitamin D 3 to promote muscle protein synthesis.
    Table 1:
    [Vitamin D] = 1 nM [Vitamin D] = 10 nM Without est. Ins + read Without est. Ins + read [Vit D] = 0 Without est. 14.0 * In i πι, ί 11 'Ί. 1 τ'ιΊ j! 1 14.3 * 'ψ; , '4i i .'Τ 1 ! 1 ,, 1 Ins + read9.8 *14.3 *
    Figure description
    Figure 1: Protein synthesis rate (FSR) in C2C12 myotubes after 72h pretreatments with 0, 1 or 10 nm of Vitamin D 3 1.25 (OH) 2. N = 5 for each condition. *: p <0.05 versus no stimulation for the same concentration of vitamin D. $: p <0.05 versus 0 nM of vitamin D for the same stimulation.
    BIBLIOGRAPHIC REFERENCES
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    6. Bouillon, R., et al., Vitamin D deficiency. N Engl J Med, 2007. 357 (19): pages 1980-1; replica of the author 1981-2.
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    权利要求:
    Claims (13)
    [1]
    1. Use of vitamin D and L-leucine in its free form, characterized by the fact that it is for the manufacture of a medicine for the prevention and / or treatment of a disease or condition involving loss of muscle mass in an adult mammal, where vitamin D and L-leucine are present in a nutritional composition and at least 20% by weight of Lleucine is in free form in relation to the total amount of leucine.
    [2]
    2. Use according to claim 1, characterized by the fact that said vitamin D is supplied in an amount of 800 IU per daily dosage.
    [3]
    3. Use according to claim 1, characterized by the fact that said vitamin D is vitamin D2, vitamin D3 or a mixture thereof.
    [4]
    Use according to any one of claims 1 to 3, characterized in that leucine is supplied in a daily dosage of 1 to 10 g.
    [5]
    Use according to any one of claims 1 to 4, characterized by the fact that the amount of vitamin D is 1,000 IU or more per daily dose, but not so high as to cause toxicity in the individual to whom it is administered.
    [6]
    Use according to any one of claims 1 to 5, characterized in that the composition further comprises a source of proteinaceous material, preferably whey.
    [7]
    Use according to any one of claims 1 to 6, characterized in that the composition comprises leucine, valine and isoleucine in a leucine: valine: isoleucine ratio of about 1.73: 1: 1.
    [8]
    Use according to any one of claims 1 to 7, characterized in that the composition is a nutritional composition additionally comprising at least one of a fat source, a digestible carbohydrate source, a dietary fiber source and a source of micronutrient.
    [9]
    9. Use according to any one of claims 1 to 8,
    Petition 870190063502, of 07/08/2019, p. 8/14
    2/2 characterized by the fact that the composition is a low-calorie composition, the energy of which does not exceed 100 kcal / ml.
    [10]
    Use according to any one of claims 1 to 9, characterized by the fact that the adult mammal is an elderly human being.
    5
    [11]
    11. Use according to any one of claims 1 to 10, characterized by the fact that it is for the treatment and / or prevention of sarcopenia, insufficient synthesis of muscle proteins, muscle breakdown, muscle proteolysis, muscle atrophy, muscular dystrophy, catabolism muscle, loss of muscle mass, loss of muscle strength, loss of physical capacity and loss of physical performance.
    [12]
    Use according to any one of claims 1 to 11, characterized by the fact that it is for the treatment and / or prevention of muscle decline and / or loss of muscle mass in an individual during or after maintaining body weight, during or after power restriction, during
    15 or after bed rest or during recovery after physical trauma.
    [13]
    13. Use according to claim 12, characterized by the fact that the individual is suffering from overweight or obesity, said individual is following a weight loss program, an energy restriction program and / or a fitness program Exercises.
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    法律状态:
    2017-10-24| B07D| Technical examination (opinion) related to article 229 of industrial property law|
    2018-03-27| B15K| Others concerning applications: alteration of classification|Ipc: A61K 31/593 (2006.01), A23L 33/155 (2016.01), A23L |
    2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|
    2018-05-02| B07G| Grant request does not fulfill article 229-c lpi (prior consent of anvisa)|
    2019-04-09| B07A| Technical examination (opinion): publication of technical examination (opinion)|
    2019-08-20| B09A| Decision: intention to grant|
    2019-10-29| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 06/07/2011, OBSERVADAS AS CONDICOES LEGAIS. (CO) 20 (VINTE) ANOS CONTADOS A PARTIR DE 06/07/2011, OBSERVADAS AS CONDICOES LEGAIS |
    优先权:
    申请号 | 申请日 | 专利标题
    PCT/NL2010/050436|WO2012005568A1|2010-07-07|2010-07-07|Nutritional composition for the stimulation of muscle protein synthesis|
    PCT/NL2011/050488|WO2012005582A1|2010-07-07|2011-07-06|Nutritional composition for the stimulation of muscle protein synthesis|
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